The role of HIF in angiogenesis, lymphangiogenesis, and tumor microenvironment in urological cancers.

Typically associated with solid tumors, hypoxia contributes to tumor angiogenesis and lymphangiogenesis through various molecular mechanisms. Accumulating studies indicate that hypoxia-inducible factor is the key transcription factor coordinating endothelial cells to respond to hypoxia in urological cancers, mainly renal cell carcinoma, prostate cancer, and bladder cancer. Moreover, it has been suggested that tumor hypoxia in tumor microenvironment simultaneously recruits stromal cells to suppress immune activities. This review summarizes the mechanisms by which HIF regulates tumorigenesis and elaborates on the associations between HIF and angiogenesis, lymphangiogenesis, and tumor microenvironment in urological cancers.

Veno-venous extracorporeal membrane oxygenation support in the resuscitation from extreme metabolic acidosis (pH < 6.5) after drowning cardiac arrest: a case report.

BACKGROUND: Resuscitation in drowning victim with cardiac arrest is difficult because of severe metabolic acidosis and multiple organ dysfunction. There is insufficient evidence to support that veno-venous extracorporeal membrane oxygenation (VV-ECMO) is beneficial for patient. CASE PRESENTATION: A 44-year-old female was trapped under river when she attempted to rescue her drowning father. Furthermore, she underwent a loss of consciousness, with extreme metabolic acidosis, hypothermia and hypotension. Hence, the VV-ECMO, continuous renal replacement therapy (CRRT) and other resuscitative infusion were required. In this case, the patient did not experience any complication or neurologic deficit and reaching a complete recovery after 21 days of hospitalization. CONCLUSIONS: Our case adds further concerns in supporting a patient with extreme metabolic acidosis (pH < 6.5) and hypothermia after severe drowning cardiac arrest, including extracorporeal life support, renal support, targeted temperature management, cerebral resuscitation, etc., due to the reversible nature of this condition.

Glycyrrhizic Acid Protects Experimental Sepsis Rats against Acute Lung Injury and Inflammation.

Background: The incidence of acute lung injury/acute respiratory distress (ALI/ARDS) is high in sepsis aggravating morbidity and mortality. Glycyrrhizic acid (GA) has pharmacological activities in the treatment of inflammation and antiviral. Materials and Methods: Sepsis rats were constructed by the cecal ligation and puncture (CLP) surgery. After GA (25 and 50 mg/kg) injection, the survival rate, blood oxygen, biochemical indexes, myeloperoxidase (MPO) activity, and wet/dry weight ratio of the lung were observed. The bronchoalveolar lavage fluid was collected to count the cells and measure the level of TNF-α, IL-1ß, IL-10, and high mobility group box-1 protein (HMGB1). Lung tissue sections were taken to observe the levels of histopathological injury and apoptosis by HE and TUNEL staining. The levels of HMGB1, TLR4, p-38 MAPK, NF-κB, and ERK1/2 proteins were observed by immunohistochemistry and Western blot. Results: GA treatment improved the survival rate, blood oxygen, ALT, AST, BUN, and Scr of CLP rats. It could advance the MPO activity, the wet/dry weight ratio, histopathological injury, apoptosis, and the IL-10 level in the lung. After GA injection, the number of total cells, neutrophils, and macrophages in the CLP rats was reduced and the levels of TNF-α, IL-1ß, HMGB1, TLR4, p-38 MAPK, and ERK1/2 in the CLP rat were also repressed. Conclusions: GA treatment may improve the sepsis-induced ALI/ARDS and inflammation by inhibiting HMBG1. This study provided an experimental basis for the prevention and treatment of ALI/ARDS caused by sepsis.

Electroacupuncture Alleviates Experimental Chronic Inflammatory Pain by Inhibiting Calcium Voltage-Gated Channel-Mediated Inflammation.

BACKGROUND: Both experimental and clinical studies have shown that electroacupuncture (EA) administration ameliorates chronic inflammatory pain (CIP). However, the multifaceted mechanism underlying the effects of EA on CIP is poorly understood. In this study, the mRNA transcriptome was used to study various therapeutic targets of EA. METHODS: Using RNA-sequencing, protein-coding mRNA expression profiles of the L4-L5 dorsal root ganglion (DRG) were examined in the control (CN), complete Freund's adjuvant- (CFA-) induced CIP, and EA-treated CIP groups. A series of bioinformatics analyses was performed; "EA-reversed upregulated genes with CIP" (up-DEGs) and "EA-reversed downregulated genes with CIP" (down-DEGs) were identified. Thereafter, based on up-DEGs and down-DEGs, biological functions and signaling pathways were enriched using gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway analyses. RESULTS: In total, 189 DEGs were identified, including 134 up- and 55 down-DEGs, which were enriched in arachidonic acid metabolism (rno00590), glutamatergic synapse (rno04724), serotonergic synapse (rno04726), FoxO signaling pathway (rno04068), insulin signaling pathway (rno04910), amyotrophic lateral sclerosis (rno05014), cholinergic synapse (rno04725), ECM-receptor interaction (rno04512), and choline metabolism in cancer (rno05231). CONCLUSION: We identified a few GOs, pathways, and genes that could play key roles in the amelioration of CIP by EA. Hence, this study may provide a theoretical basis for CIP amelioration by EA.

Angiogenesis Inhibitor, Endostar, Prevents Vasa Vasorum Neovascularization in a Swine Atherosclerosis Model.

AIM: Vasa vasorum neovascularization is a key feature of atherosclerosis (AS) and is strongly associated with inflammatory infiltration, lipid deposition, intraplaque hemorrhage, and hemosiderin deposit. Here we investigate the effects of Endostar, a strong anti-angiogenic drug, on vasa vasorum neovascularization in the experimental porcine model of early AS. METHODS: Eighteen adult male Ba-Ma mini pigs were randomized into three groups, with six animals in each group. The pigs in the normal (N) group were fed a normal diet for 18 weeks, without balloon injury surgery. The animals in the atherosclerotic (AS) control and AS＋Endostar groups were fed a hypercholesterolemic diet for 12 weeks after balloon injury surgery; they received either saline or Endostar for an additional six weeks, while continuing the hypercholesterolemic diet. The atherosclerotic abdominal aorta and levels of serum lipids, TNF-alpha, IL-6, and hs-CRP were analyzed at 18 weeks. RESULTS: The AS group had a significantly higher body weight and serum lipid concentration levels than the N group (p ＜ 0.05), confirming the success of the hypercholesterolemic diet. However, no statistical differences were noted between the AS and AS＋Endostar groups. Histopathology results revealed that vasa vasorum density and intima-media thickness (IMT) had also increased in the AS group compared with those in the N group (p ＜ 0.05). The Endostar treatment significantly alleviated AS with decreased vasa vasorum density and IMT (AS vs. AS＋Endostar, p ＜ 0.05). Western blot analysis indicated that the expression of VEGF, ß-catenin, and TNF-alpha in the atherosclerotic abdominal aorta was considerably reduced by the Endostar treatment. In addition, immunohistochemistry results showed that the angiogenesis markers VEGF and ß-catenin were predominately localized in endothelial cells of the adventitial vasa vasorum. The levels of the serum inflammatory markers TNF-alpha, hs-CRP, and IL-6 were markedly higher in the AS group than in the N group (p ＜ 0.05) but showed no marked difference during the Endostar treatment, suggesting that the local inhibition of angiogenesis was not accompanied by a change in serum inflammatory markers and that the inhibitive effect of Endostar on local TNF-alpha expression could be because of the prevention of vasa vasorum neovascularization. CONCLUSIONS: Our results demonstrated that the Endostar treatment inhibited vasa vasorum neovascularization and AS progression in the experimental porcine model of early AS, supporting the role of vasa vasorum neovascularization in the development of AS and the therapeutic potential of anti-angiogenesis intervention in AS.