The Inhibition of Fibrosis and Inflammation in Obstructive Kidney Injury via the miR-122-5p/SOX2 Axis Using USC-Exos.

Background: Fibrosis and inflammation due to ureteropelvic junction obstruction substantially contributes to poor renal function. Urine-derived stem-cell-derived exosomes (USC-Exos) have therapeutic effects through paracrine. Methods: In vitro, the effects of USC-Exos on the biological functions of HK-2 and human umbilical vein endothelial cells were tested. Cell inflammation and fibrosis were induced by transforming growth factor-ß1 and interleukin-1ß, and their anti-inflammatory and antifibrotic effects were observed after exogenous addition of USC-Exos. Through high-throughput sequencing of microRNA in USC-Exos, the pathways and key microRNAs were selected. Then, the antifibrotic and anti-inflammatory effects of exosomal miR-122-5p and target genes were verified. The role of the miR-122-5p/SOX2 axis in anti-inflammatory and antifibrotic effects was verified. In vivo, a rabbit model of partial unilateral ureteral obstruction (PUUO) was established. Magnetic resonance imaging recorded the volume of the renal pelvis after modeling, and renal tissue was pathologically analyzed. Results: We examined the role of USC-Exos and their miR-122-5p content in obstructive kidney injury. These Exos exhibit antifibrotic and anti-inflammatory activities. SOX2 is the hub gene in PUUO and negatively related to renal function. We confirmed the binding relationship between miR-122-5p and SOX2. The anti-inflammatory and antifibrotic effects of miR-122-5p were inhibited, indicating that miR-122-5p has anti-inflammatory and antifibrotic effects by inhibiting SOX2 expression. In vivo, the PUUO group showed typical obstructive kidney injury after modeling. After USC-Exo treatment, the shape of the renal pelvis shown a remarkable improvement, and inflammation and fibrosis decreased. Conclusions: We confirmed that miR-122-5p from USC-Exos targeting SOX2 is a new molecular target for postoperative recovery treatment of obstructive kidney injury.

Non-alcoholic fatty liver disease and sleep disorders.

Studies have shown that non-alcoholic fatty liver disease (NAFLD) may be associated with sleep disorders. In order to explore the explicit relationship between the two, we systematically reviewed the effects of sleep disorders, especially obstructive sleep apnea (OSA), on the incidence of NAFLD, and analyzed the possible mechanisms after adjusting for confounding factors. NAFLD is independently associated with sleep disorders. Different sleep disorders may be the cause of the onset and aggravation of NAFLD. An excessive or insufficient sleep duration, poor sleep quality, insomnia, sleep-wake disorders, and OSA may increase the incidence of NAFLD. Despite that some research suggests a unidirectional causal link between the two, specifically, the onset of NAFLD is identified as a result of changes in sleep characteristics, and the reverse relationship does not hold true. Nevertheless, there is still a lack of specific research elucidating the reasons behind the higher risk of developing sleep disorders in individuals with NAFLD. Further research is needed to establish a clear relationship between NAFLD and sleep disorders. This will lay the groundwork for earlier identification of potential patients, which is crucial for earlier monitoring, diagnosis, effective prevention, and treatment of NAFLD.

A novel pyroptosis-related gene signature exhibits distinct immune cells infiltration landscape in Wilms' tumor.

BACKGROUND: Wilms' tumor (WT) is the most common renal tumor in childhood. Pyroptosis, a type of inflammation-characterized and immune-related programmed cell death, has been extensively studied in multiple tumors. In the current study, we aim to construct a pyroptosis-related gene signature for predicting the prognosis of Wilms' tumor. METHODS: We acquired RNA-seq data from TARGET kidney tumor projects for constructing a gene signature, and snRNA-seq data from GEO database for validating signature-constructing genes. Pyroptosis-related genes (PRGs) were collected from three online databases. We constructed the gene signature by Lasso Cox regression and then established a nomogram. Underlying mechanisms by which gene signature is related to overall survival states of patients were explored by immune cell infiltration analysis, differential expression analysis, and functional enrichment analysis. RESULTS: A pyroptosis-related gene signature was constructed with 14 PRGs, which has a moderate to high predicting capacity with 1-, 3-, and 5-year area under the curve (AUC) values of 0.78, 0.80, and 0.83, respectively. A prognosis-predicting nomogram was established by gender, stage, and risk score. Tumor-infiltrating immune cells were quantified by seven algorithms, and the expression of CD8( +) T cells, B cells, Th2 cells, dendritic cells, and type 2 macrophages are positively or negatively correlated with risk score. Two single nuclear RNA-seq samples of different histology were harnessed for validation. The distribution of signature genes was identified in various cell types. CONCLUSIONS: We have established a pyroptosis-related 14-gene signature in WT. Moreover, the inherent roles of immune cells (CD8( +) T cells, B cells, Th2 cells, dendritic cells, and type 2 macrophages), functions of differentially expressed genes (tissue/organ development and intercellular communication), and status of signaling pathways (proteoglycans in cancer, signaling pathways regulating pluripotent of stem cells, and Wnt signaling pathway) have been elucidated, which might be employed as therapeutic targets in the future.

NFIL3 aggravates human coronary artery endothelial cell injury by promoting ITGAM transcription in Kawasaki disease.

OBJECTIVE: High expression of nuclear factor interleukin-3 (NFIL3) and integrin Alpha M (ITGAM) was found in serum samples from Kawasaki disease (KD) patients through bioinformatics analysis. Hence, this study aimed to explore the biological functions of NFIL3 and ITGAM in KD serum-stimulated human coronary artery endothelial cells (HCAECs). METHODS: The differentially-expressed genes in KD were analyzed through bioinformatics analysis. Serum samples were obtained from 18 KD patients and 18 healthy volunteers, followed by detection of NFIL3 and ITGAM levels in KD serum. After HCAECs were transfected with sh-NFIL3, sh-ITGAM, or sh-NFIL3 + oe-ITGAM and underwent 24-h KD serum stimulation, cell viability and apoptosis and the levels of inflammation-related factors were measured. The binding between NFIL3 and ITGAM was validated by dual-luciferase and chromatin immunoprecipitation (ChIP) assays. RESULTS: NFIL3 and ITGAM were up-regulated in serum from KD patients and KD serum-stimulated HCAECs. Down-regulation of NFIL3 or ITGAM inhibited KD serum-induced cell apoptosis and inflammatory response of HCAECs and promoted cell viability. Mechanistically, NFIL3 promoted ITGAM transcription level. Up-regulation of ITGAM reversed the improvement of NFIL3 down-regulation on KD serum-induced HCAEC injury. CONCLUSION: NFIL3 aggravated KD serum-induced HCAEC injury by promoting ITGAM transcription, which provided new insights into the treatment of KD.

Roles of pyroptosis in atherosclerosis pathogenesis.

Pyroptosis is a pro-inflammatory type of regulated cell death (RCD) characterized by gasdermin protein-mediated membrane pore formation, cell swelling, and rapid lysis. Recent studies have suggested that pyroptosis is closely related to atherosclerosis (AS). Previous studies reported that pyroptosis involving endothelial cells (ECs), macrophages, and smooth muscle cells (SMCs) plays an important role in the formation and development of AS. Pyroptosis not only causes local inflammation but also amplifies the inflammatory response and it aggravates plaque instability, leading to plaque rupture and thrombosis, eventually resulting in acute cardiovascular events. In this review, we clarified some novel pathways and mechanics and presented some potential drugs.

Role of miRNAs in Rheumatoid Arthritis Therapy.

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease characterized by autoimmunity, synovial inflammation and joint destruction. Pannus formation in the synovial cavity can cause irreversible damage to the joint and cartilage and eventually permanent disability. Current conventional treatments for RA have limitations regarding efficacy, safety and cost. microRNA (miRNA) is a type of non-coding RNA (ncRNA) that regulates gene expression at the post-transcriptional level. The dysregulation of miRNA has been observed in RA patients and implicated in the pathogenesis of RA. miRNAs have emerged as potential biomarkers or therapeutic agents. In this review, we explore the role of miRNAs in various aspects of RA pathophysiology, including immune cell imbalance, the proliferation and invasion of fibroblast-like synovial (FLS) cell, the dysregulation of inflammatory signaling and disturbance in angiogenesis. We delve into the regulatory effects of miRNAs on Treg/Th17 and M1/M2 polarization, the activation of the NF-κB/NLRP3 signaling pathway, neovascular formation, energy metabolism induced by FLS-cell-induced energy metabolism, apoptosis, osteogenesis and mobility. These findings shed light on the potential applications of miRNAs as diagnostic or therapeutic biomarkers for RA management. Furthermore, there are some strategies to regulate miRNA expression levels by utilizing miRNA mimics or exosomes and to hinder miRNA activity via competitive endogenous RNA (ceRNA) network-based antagonists. We conclude that miRNAs offer a promising avenue for RA therapy with unlimited potential.

Nitric Oxide Synthases in Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by severe joint damage and disability. However, the specific mechanism of RA has not been thoroughly clarified over the past decade. Nitric oxide (NO), a kind of gas messenger molecule with many molecular targets, is demonstrated to have significant roles in histopathology and homeostasis. Three nitric oxide synthases (NOS) are related to producing NO and regulating the generation of NO. Based on the latest studies, NOS/NO signaling pathways play a key role in the pathogenesis of RA. Overproduction of NO can induce the generation and release of inflammatory cytokines and act as free radical gas to accumulate and trigger oxidative stress, which can involve in the pathogenesis of RA. Therefore, targeting NOS and its upstream and downstream signaling pathways may be an effective approach to managing RA. This review clearly summarizes the NOS/NO signaling pathway, the pathological changes of RA, the involvement of NOS/NO in RA pathogenesis and the conventional and novel drugs based on NOS/NO signaling pathways that are still in clinical trials and have good therapeutic potential in recent years, with an aim to provide a theoretical basis for further exploration of the role of NOS/NO in the pathogenesis, prevention and treatment of RA.

The value of somatosensory evoked potentials in intraoperative evaluation of indirect decompression effect of oblique lumbar interbody fusion for lumbar spinal stenosis.

PURPOSE: The aim of this study was to explore the relationship between intraoperative somatosensory evoked potential (SEP) amplitude changes and clinical outcomes of OLIF indirect decompression for degenerative lumbar spinal stenosis (DLSS). METHODS: A prospective study was performed on 201 patients who received oblique lumbar interbody fusion (OLIF) in our hospital from July 2017 to May 2021 due to single segmental DLSS. The patients were divided into three groups: group A (mild DLSS), group B (moderate DLSS), and group C (severe DLSS). The P40 amplitude during operation were recorded, and the clinical efficacy was evaluated by JOA score 1 year postoperative. ROC curves for satisfactory efficacy of P40 amplitude improvement rate and CSA improvement rate were established. Pearson correlation was used to analyze the relationship between P40 improvement rate and JOA improvement rate. RESULTS: In group A and group B, the improvement rate of JOA in P40 significantly improved group was significantly greater that in improved group and unimproved group (Pa = 0.009; Pb < 0.000). No significant among-subgroup differences in group C (all P > 0.05). In both groups A and B, there was a significant difference in the improvement rate of P40 amplitude between the satisfactory group and the ineffective group (Pa = 0.013; Pb = 0.001), while in group C, there was no statistical significance (Pc = 0.107). By variable Person correlation analysis, a significant positive correlation was obtained between JOA improvement rate and P40 amplitude improvement rate in groups A and B (r1 = 0.27, P1 = 0.02; r2 = 0.508, P2 = 0.001), no correlation between the two in group C (r3 = 0.243, P3 = 0.056). The area under the ROC for assessing surgical efficacy in terms of CSA improvement rate was 0.813 (95% CI: 0.737-0.889, P < 0.001) and 0.767 (95% CI: 0.677-0.856, P < 0.001) in group A and group B, respectively, with satisfactory efficacy cutoff points of 50.18% and 67.89%. CONCLUSION: For mild and moderate DLSS, the intraoperative P40 amplitude improvement rate can predict the improvement of clinical symptoms after surgery and can be used as a reference index to assess the effect of indirect decompression. For severe DLSS, the P40 amplitude improvement rate has limited significance in guiding indirect decompression, and OLIF indirect decompression is not the right treatment for this type of patients.

3D co-culture of macrophages and fibroblasts in a sessile drop array for unveiling the role of macrophages in skin wound-healing.

Three-dimensional (3D) heterotypic multicellular spheroid models play important roles in researches of the proliferation and remodeling phases in wound healing. This study aimed to develop a sessile drop array to cultivate 3D spheroids and simulate wound healing stage in vitro using NIH-3T3 fibroblasts and M2-type macrophages. By the aid of the offset of surface tension and gravity, the sessile drop array is able to transfer cell suspensions to spheroids via the superhydrophobic surface of each microwell. Meanwhile, each microwell has a cylinder hole at its bottom that provides adequate oxygen to the spheroid. It demonstrated that the NIH-3T3 fibroblast spheroid and the 3T3 fibroblast/M2-type macrophage heterotypic multicellular spheroid can form and maintain physiological activities within nine days. In order to further investigate the structure without destroying the entire spheroid, we reconstructed its 3D morphology using transparent processing technology and the Z-stack function of confocal microscopy. Additionally, a nano antibody-based 3D immunostaining assay was used to analyze the proliferation and differentiation characteristics of these cells. It found that M2-type macrophages were capable of promoting the differentiation of 3T3 fibroblast spheroid. In this study, a novel, inexpensive platform was constructed for developing spheroids, as well as a 3D immunofluorescence method for investigating the macrophage-associated wound healing microenvironment.

The safety, efficacy, and functional outcomes on arthroscopic fixation of posterior cruciate ligament avulsion fracture by a bio-absorbable anchor or traditional pull-out technique: A prospective cohort study.

Background: The posterior cruciate ligament avulsion fracture (PCLAF) is a special type of PCL rupture, and arthroscopic fixation for PCLAF has been recommended currently. The bio-absorbable suture anchor is a novel internal fixation for PCLAF. This study aims to estimate and compare the safety, efficacy, and functional outcomes between the bio-absorbable anchor and the traditional suture pull-out technique for arthroscopic fixation of PCLAF. Methods: This was a prospective cohort study. PCLAF patients were included from 1 January 2020, to 31 August 2021, in our department, and randomly divided into the absorbable anchor group and control group (pull-out suture fixation). Clinical assessments included: post drawer test, gravity test, anterior-posterior laxity (KT-2000), range of motion, Lysholm and International Knee Documentation Committee (IKDC) scores, total failure rate, and returning to sports rate. The minimum follow-up was 1 year (y). Results: 31 patients had accomplished the 1 year follow-up (missing rate: 13.9%). We did not face any complications such as neurovascular injury, fever, infection, un-union, or re-rupture during the follow-up. CT scan showed that all of the patients in the two groups had a well bone union at 3 months in post-operation. At 1 year follow-up, the total failure rate of the bio-absorbable anchor group (1/17, p = 0.036) was lower than the control group (5/14), and the IKDC (86.24 ± 4.35, p = 0.008) and return to sports rate (11/17, p = 0.045) of the bio-absorbable anchor group were higher than that of the control group (81.43 ± 5.06) (4/14). Conclusion: Both the bio-absorbable anchor and suture pull-out technique for arthroscopic fixation of PCLAF have acquired a well bone union and superior safety, but the bio-absorbable anchor group had better efficacy and functional outcomes than the traditional pull-out technique.

Pharmacological effects of the Cassia Seed on atherosclerosis: A meta-analysis based on network pharmacology.

BACKGROUND: The aim of this study was to shed light on the active ingredients and potential targets of Cassia Seed about anti-atherosclerosis based on network pharmacology. METHODS: The active ingredients and potential targets of Cassia Seed were obtained from traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) and SwissTargetPrediction database. Then, atherosclerosis-related targets were screened via GeneCards, online mendelian inheritance in man, therapeutic target database and DrugBank database. The common targets and protein-protein interaction (PPI) network was later identified and built. Furthermore, we used the database for annotation, visualization and integrated discovery (DAVID) database server to accomplish the enrichment analysis. The compounds-targets-pathways network was ultimately constructed by Cytoscape. RESULTS: A total of 14 active ingredients and 475 related targets were sifted from Cassia Seed. Among 574 potential atherosclerotic targets, there were 99 targets overlapped with those of Cassia Seed. Topological analysis with Cytoscape revealed that proto-oncogene tyrosine-protein kinase proto-oncogene tyrosine-protein kinase Src, transcription factor AP-1 (JUN), mitogen-activated protein kinase 8 (MAPK8), mitogen-activated protein kinase 14 (MAPK14) and catenin beta-1 were considered as the hub gene. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis suggested that the Cassia Seed had the potential to influence varieties of biological processes and pathways, including positive regulation of smooth muscle cell proliferation, inflammatory response, tumor necrosis factor (TNF) signaling pathway, vascular endothelial growth factor (VEGF) signaling pathway and arachidonic acid (ARA) metabolism. CONCLUSION: Taken together, our findings support that anti-atherosclerosis effects of Cassia Seed are characterized by multi-component, multi-target and multi-path mechanism of action.

Roles of autophagy in rheumatoid arthritis.

Autophagy, a vital mechanism restricted in tissues, exerts its cytoprotective role through the degradation mechanism of damaged or aging organelles, harmful protein aggregates and intracellular pathogens, followed by energy furnishment. However, dysfunctional autophagy is associated with the development of autoimmune diseases such as rheumatoid arthritis (RA). In pathological conditions, autophagy may be involved in the maturation, survival and proliferation of various immune and non-immune cells and plays a key role in the pathogenesis of RA. Furthermore, autophagy appears to be involved in the citrullination of T lymphocytes and the presentation of citrullinated peptides, which are presented to T lymphocytes via the major histocompatibility complex, causing immune responses and chronic inflammation, as well as bone and cartilage destruction associated with apoptosis resistance of RA fibroblast-like synoviocyte (RAFLS) and osteoclastogenesis. In this review, we have summarised the roles of autophagy in the pathogenesis of RA including citrullination, immune tolerance break, osteoclastogenesis, RA FLS cell dysplasia, apoptosis resistance, together with the therapeutic potentials of autophagy regulators.

Mitochondrial Dysfunction in Rheumatoid Arthritis.

Rheumatoid arthritis, a chronic autoimmune disease with complex etiology, is characterized by excessive proliferation of synovial cells, massive production of inflammatory cells and cartilage destruction. Studies have shown that mitochondrial dysfunction plays an important role in promoting the occurrence of RA. Mitochondria with normal structure and function are essential for the normal survival of chondrocytes and synovial cells. Once mitochondrial function is destroyed, it will affect the survival, activation and differentiation of immune cells and non-immune cells involved in the pathogenesis of RA, thus leading to the occurrence of RA. However, the mechanism of mitochondrial dysfunction in RA remains unclear. This article reviews the method of mitochondrial dysfunction leading to RA, the effects of mitochondrial dysfunction on immune cells, the etiology of mitochondrial dysfunction in RA, and the pathology of mitochondrial dysfunction in RA. We also outline some drugs that can exert therapeutic effects on RA which are associated with modulating mitochondrial activity. The understanding and summary of mitochondrial dysfunction in RA may provide new research directions for pathological intervention and prevention of RA.

Circular RNA circ_0076631 promotes coxsackievirus B3 infection through modulating viral translation by sponging miR-214-3p.

Coxsackievirus B (CVB), a member of Enterovirus genus of Picornaviridae, is the leading pathogen of viral myocarditis and dilated cardiomyopathy. The pathogenesis of CVB-induced myocarditis has not been completely elucidated, and no specific antiviral measurement is available presently. Circular RNAs (circRNAs) have been reported to be able to modulate viral replication and infection through bridging over non-coding RNAs (ncRNAs) and coding messenger RNAs (mRNAs). To date, the role of circRNAs in CVB infection is largely unknown. In this study, we found that hsa_circ_0076631 (circ_0076631) significantly promoted CVB type 3 (CVB3) replication. Further study showed that the underneath mechanism was circ_0076631 indirectly interacting with CVB3 through sponging miR-214-3p, which targeted the 3D-coding region of CVB3 genome to suppress viral translation. Knocking down circ-0076631 caused a suppression of CVB3 infection; thus, circ-0076631 may be a potential target for anti-CVB therapy.

Role of noncoding RNAs and untranslated regions in cancer: A review.

Cancer is one of the most prevalent diseases worldwide, and poses a threat to human health. Noncoding RNAs (ncRNAs) constitute most transcripts, but they cannot be translated into proteins. Studies have shown that ncRNAs can act as tumor suppressors or oncogenes. This review describes the role of several ncRNAs in various cancers, including microRNAs (miRNAs) such as the miR-34 family, let-7, miR-17-92 cluster, miR-210, and long noncoding RNAs (lncRNAs) such as HOX transcript antisense intergenic RNA (HOTAIR), Metastasis associated lung adenocarcinoma transcript 1 (MALAT1), H19, NF-κB-interacting lncRNA (NKILA), as well as circular RNAs (circRNAs) and untranslated regions (UTRs), highlighting their effects on cancer growth, invasion, metastasis, angiogenesis, and apoptosis. They function as tumor suppressors or oncogenes that interfere with different axes and pathways, including p53 and IL-6, which are involved in the progression of cancer. The characteristic expression of some ncRNAs in cancer also allows them to be used as biomarkers for early diagnosis and therapeutic candidates. There is a complex network of interactions between ncRNAs, with some lncRNAs and circRNAs acting as competitive endogenous RNAs (ceRNAs) to decoy miRNAs and repress their expression. The ceRNA network is a part of the ncRNA network and numerous ncRNAs work as nodes or hubs in the network, and disruption of their interactions can cause cancer development. Therefore, the balance and stabilization of this network are important for cancer diagnosis and treatment.

Adipose Mesenchymal Stromal Cell-Derived Exosomes Prevent Testicular Torsion Injury via Activating PI3K/AKT and MAPK/ERK1/2 Pathways.

Adipose mesenchymal stromal cell-derived exosomes (ADSC-Exos) have shown great potential in the treatment of oxidative stress induced by ischemia-reperfusion injury. However, alleviation of testicular torsion injury by ADSC-Exos has not been reported. Therefore, we investigated the protective effect of ADSC-Exos against testicular torsion-detorsion injury. ADSC-Exos were isolated by ultracentrifugation and injected into torsion-detorsion-affected testes of rats. H&E staining and sperm quality were used to evaluate the therapeutic effects of ADSC-Exos, and tissue oxidative stress was measured by determining MDA and SOD levels. In addition, TUNEL staining and immunohistological analysis (Ki67, Cleaved Caspase-3, IL-6, IL-10, CCR7, and CD163) were used to clarify the effects of ADSC-Exos on spermatogenic cell proliferation, apoptosis, and the inflammatory microenvironment in vivo. Possible signaling pathways were predicted using sequencing technology and bioinformatics analysis. The predicted signaling pathways were validated in vitro by assessing the proliferation (EdU assay), migration (transwell assay and scratch test), and apoptosis (flow cytometry, TUNEL staining, and western blotting) of spermatogenic cells. The results showed that ADSC-Exos alleviated testicular torsion-detorsion injury by attenuating oxidative stress and the inflammatory response. In addition, ADSC-Exos promoted the proliferation and migration of spermatogenic cells and inhibited their apoptosis by activating the PI3K/AKT and MAPK/ERK1/2 signaling pathways.

A ceRNA Network Composed of Survival-Related lncRNAs, miRNAs, and mRNAs in Clear Cell Renal Carcinoma.

Clear cell renal carcinoma (ccRCC) is one of the most common renal carcinomas worldwide, which has worse prognosis compared with other subtypes of tumors. We propose a potential RNA regulatory mechanism associated with ccRCC progression. Accordingly, we screened out clinical factors and the expression of RNAs and miRNAs of ccRCC from the TCGA database. 9 lncRNAs (FGF12-AS2, WT1-AS, TRIM36-IT1, AC009093.1, LINC00443, TCL6, COL18A1-AS1, AC110619.1, HOTTIP), 2 miRNAs (mir-155 and mir-21), and 3 mRNAs (COL4A4, ERMP1, PRELID2) were selected from differential expression RNAs and built predictive survival models. The survival models performed very well in predicting prognosis and were found to be highly correlated with tumor stage. In addition, the survival-related lncRNA-miRNA-mRNA (ceRNA) network was constructed by 18 RNAs including 12 mRNAs, 2 miRNAs, and 4 lncRNAs. It is found that the "ECM-receptor interaction," "Pathways in cancer," and "Chemokine signaling pathway" as the main pathways in KEGG pathway analysis. Overall, we established predictive survival model and ceRNA network based on multivariate Cox regression analysis. It may open a new approach and potential biomarkers for clinical prognosis and treatment of ccRCC patients.

Extracellular Vesicles Derived from Adipose Mesenchymal Stem Cells Promote Peritoneal Healing by Activating MAPK-ERK1/2 and PI3K-Akt to Alleviate Postoperative Abdominal Adhesion.

Peritoneal regeneration and repair can alleviate postoperative intraperitoneal adhesions, and mesenchymal stem cells (MSCs) have demonstrated the potential for peritoneal repair and regeneration. However, extracellular vesicles (EVs) are the main carriers for the MSC activity. Thus far, the roles of MSC-derived EVs on peritoneal repair are not well understood. To investigate the therapeutic effect of adipose-derived mesenchymal stem cell-derived EVs (ADSC-EVs) in peritoneal injuries, ADSC-EVs were injected in vivo via the tail vein of rats. The antiadhesion effects were evaluated following abdominal surgery. In addition, the levels of the peritoneal fibrinolysis system were determined via enzyme-linked immunosorbent assay. Expression differences in inflammatory and apoptotic markers were detected using immunofluorescence. The expression of extracellular matrix-related indexes and peritoneal healing were observed using immunohistochemistry. In vitro, rat peritoneal mesothelial cell proliferation was assessed via a 5-ethynyl-2-deoxyuridine assay. Cell migration was determined using scratch wound and transwell assays. Related signaling networks were estimated based on sequencing and bioinformatics analyses. The roles of the MAPK-ERK1/2 and PI3K-Akt signaling networks were analyzed using immunoblotting. This is the first report of the effectiveness of ADSC-EVs in the treatment of postoperative adhesions. ADSC-EVs were incorporated in vitro and induced rat peritoneal mesothelial cell proliferation and migration. This was mediated by stimulation of the MAPK-ERK1/2 and PI3K-Akt axes. ADSC-EVs promote the healing of the injured peritoneum, suggesting a promising therapeutic approach for peritoneal adhesions.

New progress in understanding roles of nitric oxide during hepatic ischemia-reperfusion injury.

Hepatic ischemia-reperfusion injury (HIRI) is a major clinical cause of morbidity and mortality in liver surgery and transplantation. Many studies have found that nitric oxide (NO) plays an important role in the HIRI and its increase or decrease can affect the progression and outcome of HIRI. However, the role of NO in HIRI is controversial and complicated. NO derived by endothelial NO synthase (eNOS) shows a protective role in HIRI, while excessive NO derived by inducible NO synthase (iNOS) accelerates inflammation and increases oxidative stress, further aggravating HIRI. Nevertheless, the overexpression of eNOS may exacerbate HIRI and iNOS-derived NO in some cases reduces HIRI. Here we review the new progress in the understanding of the roles of NO during HIRI: (1) NO possesses different roles in HIRI by increasing NO bioavailability, down-regulating leukotriene C4 synthase, inhibiting the activation of the nuclear factorκB (NFκB) pathway, enhancing cell autophagy, and reducing inflammatory cytokines and reactive oxygen species (ROS). And NO has both protective and deleterious effects by regulating apoptotic factors; (2) eNOS promotes NO production and suppresses its own overexpression, exerting a hepatoprotective effect reversely. Its activation is regulated by the PI3K/Akt and KLF2/AMPK pathways; and (3) iNOS derived NO mainly has deteriorating effects on HIRI, while it may have a protective function under some conditions. Their expression should reach a balance to reduce the adverse side and make NO protective in the treatment of HIRI. Thus, it can be inferred that NO modulating drugs may be a new direction in the treatment of HIRI or may be used as an adjunct to mitigate HIRI for the purpose of protecting the liver.

Roles of Nitric Oxide in Brain Ischemia and Reperfusion.

Brain ischemia and reperfusion (I/R) is one of the most severe clinical manifestations of ischemic stroke, placing a significant burden on both individuals and society. The only FDA-approved clinical treatment for ischemic stroke is tissue plasminogen activator (t-PA), which rapidly restores cerebral blood flow but can have severe side effects. The complex pathological process of brain I/R has been well-established in the past few years, including energy metabolism disorders, cellular acidosis, doubling of the synthesis or release of excitotoxic amino acids, intracellular calcium homeostasis, free radical production, and activation of apoptotic genes. Recently, accumulating evidence has shown that NO may be strongly related to brain I/R and involved in complex pathological processes. This review focuses on the role of endogenous NO in pathological processes in brain I/R, including neuronal cell death and blood brain barrier disruption, to explore how NO impacts specific signaling cascades and contributes to brain I/R injury. Moreover, NO can rapidly react with superoxide to produce peroxynitrite, which may also mediate brain I/R injury, which is discussed here. Finally, we reveal several therapeutic approaches strongly associated with NO and discuss their potential as a clinical treatment for ischemic stroke.