HMGB1 Upregulates RAGE to Trigger the Expression of Inflammatory Factors in the Lung Tissue in a Hypoxic Pulmonary Hypertension Rat Model.

Hypoxic pulmonary hypertension (HPH), a form of pulmonary hypertension (PH) caused by hypoxia, could cause serious complications and has a high mortality rate, and no clinically effective treatments are currently available. In this study, we established an HPH preclinical model in rats by simulating clinicopathological indicators of the disease. Our results showed that high mobility group box-1 protein (HMGB1) aggravated the clinical symptoms of HPH. We aimed at establishing protocols and ideas for the clinical treatment of HPH by identifying downstream HMGB1 binding receptors. Our investigation showed that continuous hypoxia could cause significant lung injury in rats. ELISA and western blotting experiments revealed that HPH induces inflammation in the lung tissue and increases the expression of a hypoxia-inducible factor. Testing of lung tissue proteins in vivo and in human pulmonary artery endothelial cells in vitro revealed that the HMGB1-mediated increase in the receptor for advanced glycation end products (RAGE) expression promoted inflammation. In summary, we successfully established an HPH rat model providing a new model for preclinical HPH research and elucidated the role of HMGB1 in HPH. Furthermore, we describe that HMGB1 induced inflammation in the HPH model via RAGE, causing severe lung dysfunction. This study could potentially provide novel ideas and methods for the clinical treatment of HPH.

Effect of surgical starting time and season on prognosis in octogenarians with colorectal cancer: a retrospective study.

Aim: To investigate the effect of surgical starting time and season on the prognosis of octogenarians with colorectal cancer. Patients & methods: A total of 291 patients aged 80 years or above who received elective colectomy for colorectal cancer between January 2007 and December 2018 in the National Cancer Center in China were included. Results: No significant time- or season-dependent difference in overall survival for all clinical stages was found in the study. Comparing perioperative outcomes, the morning group had a longer operative time than the afternoon group (p = 0.03), but no significant difference was found based on the season of colectomy. Conclusion: These findings provide insights into clinical outcomes for colorectal cancer patients aged more than 80 years.

Recurrent studies have demonstrated that in heart surgery, different surgical starting times can affect the patients' outcomes, mainly due to the 24-h cyclic variations in heart function. This variability also exists in bowel function. The surgical outcomes of elderly patients aged over 80 years are more susceptible to external factors due to their frailty, so we wanted to compare the differences in prognosis of elderly patients who underwent surgery at different times and seasons.

[Effects of hypoxia on the expression of HMGB1 and related inflammatory factors in human pulmonary artery smooth muscle and pulmonary artery endothelial cells].

OBJECTIVE: To investigate the effects of hypoxia on the expressions of high mobility group box-1(HMGB1), HMGB1 receptors and inflammatory factors in human pulmonary artery smooth muscle cell( HPASMC) and human pulmonary artery endothelial cells (HPAEC).The effects of HMGB1 on the proliferation and migration activity of the two kinds of cells were detected. METHODS: HPASMC and HPAEC were cultured under hypoxic conditions (Hypoxia at 1% oxygen, Hypoxia group) and normoxic conditions(Control group) . The mRNA levels of HMGB1, Toll-like receptors 2,4,9 (TLR2 , TLR4, TLR9), the receptor of advanced glycation end products(RAGE) , CD24 and IL-6 ,TNF-α,CXCL8 were detected by real-time PCR. Cell proliferation was measured by MTS. Cell migration was analysed by wound healing test. RESULTS: Compared with control group, the expressions of HMGB1 mRNA and RAGE mRNA in both HPASMC and HPAEC were increased significantly (P＜0.05 and 0.01). Meanwhile, the expressions of CD24 mRNA in HPAEC and IL-6 mRNA in HPASMC of hypoxia group were increased significantly (P＜0.05). MTS results showed that HMGB1 inhibited the proliferation of HPAEC at 345 pmol/L significantly (P＜0.01). HMGB1 had no effect on the proliferation of HPASMC. Wound healing test showed that HMGB1 had no significant effect on HPASMC and HPAEC. CONCLUSION: HMGB1 was produced by HPAEC and HPASMC induced by hypoxia. HMGB1 induces endothelial barrier dysfunction by inhibiting HPAEC proliferation. Hypoxia stimulates HPASMC to produce inflammatory cytokines.

Lysophosphatidic acid enhances human umbilical cord mesenchymal stem cell viability without differentiation via LPA receptor mediating manner.

Human umbilical cord mesenchymal stem cells (hUC-MSCs) are potential stromal cells which are regarded as the most feasible stem cell group in cell therapy. The maintenance of cell survival without differentiation is important in cell transplantation and stem cell therapy. However, negative factors exist in cell transplantation. Lysophosphatidic acid (LPA) is a non-antigenic small molecule phospholipid which induced several fundamental cellular responses, such as cell proliferation, apoptosis and migration. In this study we aimed to explore the effects of LPA on the survival and differentiation of MSCs and its availability in cell therapy. We found that LPA stimulated hUC-MSC proliferation and protected hUC-MSCs from lipopolysaccharide (LPS) induced apoptosis. We also observed that CD29, CD44, CD73, CD90 and CD105 were expressed, whereas CD34 and CD45 were not expressed in hUC-MSCs, and these makers have no change in LPA containing medium, which indicated that LPA accelerated the survival of hUC-MSCs in an undifferentiating status. We also demonstrated that higher expressed LPAR1 involved in LPA stimulated cell survival action. LPA stimulated cell proliferation was associated with LPAR1 mediated Gi/o-proteins/ERK1/2 pathway. On the other hand, LPA protected hUC-MSCs from LPS-induced apoptosis through suppressing caspase-3 activation by LPAR1 coupled with a G protein, but not Gi/o or Gq/11 in hUC-MSC. Collectively, this study demonstrated that LPA increased the proliferation and survival of hUC-MSCs without differentiation through LPAR1 mediated manner. Our findings provide that LPA as a anti-apoptotic agent having potential application prospect in cell transplantation and stem cell therapy.

[Expressions of G2A and OGR1 in peripheral blood cells of patients with hypoxia induced pulmonary hypertension].

OBJECTIVE: To detect the expression changes of proton-sensing receptor G2 accumulation (G2A) and ovarian cancer G protein-coupled receptor 1(OGR1) in human peripheral blood cells in hypoxic pulmonary hypertension patients(HPH). METHODS: Thirty-one patients with HPH were enrolled for HPH group(16 men and 15 women,age:(65.19±5.86) and thirty healthy persons were enrolled for the control group (NC group). The peripheral blood samples were collected and the mRNA expressions of G2A and OGR1 were determined by using real-time fluorescent quantitative PCR. The serum levels of tumor necrosis factor-α (TNF-α) were detected by using enzyme-linked immunosorbent assay (ELISA). RESULTS: PaCO2 was increased significantly in HPH group than that of the NC group (P<0.05). Forced expiratory volume in 1 sencond(FEV1)pro% and FEV1/forced vital capacity(FVC)in HPH group were significant lower than those of the NC group(P<0.05). The expressions of peripheral blood G2A mRNA and TNF-α in HPH group were increased dramatically than those of the NC group(P<0.05). The expressions of OGR1 mRNA in peripheral blood had no difference between HPH group and NC group. The expressions of G2A and TNF-α in HPH group were positively related to pulmonary artery pressure significantly. CONCLUSIONS: The expression of proton-sensing receptor G2A and the level of TNF-α are increased in peripheral blood cells of patients with pulmonary hypertension.The expressions of TNF-α,G2A and pulmonary artery pressure have positive correlation in the HPH group.

[The effect of noninvasive positive pressure ventilation on the expression of ubiquitin-proteasome of skeletal muscle in patients with AECOPD].

OBJECTIVE: To investigate the effect of noninvasive positive pressure ventilation( NIPPy) on the gene and protein expression of biquitin-proteasome of skeletal muscle in patients with acute exacerbation of chronic obstructive pulmonary disease(AECOPD). METHODS: Seven patients with AECOPD by NIPPV were used as the study group, meanwhile, 6 patients with AECOPD who refused NIPPV was the control group. The blood gas analysis, heart rate (HR) and mean arterial pressure (MBp) were monitored before and 14 days after treatment. A skeletal muscle biopsy was performed after 14 days of therapy. The mRNA expression of ribosomal protein S21 (RPS21), Ubiquitin, Ubiquitin combined with enzyme E2 (E2), Ubiquitin ligase E3 (E3) in skeletal muscle cell were measured by RT-PCR. The protein expression of mitochondrial aconitase (AC02), protease C3 (C3), ribosomal protein SLC16 (SLC16) were detected by Western blot. RESULTS: Forteen days after treatment, the patients in NIPPV group got much better improvement in PaCO2, PaO2 and HR than that of the patients.in the control group (P < 0.05). The gene expression of RPS21,Ubiquitin, E2 and E3 in skeletal muscle cell on patients with NIPPV were obviously lower than that of the control group (P < 0.05, P < 0.01). Compared with that of the control group, the protein expression of C3 and AC2 increased significantly in the NIPPV group (P < 0.01). The protein expression of SLC16 was significantly lowered in the treated group (P < 0.01). CONCLUSION: NIPPV can ameliorate the proteasome pathway and energy metabolic disorders in patients with AECOPD.

[Expression of phosphatase and tensin homolog in lower rectal cancer on neoadjuvant chemoradiotherapy].

OBJECTIVE: To explore the expression of phosphatase and tensin homolog deleted on chromosome ten (PTEN) in low rectal cancer on neoadjuvant chemoradiotherapy with capecitabine plus radiotherapy. METHODS: Sixty-six patients with low rectal cancer on therapy with capecitabine (1650 mg×m(-2)×d(-1) in 2 divided doses) for two course and concurrent radiotherapy (50 Gy, 2 Gy/day, 5 days a week). Then the investigators analyzed the relationship between the preoperative neoadjuvant chemoradiotherapy and prognosis and measured the expression of PTEN during neoadjuvant chemoradiotherapy. RESULTS: 92.4% (61/66) of patients received neoadjuvant chemoradiotherapy as planned. 87.9% (58/66) tumor stages were down-staged, tumor size decreased while the distance from anal edge increased. And curative resection with sphincter-sparing was carried out in all patients. The rate of sphincter preservation was 90.9% (60/66). Among which, 85.5% patients showed an excellent function of sphincter. The 2-year survival rate was 87.9% (58/66). The survival period was an average of 35.3 months (range: 25-60). The PTEN mRNA and protein expression in cancer tissues on neoadjuvant chemoradiotherapy were significantly higher than those before neoadjuvant chemoradiotherapy (P=0.0079, 0.0269). CONCLUSIONS: The preoperative neoadjuvant chemoradiotherapy in lower rectal cancer patients has shown its efficacy in down-staging cancer, enhancing resectability, offering sphincter preservation, up-regulating PTEN expression, promoting the apoptosis of cancer cell and achieving a better survival rate. Thus preoperative neoadjuvant chemoradiotherapy is an effective adjuvant measure.