Double-negative T cells regulate the progression of liver fibrosis through Th9 cells differentiation.

Our previous study found that double negative T cells (DNTs) could promote the NLRP3 activation through high expression of TNF-α, thereby leading to hepatic fibrosis progression. We focused on investigating the role and mechanism of DNTs in regulating the Th9 cells differentiation in liver fibrosis. In our results, among patients with liver fibrosis, the proportions of peripheral blood DNTs and Th9 cells were up-regulated and positively correlated. While promoting the progression of liver fibrosis in mice, DNTs could elevate the proportion of Th9 cells and activate the TNFR2-STAT5-NF-κB pathway. The use of IL-9 and TNF-α monoclonal antibodies (mAbs) inhibited the effect of DNTs and lowered the proportion of Th9 cells in tissues. In vitro experiments showed that DNTs could promote the Th9 cells differentiation of Naive T cells, while TNF-α mAbs could inhibit such effect of DNTs to lower the proportion of Th9 cells. We found that DNTs can activate TNFR2-STAT5-NF-κB pathway by secreting TNF-α, thereby promoting the Th9 Cells differentiation to facilitate the progression of liver fibrosis. There is interaction between DNTs and Th9 cells.

Environmental toxin chlorpyrifos induces liver injury by activating P53-mediated ferroptosis via GSDMD-mtROS.

AIM: We investigate the mechanism whereby chlorpyrifos (CHI), an environmental toxin, causes liver injury by inducing ferroptosis in hepatocytes. METHODS: The toxic dose (LD50 = 50 µM) of CHI for inducing AML12 injury in normal mouse hepatocytes was determined, and the ferroptosis-related indices were measured, including the levels of SOD, MDA and GSH-Px, as well as the cellular content of iron ions. JC-1 and DCFH-DA assays were employed to detect the mtROS levels, the levels of mitochondrial proteins (GSDMD, NT-GSDMD), as well as the cellular levels of ferroptosis-related proteins (P53, GPX4, MDM2, SLC7A11). We knocked out the GSDMD and P53 in AML12 and observed the CHI-induced ferroptosis of ALM12 after applying YGC063, an ROS inhibitor. In animal experiments, we explored the effect of CHI on liver injury by using conditional GSDMD-knockout mice (C57BL/6 N-GSDMDem1(flox)Cya) and ferroptosis inhibitor Fer-1. Small molecule-protein docking and Pull-down assay were employed to verify the association between CHI and GSDMD. RESULTS: We found that CHI could induce ferroptosis of AML12. CHI promoted the cleavage of GSDMD, leading to upregulation of mitochondrial NT-GSDMD expression, as well as ROS levels. P53 activation promoted the ferroptosis. Knock out of GSDMD and P53 could inhibit the CHI-induced ferroptosis, and YGC063 could also inhibit ferroptosis. In mice experiments, GSDMD knockout or Fer-1 intervention could significantly inhibit the CHI-induced liver injury. CHI promoted the cleavage of GSDMD by binding to its SER234 site. CONCLUSION: CHI can bind to GSDMD to promote its cleavage, while NT-GSDMD can open mitochondrial membrane to promote the mtROS release. Cytoplasmic upregulation of ROS levels can facilitate the P53-mediated ferroptosis. GSDMD-mtROS is the primary mechanism whereby CHI induces ferroptosis in hepatocytes.

Inhibition of LDL receptor-related protein 3 suppresses chondrogenesis of stem cells, inhibits proliferation, and promotes apoptosis.

Articular cartilage defects remain the most common and challenging joint disease. Cartilage lacks the self-healing capacity after injury due to its avascularity. Recently, stem cell-based therapy has been applied for cartilage regeneration. However, the critical target for stem cells during chondrogenesis remains unclear. We first reported that LDL receptor-related protein 3 (LRP3) expression was markedly increased during chondrogenesis in stem cells. Furthermore, LRP3 was an effective chondrogenic stimulator, as confirmed by knockdown and overexpression experiments and RNA sequencing. In addition, inhibition of LRP3 suppressed proliferation and induced apoptosis. Therefore, our study first defined a new chondrogenic stimulator, LRP3, with detailed clarification, which provided a novel target for stem cell-based cartilage regeneration.

TRIP6, as a target of miR-7, regulates the proliferation and metastasis of colorectal cancer cells.

This study focuses on the role of miR-7 in colorectal cancer (CRC) cells by targeting thyroid receptor interactor protein 6 (TRIP6). Here, we report that miR-7 expression was down-regulated in colorectal cancer tissues and cell lines due to DNA hypermethylation. miR-7 overexpression significantly inhibits the proliferation and migration of CRC cells in vitro. TRIP6 was found to be a direct target gene of miR-7. The proliferation inhibition of CRC cells mediated by miR-7 could be rescued after TRIP6 overexpression in vitro and in vivo. Moreover, overexpression of TRIP6 reduced miR-7 inhibitor-mediated CRC cell migration and invasion. These findings demonstrate that miR-7 could inhibit the proliferation and migration of CRC cells by targeting TRIP6 and that miR-7 might serve as a good strategy for diagnosing and treating CRC.

Expression of PD1 and BTLA on the CD8+ T Cell and γδT Cell Subsets in Peripheral Blood of Non-Small Cell Lung Cancer Patients.

Objective To investigate the expression and regulation of programmed cell death protein 1 (PD1), B lymphocyte and T lymphocyte attenuator (BTLA) in peripheral blood of patients with non-small cell lung cancer (NSCLC); to examine the correlation of the mRNA levels between PD and BTLA in NSCLC. Methods Flow cytometry was used to detect the expression of PD1 and BTLA on the surfaces of CD8+ T cells and γδ+ T cells in the peripheral blood samples collected from 32 in-patients with stage IV NSCLC and 30 healthy individuals. We compared the expression of PD1 and BTLA on the surfaces of γδ+ T cells in the NSCLC patients with bone metastasis before and after the treatment of zoledronic acid. The correlations of PD1 and BTLA, as well as their ligands were analyzed using Pearson correlation analysis with the cBioPortal data platform. Results The frequency of PD1 on the surfaces of CD8+ T cells was significantly higher than that of the γδT cells in both healthy controls (t=2.324, P=0.024) and NSCLC patients（t=2.498, P=0.015). The frequency of PD1 on CD8+ T cells, rather than on γδ+ T cells, was significantly upregulated in advanced NSCLC patients compared with that in healthy controls (t=4.829, P<0.001). The PD1+ BTLA+γδT cells of the healthy controls were significantly lower than that of the NSCLC patients (t=2.422, P=0.0185). No differences in percentage of PD1+γδ+ and BTLA+γδ+ T cells were observed in 7 NSCLC patients with bone metastasis before and after zoledronic acid treatment. PD1 was positively correlated with BTLA in both lung adenocarcinoma (r=0.54; P<0.05) and lung squamous cell carcinoma (r=0.78; P<0.05). Conclusions The upregulation of co-inhibitory molecules occurs on the surfaces of both CD8+ T cells and γδT cells in advanced NSCLC, suggesting that these molecules were involved in regulating the inactivation of CD8+ T cells and γδ+ T cells, immune escape and tumor invasion.

Thalassotalea atypica sp. nov., isolated from seawater, and emended description of Thalassotalea eurytherma.

A novel Gram-stain-negative, straight or slightly curved rod-shaped, non-spore-forming, non-flagellated, strictly aerobic strain, designated RZG4-3-1T, was isolated from coastal seawater of Rizhao, China (119.625° E 35.517° N). The organism grew optimally at 24-28 °C, at pH 7.0 and in the presence of 2.0 % (w/v) NaCl. The strain required seawater or artificial seawater for growth, and NaCl alone did not support growth. Strain RZG4-3-1T contained ubiquinone 8 (Q-8) as the major respiratory quinone and contained C16 : 1ω7c and/or C16 : 1ω6c and C16 : 0 as the dominant fatty acids. The polar lipids of strain RZG4-3-1T were phosphatidylethanolamine, phosphatidylglycerol and one unidentified aminophospholipid. The DNA G+C content of strain RZG4-3-1T was 40.1 mol%. Strain RZG4-3-1T exhibited the highest 16S rRNA gene sequence similarity value (96.0 %) to Thalassotalea eurytherma JCM 18482T. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain RZG4-3-1T belonged to the genus Thalassotalea. On the basis of polyphasic analyses, strain RZG4-3-1T represents a novel species of the genus Thalassotalea, for which the name Thalassotalea atypica sp. nov. is proposed. The type strain is RZG4-3-1T (=JCM 31894T=KCTC 52745T=MCCC 1K03276T). An emended description of Thalassotalea eurytherma is also provided.

The diagnosis and arthroscopic treatment of angioleiomyoma presenting loose body in the knee joint: two case reports.

BACKGROUND: Angioleiomyoma is a very rare benign solitary soft tissue neoplasm originating from smooth muscle layer of blood vessels. The tumor is usually located in the subcutis or the superficial fasciae, but less often in the deep fasciae, especially rare in the knee joint cavity. Diagnosis is frequently delayed or misdiagnosed as loose body or anterior knee pain because of its rare occurrence and poor awareness of physicians. Few studies have presented intra-articular angioleiomyoma and such cases become rarer and more difficult to diagnose when it presents as loose body. CASE PRESENTATION: Two patients, a middle-aged man and an old woman, presented to our outpatient clinic with persistent anterior knee pain and both of them suffered from a solitary mass in the right knee that had slowly enlarged. One of two patients showed negative in the routine radiographic imaging and the other showed a "loose body" beside the lateral femoral condyle in the knee. MRI showed both a well-demarcated intra-articular mass of isointense signal to muscle on T1-weighted images and heterogeneous intensity on T2-weighted images. Their tumors were excised under arthroscopy finally, with the pathological results revealed vascular leiomyomas. They both recovered well with pain free after operation and no signs of recurrence were seen at the 7-year follow-up. CONCLUSIONS: This case report illustrates the atypical locations of angioleiomyoma in the knee joint should arouse our attention and be included in the differential diagnosis of nodular lesions mimicking loose bodies.

Simulated physiological stretch-induced proliferation of human bladder smooth muscle cells is regulated by MMPs.

Mechanical stimulation is an essential factor for organisms to develop normally. In bladder development matrix metalloproteinases (MMPs) play an important role through structure remodeling and regulating the cell proliferation. In this study, we investigated the simulated physiological stretch induced proliferation of HBSMCs; MMPs/TIMPs expression in stretch and non-stretch groups. HBSMCs were exposed to cyclic stretch with defined parameters (5%, 10% and 15% elongation). The expression of MMPs and TIMPs in each parameter and non-stretch groups was examined at the transcriptional and translational levels respectively. 5-Ethynyl-2'-deoxyuridine (EdU) assay was used to assess cell proliferation. In the presence of the broad spectrum MMPs inhibitor (Batimastat), cells proliferation, MMPs and tissue inhibitors of metalloproteinases (TIMPs) expression were assessed again. Compared with non-stretch group, HBSMCs in stretch groups showed higher proliferation. The expression of MMP-1, 2, 3, 7 was up-regulated in stretch groups, and it remained at the same high level in 10% and 15% stretch groups. TIMP-1, 2 expression only increased under 15% stretch. Stretch resulted in elevated cell proliferation was abolished by Batimastat. In conclusion, the proliferation of HBSMCs induced by stretch was resulted from the stretch-induced MMPs expression and release.

The role of mirabegron in overactive bladder: a systematic review and meta-analysis.

OBJECTIVE: To present a systematic review assessing the efficacy and safety of mirabegron for overactive bladder (OAB). MATERIALS AND METHODS: A literature search was performed using the Cochrane Library, MEDLINE, EMBASE and Science Citation Index Expanded. The literature reviewed included meta-analyses, randomized and nonrandomized prospective studies. We utilized mean difference (MD) to measure the mean number of incontinence episodes and the mean number of micturitions, and OAB questionnaire (OAB-q) and odds ratio (OR) to measure adverse events rates. We used the Cochrane Collaboration's Review Manager 5.1 software for statistical analysis. RESULTS: We identified six publications that strictly met our eligibility criteria. Meta-analysis of extractable data showed that mirabegron was more effective than placebo in treating OAB despite different drug dosages in the efficacy end points: mean number of incontinence episodes per 24 h (MD -0.54; 95% CI -0.63, -0.45; p = 0.001), mean number of micturitions per 24 h (MD -0.55; 95% CI -0.63, -0.47; p = 0.001), OAB-q (MD -4.49; 95% CI -6.27, -2.71; p = 0.001) and adverse events (OR 0.99; 95% CI 0.83, 1.19; p = 0.92). When compared to tolterodine, mirabegron was more effective in terms of mean number of incontinence episodes per 24 h (MD -0.25; 95% CI -0.43, -0.06; p = 0.009). However, there were no differences between mirabegron and tolterodine in mean number of micturitions per 24 h (MD -0.17; 95% CI -0.35, 0.01; p = 0.07) and OAB-q (MD -1.09; 95% CI -2.51, 0.33; p = 0.13). Mirabegron also had a lower adverse reaction rate (OR 0.9; 95% CI 0.8, 1.0; p = 0.04). CONCLUSIONS: In this diverse population, mirabegron was an effective and safe pharmacologic therapy for OAB.

[Retracted] MicroRNA­642a­5p inhibits colon cancer cell migration and invasion by targeting collagen type I α1.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the cell invasion assay data shown in Fig. 6B on p. 940, and western blot data featured in Fig. 7B on p. 942, had already appeared in previously published articles written by different authors at different research institutes. Owing to the fact that the contentious data in the above article had already been published prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 45: 933­944, 2021; DOI: 10.3892/or.2020.7905].