MiRNA-100 ameliorates diabetes mellitus-induced erectile dysfunction by modulating autophagy, anti-inflammatory, and antifibrotic effects.

BACKGROUND: Diabetes mellitus-induced erectile dysfunction (DMED) has become a common disease in adult men that can seriously reduce the quality of life of patients, and new therapies are urgently needed. miRNA-100 has many targets and can induce autophagy and reduce fibrosis by inhibiting the mTOR pathway and the TGF-ß pathway. However, no research has been conducted with miR-100 in the field of DMED, and the specific mechanism of action is still unclear. OBJECTIVES: To ascertain the effects of miR-100 on corpus cavernosum tissue of DMED rats and vascular endothelial cells in a high glucose environment and to elucidate the relevant mechanisms in autophagy, fibrosis and inflammation to find a new approach for the DMED therapy. METHODS: Thirty rats were divided into three groups: the control group, the DMED group, and the DMED + miR-100 group. Using intraperitoneal injections of streptozotocin, all rats except the control group were modeled with diabetes mellitus, which was verified using the apomorphine (APO) test. For rats in the DMED + miR-100 group, rno-miR-100-5p agomir (50 nmol/kg, every 2 days, 6 times in total) was injected via the tail vein. After 13 weeks, the erectile function of each rat was assessed using cavernous manometry, and the corpus cavernosum tissue was harvested for subsequent experiments. For cellular experiments, human coronary microartery endothelial cells (HCMEC) were divided into four groups: the control group, the high-glucose (HG, 40 mM) group, the HG + mimic group, and the HG + inhibitor group. The cells were cultured for 6 days and collected for subsequent experiments 2 days after transfection. RESULTS: Diabetic modeling impaired the erectile function in rats, and miR-100 reversed this effect. By measuring autophagy-related proteins such as mTOR/Raptor/Beclin1/p62/LC3B, we found that miR-100 could suppress the expression of mTOR and induce autophagy. The analysis of the eNOS/NO/cGMP axis function indicated that impaired endothelial function was improved by miR-100. By evaluating the TGF-ß1/CTGF/Smad2/3 and NF-κB/TNF-α pathways, we found that miR-100 could lower the level of inflammation and fibrosis, which contributed to the improvement of the erectile function. Cellular experiments can be used as supporting evidence for these findings. CONCLUSION: MiR-100 can improve the erectile function by inhibiting mTOR and thus inducing autophagy, improving the endothelial function through the eNOS/NO/cGMP axis, and exerting antifibrotic and anti-inflammatory effects, which may provide new ideas and directions for the treatment of DMED.

STX4 as a potential biomarker for predicting prognosis and guiding clinical treatment decisions in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) represents a frequent subtype of kidney cancer, with the prognosis remaining poor for individuals with metastatic disease. Given its resistance to both radiation and chemotherapy, targeted therapies and immunotherapies have emerged as critical for effective ccRCC treatment. Within this context, the SNARE protein STX4, which is associated with malignant cancer cell migration, provides a promising focus. The underlying mechanism, however, requires further illumination. Furthermore, the influence of STX4 on the ccRCC tumor microenvironment remains to be determined. In our research, we utilized multiple databases and immunohistochemical staining to confirm differential STX4 expression and its prognostic implications. We evaluated the potential tumor-promoting function of STX4 in ccRCC cell lines through molecular studies. Additionally, we conducted functional enrichment analysis to delve deeper into the underlying mechanisms and performed immune infiltration and drug sensitivity analyses to assess the potential of STX4 as a prognostic biomarker and therapeutic target. Our study reveals that STX4 contributes to cancer progression by enhancing AKT expression and stimulating the activation of VEGF signaling pathways. Additionally, STX4 further fosters CD8+ T-cell infiltration and diminishes the percentage of CAFs and M2-TAMs. Our findings suggest that patients presenting higher STX4 levels may exhibit enhanced responsiveness to immunotherapy and higher sensitivity to the medications axitinib and everolimus. Finally, we propose STX4 expression assessment as a novel approach to predict patient response to respective immunotherapies and targeted treatments, hence potentially improving patient outcomes.

Approaches to Improving the Selectivity of Nanozymes.

Nanozymes mimic enzymes and that includes their selectivity. To achieve selectivity, significant inspiration for nanoparticle design can come from the geometric and molecular features that make enzymes selective catalysts. The two central features enzymes use are control over the arrangement of atoms in the active site and the placing of the active site down a nanoconfined substrate channel. The implementation of enzyme-inspired features has already been shown to both improve activity and selectivity of nanoparticles for a variety of catalytic and sensing applications. The tuning and control of active sites on metal nanoparticle surfaces ranges from simply changing the composition of the surface metal to sophisticated approaches such as the immobilization of single atoms on a metal substrate. Molecular frameworks provide a powerful platform for the implementation of isolated and discrete active sites while unique diffusional environments further improve selectivity. The implementation of nanoconfined substrate channels around these highly controlled active sites offers further ability to control selectivity through altering the solution environment and transport of reactants and products. Implementing these strategies together offers a unique opportunity to improve nanozyme selectivity in both sensing and catalysis.

Organoid-on-a-chip: Current challenges, trends, and future scope toward medicine.

In vitro organoid models, typically defined as 3D multicellular aggregates, have been extensively used as a promising tool in drug screening, disease progression research, and precision medicine. Combined with advanced microfluidics technique, organoid-on-a-chip can flexibly replicate in vivo organs within the biomimetic physiological microenvironment by accurately regulating different parameters, such as fluid conditions and concentration gradients of biochemical factors. Since engineered organ reconstruction has opened a new paradigm in biomedicine, innovative approaches are increasingly required in micro-nano fabrication, tissue construction, and development of pharmaceutical products. In this Perspective review, the advantages and characteristics of organoid-on-a-chip are first introduced. Challenges in current organoid culture, extracellular matrix building, and device manufacturing techniques are subsequently demonstrated, followed by potential alternative approaches, respectively. The future directions and emerging application scenarios of organoid-on-a-chip are finally prospected to further satisfy the clinical demands.

Effect of Thermophilic Microbial Agents on Crude Fiber Content, Carbohydrate-Active Enzyme Genes, and Microbial Communities during Chinese Medicine Residue Composting.

The objective of this study was to investigate the impact of thermophilic bacteria on crude fiber content, carbohydrate-active enzyme (CAZyme) genes, and associated microbial communities during Chinese medicine residues composting. The study examines changes over 15 days of composting with (T) and without (CK) thermophilic microbial agents. Results show that the group T compost temperature reached a maximum of 71.0 °C and remained above 70 °C for 2 days, while the group CK maximum temperature was only 60.9 °C. On Day 15, the seed germination index (GI) of group T reached 98.7%, while the group CK GI was only 56.7%. After composting, the degradation rates of cellulose, hemicellulose, and lignin in group T increased by 5.1, 22.5, and 18.5%, respectively, compared to those in group CK. Thermophilic microbial agents changed the microbial communities related to CAZymes, increasing unclassified_o_Myxococcales and Sphaerobacter abundance and reducing Acinetobacter and Sphingobacterium abundance. Thermophilic microbial agents also increased the abundance of the GT4, GT2_Glycos_transf_2, and AA3 gene families. These results show that thermophilic microbial agents can increase composting temperature, accelerate compost maturation, and promote crude fiber degradation. Therefore, they have broad application potential.

CPT2-mediated fatty acid oxidation inhibits tumorigenesis and enhances sorafenib sensitivity via the ROS/PPARγ/NF-κB pathway in clear cell renal cell carcinoma.

Kidney cancer is a common kind of tumor with approximately 400,000 new diagnoses each year. Clear cell renal cell carcinoma (ccRCC) accounts for 70-80% of all renal cell carcinomas. Lipid metabolism disorder is a hallmark of ccRCC. With a better knowledge of the importance of fatty acid oxidation (FAO) in cancer, carnitine palmitoyltransferase 2 (CPT2) has gained prominence as a major mediator in the cancer metabolic pathway. However, the biological functions and mechanism of CPT2 in the progression of ccRCC are still unclear. Herein, we performed assays in vitro and in vivo to explore CPT2 functions in ccRCC. Moreover, we discovered that CPT2 induced FAO, which inhibited the generation of reactive oxygen species (ROS) by increasing nicotinamide adenine dinucleotide phosphate (NADPH) production. Additionally, we demonstrated that CPT2 suppresses tumor proliferation, invasion, and migration by inhibiting the ROS/ PPARγ /NF-κB pathway. Gene set enrichment analysis (GSEA) and drug sensitivity analysis showed that high expression of CPT2 in ccRCC was associated with higher sorafenib sensitivity, which was also validated in vitro and in vivo. In summary, our results suggest that CPT2 acts as a tumor suppressor in the development of ccRCC through the ROS/PPARγ/NF-κB pathway. Moreover, CPT2 is a potential therapeutic target for increasing sorafenib sensitivity in ccRCC.

Small-sample learning reveals propionylation in determining global protein homeostasis.

Proteostasis is fundamental for maintaining organismal health. However, the mechanisms underlying its dynamic regulation and how its disruptions lead to diseases are largely unclear. Here, we conduct in-depth propionylomic profiling in Drosophila, and develop a small-sample learning framework to prioritize the propionylation at lysine 17 of H2B (H2BK17pr) to be functionally important. Mutating H2BK17 which eliminates propionylation leads to elevated total protein level in vivo. Further analyses reveal that H2BK17pr modulates the expression of 14.7-16.3% of genes in the proteostasis network, and determines global protein level by regulating the expression of genes involved in the ubiquitin-proteasome system. In addition, H2BK17pr exhibits daily oscillation, mediating the influences of feeding/fasting cycles to drive rhythmic expression of proteasomal genes. Our study not only reveals a role of lysine propionylation in regulating proteostasis, but also implements a generally applicable method which can be extended to other issues with little prior knowledge.

Current microfluidic platforms for reverse engineering of cornea.

According to the World Health Organization, corneal blindness constitutes 5.1% of global blindness population. Surgical outcomes have been improved significantly in the treatment of corneal blindness. However, corneal transplantation is limited by global shortage of donor tissue, prompting researchers to explore alternative therapies such as novel ocular pharmaceutics to delay corneal disease progression. Animal models are commonly adopted for investigating pharmacokinetics of ocular drugs. However, this approach is limited by physiological differences in the eye between animals and human, ethical issues and poor bench-to-bedside translatability. Cornea-on-a-chip (CoC) microfluidic platforms have gained great attention as one of the advanced in vitro strategies for constructing physiologically representative corneal models. With significant improvements in tissue engineering technology, CoC integrates corneal cells with microfluidics to recapitulate human corneal microenvironment for the study of corneal pathophysiological changes and evaluation of ocular drugs. Such model, in complement to animal studies, can potentially accelerate translational research, in particular the pre-clinical screening of ophthalmic medication, driving clinical treatment advancement for corneal diseases. This review provides an overview of engineered CoC platforms with respect to their merits, applications, and technical challenges. Emerging directions in CoC technology are also proposed for further investigations, to accentuate preclinical obstacles in corneal research.

The role of calcium channels in prostate cancer progression and potential as a druggable target for prostate cancer treatment.

Prostate cancer (PCa) is the most diagnosed cancer among men. Discovering novel prognostic biomarkers and potential therapeutic targets are critical. Calcium signaling has been implicated in PCa progression and development of treatment resistance. Altered modification of Ca2+ flows leads to serious pathophysiological processes, such as malignant transformation, tumor proliferation, epithelial to mesenchymal transition, evasion of apoptosis, and treatment resistance. Calcium channels control and contribute to these processes. PCa has shown defective Ca2+ channels, which subsequently promotes tumor metastasis and growth. Store-operated Ca2+ entry channels such as Orai and STIM channels and transient receptor potential channels play a significant role in PCa pathogenesis. Pharmacological modulation of these calcium channels or pumps has been suggested as a practical approach. In this review, we discuss the role of calcium channels in PCa development and progression, and we identify current novel discoveries of drugs that target specific calcium channels for the treatment of PCa.

Identification of predictive factors for outcomes after robot-assisted partial nephrectomy based on three-dimensional reconstruction of preoperative enhanced computerized tomography.

Background: Information from the RENAL score is limited. This study aimed to identify new parameters based on three-dimensional (3D) reconstruction of preoperative enhanced computerized tomography (CT) for predicting outcomes after robot-assisted partial nephrectomy (RPN). Materials and methods: The records of kidney cancer patients who underwent RPN at Tongji Hospital from March 2015 to July 2019 were reviewed. Demographic data, laboratory examinations, postoperative hospitalization time, and enhanced CT were retrospectively collected. Some tumor parameters were obtained from 3D reconstruction of CT data. The association between these predictive factors and outcomes after RPN was analyzed. Results: A larger tumor bed area (TBA) was associated with a longer warm ischemia time (WIT) (P-value <0.001) and tumor resection time (P-value <0.001). Moreover, TBA was significantly associated with the elevation of postoperative creatinine (P-value = 0.005). TBA (P = 0.008), distance from the tumor to the first bifurcation of the renal artery (DTA) (P <0.034), and RENAL score (P = 0.005) were significantly associated with WIT in univariate logistic regression. In multivariate logistic regression, TBA (P = 0.026) and DTA (P = 0.048) were independent risk factors for prolonged WIT (over 25 min). The predictive effect of the combination of TBA, DTA, and RENAL score was higher than the predictive effect of RENAL score alone for WIT (area under curve: 0.786 versus 0.72). Conclusion: TBA and DTA are independently associated with the WIT of RPN, which provides additional assessment value for the complexity of kidney cancer in RPN over the RENAL score.

Outcomes of Surgical Treatment for Graves' Disease: A Single-Center Experience of 216 Cases.

BACKGROUND: The role of surgery in the treatment of Graves' disease (GD) needs to be revisited. The aims of the present retrospective study were to evaluate the outcomes of the current surgical strategy as a definitive treatment of GD at our center and to explore the clinical association between GD and thyroid cancer. METHODS: A patient cohort of 216 cases from 2013 to 2020 was involved in this retrospective study. The data of the clinical characteristics and follow-up results were collected and analyzed. RESULTS: There were 182 female and 34 male patients. The mean age was 43.9 ± 15.0 years old. The mean duration of GD reached 72.2 ± 92.7 months. Of the 216 cases, 211 had been treated with antithyroid drugs (ATDs) and hyperthyroidism had been completely controlled in 198 cases. A total (75%) or near-total (23.6%) thyroidectomy was performed. Intraoperative neural monitoring (IONM) was applied to 37 patients. The failure of ATD therapy (52.3%) was the most common surgical indication, followed by suspicion of a malignant nodule (45.8%). A total of 24 (11.1%) patients had hoarseness after the operation and 15 (6.9%) patients had transient vocal cord paralysis; 3 (1.4%) had this problem permanently. No bilateral RLN paralysis occurred. A total of 45 patients had hypoparathyroidism and 42 of them recovered within 6 months. Sex showed a correlation with hypoparathyroidism through a univariate analysis. A total of 2 (0.9%) patients underwent a reoperation because of hematomas. A total of 104 (48.1%) cases were diagnosed as thyroid cancer. In most cases (72.1%), the malignant nodules were microcarcinomas. A total of 38 patients had a central compartment node metastasis. A lateral lymph node metastasis occurred in 10 patients. Thyroid carcinomas were incidentally discovered in the specimens of 7 cases. The patients with concomitant thyroid cancer had a significant difference in body mass index, duration of GD, gland size, thyrotropin receptor antibodies and nodule(s) detected. CONCLUSION: Surgical treatments for GD were effective, with a relatively low incidence of complications at this high-volume center. Concomitant thyroid cancer is one of the most important surgical indications for GD patients. Careful ultrasonic screening is necessary to exclude the presence of malignancies and to determine the therapeutic plan.

Integrated analysis to identify the AC005154.6/hsa-miR-29c-3p/CCNL2 axis as a novel prognostic biomarker associated with immune infiltration in prostate cancer.

BACKGROUND: Prostate cancer (PCa) is currently the major malignancy in men. It is becoming increasingly clear that competitive endogenous RNA (ceRNA) regulation networks are important in a wide variety of cancers. Nevertheless, there is still much to learn about the biological functions of the ceRNA network in prostate cancer. METHODS: The ceRNA network was constructed using the "GDCRNATools" package. Based on survival analysis, we obtained AC005154.6/hsa-miR-29c-3p/CCNL2 for further analysis. The prognostic model based on this ceRNA network was constructed by univariate and multivariate Cox regression methods. Furthermore, functional enrichment analysis, mutation landscape analysis, immune infiltration analysis, drug sensitivity analysis, methylation analysis, pan-cancer analysis, and molecular experiments of CCNL2 were carried out to investigate the role of CCNL2 in tumorigenesis. RESULTS: We identified the AC005154.6/CCNL2 axis as a risk factor that can promote the progression of prostate cancer by bioinformatics analysis and molecular experiments. Immune infiltration analysis suggested that CCNL2 may act as a novel biomarker for treatment decisions. The methylation level of CCNL2 was significantly decreased in tumor samples, possibly contributing to the upregulation of CCNL2 in prostate cancer. Moreover, CCNL2 is differentially expressed in multiple cancers and is tightly correlated with immune infiltration. CONCLUSION: The current study constructed a ceRNA network, AC005154.6/hsa-miR-29c-3p/CCNL2. Potentially, this biomarker can be used for early diagnosis and decision-making about prostate cancer treatment.

Biobased and Programmable Electroadhesive Metasurfaces.

Electroadhesion has shown the potential to deliver versatile handling devices because of its simplicity of actuation and rapid response. Current electroadhesion systems have, however, significant difficulties in adapting to external objects with complex shapes. Here, a novel concept of metasurface is proposed by combining the use of natural fibers (flax) and shape memory epoxy polymers in a hygromorphic and thermally actuated composite (HyTemC). The biobased material composite can be used to manipulate adhesive surfaces with high precision and controlled environmental actuation. The HyTemC concept is preprogrammed to store controllable moisture and autonomous desorption when exposed to the operational environment, and can reach predesigned bending curvatures up to 31.9 m-1 for concave and 29.6 m-1 for convex shapes. The actuated adhesive surface shapes are generated via the architected metasurface structure, incorporating an electroadhesive component integrated with the programmable biobased materials. This biobased metasurface stimulated by the external environment provides a large taxonomy of shapes─from flat, circular, single/double concave, and wavy, to piecewise, polynomial, trigonometric, and airfoil configurations. The objects handled by the biobased metasurface can be fragile because of the high conformal matching between contacting surfaces and the absence of compressive adhesion. These natural fiber-based and environmentally friendly electroadhesive metasurfaces can significantly improve the design of programmable object handling technologies, and also provide a sustainable route to lower the carbon and emission footprint of smart structures and robotics.

Bioprocess Engineering, Transcriptome, and Intermediate Metabolite Analysis of L-Serine High-Yielding Escherichia coli W3110.

L-serine is widely used in the food, cosmetic, and pharmaceutical industries. However, the complicated metabolic network and regulatory mechanism of L-serine production lead to the suboptimal productivity of the direct fermentation of L-serine and limits its large-scale industrial production. In this study, a high-yield L-serine production Escherichia coli strain was constructed by a series of defined genetic modification methodologies. First, L-serine-mediated feedback inhibition was removed and L-serine biosynthetic pathway genes (serAfr, serC, and serB) associated with phosphoglycerate kinase (pgk) were overexpressed. Second, the L-serine conversion pathway was further examined by introducing a glyA mutation (K229G) and deleting other degrading enzymes based on the deletion of initial sdaA. Finally, the L-serine transport system was rationally engineered to reduce uptake and accelerate L-serine export. The optimally engineered strain produced 35 g/L L-serine with a productivity of 0.98 g/L/h and a yield of 0.42 g/g glucose in a 5-L fermenter, the highest productivity and yield of L-serine from glucose reported to date. Furthermore, transcriptome and intermediate metabolite of the high-yield L-serine production Escherichia coli strain were analyzed. The results demonstrated the regulatory mechanism of L-serine production is delicate, and that combined metabolic and bioprocess engineering strategies for L-serine producing strains can improve the productivity and yield.

Identification of Calcium Channel-Related Gene P2RX2 for Prognosis and Immune Infiltration in Prostate Cancer.

Prostate cancer is one of the most common malignancies in men. Calcium signaling is implicated in the progression of prostate cancer and plays a critical role in immune cell function. However, whether specific calcium channel-related genes play a crucial role in the immune cell infiltration levels of prostate cancer requires further research. In this study, we performed an integrated analysis of transcriptional, clinical, and somatic mutation data from The Cancer Genome Atlas database and identified the hub calcium channel-related gene P2RX2 to be associated with the prognosis and immune infiltration of prostate cancer. P2RX2 expression was positively correlated with immune cell infiltration levels and the expression of immune checkpoint genes, and downregulation of P2RX2 led to poor survival in patients with prostate cancer. Furthermore, we validated the molecular and clinical characteristics of P2RX2 by using multiple databases and conducting in-vitro experiments. Additionally, drug sensitivity analysis revealed that patients with low P2RX2 expression were sensitive to docetaxel and Bicalutamide. In conclusion, we revealed an association between calcium channel-related genes and prostate cancer, and identified P2RX2 as a biomarker for early diagnosis, prognosis prediction, and aiding treatment decisions for patients with prostate cancer.

A cuproptosis-related lncRNA signature identified prognosis and tumour immune microenvironment in kidney renal clear cell carcinoma.

Kidney renal clear cell carcinoma (KIRC) is a heterogeneous malignant tumor with high incidence, metastasis, and mortality. The imbalance of copper homeostasis can produce cytotoxicity and cause cell damage. At the same time, copper can also induce tumor cell death and inhibit tumor transformation. The latest research found that this copper-induced cell death is different from the known cell death pathway, so it is defined as cuproptosis. We included 539 KIRC samples and 72 normal tissues from the Cancer Genome Atlas (TCGA) in our study. After identifying long non-coding RNAs (lncRNAs) significantly associated with cuproptosis, we clustered 526 KIRC samples based on the prognostic lncRNAs and obtained two different patterns (Cuproptosis.C1 and C2). C1 indicated an obviously worse prognostic outcome and possessed a higher immune score and immune cell infiltration level. Moreover, a prognosis signature (CRGscore) was constructed to effectively and accurately evaluate the overall survival (OS) of KIRC patients. There were significant differences in tumor immune microenvironment (TIME) and tumor mutation burden (TMB) between CRGscore-defined groups. CRGscore also has the potential to predict medicine efficacy.

A predictive signature based on enhancer RNA associates with immune infiltration and aids treatment decision in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a prevalent urinary malignancy. Despite the recent development of better diagnostic tools and therapy, the five-year survival rate for individuals with advanced and metastatic ccRCC remains dismal. Unfortunately, ccRCC is less susceptible to radiation and chemotherapy. Consequently, targeted therapy and immunotherapy play a crucial role in the treatment of ccRCC. Enhancer RNAs (eRNAs) are noncoding RNAs transcribed by enhancers. Extensive research has shown that eRNAs are implicated in a variety of cancer signaling pathways. However, the biological functions of eRNAs have not been systematically investigated in ccRCC. In this study, we conducted a comprehensive investigation of the role of eRNAs in the onset and management of ccRCC. Patient prognosis-influencing eRNAs and target genes were chosen to construct a predictive signature. On the basis of the median riskscore, ccRCC patients were split into high- and low-risk subgroups. The prediction efficiency was assessed in several cohorts, and multi-omics analysis was carried out to investigate the differences and underlying mechanisms between the high- and low-risk groups. In addition, we investigated its potential to facilitate clinical treatment choices. The riskscore might be used to forecast a patient's response to immunotherapy and targeted therapy, giving a revolutionary method for selecting treatment regimens with pinpoint accuracy.

Comprehensive analysis to identify the RP11-478C19.2/ E2F7 axis as a novel biomarker for treatment decisions in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC), accounting for 70-80% of all renal cell carcinomas, is a common malignancy. Survival rates decrease significantly in patients with advanced and metastatic ccRCC. Furthermore, ccRCC is less responsive to radiation and chemotherapy than other cancers. Therefore, targeted therapy and immunotherapy are particularly important for ccRCC management. A growing body of literature recognizes that competitive endogenous RNA (ceRNA) regulatory networks play a crucial role in various cancers. However, the biological functions of the ceRNA network in ccRCC require further investigation. In this study, we built the ceRNA network for ccRCC using the "GDCRNATools" package. After survival analysis, the RP11-478C19.2/hsa-miR-181b-5p, hsa-miR-181a-5p, and hsa-miR-181c-5p/E2F7 axes were obtained for further analysis. Unsupervised clustering was conducted basing on this ceRNA network. The results indicated that the prognosis and immune infiltration levels differed between the two clusters. Furthermore, we conducted correlation analysis, immune infiltration analysis, tumor mutation burden analysis, GSEA analysis, drug sensitivity analysis and pan-cancer analysis of E2F7 to explore its potential role in oncogenesis. Experiments in vitro were performed to confirm the pro-oncogenic impact of E2F7. The results suggest that the RP11-478C19.2/E2F7 axis might be a biomarker for the inclusion of cabozantinib, pazopanib, sunitinib, and immunotherapy in the therapeutic regimen. In summary, we found that the ceRNA-based RP11-478C19.2/E2F7 axis is involved in ccRCC and that it could be a novel biomarker for treatment decisions and a possible therapeutic target to increase the success of targeted therapy and immunotherapy in ccRCC.

Assessment of pulmonary infectious disease treatment with Mongolian medicine formulae based on data mining, network pharmacology and molecular docking.

Objective: Pulmonary infectious diseases (PID) include viral pneumonia (VP) and pulmonary tuberculosis (PT). Mongolian medicine (MM) is an effective treatment option in China, however, the core group medicines (CGMs) in the treatment of PID and their underlying therapeutic mechanisms remain unclear. In this study, through the method of data mining, the CGMs of MM for the treatment of PID were excavated, and the possible mechanism of action of the CGMs in the treatment of PID was explored by using network pharmacology. Methods: First, 89 MM formulae for the treatment of pulmonary infectious diseases collected from Gan Lu Si Bu, Meng Yi Jin Kui, People's Republic of China Ministry of Health Drug Standards (Mongolian Medicine Volume), Standard of Mongolian Medicine Preparations in Inner Mongolia (2007 Edition), and Standard of Mongolian Medicine Preparations in Inner Mongolia (2014 Edition). The CGMs of MM for PID were excavated through association rule analysis and cluster analysis. Then, the active ingredients and potential targets of the CGMs were obtained from TCMSP, TCMIP, BATMAN-TCM databases. PID targets information was collected from OMIM, GeneCards, and DrugBank databases. The possible targets of CGMs treatment for PID were obtained by intersection. The PPI network was constructed through the STRING database, and the topology analysis of the network was performed. Through the enrichment analysis of the intersection targets by R language, the main action pathways and related target proteins of CGMs in the treatment of PID were screened out. The results were verified by molecular docking. Results: A total of 89 formulae were included, involving 164 MM herbs. The efficacy of the drugs was mainly cough-suppressing and panting-calming herbs, and heat-clearing herbs. The nature and flavor were mainly bitter and cold. The CGMs of MM to treatment of PID was excavated as the classic famous formula Sanzi Decoction (Toosendan Fructus-Chebulae Fructus-Gardeniae Fructus). A total of 28 candidate components and 237 predicted targets of CGMs were collected, and 61 common targets with PID were obtained, including key compounds such as quercetin, kaempferol, ß-sitosterol and stigmastero and key targets such as VEGFA, IL6, TP53, AKT1. KEGG enrichment analysis yielded AGE-RAGE signaling pathways, IL-17 signaling pathways, and TNF signaling pathways. Molecular docking results showed that the key targets were well matched with the potential active ingredients of CGMs. Conclusion: This study found that MM commonly used cough-suppressing and panting-calming herbs in combination with heat-clearing herbs to treat PID, and the CGMs for the treatment of PID is "Toosendan Fructus-Chebulae Fructus-Gardeniae Fructus". CGMs mainly play a role in the treatment of PID by acting on VEGFA, IL6, TP53, AKT1 and other targets, regulating AGE-RAGE signaling pathways, IL-17 signaling pathways, and TNF signaling pathways.

Lymphatic endothelial sphingosine 1-phosphate receptor 1 enhances macrophage clearance via lymphatic system following myocardial infarction.

Lymphatic endothelial cell homeostasis plays important roles in normal physiological cardiac functions, and its dysfunction significantly influences pathological cardiac remodeling after myocardial infarction (MI). Our results revealed that sphingosine 1-phosphate receptor 1 (S1pr1) expression in cardiac lymphatic endothelial cells (LECs) was sharply changed after MI. It has been shown that S1pr1 tightly controlled LEC functions and homeostasis. We thus hypothesized that lymphatic endothelial S1pr1 might be involved in post-MI cardiac remodeling. We generated LEC-conditional S1pr1 transgenic mice, in which S1pr1 expression was reduced in cardiac LECs. We performed the left anterior descending coronary artery (LAD) ligation operation to induce MI in these mice. Cardiac functions and remodeling were examined by echocardiography analysis and serial histological analysis. Meanwhile, we performed adoptive cell transfer experiments to monitor macrophage trafficking in post-MI myocardium and their draining lymphatic system. Furthermore, in vitro cell culture experiments and mechanism studies were undertaken to uncover the molecular mechanism by which LEC-S1pr1 regulated cardiac inflammation and remodeling after MI. Our results showed that S1pr1 expression significantly decreased in cardiac LECs after MI. Our in vivo experiments showed that the reduced expression of LEC-S1pr1 deteriorated cardiac function and worsened pathological cardiac remodeling after MI. Our further results demonstrated that the reduced expression of LEC-S1pr1 did not influence macrophage infiltration in an early inflammatory phase of MI, but significantly affected macrophages clearance in the later phase of MI via afferent cardiac lymphatics, and thus influenced inflammatory responses and cardiac outcome after MI. Further study showed that S1P/S1pr1 activated ERK signaling pathway and enhanced CCL2 expression, which promoted macrophage trafficking in a paracrine manner. This study reveals that cardiac lymphatic endothelial cells tightly control macrophage trafficking via lymphatic vessels in injured hearts via S1P/S1pr1/ERK/CCL2 pathway and thus regulate post-MI immune modulation and heart repair. This study highlights the importance of cardiac lymphatic vessel system in orchestrating post-MI immune responses and cardiac remodeling by regulating macrophage transit in injured hearts. Our finding implies that a feasible modulation of S1pr1 signaling in LECs might provide a promising target to resolve excessive inflammation and to ameliorate adverse cardiac remodeling after MI.