•Inhibition of immunoproteasome LMP2 enhances angiogenesis and outcome in cerebral ischemia/reperfusion rats.•Immunoproteasome regulates the degradation of HIF-1α.•HIF-1α pathway involves in cerebral ...angiogenesis following stroke.•HIF-1α acts as a key mediator during inhibition LMP2 enhancing angiogenesis response.
Angiogenesis after ischemic stroke contributes to the restoration of blood supply in the ischemic zone. Strategies to improve angiogenesis may facilitate the function recovery after stroke. Growing evidence shows that proteasome inhibitors enhance angioneurogenesis and induces a long-term neuroprotection after cerebral ischemia in rodents’ models. We have previously reported that inhibition of the immunoproteasome subunit low molecular mass peptide 2 (LMP2) offers a strong neuroprotection in ischemic stroke rats. However, there are no data available to show the relationship between immunoproteasome and angiogenesis under ischemia stroke context. In this study, we identified that inhibition of immunoproteasome LMP2 was able to enhance angiogenesis and facilitate neurological functional recovery in rats after focal cerebral ischemia/reperfusion. In vitro, oxygen-glucose deprivation and reperfusion (OGD/R) significantly enhanced the expression of immunoproteasome LMP2 and proteasome activities in primary culture astrocytes, but these beneficial effects were abolished by knockdown of LMP2 with siRNA transfection. Along with this, protein abundance of HIF-1α was significantly increased by inhibition LMP2 in vivo and in vitro and was associated with angiogenesis and cell fates. However, these beneficial effects were partly abolished by HIF-1α inhibitor 2-methoxyestradiol (2ME). Taken together; this study highlights an important role for inhibition of LMP2 in promoting angiogenesis events in ischemic stroke, and point to HIF-1α as a key mediator of this response, suggesting that immunoproteasome inhibitors may be a promising strategy for stroke treatment.
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Advanced titanium (Ti) based bone implant with both angiogenesis and osteogenesis stimulating activities for enhanced clinical performance is stringently needed. In the present work, ...TiO2/calcium-phosphate (TCP) coatings on Ti doped with cobalt (Co) of various amounts (designated as C2-TCP, C7-TCP, and C13-TCP where the Arabic numbers indicate the mean Co contents) are developed by a simple micro-arc oxidation procedure. The Co doped TCP coatings possess a microporous structure (pore size of 3–4μm in average diameter) which is evenly covered by nano-grains of 30–60nm in size. Successful Co incorporation in TCP is determined by X-ray photoelectron spectroscopy. The microstructure, TiO2 phase compositions, surface roughness, and wettability of TCP are not apparently affected by the Co incorporation. The Co doped coatings bond firmly to the Ti substrate and show good long-term adhesion strength stability in biological environment. Then the behaviors of rat bone marrow stem cells (MSCs) on the Co-incorporated TCP are evaluated. The Co incorporation leads to enhanced expression of the markers for both angiogenesis and osteogenesis, and the effects are positively related to the incorporated Co amount. Overdose of Co incorporation (C13-TCP) can induce certain cytotoxicity and an optimal dose of Co incorporation is essential to get the enhanced angiogenic and osteogenic activities without showing cytotoxicity. Between C2-TCP and C7-TCP that show no significant cytotoxicity, C7-TCP exhibits higher angiogenic and osteogenic activities. In conclusion, the Co doping is feasible to enhance the angiogenic and osteogenic activities of orthopedic and dental Ti implants for potentially improved clinical performance.
TiO2/calcium-phosphate coatings on Ti doped with cobalt are developed by a simple micro-arc oxidation procedure. The Co doped coatings bond firmly to the Ti substrate and show good long-term adhesion strength stability in biological environment. Furthermore, the cobalt doping is feasible to enhance the angiogenic and osteogenic activities of orthopedic and dental Ti implants for potentially improved clinical performance.
To investigate the expression of CD73 and hypoxia-inducible factor-1α (HIF-1α) in human gastric carcinoma, and explore their clinical significance and prognostic value.
CD73 and HIF-1α expressions ...were detected by immunohistochemistry in consecutive sections of tissue samples from 68 gastric carcinoma patients. The peritumor tissues 2 cm away from the tumor were obtained and served as controls. The presence of CD73 and HIF-1α was analyzed by immunohistochemistry using the Envision technique.
CD73 and HIF-1α expressions in gastric carcinoma were significantly higher than those in gastric mucosal tissues as control (P < 0.001) and showed a close correlation (Spearman r = 0.390, P = 0.001). Overexpression of CD73 was positively correlated with differentiation of tumor (P = 0.000), histopathology (P = 0.041), depth of invasion (P < 0.001), nodal status (P = 0.003), metastasis (P = 0.013), and the American Joint Committee on Cancer (AJCC) stage (P < 0.001). High expression of HIF-1α was positively correlated with tumor diameter (P = 0.031), depth of invasion (P = 0.022), and AJCC stage (P = 0.035). The overall survival rate was low in the patients with high expression of CD73 (P < 0.001). Moreover, CD73+/HIF-1α+ patients had the worst prognosis (P < 0.001). CD73 expression was proven to be an independent predictor for patients with gastric carcinoma by both multivariate Cox regression analysis (P = 0.021) and receiver operating characteristic curves (P = 0.001).
CD73 expression correlates closely with HIF-1α expression in gastric carcinoma. CD73 could be an independent prognostic indicator for gastric carcinoma.
Integrative database analysis was performed to identify novel candidate oncogene AHNAK2 overexpressed in clear cell renal cell carcinoma (ccRCC). However, the function of AHNAK2 in cancer cells is ...currently unknown. In this study, we first confirmed the upregulation of AHNAK2 in ccRCC tissues compared with adjacent normal tissues in 15 pairs of samples. Then we analyzed AHNAK2 expression in a large cohort of ccRCC patient samples (n = 355), and found that up-regulation of AHNAK2 was positively correlated with tumor progression and poor survival (
= 0.032). Knockdown of AHNAK2 inhibited cancer cell proliferation, colony formation and migration in vitro and tumorigenic ability in vivo. Meanwhile, knockdown of AHNAK2 impaired the cell oncologic-metabolism by inhibiting lipid synthesis. Moreover, we observed that expression of AHNAK2 was greatly upregulated, at least in part, by hypoxia in cancer cells. By using chromatin immune-precipitation (CHIP) and promoter-luciferase reporter assays, we identified that upregulation of AHNAK2 induced by hypoxia was hypoxia-inducible factor-1α (HIF1α)-dependent. Knockdown of AHNAK2 impaired hypoxia-induced epithelial-mesenchymal transition (EMT) and stem cell-like properties. Considered together, we reveal that AHNAK2 is upregulated in cancer cells and hypoxic upregulation of AHNAK2 can drive tumorigenesis and progression by supporting EMT and cancer cell stemness. Thus, AHNAK2 is a novel prognostic marker and an oncogenic protein for ccRCC.
Sustained tissue hypoxia is associated with many pathophysiological conditions, including chronic inflammation, chronic wounds, slow-healing fractures, microvascular complications of diabetes, and ...metastatic spread of tumors. This extended deficiency of oxygen (O
) in the tissue sets creates a microenvironment that supports inflammation and initiates cell survival paradigms. Elevating tissue carbon dioxide levels (CO
) pushes the tissue environment toward "thrive mode," bringing increased blood flow, added O
, reduced inflammation, and enhanced angiogenesis. This review presents the science supporting the clinical benefits observed with the administration of therapeutic CO
. It also presents the current knowledge regarding the cellular and molecular mechanisms responsible for the biological effects of CO
therapy. The most notable findings of the review include (a) CO
activates angiogenesis not mediated by hypoxia-inducible factor 1a, (b) CO
is strongly anti-inflammatory, (c) CO
inhibits tumor growth and metastasis, and (d) CO
can stimulate the same pathways as exercise and thereby, acts as a critical mediator in the biological response of skeletal muscle to tissue hypoxia.
Hypoxia‑inducible factor‑1α (HIF‑1α) is essential for regulating the osteogenic differentiation of periodontal ligament cells (PDLCs). The regulatory mechanism of HIF‑1α transcription is still not ...clear. Recently, two long non‑coding RNAs, HIF1A antisense RNA 1 (HIF1A‑AS1) and HIF1A antisense RNA 2 (HIF1A‑AS2), were found to regulate HIF‑1α mRNA, but the regulatory mechanisms among HIF‑1α, HIF1A‑AS1 and HIF1A‑AS2 have not been well studied. We hypothesized that HIF1A‑AS1 and HIF1A‑AS2 play important roles in the osteogenic differentiation of PDLCs by regulating HIF‑1α. In the present study, we showed that expression levels of HIF1A‑AS1, HIF1A‑AS2, HIF‑1α and osteogenic biomarkers were time‑dependent under hypoxia. Even though both HIF1A‑AS1 and HIF1A‑AS2 were complementary to HIF‑1α mRNA, only HIF1A‑AS2 showed an inhibitory effect on HIF‑1α in PDLCs. Moreover, HIF‑1α had positive regulatory effects on HIF1A‑AS1 and HIF1A‑AS2. HIF‑1α promoted the osteogenic differentiation of PDLCs, and HIF1A‑AS2 had a negative effect on the osteogenic differentiation of PDLCs. Altogether, the present study revealed the complex relationships among HIF1A‑AS1, HIF1A‑AS2 and HIF‑1α, as well as their roles in regulating the osteogenic differentiation of PDLCs. These findings provide a theoretical basis for promoting periodontal tissue regeneration and repair during orthodontic tooth movement.
Renal ischemia-reperfusion (I/R) injury is associated with markedly reduced protein expression of aquaporins (AQPs). Membrane G protein-coupled bile acid receptor-1 (TGR5) has shown protective roles ...in some kidney diseases. The purpose of the current study was to investigate whether activation of TGR5 prevented the decreased protein expression of AQPs in rodents with renal I/R injury and potential mechanisms. TGR5 agonist lithocholic acid (LCA) treatment reduced polyuria after renal I/R injury in rats. LCA prevented the decreased abundance of AQP2 protein and upregulated hypoxia-inducible factor (HIF)-1α protein expression, which were associated with decreased protein abundance of NF-κB p65 and IL-1β. After renal I/R, mice with
gene deficiency exhibited further decreases in AQP2 and HIF-1α protein abundance and increases of IL-1β and NF-κB p65 protein expression compared with wild-type mice. In primary cultured inner medullary collecting duct cells with hypoxia/reoxygenation, LCA induced markedly increased protein expression of AQP2 and HIF-1α, which were partially prevented by the PKA inhibitor H89. FG4592, a prolyl-4-hydroxylase domain-containing protein inhibitor, increased HIF-1α and AQP2 protein abundance in association with decreased NF-κB p65 protein expression in inner medullary collecting duct cells with hypoxia/reoxygenation. In conclusion, TGR5 stimulation by LCA prevented downregulation of renal AQPs in kidney with I/R injury, likely through activating HIF-1α signaling and suppressing inflammatory responses.
Stimulation of the membrane G protein-coupled bile acid receptor TGR5 by lithocholic acid (LCA) reduced polyuria in rats with renal ischemia-reperfusion (I/R) injury. LCA increased abundance of aquaporin-2 (AQP2) protein and upregulated hypoxia-inducible factor (HIF)-1α protein expression in association with decreased NF-κB p65 and IL-1β. After I/R, mice with tgr5 gene deficiency exhibited more severe decreases in AQP2 and HIF-1α protein abundance and inflammatory responses. TGR5 activation exhibits a protective role in acute renal injury induced by I/R.
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