Zhangjiagang First People's Hospital

OBJECTIVES: The aim of this study was to explore the difference in target vessel failure (TVF) 3 years after intravascular ultrasound (IVUS) guidance versus angiographic guidance among all comers undergoing second-generation drug-eluting stent (DES) implantation. BACKGROUND: The multicenter randomized ULTIMATE (Intravascular Ultrasound Guided Drug Eluting Stents Implantation in "All-Comers" Coronary Lesions) trial showed a lower incidence of 1-year TVF after IVUS-guided DES implantation among all comers compared with angiographic guidance. However, the 3-year clinical outcomes of the ULTIMATE trial remain unknown. METHODS: A total of 1,448 all comers undergoing DES implantation who were randomly assigned to either IVUS guidance or angiographic guidance in the ULTIMATE trial were followed for 3 years. The primary endpoint was the risk for TVF at 3 years. The safety endpoint was definite or probable stent thrombosis (ST). RESULTS: At 3 years, TVF occurred in 47 patients (6.6%) in the IVUS-guided group and in 76 patients (10.7%) in the angiography-guided group (p = 0.01), driven mainly by the decrease in clinically driven target vessel revascularization (4.5% vs. 6.9%; p = 0.05). The rate of definite or probable ST was 0.1% in the IVUS-guided group and 1.1% in the angiography-guided group (p = 0.02). Notably, the IVUS-defined optimal procedure was associated with a significant reduction in 3-year TVF relative to that with the suboptimal procedure. CONCLUSIONS: IVUS-guided DES implantation was associated with significantly lower rates of TVF and ST during 3-year follow-up among all comers, particularly those who underwent the IVUS-defined optimal procedure compared with those with angiographic guidance. (Intravascular Ultrasound Guided Drug Eluting Stents Implantation in "All-Comers" Coronary Lesions; NCT02215915).

Acute lung injury (ALI) is a critical clinical condition with a high mortality rate, characterized with excessive uncontrolled inflammation and apoptosis. Recently, microRNAs (miRNAs) have been found to play crucial roles in the amelioration of various inflammation-induced diseases, including ALI. However, it remains unknown the biological function and regulatory mechanisms of miRNAs in the regulation of inflammation and apoptosis in ALI. The aim of this study is to identify and evaluate the potential role of miRNAs in ALI and reveal the underlying molecular mechanisms of their effects. Here, we analyzed microRNA expression profiles in lung tissues from LPS-challenged mice using miRNA microarray. Because microRNA-27a (miR-27a) was one of the miRNAs being most significantly downregulated, which has an important role in regulation of inflammation, we investigated its function. Overexpression of miR-27a by agomir-27a improved lung injury, as evidenced by the reduced histopathological changes, lung wet/dry (W/D) ratio, lung microvascular permeability and apoptosis in the lung tissues, as well as ameliorative survival of ALI mice. This was accompanied by the alleviating of inflammation, such as the reduced total BALF cell and neutrophil counts, decreased levels of tumor necrosis factor alpha (TNF-α), interleukin-1 (IL-6) interleukin-1β (IL-1β) and myeloperoxidase (MPO) activity in BAL fluid. Toll-like receptor 4 (TLR4), an important regulator of the nuclear factor kappa-B (NF-κB) signaling pathway, was identified as a novel target of miR-27a in RAW264.7 cells. Furthermore, our results showed that LPS stimulation increased the expression of MyD88 and NF-κB p65 (p-p65), but inhibited the expression of inhibitor of nuclear factor-κB-α (IκB-α), suggesting the activation of NF-κB signaling pathway. Further investigations revealed that agomir-miR-27a reversed the promoting effect of LPS on NF-κB signaling pathway. The results here suggested that miR-27a alleviates LPS-induced ALI in mice via reducing inflammation and apoptosis through blocking TLR4/MyD88/NF-κB activation.

The human insulin-like growth factor 2 (IGF2) mRNA binding proteins 2 (IGF2BP2/IMP2) is an RNA-binding protein that regulates multiple biological processes. Previously, IGF2BP2 was thought to be a type 2 diabetes (T2D)-associated gene. Indeed IGF2BP2 modulates cellular metabolism in human metabolic diseases such as diabetes, obesity and fatty liver through post-transcriptional regulation of numerous genes in multiple cell types. Emerging evidence shows that IGF2BP2 is an N6-methyladenosine (m6A) reader that participates in the development and progression of cancers by communicating with different RNAs such as microRNAs (miRNAs), messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs). Additionally, IGF2BP2 is an independent prognostic factor for multiple cancer types. In this review, we summarize the current knowledge on IGF2BP2 with regard to diverse human metabolic diseases and its potential for cancer prognosis.

Hypoxia-inducible factor (HIF) is a main heterodimeric transcription factor that regulates the cellular adaptive response to hypoxia by stimulating the transcription of a series of hypoxia-inducible genes. HIF is frequently upregulated in solid tumors, and the overexpression of HIF can promote tumor progression or aggressiveness by blood vessel architecture and altering cellular metabolism. In this review, we focused on the pivotal role of HIF in tumor angiogenesis and energy metabolism. Furthermore, we also emphasized the possibility of HIF pathway as a potential therapeutic target in cancer.

Exosomal circRNA serves a novel genetic information molecule, facilitating communication between tumor cells and microenvironmental cells, such as immune cells, fibroblasts, and other components, thereby regulating critical aspects of cancer progression including immune escape, tumor angiogenesis, metabolism, drug resistance, proliferation and metastasis. Interestingly, microenvironment cells have new findings in influencing tumor progression and immune escape mediated by the release of exosomal circRNA. Given the intrinsic stability, abundance, and broad distribution of exosomal circRNAs, they represent excellent diagnostic and prognostic biomarkers for liquid biopsy. Moreover, artificially synthesized circRNAs may open up new possibilities for cancer therapy, potentially bolstered by nanoparticles or plant exosome delivery strategies. In this review, we summarize the functions and underlying mechanisms of tumor cell and non-tumor cell-derived exosomal circRNAs in cancer progression, with a special focus on their roles in tumor immunity and metabolism. Finally, we examine the potential application of exosomal circRNAs as diagnostic biomarkers and therapeutic targets, highlighting their promise for clinical use.

The leucine-rich repeat kinase 2 (LRRK2) gene and α-synuclein gene (SNCA) are the key influencing factors of Parkinson's disease (PD). It is reported that dysfunction of LRRK2 may influence the accumulation of α-synuclein and its pathology to alter cellular functions and signaling pathways by the kinase activation of LRRK2. The accumulation of α-synuclein is one of the main stimulants of microglial activation. Microglia are macrophages that reside in the brain, and activation of microglia is believed to contribute to neuroinflammation and neuronal death in PD. Therefore, clarifying the complex relationship among LRRK2, α-synuclein and microglials could offer targeted clinical therapies for PD. Here, we provide an updated review focused on the discussion of the evidence supporting some of the key mechanisms that are important for LRRK2-dependent neurodegeneration in PD.

osteoclast differentiation, hydroxyapatite resorption activity, and expression of osteoclastogenesis-related genes, such as NFATc1, MMP9, CTSK, Acp5 and c-Fos, in RANKL-induced bone marrow macrophages (BMMs) and RAW264.7 cells. It also reduced intracellular ROS levels by suppressing expression of TRAF6 and NADPH oxidase 1 (NOX1) and increasing expression of antioxidant enzymes such as heme oxygenase-1 (HO-1). Puerarin inhibited TRAF6/ROS-dependent activation of the MAPK and NF-κB signaling pathways in RANKL-induced RAW264.7 cells, and these effects were partially reversed by HO-1 silencing or TRAF6 overexpression. These findings suggest puerarin alleviates loss of bone mass in the OVX-model mice by suppressing osteoclastogenesis via inhibition of the TRAF6/ROS-dependent MAPK/NF-κB signaling pathway.

BACKGROUND: Circular RNAs (circRNAs) play important roles in cancer development and progression. The purpose of this study is to identify aberrantly expressed circRNAs in gastric cancer (GC), unravel their roles in GC progression, and provide new targets for GC diagnosis and therapy. METHODS: Bioinformatic analyses were performed to identify the aberrantly expression of hsa_circ_0061137 (termed as circDIDO1) in GC. Gain- and loss-of-function studies were performed to examine the biological roles of circDIDO1 in GC progression. Tagged RNA affinity purification, mass spectrometry, immunofluorescence, co-immunoprecipitation, and Western blot were used to identify circRNA-interacting and circRNA-encoded proteins. RNA sequencing, qRT-PCR, and Western blot were performed to analyze circRNA-regulated downstream target genes and signaling pathways. Mouse tumor models were used to analyze the effects of circDIDO1 on GC growth and metastasis. RESULTS: CircDIDO1 was transcribed from human DIDO1 (death-inducer obliterator 1) gene and formed by back-splicing of exons 2-6 of the linear transcript. circDIDO1 was down-regulated in GC tissues and its low levels were associated with larger tumor size, distal metastasis, and poor prognosis. CircDIDO1 overexpression inhibited while knockdown promoted GC cell proliferation, migration and invasion. CircDIDO1 overexpression suppressed GC growth and metastasis in mouse tumor models. Mechanistically, circDIDO1 encoded a novel 529aa protein that directly interacted with poly ADP-ribose polymerase 1 (PARP1) and inhibited its activity. CircDIDO1 also specifically bound to peroxiredoxin 2 (PRDX2) and promoted RBX1-mediated ubiquitination and degradation of PRDX2, which led to the inactivation of its downstream signaling pathways. CONCLUSIONS: CircDIDO1 is a new circRNA that has tumor suppressor function in GC and it may serve as a potential prognostic biomarker and therapeutic target for GC.

N6-methyladenosine (m6A) modification is a dynamic and reversible post-transcriptional modification and the most prevalent internal RNA modification in eukaryotic cells. YT521-B homology domain family 2 (YTHDF2) is a member of m6A "readers" and its role in human diseases remains unclear. Accumulating evidence suggests that YTHDF2 is greatly implicated in many aspects of human cancers and non-cancers through various mechanisms. YTHDF2 takes a great part in multiple biological processes, such as migration, invasion, metastasis, proliferation, apoptosis, cell cycle, cell viability, cell adhesion, differentiation and inflammation, in both human cancers and non-cancers. Additionally, YTHDF2 influences various aspects of RNA metabolism, including mRNA decay and pre-ribosomal RNA (pre-rRNA) processing. Moreover, emerging researches indicate that YTHDF2 predicts the prognosis of different cancers. Herein, we focus on concluding YTHDF2-associated mechanisms and potential biological functions in kinds of cancers and non-cancers, and its prospects as a prognostic biomarker.

To parallelly compare the efficacy of neoadjuvant immunotherapy (tislelizumab), neoadjuvant chemotherapy (gemcitabine and cisplatin), and neoadjuvant combination therapy (tislelizumab + GC) in patients with muscle-invasive bladder cancer (MIBC) and explore the efficacy predictors, we perform a multi-center, real-world cohort study that enrolls 253 patients treated with neoadjuvant treatments (combination therapy: 98, chemotherapy: 107, and immunotherapy: 48) from 15 tertiary hospitals. We demonstrate that neoadjuvant combination therapy achieves the highest complete response rate and pathological downstaging rate compared with neoadjuvant immunotherapy or chemotherapy. We develop and validate an efficacy prediction model consisting of pretreatment clinical characteristics, which can pinpoint candidates to receive neoadjuvant combination therapy. We also preliminarily reveal that patients who achieve pathological complete response after neoadjuvant treatments plus maximal transurethral resection of the bladder tumor may be safe to receive bladder preservation therapy. Overall, this study highlights the benefit of neoadjuvant combination therapy based on tislelizumab for MIBC.

PURPOSE: Epidemiologic studies exploring causal associations between serum lipids and breast cancer risk have reported contradictory results. We conducted a meta-analysis of prospective cohort studies to evaluate these associations. METHODS: Relevant studies were identified by searching PubMed and EMBASE through April 2015. We included prospective cohort studies that reported relative risk (RR) estimates with 95% confidence intervals (CIs) for the associations of specific lipid components (i.e., total cholesterol [TC], high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], and triglycerides [TG]) with breast cancer risk. Either a fixed- or a random-effects model was used to calculate pooled RRs. RESULTS: Fifteen prospective cohort studies involving 1,189,635 participants and 23,369 breast cancer cases were included in the meta-analysis. The pooled RRs of breast cancer for the highest versus lowest categories were 0.96 (95% CI: 0.86-1.07) for TC, 0.92 (95% CI: 0.73-1.16) for HDL-C, 0.90 (95% CI: 0.77-1.06) for LDL-C, and 0.93 (95% CI: 0.86-1.00) for TG. Notably, for HDL-C, a significant reduction of breast cancer risk was observed among postmenopausal women (RR = 0.77, 95% CI: 0.64-0.93) but not among premenopausal women. Similar trends of the associations were observed in the dose-response analysis. CONCLUSIONS: Our findings suggest that serum levels of TG but not TC and LDL-C may be inversely associated with breast cancer risk. Serum HDL-C may also protect against breast carcinogenesis among postmenopausal women.

BACKGROUND: Provisional stenting is effective for anatomic simple bifurcation lesions. Double kissing crush stenting reduces the 1-year rate of target lesion revascularization. This study aimed to investigate the 5-year clinical results of the DKCRUSH-II study (Randomized Study on Double Kissing Crush Technique Versus Provisional Stenting Technique for Coronary Artery Bifurcation Lesions). METHODS AND RESULTS: A total of 370 patients with coronary bifurcation lesions who were randomly assigned to either the double kissing crush or provisional stenting group in the DKCRUSH-II study were followed for 5 years. The primary end point was the occurrence of a major adverse cardiac event at 5 years. Patients were classified by simple and complex bifurcation lesions according to the DEFINITION criteria (Definitions and Impact of Complex Bifurcation Lesions on Clinical Outcomes After Percutaneous Coronary Intervention Using Drug-Eluting Stents). At 5 years, the major adverse cardiac event rate (23.8%) in the provisional stenting group was insignificantly different to that of the double kissing group (15.7%; P=0.051). However, the difference in the target lesion revascularization rate between 2 groups was sustained through the 5-year follow-up (16.2% versus 8.6%; P=0.027). The definite and probable stent thrombosis rate was 2.7% in each group (P=1.0). Complex bifurcation was associated with a higher rate of target lesion revascularization (21.6%) at 5 years compared with 11.1% in patients with a simple bifurcation (P=0.037), with an extremely high rate in the provisional stenting group (36.8% versus 12.5%, P=0.005) mainly because of final kissing balloon inflation (19.4% versus 5.2%; P=0.036). CONCLUSIONS: The double kissing crush stenting technique for coronary bifurcation lesions is associated with a lower rate of target lesion revascularization. The optimal stenting approach based on the lesions' complexity may improve the revascularization for patients with complex bifurcations. CLINICAL TRIAL REGISTRATION: URL: http://www.chictr.org. Unique identifier: ChiCTR-TRC-0000015.

BACKGROUND: Effective gastric carcinoma (GC) chemotherapy is subject to many in vitro and in vivo barriers, such as tumor microenvironment and multidrug resistance. MATERIALS AND METHODS: Herein, we developed a hyaluronic acid (HA)-modified silica nanoparticle (HA-SiLN/QD) co-delivering quercetin and doxorubicin (DOX) to enhance the efficacy of GC therapy (HA-SiLN/QD). The HA modification was done to recognize overexpressed CD44 receptors on GC cells and mediate selective tumor targeting. In parallel, quercetin delivery decreased the expression of Wnt16 and P-glycoprotein, thus remodeling the tumor microenvironment and reversed multidrug resistance to facilitate DOX activity. RESULTS: Experimental results demonstrated that HA-SiLN/QD was nanoscaled particles with preferable stability and sustained release property. In vitro cell experiments on SGC7901/ADR cells showed selective uptake and increased DOX retention as compared to the DOX mono-delivery system (HA-SiLN/D). CONCLUSION: In vivo anticancer assays on the SGC7901/ADR tumor-bearing mice model also revealed significantly enhanced efficacy of HA-SiLN/QD than mono-delivery systems (HA-SiLN/Q and HA-SiLN/D).

T cells modified with chimeric antigen receptor are an attractive strategy to treat Epstein-Barr virus (EBV) associated malignancies. The EBV latent membrane protein 1 (LMP1) is a 66-KD integral membrane protein encoded by EBV that consists of transmembrane-spanning loops. Previously, we have identified a functional signal chain variable fragment (scFv) that specifically recognizes LMP1 through phage library screening. Here, we constructed a LMP1 specific chimeric antigen receptor containing anti-LMP1 scFv, the CD28 signalling domain, and the CD3ζ chain (HELA/CAR). We tested its functional ability to target LMP1 positive nasopharyngeal carcinoma cells. HELA/CAR cells were efficiently generated using lentivirus vector encoding the LMP1-specific chimeric antigen receptor to infect activated human CD3+ T cells. The HELA/CAR T cells displayed LMP1 specific cytolytic action and produced IFN-γ and IL-2 in response to nasopharyngeal carcinoma cells overexpressing LMP1. To demonstrate in vivo anti-tumor activity, we tested the HELA/CAR T cells in a xenograft model using an LMP1 overexpressing tumor. Intratumoral injection of anti-LMP1 HELA/CAR-T cells significantly reduced tumor growth in vivo. These results show that targeting LMP1 using HELA/CAR cells could represent an alternative therapeutic approach for patients with EBV-positive cancers.

PURPOSE: Allergic rhinitis (AR) is an inflammatory disorder of the upper airway. Exosomes or extracellular vesicles are nanosized vesicles of endosomal origin released from inflammatory and epithelial cells that have been implicated in allergic diseases. In this study, we characterized the microRNA (miRNA) content of exosomes in AR. METHODS: Extracellular vesicles were isolated from nasal mucus from healthy control subjects (n=10) and patients with severe AR (n=10). Vesicle RNA was analyzed by using a TaqMan microRNA assays Human Panel-Early Access kit (Applied Biosystems, Foster City, CA, USA) containing probes for 366 human miRNAs, and selected findings were validated with quantitative RT-PCR. Target prediction and pathway analysis for the differentially expressed miRNAs were performed using DIANA-mirPath. RESULTS: Twenty-one vesicle miRNAs were up-regulated and 14 miRNAs were under-regulated significantly (P<0.05) in nasal mucus from AR patients when compared to healthy controls. Bioinformatic analysis by DIANA-mirPath demonstrated that 32 KEGG biological processes were significantly enriched (P<0.05, FDR corrected) among differentially expressed vesicle miRNA signatures. Among them, the B-cell receptor signaling pathway (P=3.709E-09), the natural killer cell-mediated cytotoxicity (P=8.466E-05), the T-cell receptor signaling pathway (P=0.00075), the RIG-I-like receptor signaling pathway (P=0.00127), the Wnt signaling pathway (P=0.00130), endocytosis (P=0.00440), and salivary secretion (P=0.04660) were the most prominent pathways enriched in quantiles with differential vesicle miRNA patterns. Furthermore, miR-30-5p, miR-199b-3p, miR-874, miR-28-3p, miR-203, and miR-875-5p, involved in B-cell receptor and salivary secretion signaling pathways, were selected for validation using independent samples from 44 AR patients and 20 healthy controls. MiR-30-5p and miR-199b-3p were significantly increased in extracellular vesicles from nasal mucus when compared to healthy controls, while miR-874 and miR-28-3p were significantly down-regulated. In addition, miRNA-203 was significantly increased in AR patients, while miRNA-875-5p was found to be significantly decreased in AR patients. CONCLUSIONS: This study demonstrated that vesicle miRNA may be a regulator for the development of AR.

Fibrosis, an excessive self-repair response, is an age-related pathological process that universally affects various major organs such as the heart, liver, kidney, and lungs. Continuous accumulation of pathological tissue fibrosis destroys structural integrity and causes loss of function, with consequent organ failure and increased mortality. Although some differences exist in the triggering mechanisms and pathophysiologic manifestations of organ-specific fibrosis, they usually share similar cascading responses and features, including chronic inflammatory stimulation, parenchymal cell injury, and macrophage recruitment. Macrophages, due to their high plasticity, can polarize into different phenotypes in response to varied microenvironments and play a crucial role in the development of organ fibrosis. This review examined the relationship between macrophages and the pathogenesis of organ fibrosis. Moreover, it analyzed how fibrosis can be modulated by targeting macrophages, which may become a novel and promising therapeutic strategy for fibrosis.

Aims: This study aimed to assess the acute effect of selective His bundle pacing (S-HBP), non-selective His bundle pacing (NS-HBP), and right ventricular septum pacing (RVSP) on electrical synchrony and left ventricular (LV) mechanical synchrony using electrocardiogram and phase analysis of gated single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI). Methods and results: Totally 39 patients eligible for pacemaker were enrolled. Thirty-seven patients underwent successful His bundle pacing (HBP) including S-HBP in 23 and NS-HBP in 14 patients, respectively. Thirty-one patients simultaneously underwent backup RVSP. Twenty-three patients received SPECT MPI scans under different pacing modes, including S-HBP low- and high-output, NS-HBP low- and high-output, and RVSP mode. The paced QRS duration (QRSd) in the S-HBP low- and high-output mode and in the NS-HBP high-output mode were similarly compared with the baseline intrinsic QRSd. QRS duration in the NS-HBP low-output mode was slightly longer than the baseline. QRS duration was the longest in the RVSP group. Left ventricular mechanical synchrony parameters in both the S-HBP and the NS-HBP groups were remarkably better than those in the RVSP group. Moreover, LV mechanical synchrony parameters were much better in the S-HBP groups and NS-HBP high-output group. Conclusion: Selective His bundle pacing and high-output NS-HBP could restore normal electrical and LV mechanical synchrony.

Wear-particle-induced chronic inflammation and osteoclastogenesis have been identified as critical factors of aseptic loosening. Although strontium is known to be involved in osteoclast differentiation, its effect on particle-induced inflammatory osteolysis remains unclear. In this study, we investigate the potential impact and underling mechanism of strontium on particle-induced osteoclast activation and chronic inflammation in vivo and in vitro. As expected, strontium significantly inhibited titanium particle-induced inflammatory infiltration and prevented bone loss in a murine calvarial osteolysis model. Interestingly, the number of mature osteoclasts decreased after treatment with strontium in vivo, suggesting osteoclast formation might be inhibited by strontium. Additionally, low receptor activator of nuclear factor-κB ligand (RANKL), tumor necrosis factor-α, interleukin-1β, interleukin-6 and p65 immunochemistry staining were observed in strontium-treatment groups. In vitro, strontium obviously decreased osteoclast formation, osteoclastogenesis-related gene expression, osteoclastic bone resorption and pro-inflammatory cytokine expression in bone-marrow-derived macrophages in a dose-dependent manner. Furthermore, we demonstrated that strontium impaired osteoclastogenesis by blocking RANKL-induced activation of NF-κB pathway. In conclusion, our study demonstrated that strontium can significantly inhibit particle-induced osteoclast activation and inflammatory bone loss by disturbing the NF-κB pathway, and is an effective therapeutic agent for the treatment of wear particle-induced aseptic loosening.

OBJECTIVES: The main target of current drugs for alleviating bone loss is osteoclasts. However, the long-term application of such drugs will also cause side effects. Therefore, it is of great need to develop new and safer therapeutics for osteoporosis. In recent years, drug development based on gut microbiota has gradually attracted attention. This manuscript investigates the inhibitory effect of urolithin B (UB) on osteoclastogenesis and differentiation in vitro and in ovariectomized (OVX) mice. MATERIALS AND METHODS: CCK-8 was used to analyse the cytotoxicity of UB; BMMs cells were differentiated into osteoclasts by RANKL, and respectively treated with 1, 5, and 25 μmol/L UB during this process. After one week of intervention, tartrate-resistant acid phosphatase (TRAP) staining was used to analyse the number and average area of osteoclasts. F-actin staining and immunofluorescence staining were conducted to evaluate the morphology and function of osteoclasts. Bone resorption function of osteoclasts was detected by Pit Formation Assay. The expression of osteoclast-related protein genes in RAW264.7 cells were investigated via western blot and RT-PCR assays. Western blot analysis of RANKL-mediated activation of MAPK/NF-κB pathway after 0, 5, 15, 30, 60 min of intervention. For in vivo experiments, OVX mice received intraperitoneal injection of 10, 50 mg/kg every two days, 8 weeks later, the femurs of mice were taken for morphological analysis, and the serum content of CTX-1, a bone metabolism index, was analysed. RESULTS: UB could inhibit the osteoclast differentiation of rankl-induced bone marrow macrophages (BMMs) and RAW264.7 cells in vitro, suppress the uptake activity of hydroxyapatite and expression of osteoclast-related gene MMP9, CTSK, NFATc1 and c-fos. Furthermore, UB repressed the rankl-induced phosphorylation and degradation of IκB and the phosphorylation of P65 in the NF-κB pathway of RAW264.7 cells, and also down-regulated the phosphorylation level of ERK in the MAPK pathway. For in vivo studies, UB-treated OVX mice showed more significant improved various parameters of distal femur compared with the control group, with fewer NFATc1, MMP9 and TRAP-positive osteoclasts in bone tissues, and less serum content of CTX-1. CONCLUSION: Urolithin B attenuated bone loss in OVX mice by inhibiting the formation and activation of osteoclasts via down-regulation of the ERK/NF-κB signalling pathway.

Inflammation plays a critical role in the development of diabetic cardiomyopathy (DCM), which has been identified as a major predisposing factor for heart failure in diabetic patients. Previous studies indicated that ivabradine (a specific agent for heart rate [HR] reduction) has anti-inflammatory properties, but its role in DCM remains unknown. This study investigated whether ivabradine exerts a therapeutic effect in DCM. C57BL/6J mice were injected intraperitoneally with streptozotocin (STZ) to induce diabetes; then administered with ivabradine or saline (control). After 12 weeks, the surviving mice were analyzed to determine the cardioprotective effect of ivabradine against DCM. Although treatment with ivabradine did not affect blood glucose levels, it attenuated tumor necrosis factor-α, interleukin-1β, and interleukin-6 messenger RNA (mRNA) expression, inhibited c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38 MAPK) activation, reduced histological abnormalities, myocardial apoptosis and collagen deposition, and improved cardiac function in the diabetic mice. Interestingly, the anti-inflammatory and antiapoptotic properties of ivabradine, but not its inhibitory effect on JNK and p38 MAPK, were observed in high-glucose-cultured neonatal rat ventricular cardiomyocytes. Attenuating inflammation and apoptosis via intramyocardial injection of lentiviruses carrying short hairpin RNA targeting JNK and p38 MAPK validated that the anti-inflammatory and antiapoptotic effects of ivabradine were partly attributed to JNK and p38 MAPK inactivation in diabetic mice. In summary, these data indicate that ivabradine-mediated improvement of cardiac function in STZ-induced diabetic mice may be partly attributed to inhibition of JNK/p38 MAPK-mediated inflammation and apoptosis, which is dependent on the reduction in HR.