Long Noncoding RNA-Maternally Expressed Gene 3 Contributes to Hypoxic Pulmonary Hypertension.

The expression and function of long noncoding RNAs (lncRNAs) in the development of hypoxic pulmonary hypertension (HPH), especially in the proliferation of pulmonary artery smooth muscle cells (PASMCs), are largely unknown. Herein, we examined the expression and role of lncRNA-maternally expressed gene 3 (lncRNA-MEG3) in HPH. lncRNA-MEG3 was significantly increased and primarily localized in the cytoplasm of hypoxic PASMCs. lncRNA-MEG3 knockdown by lung-specific delivery of small interfering RNAs (siRNAs) significantly inhibited the development of HPH in vivo. Silencing of lncRNA-MEG3 by siRNAs and gapmers attenuated proliferation and cell-cycle progression in both PASMCs from idiopathic pulmonary arterial hypertension (iPAH) patients (iPAH-PASMCs) and hypoxia-exposed PASMCs in vitro. Mechanistically, we found that lncRNA-MEG3 interacts with and leads to the degradation of microRNA-328-3p (miR-328-3p), leading to upregulation of insulin-like growth factor 1 receptor (IGF1R). Additionally, higher expression of lncRNA-MEG3 and IGF1R and lower expression of miR-328-3p were observed in iPAH-PASMCs and relevant HPH models. These data provide insights into the contribution of lncRNA-MEG3 to HPH. Upregulation of lncRNA-MEG3 sequesters cytoplasmic miR-328-3p, eventually leading to expression of IGF1R, revealing a regulatory mechanism by lncRNAs in hypoxia-induced PASMC proliferation.

Uniportal Thoracoscopic Wedge Resection of Lung Nodules: Paravertebral Blocks Are Better Than Intercostal Blocks.

Background. Regional analgesia for tubeless, uniport, thoracoscopic wedge resection of benign peripheral nodules is generally performed by intercostal nerve block (INB). We examined the effectiveness of thoracic paravertebral block (PVB), in comparison to the traditional intercostal blocks, for the procedure. Methods. Between July 2016 and December 2016, 20 consecutive patients with solitary benign peripheral lung nodules underwent tubeless uniport thoracoscopic wedge resection using thoracic PVB (PVB group). The clinical outcomes were compared with those of 20 other consecutive patients who underwent the same procedure under the conventional INB, between January 2016 and July 2016 (INB group). In both groups, the procedures were performed without endotracheal intubation, urinary catheterization, or chest tube drainage. Results. The clinical data of patients in both groups were comparable in terms of demographic and baseline characteristics, operative and anesthetic characteristics, puncture-related complications, and postoperative anesthetic adverse events. No puncture-related complications occurred during the perioperative period in either group. The threshold values for mechanical pain at postoperative hours 4 and 8 were significantly higher in the PVB group than in the INB group. Furthermore, the incidence of nausea or vomiting in the PVB group was significantly less than that in the INB group. None of the patients required reintervention or readmission to our hospital. Conclusions. Tubeless uniportal thoracoscopic wedge resection for solitary benign peripheral lung nodules using thoracic PVB for regional analgesia is a feasible and safe procedure. Moreover, we found that thoracic PVB is less painful than INB.

Reactive oxygen species effect PASMCs apoptosis via regulation of dynamin-related protein 1 in hypoxic pulmonary hypertension.

The high level of reactive oxygen species and up-regulation of mitochondrial fission protein dynamin-related protein-1, both of which involved in pulmonary artery smooth muscle cells (PASMCs) apoptosis, have been detected in the lungs of rodent pulmonary arterial hypertension models. However, the regulatory mechanisms between ROS and DRP1 are poorly understood. In this study, ROS inhibitor, hypoxic rodent PAH models, small interfering RNA, polymerase chain reaction, Western blot, flow cytometry, immunohistochemistry and immunofluorescence were used. We determined that ROS, mainly derive from mitochondria, mediate mitochondria fission of PASMCs contributing to pulmonary vascular remodeling. Meanwhile, we also observed that hypoxia-induced DRP1 expression depends on ROS generation, especially mitochondrial ROS (mROS). Moreover, the levels of ROS and mROS evoked by hypoxia were regulated by DRP1. Furthermore, we verified the apoptosis suppression of PASMCs under hypoxia due to the interaction between ROS/mROS and DRP1. Our study reveals a novel mechanism of hypoxia-induced pulmonary vascular remodeling, suggesting a new therapeutic strategy which is targeting on the positive feedback of ROS/mROS-DRP1 for the treatment of PAH.

Uniportal versus triportal video-assisted thoracic surgery in the treatment of tuberculous empyema.

OBJECTIVE: To examine the effectiveness of decortication to treat chronic tuberculous empyema (TE) using uniport video-assisted thoracoscopic surgery (VATS) versus conventional triport VATS. METHODS: Data from consecutive patients with stage II or III TE who underwent decortication with either uniport VATS (uniportal group) between July and December 2017, or triport VATS between January and July 2018 (triportal group), were retrospectively analysed. VATS procedures were performed under general anaesthesia with double lumen endotracheal intubation and clinical outcomes were compared between the two groups. RESULTS: Clinical data were comparable between the groups (20 patients in each) regarding demographic and baseline characteristics, operative and postoperative characteristics, surgical procedure-related complications, and postoperative adverse events. No surgical procedure-related complications occurred during the perioperative period in either group. Threshold values for mechanical pain at 8 h postoperatively were significantly higher in the triportal group versus the uniportal group. Furthermore, the incidence of nausea and vomiting was significantly lower in the uniportal versus triportal group. In the triportal group, one patient required readmission and further intervention due to recurrence. CONCLUSIONS: Uniport VATS decortication for stages II and III TE may be a feasible and safe procedure in selected patients. Moreover, uniport VATS may be less painful than triport VATS.

[Effects of qiwei granule on the protein and mRNA expressions of renal tissue transforming growth factor-beta1 in KK-Ay mice with spontaneous type 2 diabetes mellitus].

OBJECTIVE: To study the effects of Qiwei Granule (QWG) on the protein and mRNA expressions of renal tissue transforming growth factor beta1 (TGF-beta1) in KK-Ay mice with spontaneous type 2 diabetes mellitus (T2DM). METHODS: Spontaneous T2DM KK-Ay mice model was adopted. Forty-five male mice were randomly divided into three groups, i. e., the model group, the Chinese medicine group, and the Western medicine group, 15 in each group. Fifteen male C57BL/6J mice were set up as the normal control group. The mice in the Chinese medicine group and the Western medicine group were administered intragastrically with QWG (at the daily dose of 20 g/kg) and valsartan (at the daily dose of 10 mg/kg), and the treatment lasted for 12 successive weeks. The pathological changes of the kidney were observed using HE staining, PAS, and Masson staining. The protein and mRNA expressions of TGF-beta1, were detected using immunohistochemical method and Real-time fluorescent quantitative PCR. RESULTS: The renal pathological changes of mice in the model group showed hypertrophic glomeruli, widened mesenteric matrix, increased mesangial cells, vacuolar renal tubular epithelial cells, tubular ectasia, and foci atrophy. Necrosis was occasionally seen. More protein cast, mesenchymal infiltration of inflammatory cells, and interstitial fibrosis could be seen. The protein and mRNA expressions of TGF-beta1 increased more in the model group than in the normal control group. After treatment by QWG and valsartan, the renal pathological changes were obviously alleviated, and the protein and mRNA expressions of TGF-beta1 were obviously lowered (P<0.05). CONCLUSION: By inhibiting the protein and mRNA expressions of TGF-beta1, QWG could play a role in preventing and curing diabetic nephropathy.

Reconsidering the prognostic significance of tumour deposit count in the TNM staging system for colorectal cancer.

Although the occurrence of tumour deposits (TDs) without metastatic lymph nodes (mLNs) is classified as "N1c" in the 8th TNM staging system for colorectal cancer (CRC), the prognostic significance of the TD count is still controversial. A total of 39155 CRC patients were collected from the Surveillance, Epidemiology, and End Results (SEER) database. The potential associations between baseline characteristics and TD status were evaluated using the χ2 test. Cancer-specific survival (CSS) rates were calculated by using the Kaplan-Meier method, and CSS comparisons were performed by using the log-rank test. The results showed that TD count was an important prognostic factor and that the number of TDs was negatively correlated with the prognosis of CRC patients. We found that the prognostic value of one TD is equivalent to that of two mLNs based on the comparison of CSS rates. Accordingly, we proposed a novel N staging system by integrating the TD count into the N category with the ratio of TDs to mLNs being 1:2. There were no prognostic differences in patients with or without TDs in each novel N category. Weighing one TD as two mLNs in this novel TNM staging system is superior to the "N1c" classification in the 8th TNM staging system in evaluating the prognosis of CRC patients.

MiR-449a-5p mediates mitochondrial dysfunction and phenotypic transition by targeting Myc in pulmonary arterial smooth muscle cells.

MicroRNAs have been considered to participate in pulmonary arterial hypertension (PAH) and regulate numerous disease pathways in pulmonary vasculature. However, the molecular role in the pathologies has not yet been fully uncovered, particularly in the view of energy metabolism and vascular smooth muscle cell phenotypic regulation. Here, several altered miRNAs are founded in genome-wide miRNA sequencing analysis, in which miR-449a-5p was identified as a probable candidate in hypoxic PAH and verified such a decreasing trend. Moreover, we identify that miR-449a-5p plays critical role in both mitochondria metabolic dysfunction and phenotype transformation of pulmonary arterial smooth muscle cells. Subsequently, we initiate that the transcription factor Myc, which is negatively regulated by miR-449a-5p, results in the aberrant effects contributing to pulmonary arterial smooth muscle cell proliferation. Taken together, we demonstrated that the miR-449a-5p/Myc axis is indispensable for the development and progression of PAH. These results may serve as a significant implication for understanding and treatment of PAH. KEY MESSAGES: • The downregulation of miR-449a-5p occurs in both PAH-PAs and hypoxic PASMCs. • MiR-449a-5p is involved in hypoxia-induced mitochondria dysfunction of PASMCs. • MiR-449a-5p inhibits hypoxic phenotypic transition and proliferation of PASMCs. • The aberrant effects of MiR-449a-5p depend on downstream transcription factor Myc. • Myc contributes to mitochondria dysfunction and phenotype transformation in PAH.

MiR-125a regulates mitochondrial homeostasis through targeting mitofusin 1 to control hypoxic pulmonary vascular remodeling.

Abnormal pulmonary arterial smooth muscle cells (PASMCs) proliferation is an important pathological process in hypoxic pulmonary arterial hypertension. Mitochondrial dynamics and quality control have a central role in the maintenance of the cell proliferation-apoptosis balance. However, the molecular mechanism is still unknown. We used hypoxic animal models, cell biology, and molecular biology to determine the effect of mitofusin 1 (Mfn1) on hypoxia-mediated PASMCs mitochondrial homeostasis. We found that Mfn1 expression was increased in hypoxia, which was crucial for hypoxia-induced mitochondrial dysfunction and smooth muscle cell proliferation as well as hypoxia-stimulated cell-cycle transition from the G0/G1 phase to S phase. Subsequently, we studied the role of microRNAs in mitochondrial function associated with PASMC proliferation under hypoxic conditions. The promotive effect of Mfn1 on pulmonary vascular remodeling was alleviated in the presence of miR-125a agomir, and miR-125a antagomir mimicked the hypoxic damage effects to mitochondrial homeostasis. Moreover, in vivo and in vitro treatment with miR-125a agomir protected the pulmonary vessels from mitochondrial dysfunction and abnormal remodeling. In the present study, we determined that mitochondrial homeostasis, particularly Mfn1, played an important role in PASMCs proliferation. MiR-125a, an important underlying factor, which inhibited Mfn1 expression and decreased PASMCs disordered growth during hypoxia. These results provide a theoretical basis for the prevention and treatment of pulmonary vascular remodeling. KEY MESSAGES: Hypoxia leads to upregulation of mitofusin 1 (Mfn1) both in vivo and in vitro. Mfn1 is involved in hypoxia-induced PASMCs proliferation. Mfn1-mediated mitochondrial homeostasis is regulated by miR-125a. MiR-125a plays a role in PASMCs oxidative phosphorylation and glycolysis.

Effect of miR-21 on renal fibrosis by regulating MMP-9 and TIMP1 in kk-ay diabetic nephropathy mice.

MicroRNAs (miRs) play important roles in initiation and progression of many pathologic processes. However, the roles of miRs in diabetic nephropathy remain unclear. This study was to determine whether miR-21 was involved in diabetic nephropathy and to explore the relationship between miR-21 and MMP9/TIMP1 expression in diabetic nephropathy. In situ hybridization studies showed that miR-21 was primarily localized and distributed in cortical glomerular and renal tubular cells in diabetic kk-ay kidney. Real-time quantitative RT-PCR demonstrated that the expression of miR-21 was significantly increased in kk-ay mice, compared with control C57BL mice. Interestingly, miR-21 expression positively correlated with urine albumin creatine ratio (ACR), TIMP1, collagen IV (ColIV), and fibronectin (FN); while negatively correlated with creatine clearance ratio (Ccr) and MMP-9 protein. Importantly, antagomir-21 not only ameliorated Ccr and ACR but also decreased TIMP1, ColIV, and FN proteins. In conclusion, our data demonstrate that miR-21 contributes to renal fibrosis by mediating MMP9/TIMP1 and that inhibition of miR-21 may be a novel target for diabetic nephropathy.

Traditional chinese medicine tang-luo-ning ameliorates sciatic nerve injuries in streptozotocin-induced diabetic rats.

Diabetic peripheral neuropathy (DPN) is a common microvascular complication of diabetes associated with high disability rate and low quality of life. Tang-Luo-Ning (TLN) is an effective traditional Chinese medicine for the treatment of DPN. To illustrate the underlying neural protection mechanisms of TLN, the effect of TLN on electrophysiology and sciatic nerve morphology was investigated in a model of streptozotocin-induced DPN, as well as the underlying mechanism. Sciatic motor nerve conduction velocity and digital sensory nerve conduction velocity were reduced in DPN and were significantly improved by TLN or α -lipoic acid at 10 and 20 weeks after streptozotocin injection. It was demonstrated that TLN intervention for 20 weeks significantly alleviated pathological injury as well as increased the phosphorylation of ErbB2, Erk, Bad (Ser112), and the mRNA expression of neuregulin 1 (Nrg1), GRB2-associated binding protein 1 (Gab1), and mammalian target of rapamycin (Mtor) in injured sciatic nerve. These novel therapeutic properties of TLN to promote Schwann cell survival may offer a promising alternative medicine for the patients to delay the progression of DPN. The underlying mechanism may be that TLN exerts neural protection effect after sciatic nerve injury through Nrg1/ErbB2→Erk/Bad Schwann cell survival signaling pathway.