Electron Configuration Modulation Induced Stabilized 1T-MoS2 for Enhanced Sodium Ion Storage.

1T-MoS2 has become an ideal anode for sodium-ion batteries (SIBs). However, the metastable feature of 1T-MoS2 makes it difficult to directly synthesize under normal conditions. In addition, it easily transforms into 2H phase via restacking, resulting in inferior electrochemical performance. Herein, the electron configuration of Mo 4d orbitals is modulated and the stable 1T-MoS2 is constructed by nickel (Ni) introduction (1T-Ni-MoS2). The original electron configuration of Mo 4d orbitals is changed via the electron injection by Ni, which triggers the phase transition from 2H to 1T phase, thus improving the electrical conductivity and accelerating the redox kinetics of the material. Consequently, 1T-Ni-MoS2 exhibits superior rate capability (266.8 mAh g-1 at 10 A g-1) and excellent cycle life (358.7 mAh g-1 at 1 A g-1 after 350 cycles). In addition, the assembled Na3V2(PO4)3/C||1T-Ni-MoS2 full cells deliver excellent electrochemical properties and show great prospects in energy storage devices.

CircPCNX Promotes PDGF-BB-Induced Proliferation and Migration of Human Aortic Vascular Smooth Muscle Cells Through Regulating miR-1278/DNMT1 Axis.

BACKGROUND: Human aortic vascular smooth muscle cells (HA-VSMCs) play vital roles in the pathogenesis of vascular diseases. Circular RNAs (circRNAs) have been reported to regulate the biological functions of HA-VSMCs. In this study, the functions of circRNA pecanex homolog (circPCNX) in platelet-derived growth factor-BB (PDGF-BB)-induced HA-VSMCs were investigated. METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to determine the expression of circPCNX, DNA methyltransferase 1 (DNMT1), and microRNA-1278 (miR-1278). 5'-Ethynyl-2'-deoxyuridine (EdU) assay, flow cytometry analysis, wound healing assay, and transwell assay were used to examine cell proliferation, cell cycle, and migration. Western blot assay was utilized to measure protein levels. RNA immunoprecipitation (RIP) assay, RNA pull down assay, and dual-luciferase reporter assay were adopted to analyze the relationships among circPCNX, miR-1278, and DNMT1. RESULTS: CircPCNX was upregulated in PDGF-BB-treated HA-VSMCs in a dose- or time-dependent manner. CircPCNX knockdown alleviated PDGF-BB-induced cell proliferation, cell cycle progression, and migration in HA-VSMCs. CircPCNX knockdown could reverse PDGF-BB-induced HA-VSMC progression by regulating DNMT1. Moreover, circPCNX was identified to regulate DNMT1 expression by sponging miR-1278. Inhibition of miR-1278 reversed circPCNX knockdown-mediated effects on cell proliferation and migration in PDGF-BB-induced HA-VSMCs. MiR-1278 overexpression suppressed PDGF-BB-stimulated HA-VSMC proliferation and migration by targeting DNMT1. CONCLUSION: CircPCNX promoted PDGF-BB-induced HA-VSMC proliferation and migration by elevating DNMT1 expression through sponging miR-1278.

MicroRNA153 induces apoptosis by targeting NFATc3 to improve vascular remodeling in pulmonary hypertension.

BACKGROUND: The present study aimed to investigate the effect of microRNA153 (miRNA153) on pulmonary hypertension (PH). METHODS: PH was induced by a single subcutaneous injection of sugen5416 (SU5416) combined with hypoxia exposure for 3 weeks (SuHx) in rats, while pulmonary arterial smooth muscle cells (PASMCs) obtained from rats were exposed to hypoxia to establish an in vitro model. Through observing the characteristic hemodynamic index in rats and by analyzing the physiological function, vascular remodeling and right ventricular hypertrophy were identified. The regulatory effects of miRNA153 on the nuclear factor of activated T cell isoform c3 (NFATc3) were measured by RT-qPCR, western blot, and immunofluorescence. Cell apoptosis was evaluated by flow cytometry. RESULTS: The miRNA153 expression was reduced and unclear translation of NFATc3 was increased in both the in vivo and in vitro models of PH. In vivo, the pulmonary arterial pressure, right ventricle/(left ventricle + interventricular septum) (RV/(LV+S)), and media vascular thickness were increased in rats with PH; however, all these parameters were suppressed by prophylactic administration of miRNA153agomir. The upregulation of NFATc3 and downregulation of the potassium voltage-gated channel subfamily A member 5 (Kv1.5) were also reversed by transfection with miRNA153agomir. In vitro, miRNA153 increased the level of Kv1.5 in hypoxic PASMCs by targeting NFATc3 and inhibiting their proliferation and apoptosis resistance. CONCLUSION: Our results confirmed that the therapeutic administration of miRNA153 promotes apoptosis and inhibits the proliferation of PASMCs to ameliorate PH, and that the NFATc3/Kv1.5 channel pathway may be involved in this process.

Species Difference in the Metabolism of Mulberrin in Vitro and Its Inhibitory Effect on Cytochrome P450 and UDP-Glucuronosyltransferase Enzymes.

This study aimed to evaluate the interspecies difference in metabolism of mulberrin and examine the interaction between mulberrin and CYP enzymes or recombinant human uridine 5'-diphosphate (UDP)-glucuronosyltransferase (UGT) enzymes. Liver microsomes from human (HLMs), Beagle dog (DLMs), minipig (PLMs), monkey (MLMs), rabbit (RLMs), rat (RAMs), and mouse (MIMs) were used to investigate metabolic diversity among different species. Additionally, recombinant human supersomes were used to confirm that metabolic enzymes are involved in the biotransformation of mulberrin. We also evaluated the influence of mulberrin on protein expression by Western blot analysis. Mulberrin metabolism showed significant interspecies differences. We found four and two metabolites in phase I and II reaction systems, respectively. In phase I metabolism profiles of mulberrin for HLMs, PLMs and MLMs conformed to the classic Michaelis-Menten kinetics, RAMs and MIMs followed biphasic kinetics; phase II reaction of mulberrin in HLMs, DLMs, PLMs, MLMs, RLMs, RAMs and MIMs followed biphasic kinetics. UGT1A1 were the major CYP isoforms responsible for the metabolism of mulberrin. Mulberrin showed potent inhibitory effects against CYP3A4, CYP2C9, CYP2E1, UGT1A1, UGT1A3 and UGT2B7 with IC50 values of 54.21, 9.93, 39.12, 3.84, 2.01, 16.36 µM, respectively. According to Western blot analysis, mulberrin can upregulate the protein expression of CYP2C19, and downregulate the expression levels of CYP3A5 and CYP2C9 in HepG2 cells as concentration increased. The interspecies comparisons can help find other species with metabolic pathways similar to those in humans for future in vivo studies.

In vitro differences in toddalolactone metabolism in various species and its effect on cytochrome P450 expression.

CONTEXT: Toddalolactone, the main component of Toddalia asiatica (L.) Lam. (Rutaceae), has anticancer, antihypertension, anti-inflammatory, and antifungal activities. OBJECTIVE: This study investigated the metabolic characteristics of toddalolactone. MATERIALS AND METHODS: Toddalolactone metabolic stabilities were investigated by incubating toddalolactone (20 µM) with liver microsomes from humans, rabbits, mice, rats, dogs, minipigs, and monkeys for 0, 30, 60, and 90 min. The CYP isoforms involved in toddalolactone metabolism were characterized based on chemical inhibition studies and screening assays. The effects of toddalolactone (0, 10, and 50 µM) on CYP1A1 and CYP3A5 protein expression were investigated by immunoblotting. After injecting toddalolactone (10 mg/kg), in vivo pharmacokinetic profiles using six Sprague-Dawley rats were investigated by taking 9-time points, including 0, 0.25, 0.5, 0.75, 1, 2, 4, 6 and 8 h. RESULTS: Monkeys showed the greatest metabolic capacity in CYP-mediated and UGT-mediated reaction systems with short half-lives (T1/2) of 245 and 66 min, respectively, while T1/2 of humans in two reaction systems were 673 and 83 min, respectively. CYP1A1 and CYP3A5 were the major CYP isoforms involved in toddalolactone biotransformation. Induction of CYP1A1 protein expression by 50 µM toddalolactone was approximately 50% greater than that of the control (0 µM). Peak plasma concentration (Cmax) for toddalolactone was 0.42 µg/mL, and Tmax occurred at 0.25 h post-dosing. The elimination t1/2 was 1.05 h, and the AUC0-t was 0.46 µg/mL/h. CONCLUSIONS: These findings demonstrated the significant species differences of toddalolactone metabolic profiles, which will promote appropriate species selection in further toddalolactone studies.

In Vitro Metabolism of Auriculasin and Its Inhibitory Effects on Human Cytochrome P450 and UDP-Glucuronosyltransferase Enzymes.

Auriculasin has a wide range of pharmacological effects, including anticancer and anti-inflammatory effects. In this work, we explored the metabolic characteristics and inhibitory effect of auriculasin against cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT) enzymes in vitro. Auriculasin inhibited UGT1A6, UGT1A8, UGT1A10, UGT2B7, CYP2C9, and CYP3A4 strongly at a concentration of 100 µM. Different species showed significant differences in auriculasin metabolism, and metabolic characteristics were similar between pig and human. We identified seven metabolites, and hydroxylated auriculasin was the main metabolite. In addition, CYP2D6, CYP2C9, CYP2C19, and CYP2C8 were the major CYP isoforms involved in the metabolism of auriculasin. Molecular docking studies showed that noncovalent interactions between auriculasin and the CYPs are dominated by hydrogen bonding, π-π stacking, and hydrophobic interactions. Our in vitro study provides insights into the pharmacological and toxicological mechanisms of auriculasin.

The significant effect of chronic intermittent hypoxia on prostaglandin D2 biosynthesis in rat brain.

Obstructive sleep apnea (OSA) is a common disorder characterized by chronic intermittent hypoxia (CIH). Excessive daytime sleepiness (EDS) is one of severe complications frequently associated with OSA. Lipocalin-type prostaglandin synthase (L-PGDS) is potentially responsible for the production of prostaglandin D2 (PGD2) which is an endogenous sleep inducer. To date, whether the content of PGD2 and PGDS is related to intermittent hypoxia has never been reported. The aim of this study was to compare the content of PGD2 and L-PGDS in rats' brains with and without intermittent hypoxia. Adult male Wistar rats (n = 48; 8-10 weeks) were averagely divided into two groups. One was control group, and the other group was exposed to IH (12 h/day for 6 weeks). In each group there are four time-points including 0, 2, 4 and 6 weeks, and six rats were killed and studied at each time-point. At the end of 0, 2, 4 and 6 weeks, the concentrations of PGD2 in brains were measured by LC-MS/MS. In addition, the expressions of L-PGDS protein and mRNA in brains were investigated by western blotting and real-time polymerase chain reaction (RT-PCR), respectively. The results showed the concentrations of PGD2 in CIH rat brains were higher than those in control groups from the second week. At the end of 6 weeks, the concentrations of PGD2 in CIH and control groups were 11.1 and 5.9 ng/g, respectively. The levels of L-PGDS protein and mRNA followed the same trend during the whole 6 weeks. The results will provide a new idea to explore that patients with OSA are always accompanied by excessive daytime sleepiness.

The different metabolism of morusin in various species and its potent inhibition against UDP-glucuronosyltransferase (UGT) and cytochrome p450 (CYP450) enzymes.

1. The aim of this study was to investigate the inhibitory effect of morusin on Glucuronosyltransferase (UGT) isoforms and cytochrome P450 enzymes (CYP450s). We also investigated the metabolism of morusin in human, rat, dog, monkey, and minipig liver microsomes. 2. 100 µM of morusin exhibited strong inhibition on all UGTs and CYP450s. The half inhibition concentration (IC50) values for CYP3A4, CYP1A2, CYP2C9, CYP2E1, UGT1A6, UGT1A7, and UGT1A8 were 2.13, 1.27, 3.18, 9.28, 4.23, 0.98, and 3.00 µM, and the inhibition kinetic parameters (Ki) were 1.34, 1.16, 2.98, 6.23, 4.09, 0.62, and 2.11 µM, respectively. 3. Metabolism of morusin exhibited significant species differences. The quantities of M1 from minipig, monkey, dog, and rat were 7.8, 11.9, 2.0, and 6.3-fold of human levels. The Km values in HLMs, RLMs, MLMs, DLMs, and PLMs were 7.84, 22.77, 14.32, 9.13, and 22.83 µM, and Vmax for these species were 0.09, 1.23, 1.43, 0.15, and 0.75 nmol/min/mg, respectively. CLint (intrinsic clearance) values (Vmax/Km) for morusin obeyed the following order: monkey > rat > minipig > dog > human. CLH (hepatic clearance) values for humans, dogs, and rats were calculated to be 8.28, 17.38, and 35.12 mL/min/kg body weight, respectively. 4. This study provided vital information to understand the inhibitory potential and metabolic behavior of morusin among various species.

A novel improved total variation algorithm for the elimination of scratch-type defects in high-voltage cable cross-sections.

In the quality inspection process of high-voltage cables, several commonly used indicators include cable length, insulation thickness, and the number of conductors within the core. Among these factors, the count of conductors holds particular significance as a key determinant of cable quality. Machine vision technology has found extensive application in automatically detecting the number of conductors in cross-sectional images of high-voltage cables. However, the presence of scratch-type defects in cut high-voltage cable cross-sections can significantly compromise the precision of conductor count detection. To address this problem, this paper introduces a novel improved total variation (TV) algorithm, marking the first-ever application of the TV algorithm in this domain. Considering the staircase effect, the direct use of the TV algorithm is prone to cause serious loss of image edge information. The proposed algorithm firstly introduces multimodal features to effectively mitigate the staircase effect. While eliminating scratch-type defects, the algorithm endeavors to preserve the original image's edge information, consequently yielding a noteworthy enhancement in detection accuracy. Furthermore, a dataset was curated, comprising images of cross-sections of high-voltage cables of varying sizes, each displaying an assortment of scratch-type defects. Experimental findings conclusively demonstrate the algorithm's exceptional efficiency in eradicating diverse scratch-type defects within high-voltage cable cross-sections. The average scratch elimination rate surpasses 90%, with an impressive 96.15% achieved on cable sample 4. A series of conducted ablation experiments in this paper substantiate a significant enhancement in cable image quality. Notably, the Edge Preservation Index (EPI) exhibits an improvement of approximately 20%, resulting in a substantial boost to conductor count detection accuracy, thus effectively enhancing the quality of high-voltage cable production.

Pyroptosis in cancer treatment and prevention: the role of natural products and their bioactive compounds.

Targeting programmed cell death (PCD) has been emerging as a promising therapeutic strategy in cancer. Pyroptosis, as a type of PCDs, leads to the cleavage of the gasdermin family and the secretion of pro-inflammatory factors. Gasdermin D (GSDMD) and gasdermin E (GSDME) are the two main executors of pyroptosis. Pyroptosis in tumor and immune cells is essential for tumor progression. Natural products, especially Chinese medicinal herb and their bioactive compounds have recently been regarded as anti-tumor agents that regulate cell pyroptosis under different circumstances. Here, we review the underlying mechanisms of natural products that activate pyroptosis in tumor cells and inhibit pyroptosis in immune cells. Pyroptosis activation in tumor cells leads to tumor cell death, yet pyroptosis inhibition in immune cells may prevent tumor occurrence. Elucidation of the signaling pathways involved in pyroptosis contributes to the understanding of the anti-tumor role of natural products and their potential clinical applications. Therefore, we outline a promising strategy for cancer therapy and prevention using natural products via modulation of pyroptosis.

Micro-power negative pressure wound technique reduces risk of incision infection following loop ileostomy closure.

BACKGROUND: Prophylactic loop ileostomy is an effective way to reduce the clinical severity of anastomotic leakage following radical resection of rectal cancer. Incisional surgical site infection (SSI) is a common complication after ileostomy closure. AIM: To evaluate the efficacy and safety of the micro-power negative pressure wound technique (MPNPWT) in preventing incisional SSI. METHODS: This was a prospective, randomized controlled clinical trial conducted at a single center. A total of 101 consecutive patients who underwent ileostomy closure after rectal cancer surgery with a prophylactic ileostomy were enrolled from January 2019 to December 2021. Patients were randomly allocated into an MPNPWT group and a control group. The MPNPWT group underwent intermittent suturing of the surgical incision with 2-0 Prolene and was covered with a micro-power negative pressure dressing. The surgical outcomes were compared between the MPNPWT (n = 50) and control (n = 51) groups. Risk factors for incisional SSI were identified using logistic regression. RESULTS: There were no differences in baseline characteristics between the MPNPWT (n = 50) and control groups (n = 51). The incisional SSI rate was significantly higher in the control group than in the MPNPWT group (15.7% vs 2.0%, P = 0.031). However, MPNPWT did not affect other surgical outcomes, including intra-abdominal complications, operative time, and blood loss. Postoperative hospital stay length and hospitalization costs did not differ significantly between the two groups (P = 0.069 and 0.843, respectively). None of the patients experienced adverse effects of MPNPWT, including skin allergy, dermatitis, and pain. MPNPWT also helped heal the infected incision. Our study indicated that MPNPWT was an independent protective factor [odds ratio (OR) = 0.005, P = 0.025)] and diabetes was a risk factor (OR = 26.575, P= 0.029) for incisional SSI. CONCLUSION: MPNPWT is an effective and safe way to prevent incisional SSI after loop ileostomy closure.

Role of KLF4/NDRG1/DRP1 axis in hypoxia-induced pulmonary hypertension.

N-myc downstream regulated gene 1 (NDRG1) has recently drawn increasing attention because of its involvement in angiogenesis, cell proliferation, and differentiation. We used in vitro [human pulmonary artery smooth muscle cells (hPASMCs)] and in vivo (rat) models under hypoxic conditions and found a vital role of NDRG1 in reducing apoptosis and increasing proliferation and migration by overexpressing and knocking down NDRG1. We also proved that hypoxia induced the protein expression of dynamin-related protein 1 (DRP1) and stimulated The phosphatidylinositol-3-kinase (PI3K)/ Protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathways, and these effects were reversed by NDRG1 knockdown. The relationship between NDRG1 and DRP1 and the PI3K/Akt/mTOR pathway was further evaluated by adding mdivi-1 (DRP1 inhibitor) or LY294002 (PI3K inhibitor). NDRG1 was found to regulate the proliferation, apoptosis, and migration of hypoxia-treated hPASMCs via DRP1 and PI3K/Akt/mTOR signaling pathways. We explored the upstream regulators of NDRG1 using in vivo and in vitro hypoxia models. Hypoxia was found to upregulate and downregulate KLF transcription factor 4 (KLF4) protein expression in the cytoplasm and nucleus, respectively. Further, we showed that KLF4 regulated the proliferation and migration of hypoxia-treated hPASMCs via NDRG1. These results indicated a link between KLF4, NDRG1, and DRP1 for the first time, providing new ideas for treating hypoxic pulmonary hypertension.

A WGCNA-based cancer-associated fibroblast risk signature in colorectal cancer for prognosis and immunotherapy response.

Background: Cancer-associated fibroblasts (CAFs) are notably involved in colorectal cancer (CRC) tumorigenesis, progression, and treatment failure. In this article, we report the in silico development of a CAF-related prognostic signature for CRC. Methods: We separately downloaded CRC transcription data from The Cancer Genome Atlas and the Gene Expression Omnibus database. Deconvolution algorithms, including Estimating the Proportions of Immune and Cancer Cells and the Microenvironment Cell Population-counter, were used to calculate CAF abundance, while the Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression algorithm was used to calculate the stromal score. Weighted gene co-expression network analysis (WGCNA) and the least absolute shrinkage and selection operator algorithm were used to identify CAF-related genes and prognostic signatures. Results: We identified a three-gene, prognostic, CAF-related signature and defined risk groups based on the Riskscores. Multidimensional validations were applied to evaluate the robustness of the signature and its correlation with clinical parameters. We utilized Tumor Immune Dysfunction and Exclusion (TIDE) and oncoPredict algorithms to predict therapy responses and found that patients in low-risk groups are more sensitive to immunotherapy and chemotherapy drugs such as 5-fluorouracil and oxaliplatin. Finally, we used the Cancer Cell Line Encyclopedia and Human Protein Atlas databases to evaluate the mRNA and protein levels encoded by the signature genes. Conclusions: This novel CAF-related three-gene signature is expected to become a potential prognostic biomarker in CRC and predict chemotherapy and immunotherapy responses. It may be of considerable value for studying the tumor microenvironment in CRC.

BMAL1 promotes colorectal cancer cell migration and invasion through ERK- and JNK-dependent c-Myc expression.

BACKGROUND: Cancer metastasis is still a life threat to patients with colorectal cancer (CRC). Brain and muscle ARNT-like protein 1 (BMAL1) is an important biological proteins that can regulate the behavior of cancer cells and their response to chemotherapy. However, the role of BMAL1 in the tumorigenic phenotype of CRC remains unclear. Here, we aim to investigate the functional role and mechanisms of BMAL1 in CRC. METHODS: The mRNA expression of BMAL1 was studied using the Cancer Genome Atlas (TCGA) databases. The protein level in clinical tissues was confirmed by immunohistochemistry (IHC). The effects of BMAL1 on the epithelial-to-mesenchymal transition (EMT) and proliferation of CRC cell lines (including BMAL1 overexpressed or silencing cells) were studied by Transwell, wound healing, CCK-8 and colony formation experiments. A series of experiments were conducted to demonstrate the mechanisms of BMAL1 regulating EMT and cancer proliferation in vitro and in vivo. RESULTS: We found that BMAL1 expression was closely related to the poor prognosis of CRC. BMAL1 overexpression promoted cell proliferation and migration. Mechanistically, we found that BMAL1 may activate the epithelial-to-mesenchymal transition (EMT) pathway and induce the ß-catenin release further promotes the expression of oncogene c-Myc and the migration of colorectal cells by activating MAPK pathway. However, BMAL1 silencing achieved the opposite effect. In addition, blocking MAPK-signaling pathway with specific inhibitors of ERK1/2 and JNK can also downregulate the expressions of c-Myc in vitro. Taken together, these results suggested that the BMAL1/ c-Myc-signaling pathway may regulate the metastasis of CRC through the JNK/ERK1/2 MAPK-dependent pathway. CONCLUSIONS: Our study showed that BMAL1 promotes CRC metastasis through MAPK-c-Myc pathway. These results deepen our understanding of the relationship between BMAL1 and tumorigenic phenotypes, which may become a promising therapeutic target for BMAL1 overexpressing CRC.

[Corrigendum] MicroRNA­153 attenuates hypoxia­induced excessive proliferation and migration of pulmonary arterial smooth muscle cells by targeting ROCK1 and NFATc3.

Subsequently to the publication of the above paper, the authors have realized that the image chosen to represent the 'Mimic control' experiment in Fig. 4G was inadvertently selected incorrectly; the data originated from the same source as that chosen (correctly) for the 'Inhibitor control' experiment in the same figure. The revised version of Fig. 4, now containing the correct data for the 'Mimic control' experiment in Fig. 4G, is shown below. Note that this error did not quantitatively affect either the results or the overall conclusions of this study. All the authors agree with the publication of this corrigendum, and are grateful to the Editor of Molecular Medicine Reports for allowing them the opportunity to publish this. They also wish to apologize to the readership of the Journal for any inconvenience caused. [Molecular Medicine Reports 23: 194, 2021; DOI: 10.3892/mmr.2021.11833].

RIOK1 is associated with non-small cell lung cancer clinical characters and contributes to cancer progression.

Lung cancer is one of the most common malignant tumors and is currently the leading cause of cancer-related deaths worldwide. Although the treatment strategy has been significantly improved, the prognosis of lung cancer patients is still quite poor. RIOK1 has been reported to be highly expressed in non-small cell lung cancer (NSCLC), however, its clinical significance and biological function are still largely unknown in lung cancer. Using western blot and immunohistochemistry, we showed that RIOK1 was highly expressed in NSCLC tissues and correlated with advanced stage and poor prognosis. Furthermore, knockdown of RIOK1 could inhibit proliferation, migration, and invasion in NSCLC cells and tumorigenesis in vivo through AKT, Cyclin B1, MMP2, and EMT pathway. Furthermore, cell viability and apoptosis assays demonstrated that RIOK1 maintained NSCLC cell survival and reduced apoptosis rate when cells were treated with cisplatin. Western blot analysis demonstrated that RIOK1 depletion caused up-regulated protein expression of cleaved PARP and Caspase-3 in NSCLC cells. These findings revealed a novel function of RIOK1 in non-small cell lung cancer progression and suggest that RIOK1 might become a promising diagnostic and therapeutic target for this disease.

MicroRNA­153 attenuates hypoxia­induced excessive proliferation and migration of pulmonary arterial smooth muscle cells by targeting ROCK1 and NFATc3.

The aim of the present study was to explore the effect of microRNA (miR)­153 on the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) in a hypoxic condition by targeting ρ­associated, coiled­coil­containing protein kinase 1 (ROCK1) and nuclear factor of activated T cells cytoplasmic 3 (NFATc3). The right ventricular systolic pressure, right ventricular hypertrophy index, medial wall thickness and medial wall area were studied at different time­points after rats were exposed to hypoxia. Western blot analysis was used to detect ROCK1 and NFATc3 protein levels. In addition, reverse transcription­quantitative (RT­q) PCR was performed to confirm the mRNA levels of miR­153, ROCK1 and NFATc3 in human (H)PASMCs under hypoxic conditions. Transfected cells were then used to evaluate the effect of miR­153 on cell proliferation and migration abilities. The association between miR­153 and ROCK1 or NFATc3 was identified through double luciferase assays. Hypoxia induced pulmonary vascular remodeling and pulmonary arterial hypertension, which resulted from the abnormal proliferation of HPASMCs. ROCK1 and NFATc3 were the target genes of miR­153 and miR­153 mimic inhibited the protein expressions of ROCK1 and NFATc3 in HPASMCs and further inhibited cell proliferation and migration under hypoxic conditions. By contrast, the miR­153 inhibitor promoted the proliferation and migration of HPASMCs. miR­153 regulated the proliferation and migration of HPASMCs under hypoxia by targeting ROCK1 and NFATc3.

Pyrvinium pamoate inhibits cell proliferation through ROS-mediated AKT-dependent signaling pathway in colorectal cancer.

The use of the anthelmintic drug pyrvinium pamoate (PP) in cancer therapy has been extensively investigated in the last decade. PP has been shown to have an inhibitory effect in colorectal cancer (CRC), but the underlying mechanism remains elusive. We aimed to investigate the antitumor activity and mechanisms of PP in CRC. In the present study, we used CCK-8 assays, colony formation assays, and western blotting to reveal that PP effectively suppressed CRC cell proliferation and the AKT-dependent signaling pathway in a concentration-dependent and time-dependent manner. Flow cytometric analysis and fluorescence microscopy demonstrated that PP increased intracellular reactive oxygen species (ROS) accumulation. We found that the inhibitory effect of PP on cell proliferation and AKT protein expression induced by PP could be partially reversed by N-acetyl-L-cysteine (NAC), an ROS scavenger. In addition, the results also demonstrated that PP inhibited cell migration by modulating epithelial-to-mesenchymal transition (EMT)-related proteins, including E-cadherin and vimentin. In conclusion, our data suggested that PP effectively inhibited cell proliferation through the ROS-mediated AKT-dependent signaling pathway in CRC, further providing evidence for the use of PP as an antitumor agent.

Exosomes secreted by FNDC5-BMMSCs protect myocardial infarction by anti-inflammation and macrophage polarization via NF-κB signaling pathway and Nrf2/HO-1 axis.

BACKGROUND: Exosomes are considered a substitute for stem cell-based therapy for myocardial infarction (MI). FNDC5, a transmembrane protein located in the cytoplasm, plays a crucial role in inflammation diseases and MI repair. Furthermore, our previous study found that FNDC5 pre-conditioning bone marrow-derived mesenchymal stem cells (BMMSCs) could secrete more exosomes, but little was known on MI repair. METHODS: Exosomes isolated from BMMSCs with or without FNDC5-OV were injected into infarcted hearts. Then, cardiomyocytes apoptosis and inflammation responses were detected. Furthermore, exosomes were administrated to RAW264.7 macrophage with LPS treatment to investigate its effect on inflammation and macrophage polarization. RESULTS: Compared with MSCs-Exo, FNDC5-MSCs-Exo had superior therapeutic effects on anti-inflammation and anti-apoptosis, as well as polarizing M2 macrophage in vivo. Meanwhile, the in vitro results also showed that FNDC5-MSCs-Exo decreased pro-inflammatory secretion and increased anti-inflammatory secretion under LPS stimulation, which partly depressed NF-κB signaling pathway and upregulated Nrf2/HO-1 Axis. CONCLUSIONS: FNDC5-BMMSCs-derived exosomes play anti-inflammation effects and promote M2 macrophage polarization via NF-κB signaling pathway and Nrf2/HO-1 Axis, which may develop a promising cell-free therapy for MI.

MicroRNA-181b Serves as a Circulating Biomarker and Regulates Inflammation in Heart Failure.

Heart failure (HF) is the typical terminal stage of cardiac diseases involving inflammatory states. The function of microRNAs (miRNAs) in the progress of HF remains poorly understood. In this study, real-time PCR results showed a decreased expression of miRNA-181b (miR-181b) in HF patients compared with healthy individuals. Besides, miR-181b expressions were negatively correlated with hypersensitive C-reactive protein (hsCRP) levels in the serum of HF patients. Receiver operator characteristic (ROC) curve analysis showed that miR-181b was a diagnostic predictor of HF, and the area under the curve was 0.970 (DCM-induced HF group) and 0.962 (ICM-induced HF group). Strikingly, in HF rats induced by isoproterenol (ISO), the expression of miR-181b of heart tissue was suppressed before tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6) increase, as revealed by western blot and real-time PCR. Besides, the overexpression of miR-181b also decreased the expression of TNF-α, IL-1ß, and IL-6 in lipopolysaccharide- (LPS-) induced neonatal cardiomyocytes. In conclusion, our results revealed that miR-181b might be a potential biomarker for HF and provided a novel target for anti-inflammatory therapy.