Comprehensive profiling of lipid metabolic reprogramming expands precision medicine for HCC.

BACKGROUND AND AIMS: Liver HCC is the second leading cause of cancer-related deaths worldwide. The heterogeneity of this malignancy is driven by a wide range of genetic alterations, leading to a lack of effective therapeutic options. In this study, we conducted a systematic multi-omics characterization of HCC to uncover its metabolic reprogramming signature. APPROACH AND RESULTS: Through a comprehensive analysis incorporating transcriptomic, metabolomic, and lipidomic investigations, we identified significant changes in metabolic pathways related to glucose flux, lipid oxidation and degradation, and de novo lipogenesis in HCC. The lipidomic analysis revealed abnormal alterations in glycerol-lipids, phosphatidylcholine, and sphingolipid derivatives. Machine-learning techniques identified a panel of genes associated with lipid metabolism as common biomarkers for HCC across different etiologies. Our findings suggest that targeting phosphatidylcholine with saturated fatty acids and long-chain sphingolipid biosynthesis pathways, particularly by inhibiting lysophosphatidylcholine acyltransferase 1 ( LPCAT1 ) and ceramide synthase 5 ( CERS5 ) as potential therapeutic strategies for HCC in vivo and in vitro. Notably, our data revealed an oncogenic role of CERS5 in promoting tumor progression through lipophagy. CONCLUSIONS: In conclusion, our study elucidates the metabolic reprogramming nature of lipid metabolism in HCC, identifies prognostic markers and therapeutic targets, and highlights potential metabolism-related targets for therapeutic intervention in HCC.

Excitotoxicity and oxidative damages induced by methylmercury in rat cerebral cortex and the protective effects of tea polyphenols.

Methylmercury (MeHg) is a highly neurotoxic environmental pollutant that has a high appetency to the central nervous system. The underlying mechanisms of MeHg-induced neurotoxicity have not been elucidated clearly until now. Therefore, to explore the mechanisms contribute to MeHg-induced neurotoxicity, rats were exposed to different dosage of methylmercury chloride (CH3 ClHg) (0, 4, and 12 µmol kg(-1)) for 4 weeks to evaluate the neurotoxic effects of MeHg. In addition, considering the antioxidative properties of tea polyphenols (TP), 1 mmol kg(-1) TP was pretreated to observe the possible protective effects on MeHg-induced neurotoxicity. Then Hg, glutamate (Glu) and glutamine (Gln) levels, glutamine synthetase (GS), phosphate-activated glutaminase (PAG), Na(+)-K(+)-ATPase, and Ca(2+)-ATPase activities, intracellular Ca(2+) level were examined, glutathione (GSH), malondialdehyde (MDA), protein sulfhydryl, carbonyl, 8-hydroxy-2-deoxyguanosine (8-OHdG), and reactive oxygen species (ROS) levels, N-methyl-D-aspartate receptors (NMDARs) mRNA and protein expressions, apoptosis level and morphological changes in the cerebral cortex were also investigated. Study results showed that compared with those in control, exposure to CH3 ClHg resulted in excitotoxicity in a concentration-dependent manner, which was shown by the Glu-Gln cycle disruption and intracellular Ca(2+) homeostasis disturbance. On the other hand, CH3 ClHg exposure resulted in oxidative damages of brain, which were supported by the significant changes on GSH, MDA, sulfhydryl, carbonyl, 8-OHdG, and ROS levels. Moreover, apoptosis rate increased obviously and many morphological changes were found after CH3 ClHg exposure. Furthermore, this research indicated that TP pretreatment significantly mitigated the toxic effects of MeHg. In conclusion, findings from this study indicated that exposure to MeHg could induce excitotoxicity and oxidative damage in cerebral cortex while TP might antagonize the MeHg-induced neurotoxicity.

Prognostic and Clinical Significance of Cyclooxygenase-2 Overexpression in Endometrial Cancer: A Meta-Analysis.

Objective: Cyclooxygenase-2 (COX-2) is a critical enzyme associated with inflammation and tumorigenesis. Although several studies have compared the expression of COX-2 in endometrial cancer tissues and normal tissues, the results have been inconsistent thus far. This study aims to conduct a meta-analysis to elucidate the role of COX-2 in the determination of the risk, prognosis, and clinical features of endometrial cancer. Methods: We retrieved the suitable studies on the association between COX-2 expression and endometrial cancer from PubMed, EMBASE, and Web of Science databases that were published between 1999 and September 31st, 2019. The hazard ratio (HR) and 95% confidence intervals (CIs) were retrieved to assess the relationship between COX-2 expression and the prognosis of endometrial cancer. The odds ratio (OR) and 95% CIs were calculated to evaluate the correlation between COX-2 expression and the risk and clinical features of endometrial cancer. Results: To investigate the association between COX-2 expression and the susceptibility, clinical features, and prognosis of endometrial cancer, we performed a meta-analysis on data from selected studies that collectively involved 273 normal individuals and 1,376 patients with endometrial cancer. Overall, the pooled analysis indicated that COX-2 expression was significantly associated with susceptibility (Caucasians, OR = 3.94, 95% CI = 2.17-7.17, P < 0.05; Asians, OR = 20.51, 95% CI = 8.54-49.26, P < 0.05), cancer stage (OR = 3.01, 95% CI = 1.95-4.67, P < 0.05), myometrial invasion (OR = 1.59, 95% CI = 1.17-2.15, P < 0.05), lymph node metastasis (OR = 1.63, 95% CI = 1.18-2.26, P < 0.05), and prognosis (OR = 2.91, 95% CI = 1.17-4.66, P < 0.05) in endometrial cancer. Conclusions: Our findings suggested that COX-2 overexpression is significantly associated with poor prognosis and advanced clinical features in endometrial cancer. Therefore, COX-2 may function as an effective prognostic biomarker and a potential therapeutic target for endometrial cancer.

The poor recovery of neuromyelitis optica spectrum disorder is associated with a lower level of CXCL12 in the human brain.

Neuromyelitis optica spectrum disorders (NMOSDs) are blindness-causing neuritis. In NMOSD patients, NMO-IgG evokes astrocytopathy that in turn causes demyelination. While measurement of NMO-IgG titer will help neurologists make the diagnosis of NMOSDs, it is not sufficient to evaluate the severity of astrocytopathy. In this study, we compared the different levels of an astrocyte biomarker in cerebrospinal fluid of NMOSD patients with good or poor recovery, and then linked their differences to the changes in remyelinating promoter (CXCL12) levels. Our results indicate that NMO-IgG down-regulated CXCL12 and impaired the remyelinating process, this may be a mechanism contributing to the poor recovery of NMOSDs.

Exploring cross-talk between oxidative damage and excitotoxicity and the effects of riluzole in the rat cortex after exposure to methylmercury.

Methylmercury (MeHg) is a ubiquitous environmental toxin that causes neurologic and developmental diseases. Oxidative damage and excitotoxicity are putative mechanisms, which underlie MeHg-induced neurotoxicity. In this study, the cross-talk between the oxidative damage and excitotoxicity pathways and the protective effects of riluzole in the rat cortex were explored. Rats were injected with MeHg and/or riluzole, and cold vapor atomic fluorescence spectrometry, hematoxylin and eosin staining, flow cytometry, fluorescence assays, spectrophotometry, real-time PCR, and Western blotting were used to evaluate neurotoxicity. The present study showed that (1) MeHg accumulated in the cerebral cortex and caused pathology. (2) MeHg caused oxidative damage by inducing glutathione (GSH) depletion, reactive oxygen species (ROS) production, inhibition of antioxidant enzyme activity, and alteration of the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. (3) MeHg disrupted the glutamate transporters (GluTs), glutamate-glutamine cycle, and N-methyl-D-aspartate receptor expression and induced excitotoxicity. (4) Excitotoxicity resulted in disruption of GSH synthesis, calcium overloading, oxidative damage, and excessive ROS production. (5) Pretreatment with riluzole antagonized MeHg neurotoxicity by down regulating cross-talk between the oxidative damage and excitotoxicity pathways. In conclusion, the cross-talk between the oxidative damage and excitotoxicity pathways caused by MeHg exposure was linked by GluTs and calcium and inhibited by riluzole treatment.

Protective effects of memantine against methylmercury-induced glutamate dyshomeostasis and oxidative stress in rat cerebral cortex.

Methylmercury (MeHg) is one of the ubiquitous environmental toxicant that leads to long-lasting neurological deficits in animals and humans. The identification of the underlying mechanisms has been a main focus of research in the neurotoxicology field. Glutamate (Glu) dyshomeostasis and oxidative stress have been identified as two critical mechanisms mediating MeHg-induced neurotoxicity. However, little has been known of the interaction between these two mechanisms that play in MeHg poisoning in vivo. We, therefore, developed a rat model of MeHg subchronic poisoning to evaluate its neurotoxic effects and investigated the neuroprotective role of memantine, a low-affinity, noncompetitive N-methyl-D-aspartate receptors (NMDARs) antagonist, against MeHg-induced neurotoxicity. Ninety rats were randomly divided into five groups: control, memantine control, MeHg-treated (4 and 12 µmol/kg), and memantine pretreated. Administration of 12 µmol/kg MeHg for 4 weeks significantly elevated total Hg levels, disrupted Glu metabolism, overexcited NMDARs, and led to intracellular calcium overload, which might be critical to excessive reactive oxygen species (ROS) formation in cerebral cortex. Meanwhile, MeHg administration reduced non-enzymatic (non-protein sulfhydryl, NPSH) and enzymatic (superoxide dismutase, SOD and glutathione peroxidase, GSH-Px) antioxidants; caused lipid, protein, and DNA oxidative damage; and enhanced neurocyte apoptosis in cerebral cortex. Moreover, glutamate/aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1) appear to be inhibited by MeHg exposure. Pretreatment with memantine at a dose of 5 µmol/kg significantly prevented MeHg-induced alterations of Glu metabolism and oxidative stress, alleviated neurocyte apoptosis, and pathological injury. In conclusion, the results suggested that Glu dyshomeostasis and oxidative stress resulting from MeHg exposure contributed to neuronal injury. Memantine possesses the ability to attenuate MeHg-induced neurotoxicity through mechanisms involving its NMDARs-binding properties and indirect antioxidation.

MK-801 protects against intracellular Ca(2+) overloading and improves N-methyl-D-aspartate receptor expression in cerebral cortex of methylmercury-poisoned rats.

Overexposure to methylmercury (MeHg) has been known to induce neurotoxicity. The objective of this study is to explore mechanisms that contribute to MeHg-induced nerve cell apoptosis focusing on the alteration of intracellular Ca(2+) homeostasis and expression of N-methyl-D-aspartate receptors (NMDARs) subunits in rat cerebral cortex and whether MK801, a non-competitive NMDAR antagonist, could attenuate MeHg-induced neurotoxicity. Fifty rats were randomly divided into five groups of 10 animals in each group: control group, MK801 control group, MeHg-treated group (4 and 12 µmol/kg) and MK801 pre-treated group. Administration of MeHg at a dose of 12 µmol/kg for 4 weeks significantly increased in intracellular [Ca(2+)](i) and total Hg levels and that enhanced neurocyte apoptosis rate in cerebral cortex. In addition, the inhibitory effect of MeHg on Na(+)-K(+)-ATPase and Ca(2+)-ATPases might be one of the reasons that cause a significant increase of [Ca(2+)](i) in neurocyte. Over activated by increased cytosolic Ca(2+) loading, calpains degraded NMDAR subunits leading ultimately to nerve cell damage. However, pretreatment with MK801 at a dose of 0.3 µmol/kg could prevent Ca(2+) homeostasis dysregulation and alleviate the neurocyte apoptosis. In conclusion, the neuroprotective effects of MK801 appeared to be mediated not only via its NMDA receptor binding properties but also by maintaining intracellular calcium homeostasis.

Oxidative stress involvement in manganese-induced alpha-synuclein oligomerization in organotypic brain slice cultures.

Overexposure to manganese (Mn) has been known to induce neuronal damage. However, little is known of the role that reactive oxygen species (ROS) play in protein aggregation resulting from Mn exposure. The current study investigated whether oxidative stress is involved in manganese-induced alpha-synuclein oligomerization in organotypic brain slices. After application of Mn (0-400µM) for 24h, there was a dose-dependent increase in average percentage of propidium iodide positive (PI(+)) nuclei in slices and levels of lactate dehydrogenase (LDH) in the culture medium. Moreover, the treatment with Mn resulted in a dose-dependent increase in neurocyte apoptosis, ROS level, and decrease in superoxide dismutase (SOD) activity. Mn also caused oxidative damage in cell lipid and protein. At the same time, the exposure of Mn leaded to significantly increase in the expression of alpha-synuclein mRNA and protein. Alpha-synuclein oligomerization occurred in Mn-treated slices, especially on membrane-bound form. It indicated that alpha-synuclein oligomers were more likely to combination cell membranes and resulting in membrane damage. Mn-induced neurocyte damage and alpha-synuclein oligomerization were also partially alleviated by the pretreatment with GSH and aggravated by H2O2 pretreatment. The findings revealed Mn might exert its neurotoxic effects by oxidative stress-mediated alpha-synuclein oligomerization in organotypic brain slices.

Effect of grape seed proanthocyanidin extracts on methylmercury-induced neurotoxicity in rats.

As a highly toxic environmental pollutant, methylmercury (MeHg) can cause neurotoxicity in animals and humans. Considering the antioxidant property of grape seed proanthocyanidin extracts (GSPE), this study was aimed to evaluate the effect of GSPE on MeHg-induced neurotoxicity in rats. Rats were exposed to MeHg by intraperitoneal injection (4, 12 µmol/kg, respectively) and GSPE was administered by gavage (250 mg/kg) 2 h later. After a 4-week treatment, phosphate-activated glutaminase, glutamine synthetase, glutathione peroxidase and superoxide dismutase activities, glutamate, glutamine, malondialdehyde and glutathione contents in cerebral cortex were measured. Reactive oxygen species (ROS) and apoptosis were also estimated in cells. The results showed that the MeHg-induced neurotoxicity was significantly attenuated. GSPE significantly decreased the production of ROS, counteracted oxidative damage and increased the antioxidants and antioxidant enzymes activities in rats prior to MeHg exposure. Moreover, the effects on the rate of apoptotic cells and the disturbance of glutamate homeostasis were correspondingly modulated. These observations highlighted the potential of GSPE in offering protection against MeHg-induced neurotoxicity.

Effects of lycopene and proanthocyanidins on hepatotoxicity induced by mercuric chloride in rats.

To evaluate the protective potential of lycopene (Lyc) and proanthocyanidins (PCs) against mercuric chloride (HgCl(2))-induced hepatotoxicity, the study focused on the mechanism of oxidative stress. Firstly, the rats were subcutaneously (s.c.) injected with 0, 2.2, 4.4, and 8.8 µmol/kg HgCl(2). Additionally, 40 mg/kg Lyc and 450 mg/kg PCs were given to the rats intragastrically (i.g.) before exposure to 8.8 µmol/kg HgCl(2). Then, body weight, liver weight coefficient, mercury (Hg) contents, histological feature, ultrastructure, apoptosis, reactive oxygen species (ROS), glutathione (GSH), glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and malondialdehyde (MDA) in the liver were measured. Lactate dehydrogenase (LDH) and alanine transaminase (ALT) in serum were determined. After exposure to different concentrations of HgCl(2), it was found that Hg contents, pathological and ultrastructure injury, activities of LDH and ALT, apoptosis, and levels of ROS, GSH, and MDA increased and the activities of SOD and GSH-Px decreased in a concentration-dependent manner. Further investigation found that pretreatment with Lyc and PCs inhibited ROS production, protected antioxidant enzymes, and reversed hepatotoxicity. We concluded that Lyc and PCs had hepatoprotective effects on HgCl(2)-induced toxicity by antagonizing oxidative stress in rat liver.

Protective effects of MK-801 on methylmercury-induced neuronal injury in rat cerebral cortex: involvement of oxidative stress and glutamate metabolism dysfunction.

Methylmercury (MeHg) is one of the ubiquitous environmental toxicants, which can induce oxidative stress and an indirect excitotoxicity caused by altered glutamate (Glu) metabolism. However, little is known of the interaction between oxidative stress and Glu metabolism play in MeHg poisoning rats. We have investigated the neuroprotective role of MK-801, a non-competitive N-methyl-d-aspartate receptors (NMDAR) antagonist, against MeHg-induced neurotoxicity. Fifty rats were randomly divided into five groups of 10 animals in each group: control group, MK-801 control group, MeHg-treated group (4 and 12 µmol/kg) and MK-801 pre-treated group. Administration of MeHg at a dose of 12 µmol/kg for four weeks significantly increased in ROS and total Hg levels and that caused lipid, protein and DNA peroxidative damage in cerebral cortex. In addition, MeHg also reduced nonenzymic (reduced glutathione, GSH) and enzymic (glutathione peroxidase, GPx and superoxide dismutase, SOD) antioxidants and enhanced neurocyte apoptosis rate in cerebral cortex. MeHg-induced ROS production appears to inhibit the activity of the glutamine synthetase (GS), leading to Glu metabolism dysfunction. Pretreatment with MK-801 at a dose of 0.3 µmol/kg prevented the alterations of the activities of PAG and GS and oxidative stress. In addition, pretreatment with MK-801 significantly alleviated the neurocyte apoptosis rate and histopathological damage. In conclusion, the results suggested ROS formation resulting from MeHg- and Glu-induced oxidative stress contributed to neuronal injury. MK-801 possesses the ability to attenuate MeHg-induced neurotoxicity in the cerebral cortex through mechanisms involving its NMDA receptor binding properties and antioxidation.

Riluzole-triggered GSH synthesis via activation of glutamate transporters to antagonize methylmercury-induced oxidative stress in rat cerebral cortex.

OBJECTIVE: This study was to evaluate the effect of riluzole on methylmercury- (MeHg-) induced oxidative stress, through promotion of glutathione (GSH) synthesis by activating of glutamate transporters (GluTs) in rat cerebral cortex. METHODS: Eighty rats were randomly assigned to four groups, control group, riluzole alone group, MeHg alone group, and riluzole + MeHg group. The neurotoxicity of MeHg was observed by measuring mercury (Hg) absorption, pathological changes, and cell apoptosis of cortex. Oxidative stress was evaluated via determining reactive oxygen species (ROS), 8-hydroxy-2-deoxyguanosine (8-OHdG), malondialdehyde (MDAs), carbonyl, sulfydryl, and GSH in cortex. Glutamate (Glu) transport was studied by measuring Glu, glutamine (Gln), mRNA, and protein of glutamate/aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1). RESULT: (1) MeHg induced Hg accumulation, pathological injury, and apoptosis of cortex; (2) MeHg increased ROS, 8-OHdG, MDA, and carbonyl, and inhibited sulfydryl and GSH; (3) MeHg elevated Glu, decreased Gln, and downregulated GLAST and GLT-1 mRNA expression and protein levels; (4) riluzole antagonized MeHg-induced downregulation of GLAST and GLT-1 function and expression, GSH depletion, oxidative stress, pathological injury, and apoptosis obviously. CONCLUSION: Data indicate that MeHg administration induced oxidative stress in cortex and that riluzole could antagonize this situation through elevation of GSH synthesis by activating of GluTs.

The protective effects of tea polyphenols and schisandrin B on nephrotoxicity of mercury.

Mercury (Hg) is an occupational and environmental contaminant that is a well-recognized health hazard. To approach the concrete mechanisms of mercury nephrotoxicity and find out a new way to prevent it, the rats were subcutaneously injected with different dosages of mercuric chloride (HgCl(2))--0, 2.2, 4.4, and 8.8 µmol/kg. The levels of Hg, blood urea nitrogen (BUN), urine protein, glutathione (GSH), malondialdehyde (MDA) and activities of N-acetyl-beta-D-glucosaminidase (NAG), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) were investigated, and the levels of reactive oxygen species (ROS) and apoptosis and the pathological changes were also observed. In addition, the effects of 1 mmol/kg tea polyphenols (TP) and 0.04 mmol/kg schisandrin B (Sch B) were studied at 8.8 µmol/kg HgCl(2). It was observed that the levels of Hg, BUN, urine protein, GSH, and MDA and activities of NAG, ALP, and LDH increased significantly; the activities of SOD and GSH-Px decreased significantly; the levels of ROS and apoptosis increased obviously; and many pathological changes occurred dose-dependently in the HgCl(2) injection groups. Further investigation indicated that pretreatment with TP and Sch B significantly reversed the toxic effects of HgCl(2). These results suggested that TP and Sch B might antagonize the nephrotoxicity caused by HgCl(2) exposure.