PPARß/δ activation protects against hepatic ischaemia-reperfusion injury.

BACKGROUND AND AIMS: Hepatic ischaemia/reperfusion injury (HIRI) is a pathophysiological process that occurs during the liver resection and transplantation. Reportedly, peroxisome proliferator-activated receptor ß/δ (PPARß/δ) can ameliorate kidney and myocardial ischaemia/reperfusion injury. However, the effect of PPARß/δ in HIRI remains unclear. METHODS: Mouse hepatic ischaemia/reperfusion (I/R) models were constructed for in vivo study. Primary hepatocytes and Kupffer cells (KCs) isolated from mice and cell anoxia/reoxygenation (A/R) injury model were constructed for in vitro study. Liver injury and inflammation were investigated. Small molecular compounds (GW0742 and GSK0660) and adenoviruses were used to interfere with PPARß/δ. RESULTS: We found that PPARß/δ expression was increased in the I/R and A/R models. Overexpression of PPARß/δ in hepatocytes alleviated A/R-induced cell apoptosis, while knockdown of PPARß/δ in hepatocytes aggravated A/R injury. Activation of PPARß/δ by GW0742 protected against I/R-induced liver damage, inflammation and cell death, whereas inhibition of PPARß/δ by GSK0660 had the opposite effects. Consistent results were obtained in mouse I/R models through the tail vein injection of adenovirus-mediated PPARß/δ overexpression or knockdown vectors. Furthermore, knockdown and overexpression of PPARß/δ in KCs aggravated and ameliorated A/R-induced hepatocyte injury, respectively. Gene ontology and gene set enrichment analysis showed that PPARß/δ deletion was significantly enriched in the NF-κB pathway. PPARß/δ inhibited the expression of p-IKBα and p-P65 and decreased NF-κB activity. CONCLUSIONS: PPARß/δ exerts anti-inflammatory and anti-apoptotic effects on HIRI by inhibiting the NF-κB pathway, and hepatocytes and KCs may play a synergistic role in this phenomenon. Thus, PPARß/δ is a potential therapeutic target for HIRI.

[Analysis of the causes of residual back pain in the early and late stages after percutaneous vertebral augmentation].

OBJECTIVE: To explore the influencing factors of the residual back pain in patient with osteoporotic vertebral compression fractures(OVCFs) in the early and late stages after percutaneous vertebral augmentation(PVA), and analyze the correlation between these factors and the residual back pain after PVA. METHODS: From March 2018 to December 2019, 312 patients with OVCFs who treated with PVA were collected. According to the inclusion and exclusion criteria, a total of 240 patients were included in this retrospective study. There were 59 males and 181 females, aged from 50 to 95 years old with an average of (76.11±10.72) years old, and 50 cases of fractures located in the thoracic region (T5-T10), 159 cases in the thoracolumbar region (T11-L2), and 31 cases in the lumbar region (L3 and below). The first day after PVA was regarded as the early postoperative period, and the seventh day was regarded as the late postoperative period. According to the visual analogue scale (VAS), the patients were divided into 4 groups:early postoperative pain relief group(group A, VAS≤4 scores), there were 121 patients, including 29 males and 92 females, aged from 50 to 90 years with an average of (75.71±11.00) years;early postoperative pain relief was not an obvious group (group B, VAS >4 scores), there were 119 patients, including 30 males and 89 females, aged from 53 to 95 years with an average of (76.51±10.46) years; late postoperative pain relief group (group C, VAS≤ 4 scores), there were 172 patients, including 42 males and 130 females, aged from 50 to 95 years with an average of (76.20±10.68) years; late postoperative pain relief was not obvious group (group D, VAS>4 scores), there were 68 patients, including 17 males and 51 females, aged from 53 to 94 years old with an average of (75.88±10.91) years old. The age, gender, bone mineral density(BMD), injured vertebral segment, preoperative thoracolumbar fascial condition, surgical methods, single or bilateral puncture, the amount of bone cement injection, anterior vertebral height recovery rate and central vertebral height recovery rate in the 4 groups were analyzed by univariate analysis. The statistically significant factors were put into a Logistic regression to analyze the correlation between these factors and residual back pain after PVA. RESULTS: Univariate analysis showed that the residual back pain in the early stage after PVA was correlated with BMD, preoperative thoracolumbar fascial injury, single or bilateral puncture, the amount of bone cement injection, anterior vertebral height recovery rate and central vertebral height recovery rate(P<0.05). The residual back pain in the late postoperative period was related to BMD, injured vertebral segment, surgical methods, the amount of bone cement injection, anterior vertebral height recovery rate and central vertebral height recovery rate(P<0.05). Multivariate Logistic regression analysis showed that thoracolumbar fascial injury(OR=4.938, P=0.001), single or bilateral puncture(OR=5.073, P=0.002) were positively correlated with the residual back pain in the early stage after PVA(B>0), which were risk factors;the BMD (OR=0.211, P=0.000) and anterior vertebral height recovery rate (OR=0.866, P=0.001) were negatively correlated with the residual back pain in the early stage after PVA(B<0), which were protective factors. In the late stage after PVA, the BMD(OR=0.448, P=0.003), the amount of bone cement injection (OR=0.648, P=0.004) and anterior vertebral height recovery rate (OR=0.820, P=0.000) were negatively correlated with residual back pain(B<0), which were protective factors. CONCLUSION: The decrease of BMD, injury of the thoracolumbar fascia, single or bilateral puncture, poor recovery of anterior vertebral height and insufficient injection of bone cement are closely related to the occurrence of residual back pain after PVA, which affect the relief of residual back pain in the early and late postoperative periods.

LncRNA Hnf4αos exacerbates liver ischemia/reperfusion injury in mice via Hnf4αos/Hnf4α duplex-mediated PGC1α suppression.

LncRNAs are involved in the pathophysiologic processes of multiple diseases, but little is known about their functions in hepatic ischemia/reperfusion injury (HIRI). As a novel lncRNA, the pathogenetic significance of hepatic nuclear factor 4 alpha, opposite strand (Hnf4αos) in hepatic I/R injury remains unclear. Here, differentially expressed Hnf4αos and Hnf4α antisense RNA 1 (Hnf4α-as1) were identified in liver tissues from mouse ischemia/reperfusion models and patients who underwent liver resection surgery. Hnf4αos deficiency in Hnf4αos-KO mice led to improved liver function, alleviated the inflammatory response and reduced cell death. Mechanistically, we found a regulatory role of Hnf4αos-KO in ROS metabolism through PGC1α upregulation. Hnf4αos also promoted the stability of Hnf4α mRNA through an RNA/RNA duplex, leading to the transcriptional activation of miR-23a and miR-23a depletion was required for PGC1α function in hepatoprotective effects on HIRI. Together, our findings reveal that Hnf4αos elevation in HIRI leads to severe liver damage via Hnf4αos/Hnf4α/miR-23a axis-mediated PGC1α inhibition.

LINC00504 Promotes the Malignant Biological Behavior of Breast Cancer Cells by Upregulating HMGB3 via Decoying MicroRNA-876-3p.

PURPOSE: Long intergenic non-protein coding RNA 504 (LINC00504) is a long non-coding RNA that has an important regulatory role in a variety of human cancers. In this study, LINC00504 expression in breast cancer tissues and cell lines was detected. Studies were also conducted to determine the impact of LINC00504 on the tumor behavior of breast cancer cells. The potential mechanisms underlying the oncogenic role of LINC00504 in breast cancer cells were elucidated in detail. METHODS: Expression of LINC00504 in breast cancer was analyzed by quantitative real-time polymerase chain reaction. The effects of LINC00504 on proliferation, apoptosis, in vitro migration and invasion, and in vivo tumor growth were elucidated using Cell Counting Kit-8 assay, flow cytometry, Transwell assays, and tumor xenograft models, respectively. Bioinformatics analyses in conjunction with RNA immunoprecipitation, luciferase reporter assays, and rescue experiments were conducted to investigate the underlying molecular mechanisms. RESULTS: LINC00504 was upregulated in breast cancer tissues and cell lines. Knocking down LINC00504 suppressed breast cancer cell proliferation, migration, and invasion and facilitated apoptosis in vitro. In addition, tumor growth in vivo was significantly inhibited by LINC00504 depletion. Regarding the underlying mechanism, LIN00504 could function as a competing endogenous RNA in breast cancer by sponging microRNA-876-3p (miR-876-3p), resulting in the upregulation of high mobility group box 3 (HMGB3). Rescue experiments further revealed that miR-876-3p downregulation or HMGB3 upregulation effectively reversed the inhibitory effects of LIN00504 deficiency on breast cancer cells. CONCLUSION: The LIN00504-miR-876-3p-HMGB3 axis shows carcinogenic effects in modulating the biological behavior of breast cancer cells. This pathway may represent an effective target for CRC diagnosis and anticancer therapy.

PGC-1α Protects against Hepatic Ischemia Reperfusion Injury by Activating PPARα and PPARγ and Regulating ROS Production.

Peroxisome proliferator-activated receptors (PPARs) α and γ have been shown to be protective in hepatic ischemia/reperfusion (I/R) injury. However, the precise role of PPARγ coactivator-1α (PGC-1α), which can coactivate both of these receptors, in hepatic I/R injury, remains largely unknown. This study was designed to test our hypothesis that PGC-1α is protective during hepatic I/R injury in vitro and in vivo. Our results show that endogenous PGC-1α is basally expressed in normal livers and is moderately increased by I/R. Ectopic PGC-1α protects against hepatic I/R and hepatocyte anoxia/reoxygenation (A/R) injuries, whereas knockdown of endogenous PGC-1α aggravates such injuries, as evidenced by assessment of the levels of serum aminotransferases and inflammatory cytokines, necrosis, apoptosis, cell viability, and histological examination. The EMSA assay shows that the activation of PPARα and PPARγ is increased or decreased by the overexpression or knockdown of PGC-1α, respectively, during hepatic I/R and hepatocyte A/R injuries. In addition, the administration of specific antagonists of either PPARα (MK886) or PPARγ (GW9662) can effectively decrease the protective effect of PGC-1α against hepatic I/R and hepatocyte A/R injuries. We also demonstrate an important regulatory role of PGC-1α in reactive oxygen species (ROS) metabolism during hepatic I/R, which is correlated with the induction of ROS-detoxifying enzymes and is also dependent on the activations of PPARα and PPARγ. These data demonstrate that PGC-1α protects against hepatic I/R injury, mainly by regulating the activation of PPARα and PPARγ. Thus, PGC-1α may be a promising therapeutic target for the protection of the liver against I/R injury.

The PGC1α/NRF1-MPC1 axis suppresses tumor progression and enhances the sensitivity to sorafenib/doxorubicin treatment in hepatocellular carcinoma.

Targeting energy metabolism holds the potential to effectively treat a variety of malignant diseases, and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) is a key regulator of energy metabolism. However, PGC1α's role in cancer, especially in hepatocellular carcinoma (HCC) remains largely unknown. In the present study, we reported that PGC1α was significantly downregulated in HCC cell lines and specimens. Moreover, reduced expression of PGC1α in tumor cells was correlated with poor prognosis. PGC1α overexpression substantially inhibited cell proliferation and induced apoptosis in vitro and in vivo. On the contrary, the knockdown of PGC1α produced the opposite effect. The mechanism was at least partially due to the upregulation of mitochondrial pyruvate carrier 1 (MPC1) caused by PGC1α, which promoted mitochondrial biogenesis by binding to nuclear respiratory factor 1 (NRF1). Consequently, the production of cellular reactive oxygen species (ROS) caused by mitochondrial oxidation was elevated above a critical threshold for survival. Furthermore, we found that PGC1α could enhance the antitumor activity of sorafenib and doxorubicin in HCC through ROS accumulation-mediated cell death. These results indicate that PGC1α/NRF1-MPC1 axis is involved in HCC progression and could be a promising target for HCC treatment.

Sodium orthovanadate inhibits growth and triggers apoptosis of human anaplastic thyroid carcinoma cells in vitro and in vivo.

Vanadium and its compounds exhibit concentration- and time-dependent anticancer effects on various types of tumor; however, the effects of sodium orthovanadate (SOV) on anaplastic thyroid carcinoma (ATC) have not yet been reported. In the present study, the anticancer effects of SOV on ATC were evaluated. In vitro experiments, including cell viability assays, plate colony formation assays, cell cycle analysis and apoptosis analysis were used to study the role of SOV in ATC. Using in vivo experiments, the effects of SOV on the growth and apoptosis of an ATC-xenograft tumor were studied by comparing the SOV-treatment with the control group. The results revealed that treatment of the human ATC cell line 8505C with SOV inhibited cell viability, induced G2/M phase cell cycle arrest, stimulated apoptosis and reduced mitochondrial membrane potential in a concentration-dependent manner. These findings were confirmed in vivo in a nude mouse ATC xenograft model. In conclusion, the present study demonstrated that SOV inhibited human ATC by regulating proliferation, cell cycle progression and apoptosis, thus suggesting that SOV may be considered a novel option for the treatment of ATC.

PGC1α promotes cholangiocarcinoma metastasis by upregulating PDHA1 and MPC1 expression to reverse the Warburg effect.

PGC1α acts as a central regulator of mitochondrial metabolism, whose role in cancer progression has been highlighted but remains largely undefined. Especially, it is completely unknown about the effect of PGC1α on cholangiocarcinoma (CCA). Here we showed that PGC1α overexpression had no impact on CCA growth despite the decreased expression of PGC1α in CCA compared with adjacent normal tissue. Instead, PGC1α overexpression-promoted CCA metastasis both in vitro and in vivo. Mechanistically, for the first time, we illuminated that PGC1α reversed the Warburg effect by upregulating the expression of pyruvate dehydrogenase E1 alpha 1 subunit and mitochondrial pyruvate carrier 1 to increase pyruvate flux into the mitochondria for oxidation, whereas simultaneously promoting mitochondrial biogenesis and fusion to mediate the metabolic switch to oxidative phosphorylation. On the one hand, enhanced mitochondrial oxidation metabolism correlated with elevated reactive oxygen species (ROS) production; on the other hand, increased PGC1α expression upregulated the expression levels of mRNA for several ROS-detoxifying enzymes. To this end, the ROS levels, which were elevated but below a critical threshold, did not inhibit CCA cells proliferation. And the moderately increased ROS facilitated metastatic dissemination of CCA cells, which can be abrogated by antioxidants. Our study suggests the potential utility of developing the PGC1α-targeted therapies or blocking PGC1α signaling axis for inhibiting CCA metastasis.