Nuclear respiratory factor 1 drives hepatocellular carcinoma progression by activating LPCAT1-ERK1/2-CREB axis.

BACKGROUND: Nuclear respiratory factor 1 (NRF1) is a transcription factor that participates in several kinds of tumor, but its role in hepatocellular carcinoma (HCC) remains elusive. This study aims to explore the role of NRF1 in HCC progression and investigate the underlying mechanisms. RESULTS: NRF1 was overexpressed and hyperactive in HCC tissue and cell lines and high expression of NRF1 indicated unfavorable prognosis of HCC patients. NRF1 promoted proliferation, migration and invasion of HCC cells both in vitro and in vivo. Mechanistically, NRF1 activated ERK1/2-CREB signaling pathway by transactivating lysophosphatidylcholine acyltransferase 1 (LPCAT1), thus promoting cell cycle progression and epithelial mesenchymal transition (EMT) of HCC cells. Meanwhile, LPCAT1 upregulated the expression of NRF1 by activating ERK1/2-CREB signaling pathway, forming a positive feedback loop. CONCLUSIONS: NRF1 is overexpressed in HCC and promotes HCC progression by activating LPCAT1-ERK1/2-CREB axis. NRF1 is a promising therapeutic target for HCC patients.

MiR-484 promotes nonalcoholic fatty liver disease progression in mice via downregulation of Sorbs2.

OBJECTIVE: MicroRNA 484 (miR-484) plays a pivotal role in the development and progression of different diseases and is typically described as a mitochondrial regulator. Whether miR-484 is involved in lipid metabolism or exerts a role in nonalcoholic fatty liver disease remains unclear. METHODS: miR-484 levels were examined in the livers of male mice fed a high-fat diet and in hepatocytes treated with free fatty acids. Sorbin and SH3 structural domain-containing protein 2 (Sorbs2) were identified as a novel target of miR-484 by sequencing mRNA in the livers of miR-484 knockout mice. Sorbs2 liver-specific knockdown mice were constructed by tail vein injection of adeno-associated virus vector to miR-484 knockout mice. In addition, genetic manipulation of SORBS2 was performed in human hepatocyte lines, mouse primary hepatocytes, and the liver. RESULTS: Serum and hepatic miR-484 levels are upregulated in nonalcoholic fatty liver disease mice. miR-484 knockdown ameliorated hepatocyte steatosis, whereas miR-484 overexpression increased hepatocyte lipid load. miR-484 knockdown-mediated alleviation of hepatic steatosis, liver injury, inflammation, and apoptosis was compromised after high-fat diet-induced knockdown of Sorbs2 in mouse liver and free fatty acid-induced primary mouse hepatocytes. CONCLUSIONS: These results identify Sorbs2-mediated mitochondrial ß-oxidation and apoptosis that promote miR-484 knockdown-mediated remission of hepatic steatosis.

Alpha-ketoglutarate alleviates cadmium-induced inflammation by inhibiting the HIF1A-TNFAIP3 pathway in hepatocytes.

The threat to public health posed by rapidly increasing levels of cadmium (Cd) in the environment is receiving worldwide attention. Although, Cd is known to be absorbed into the body and causes non-negligible damage to the liver, the detailed mechanisms underlying its hepatoxicity are incompletely understood. In the present study, investigated the effect of TNFAIP3 and α-ketoglutarate (AKG) on Cd-induced liver inflammation and hepatocyte death. Male C57BL/6 mice were exposed to cadmium chloride (1.0 mg/kg) while being fed a diet with 2 % AKG for two weeks. We found that Cd induced hepatocyte injury and inflammatory infiltration. In addition, TNFAIP3 expression was inhibited in the liver tissues and cells of CdCl2-treated mice. Mouse hepatocyte-specific TNFAIP3 overexpression by tail vein injection of an adeno-associated virus (AAV) vector effectively alleviated Cd-induced hepatic necrosis and inflammation, which was mediated by the NF-κB signaling pathway. Notably, this inhibitory effect of TNFAIP3 on Cd-induced liver injury was dependent on AKG. Exogenous addition of AKG prevented Cd exposure-induced increases in serum ALT, AST and LDH levels, production of pro-inflammatory cytokines, activation of the NF-κB signaling pathway, and even significantly reduced Cd-induced oxidative stress and hepatocyte death. Mechanistically, AKG exerted its anti-inflammatory effect by promoting the hydroxylation and degradation of HIF1A to reduce its Cd-induced overexpression in vivo and in vitro, avoiding the inhibition of the TNFAIP3 promoter by HIF1A. Moreover, the protective effect of AKG was significantly weaker in Cd-treated primary hepatocytes transfected with HIF1A pcDNA. Overall, our results reveal a novel mechanism of Cd-induced hepatotoxicity.

HIG1 domain family member 1A is a crucial regulator of disorders associated with hypoxia.

Mitochondria play a central role in cellular energy conversion, metabolism, and cell proliferation. The regulation of mitochondrial function by HIGD1A, which is located on the inner membrane of the mitochondria, is essential to maintain cell survival under hypoxic conditions. In recent years, there have been shown other cellular pathways and mechanisms involving HIGD1A diametrically or through its interaction. As a novel regulator, HIGD1A maintains mitochondrial integrity and enhances cell viability under hypoxic conditions, increasing cell resistance to hypoxia. HIGD1A mainly targets cytochrome c oxidase by regulating downstream signaling pathways, which affects the ATP generation system and subsequently alters mitochondrial respiratory function. In addition, HIGD1A plays a dual role in cell survival in distinct degree hypoxia regions of the tumor. Under mild and moderate anoxic areas, HIGD1A acts as a positive regulator to promote cell growth. However, HIGD1A plays a role in inhibiting cell growth but retaining cellular activity under severe anoxic areas. We speculate that HIGD1A engages in tumor recurrence and drug resistance mechanisms. This review will focus on data concerning how HIGD1A regulates cell viability under hypoxic conditions. Therefore, HIGD1A could be a potential therapeutic target for hypoxia-related diseases.

Cadmium exposure induces pyroptosis in testicular tissue by increasing oxidative stress and activating the AIM2 inflammasome pathway.

High doses of cadmium (Cd) cause irreversible injury to the reproductive system, especially testicular tissue. Studies have shown that pyroptosis is involved in Cd-induced tissue damage, but whether pyroptosis is involved in damage to testicular tissue following Cd exposure remains unclear. To investigate the mechanism of pyroptosis in testicular injury induced by Cd exposure, we used 8-week-old male C57BL/6J mice subjected to consecutive 7 days of intraperitoneal injection of cadmium chloride (CdCl2) at concentrations of 0, 1.0 and 3.0 mg/kg. The results indicated that 3.0 mg/kg CdCl2 significantly decreased serum testosterone levels, sperm concentration and sperm motility, while increased LDH and IL-1ß levels. Testicular HE staining indicated that Cd exposure damaged the interstitial cells and increased the atypical residual bodies. Fluorescence results indicated that 3.0 mg/kg CdCl2 increased ROS levels, DNA damage, and the number of TUNEL-positive seminiferous tubule cells in testicular tissue. Transcriptome analysis showed that Cd exposure mainly induced inflammatory and chemokine signaling pathways in testicular tissue, with upregulated mRNA levels of Aim2, and reduced mRNA levels of Nlrp3. Further analysis showed that 3.0 mg/kg CdCl2 increased the expression of testicular HO-1, SOD2, γH2AX and PARP-1, as well as the pyroptosis-related factors GSDMD, GSDME, Caspase-1, ASC and IL-1ß. In conclusion, our results provide a possible mechanism by which Cd exposure activates the AIM2 pathway by increasing oxidative stress injury to induce pyroptosis in testicular tissue. This provides a new perspective on testicular damage caused by Cd exposure.

miR-484: A Potential Biomarker in Health and Disease.

Disorders of miR-484 expression are observed in cancer, different diseases or pathological states. There is accumulating evidence that miR-484 plays an essential role in the development as well as the regression of different diseases, and miR-484 has been reported as a key regulator of common cancer and non-cancer diseases. The miR-484 targets that have effects on inflammation, apoptosis and mitochondrial function include SMAD7, Fis1, YAP1 and BCL2L13. For cancer, identified targets include VEGFB, VEGFR2, MAP2, MMP14, HNF1A, TUSC5 and KLF12. The effects of miR-484 on these targets have been documented separately. Moreover, miR-484 is typically described as an oncosuppressor, but this claim is simplistic and one-sided. This review will combine relevant basic and clinical studies to find that miR-484 promotes tumorigenesis and metastasis in liver, prostate and lung tissues. It will provide a basis for the possible mechanisms of miR-484 in early tumor diagnosis, prognosis determination, disease assessment, and as a potential therapeutic target for tumors.

Circular DDX10 is associated with ovarian function and assisted reproductive technology outcomes through modulating the proliferation and steroidogenesis of granulosa cells.

circRNAs are present in human ovarian tissue, but how they regulate ovarian function remains unknown. In the current study, we investigated the levels of circRNAs in granulosa cells (GCs) derived from human follicular fluid, explored their correlation with female ovarian reserve function and clinical outcomes of assisted reproduction technique (ART), and investigated their effects on the biological functions of GC cell lines (COV434) in vitro. We identified that the levels of circDDX10 in GCs decreased gradually with aging (P < 0.01) and was positively correlated with AMH (r = 0.45, P < 0.01) and AFC (r = 0.32, P < 0.01), but not with FSH and estradiol (P > 0.05). Additionally, circDDX10 was related to the number of oocytes obtained, and good quality embryo rates. Silencing circDDX10 in GCs could markedly up-regulate the expression of apoptosis-related factors, reduce cell proliferation activity, inhibit the expression of steroid hormone synthesis-related factors, and prohibit the synthesis of estradiol. On the contrary, over-expression of circDDX10 had the opposite effect. circDDX10 is expected to become a novel biomarker for predicting the outcomes of ART, and may participate in the regulation of ovarian function by affecting the proliferation and apoptosis of GCs and steroid hormone synthesis.

TLR4 knockout upregulates the expression of Mfn2 and PGC-1α in a high-fat diet and ischemia-reperfusion mice model of liver injury.

AIMS: Patients with nonalcoholic fatty liver disease (NAFLD) have less tolerance to ischemia-reperfusion injury (IRI) of the liver than those with the healthy liver; hence have a higher incidence of severe complications after surgery. This study aimed to investigate the dynamics of the liver and mitochondrial damage and the impact of TLR4 knockout (TLR4KO) on Mfn2 expression in the composite model of NAFLD and IRI. MAIN METHODS: We performed high-fat diet (HFD) feeding and ischemia reperfusion (IR) on wild type (WT) and TLR4 knockout TLR4KO mice. KEY FINDINGS: The degree of structural and functional injuries to the liver and mitochondria (NAFLD and IRI) is greater than that caused by a single factor (NAFLD or IRI) or a simple superposition of both. The IL-6 and TNF-α expressions were significantly suppressed (P < .05), while PGC-1α and Mfn2 expressions were up-regulated considerably (P < .05) after TLR4KO. Furthermore, mitochondrial fusion increased, while ATP consumption and ROS production decreased significantly after TLR4KO (P < .05). The degree of reduction of compound injury by TLR4KO is more significant than the reduction degree of single factor injury. Also, TNF-α and IL-6 levels can be used predictive markers for mitochondrial damage and liver tolerance to NAFLD and IRI. SIGNIFICANCE: TLR4KO upregulates the expression of Mfn2 and PGC-1α in the composite model of NAFLD and IRI. This pathway may be related to IL-6 and TNF-α. This evidence provides theoretical and experimental basis for the subsequent Toll-like receptor 4 (TLR4) receptor targeted therapy.

Open versus closed vitrification system of human oocytes and embryos: a systematic review and meta-analysis of embryologic and clinical outcomes.

BACKGROUND: The objective of this study was to carry out a systematic review and meta-analysis of embryologic and clinical outcomes following open versus closed vitrification of human oocytes and embryos. METHODS: An electronic literature search was conducted in main electronic databases up to June 30, 2018 using the following key terms: 'oocyte', 'embryo', 'blastocyst', 'vitrification', 'cryopreservation', 'device', 'survival rate', 'pregnancy rate', etc. A meta-analysis was performed using a random effect model to estimate the value of risk ratios (RRs) and 95% confidence interval (CI). Subgroup analyses and sensitivity analyses were carried out to further confirm the results. RESULTS: Twelve (Eight prospective and four retrospective) studies comparing open versus closed vitrification of human oocytes or embryos were included. For prospective studies on oocytes, no evidence for a significant difference in cryosurvival rate (RR = 0.91, 95% CI: 0.80-1.03, P = 0.14; n = 2048) or clinical pregnancy rate (RR = 1.29, 95% CI: 0.80-2.06, P = 0.30; n = 150) was observed. Additionally, there were no significant differences between the two methods concerning secondary endpoints included positive ßHCG rate, implantation rate, miscarriage rate, ongoing pregnancy rate, live birth rate, cancellation rate, babies born per transferred blastocysts, or multiple birth rate (P > 0.05). The results of the retrospective studies were similar as the prospective studies. CONCLUSIONS: It is still impossible to conclude that closed vitrification system could be a substitution for open system in human oocyte and embryo cryopreservation based on current evidence. Therefore, more well-designed prospective studies addressing these issues are still warranted.