Myofibroblast-derived exosomes enhance macrophages to myofibroblasts transition and kidney fibrosis.

A critical event in the pathogenesis of kidney fibrosis is the transition of macrophages into myofibroblasts (MMT). Exosomes play an important role in crosstalk among cells in the kidney and the development of renal fibrosis. However, the role of myofibroblast-derived exosomes in the process of MMT and renal fibrosis progression remains unknown. Here, we examined the role of myofibroblast-derived exosomes in MMT and kidney fibrogenesis. In vitro, transforming growth factor-ß1 stimulated the differentiation of kidney fibroblasts into myofibroblasts and promoted exosome release from myofibroblasts. RAW264.7 cells were treated with exosomes derived from myofibroblasts. We found purified exosomes from myofibroblasts trigger the MMT. By contrast, inhibition of exosome production with GW4869 or exosome depletion from the conditioned media abolished the ability of myofibroblasts to induce MMT. Mice treatment with myofibroblast-derived exosomes (Myo-Exo) exhibited severe fibrotic lesion and more abundant MMT cells in kidneys with folic acid (FA) injury, which was negated by TANK-banding kinase-1 inhibitor. Furthermore, suppression of exosome production reduced collagen deposition, extracellular matrix protein accumulation, and MMT in FA nephropathy. Collectively, Myo-Exo enhances the MMT and kidney fibrosis. Blockade of exosomes mediated myofibroblasts-macrophages communication may provide a novel therapeutic target for kidney fibrosis.

Fostering idealogical and polical education via knowledge graph and KNN model: an emphasis on positive psychology.

As the primary domain of ideological and political education in higher education institutions, ideological and political courses must align with principles rooted in human psychology and education. Integrating educational psychology into ideological and political teaching in universities enhances the scientific, targeted, and forward-thinking nature of such education. The burgeoning exploration of knowledge graph applications has extended to machine translation, semantic search, and intelligent question answering. Diverging from traditional text matching, the knowledge spectrum graph transforms information acquisition in search engines. This paper pioneers a predictive system for delineating the relationship between educational psychology and ideological and political education in universities. Initially, it extracts diverse psychological mapping relationships of students, constructing a knowledge graph. By employing the KNN algorithm, the system analyzes psychological characteristics to effectively forecast the relationship between educational psychology and ideological and political education in universities. The system's functionality is meticulously detailed in this paper, and its performance is rigorously tested. The results demonstrate high accuracy, recall rates, and F1 values. The F1 score can reach 0.95enabling precise sample classification. The apex of the average curve for system response time peaks at approximately 2.5 s, maintaining an average response time of less than 3 s. This aligns seamlessly with the demands of practical online teaching requirements. The system adeptly forecasts the relationship between educational psychology and ideological and political education in universities, meeting response time requirements and thereby fostering the scientific and predictive nature of ideological and political teaching in higher education institutions.

Remimazolam attenuates inflammation and kidney fibrosis following folic acid injury.

The transition of acute kidney injury (AKI) to chronic kidney disease (CKD) is characterized by intense inflammation and progressive fibrosis. Remimazolam is widely used for procedural sedation in intensive care units, such as AKI patients. Remimazolam has been shown to possess anti-inflammatory and organ-protective properties. However, the role of remimazolam in inflammation and renal fibrosis following AKI remains unclear. Here, we explored the effects of remimazolam on the inflammatory response and kidney fibrogenesis of mice subjected to folic acid (FA) injury. Our results showed that remimazolam treatment alleviated kidney damage and dysfunction. Mice treated with remimazolam presented less collagen deposition in FA-injured kidneys compared with FA controls, which was accompanied by a reduction of extracellular matrix proteins accumulation and fibroblasts activation. Furthermore, remimazolam treatment reduced inflammatory cells infiltration into the kidneys of mice with FA injury and inhibited proinflammatory or profibrotic molecules expression. Finally, remimazolam treatment impaired the activation of bone marrow-derived fibroblasts and blunted the transformation of macrophages to myofibroblasts in FA nephropathy. Additionally, the benzodiazepine receptor antagonist PK-11195 partially reversed the protective effect of remimazolam on the FA-injured kidneys. Overall, remimazolam attenuates the inflammatory response and renal fibrosis development following FA-induced AKI, which may be related to the peripheral benzodiazepine receptor pathway.

Protein-protein interactions between RUNX3 and ZEB1 in chronic lung injury induced by methamphetamine abuse.

Methamphetamine (MA) is the most common and highly addictive substance abuse drug. Runt-related transcription factor 3 (RUNX3) and Zinc finger E-box-binding homeobox 1 (ZEB1) are associated with lung inflammation and fibrosis. However, the protein-protein interactions (PPIs) between RUNX3 and ZEB1 and its involvement in MA-induced chronic lung injury is still unclear. In this study, we evaluated lung injury using echocardiography, hematoxylin and eosin staining, and western blot analysis. The viability of alveolar epithelial cells (AECs) was assessed using cell counting kit-8. Molecular Operating Environment software, Search Tool for the Retrieval of Interacting Genes/Proteins database, co-immunoprecipitation, assay and confocal immunofluorescence assay were used to predict and identify the PPIs between RUNX3 and ZEB1. The expression of RUNX3 and ZEB1 were knockdown in AECs using siRNA. The results revealed that MA exposure increased the peak blood flow velocity of the pulmonary artery and the acceleration time of pulmonary artery blood flow. Further, exposure to MA also causes adhesion and fusion of the alveolar walls and altered AEC activity. A decrease in the expression of RUNX3 and an increase in the expression of ZEB1 and its downstream signaling molecules were observed on MA exposure. The PPIs between RUNX3 and ZEB1 were identified. Further, an increase in the protein binding rate of RUNX3-ZEB1 was observed in MA-induced lung injury. These results show interactions between RUNX3 and ZEB1. RUNX3 protects against lung injury; however, ZEB1 expression and the PPIs between ZEB1 and RUNX3 has deleterious effects on chronic lung injury induced by MA exposure. Our results provide a new therapeutic approach for the treatment of chronic lung injury due to MA exposure.

Discovery of small-molecule activators of nicotinamide phosphoribosyltransferase (NAMPT) and their preclinical neuroprotective activity.

The decline of nicotinamide adenine dinucleotide (NAD) occurs in a variety of human pathologies including neurodegeneration. NAD-boosting agents can provide neuroprotective benefits. Here, we report the discovery and development of a class of potent activators (NATs) of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD salvage pathway. We obtained the crystal structure of NAMPT in complex with the NAT, which defined the allosteric action of NAT near the enzyme active site. The optimization of NAT further revealed the critical role of K189 residue in boosting NAMPT activity. NATs effectively increased intracellular levels of NAD and induced subsequent metabolic and transcriptional reprogramming. Importantly, NATs exhibited strong neuroprotective efficacy in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN) without any overt toxicity. These findings demonstrate the potential of NATs in the treatment of neurodegenerative diseases or conditions associated with NAD level decline.

LncRNA BLACAT1 Promotes Proliferation, Migration and Invasion of Prostate Cancer Cells via Regulating miR-29a-3p/DVL3 Axis.

BACKGROUND: Long non-coding RNA bladder cancer associated transcript 1 (BLACAT1) is oncogenic in several types of cancers. However, little is known concerning its expression and function in prostate cancer. METHODS: Paired prostate cancer samples were collected, and the expression levels of BLACAT1, miR-29a-3p and disheveled segment polarity protein 3 (DVL3) were examined by quantitative real-time polymerase chain reaction (qRT-PCR); BLACAT1 shRNAs were transfected into PC-3 and LNCaP cell lines, and proliferative ability was detected by cell counting kit-8 (CCK-8) assay; qRT-PCR and Western blot were used to analyze the changes of miR-29a-3p and DVL3; dual-luciferase reporter gene assay was used to determine the regulatory relationships between miR-29a-3p and BLACAT1, and miR-29a-3p and DVL3. RESULTS: BLACAT1 expression was significantly up-regulated in cancerous tissues of prostate cancer samples and positively correlated with the expression of DVL3, while negatively associated with miR-29a-3p. After the transfection of BLACAT1 shRNAs into prostate cancer cells, the proliferative ability and metastatic ability of cancer cells were significantly inhibited; BLACAT1 shRNAs could reduce the expression of DVL3 on both mRNA and protein expressions levels, the luciferase activity of BLACAT1 reporter was inhibited by miR-29a-3p, and DVL3 was validated as a target gene of miR-29a-3p. CONCLUSION: BLACAT1 expression is abnormally up-regulated in prostate cancer tissues. BLACAT1 can modulate the proliferative and metastatic ability of prostate cancer cells and have the potential to be the "ceRNA" to regulate the expression of DVL3 by sponging miR-29a-3p.

MicroRNA-151 regulates the growth, chemosensitivity and metastasis of human prostate cancer cells by targeting PI3K/AKT.

PURPOSE: Prostate cancer causes significant mortality and microRNAs (miRs) have been shown to regulate the growth and metastasis of different cancers. In this context, the present study was designed to investigate the potential of miR-151 in the treatment of prostate cancer. METHODS: The normal and the prostate cancer cell lines (LNCaP, PC-3 and Du-145) were used in this study. The expression of miR-151 was determined by qRT-PCR. The DAPI and annexin V/propidium iodide (PI) staining were used for the detection of apoptosis. Transwell assay was used for the estimation of cell migration and invasion. Western blot analysis was used for the determination of the protein expression. RESULTS: miR-151 was downregulated in prostate cancer cells and showed inhibitory effect on cell growth which was manifested as decline in cell survival and loss of viability of cancer cells. Additionally, the chemosensitivity of prostate cancer cells to 5-FU was enhanced under miR-151 overexpression. Furthermore, miR-151 also inhibited the migration and invasion of cancer cells. The results of western blot analysis showed that miR-151 overexpression blocks the Pi3K/AKT signalling pathway in prostate cancer cells. CONCLUSION: Taken together, miR-151 has growth inhibitory effect against prostate cancer and negatively regulates the cell migration and invasion along with enhancement of chemosensitivity of cancer cells.

Acquisition of functional neurons by direct conversion: Switching the developmental clock directly.

Identifying approaches for treating neurodegeneration is a thorny task but is important for a growing number of patients. Researchers have focused on discovering the underlying molecular mechanisms of reprogramming and optimizing the technologies for acquiring neurons. Direct conversion is one of the most important processes for treating neurological disorders. Induced neurons derived from direct conversion, which bypass the pluripotency stage, are more effective, more quickly obtained, and are safer than those produced via induced pluripotent stem cells (iPSCs). Based on iPSC strategies, scientists have derived methods to obtain functional neurons by direct conversion, such as neuron-related transcriptional factors, small molecules, microRNAs, and epigenetic modifiers. In this review, we discuss the present strategies for direct conversion of somatic cells into functional neurons and the potentials of direct conversion for producing functional neurons and treating neurodegeneration.

Efficacy and Safety of Microsurgical Subinguinal Varicocelectomy with and without Testicular Delivery for Varicocele Patients: A Systematic Review and Meta-Analysis.

PURPOSE: This study reviewed the efficacy and safety of the microsurgical subinguinal varicocelectomy (MSV) with and without testicular delivery (TD) for varicocele patients. MATERIALS AND METHODS: A systematic literature search was conducted in EMBASE, PubMed, MEDLINE, Cochrane databases, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), and Google Scholar databases to identify relevant studies that reported MSV with and without TD for varicocele patients published in English or Chinese up to October 2018. The Newcastle-Ottawa Scale (NOS) and the Jadad scores were used to evaluate the methodological quality of all the included studies. We also used the Cochrane Collaboration's tool for assessing risk of bias for each study. The Review Manager Software version 5.3 was used to conduct data analysis. RESULTS: Four RCTs and three retrospective studies consisting of 993 patients were included. Meta-analysis results indicated that both of the two treatments were effective and safe. MSV with TD had a lower recurrence rate (OR = 0.20, 95% CI: 0.06 - 0.65, P = .007, I2 = 0%) and postoperative serum testosterone level (MD = -39.07, 95% CI: -51.95 - -26.18, P = .00001, I2 = 0%) compared with MSV without TD but was associated with higher postopera-tive complications rate (OR=7.35, 95% CI: 2.92-18.53, P < .0001, I2 = 0%). We found no significant differences in operation time (MD = 12.46, 95% CI:0.11-24.81,P= .05, I2 = 87%), sperm concentration (MD = 3.73, 95% CI: -2.88 - 10.35, P = .27, I2 = 81%), sperm motility (MD = 10.96, 95% CI: -11.93 - 33.86, P = .35, I2 = 99%), and pregnancy rate(OR = 0.65, 95% CI: 0.37- 1.16, P = .15, I2 = 0%). CONCLUSION: This meta-analysis compared efficacy and safety of MSV with and without TD for varicocele pa-tients. MSV with TD was associated with a higher postoperative complication rate but lower recurrence rate and postoperative serum testosterone level than MSV without TD. In terms of preoperative serum testosterone level, operation time, sperm concentration, sperm motility, and pregnancy rate, we found no significant differences.

Tet3-Mediated DNA Demethylation Contributes to the Direct Conversion of Fibroblast to Functional Neuron.

The direct conversion of somatic cells to neurons by bypassing the multipotent cell state may be a powerful approach for personalized medicine. In addition to neuronal transcription factors and multiple small molecules, we find that epigenetic modification also contributes to the direct conversion of fibroblasts to neurons. Here, we show that Tet3, a DNA dioxygenase, can rapidly and efficiently convert fibroblasts directly into functional neurons. The induced neurons (iNs) express pan and mature neuronal markers such as Tuj1, Synapsin, and neuronal nuclei (NeuN). Gene expression profiles demonstrate distinct neuron-specific gene clusters in iNs compared with primary neurons. Induced neurons display maturing firing patterns and form functional synapses. Additionally, we observe that the level of 5hmC in iNs gradually increases during the time course of transdifferentiation. These findings suggest that DNA demethylation may regulate direct lineage commitment, representing an avenue for investigating the process of transdifferentiation.

Conversion of Fibroblasts to Parvalbumin Neurons by One Transcription Factor, Ascl1, and the Chemical Compound Forskolin.

Abnormalities in parvalbumin (PV)-expressing interneurons cause neurodevelopmental disorders such as epilepsy, autism, and schizophrenia. Unlike other types of neurons that can be efficiently differentiated from pluripotent stem cells, PV neurons were minimally generated using a conventional differentiation strategy. In this study we developed an adenovirus-based transdifferentiation strategy that incorporates an additional chemical compound for the efficient generation of induced PV (iPV) neurons. The chemical compound forskolin combined with Ascl1 induced ∼80% of mouse fibroblasts to iPV neurons. The iPV neurons generated by this procedure matured 5-7 days post infection and were characterized by electrophysiological properties and known neuronal markers, such as PV and GABA. Our studies, therefore, identified an efficient approach for generating PV neurons.