Cannabidiol alleviates carbon tetrachloride-induced liver fibrosis in mice by regulating NF-κB and PPAR-α pathways.

Liver fibrosis has become a serious public health problem that can develop into liver cirrhosis and hepatocellular carcinoma and even lead to death. Cannabidiol (CBD), which is an abundant nonpsychoactive component in the cannabis plant, exerts cytoprotective effects in many diseases and under pathological conditions. In our previous studies, CBD significantly attenuated liver injury induced by chronic and binge alcohol in a mouse model and oxidative bursts in human neutrophils. However, the effects of CBD on liver fibrosis and the underlying mechanisms still need to be further explored. A mouse liver fibrosis model was induced by carbon tetrachloride (CCl4) for 10 weeks and used to explore the protective properties of CBD and related molecular mechanisms. After the injection protocol, serum samples and livers were used for molecular biology, biochemical and pathological analyses. The results showed that CBD could effectively improve liver function and reduce liver damage and liver fibrosis progression in mice; the expression levels of transaminase and fibrotic markers were reduced, and histopathological characteristics were improved. Moreover, CBD inhibited the levels of inflammatory cytokines and reduced the protein expression levels of p-NF-κB, NF-κB, p-IκBα, p-p38 MAPK, and COX-2 but increased the expression level of PPAR-α. We found that CBD-mediated protection involves inhibiting NF-κB and activating PPAR-α. In conclusion, these results suggest that the hepatoprotective effects of CBD may be due to suppressing the inflammatory response in CCl4-induced mice and that the NF-κB and PPAR-α signaling pathways might be involved in this process.

Growth differentiation factor 11 regulates high glucose-induced cardiomyocyte pyroptosis and diabetic cardiomyopathy by inhibiting inflammasome activation.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a crucial complication of long-term chronic diabetes that can lead to myocardial hypertrophy, myocardial fibrosis, and heart failure. There is increasing evidence that DCM is associated with pyroptosis, a form of inflammation-related programmed cell death. Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor ß superfamily, which regulates oxidative stress, inflammation, and cell survival to mitigate myocardial hypertrophy, myocardial infarction, and vascular injury. However, the role of GDF11 in regulating pyroptosis in DCM remains to be elucidated. This research aims to investigate the role of GDF11 in regulating pyroptosis in DCM and the related mechanism. METHODS AND RESULTS: Mice were injected with streptozotocin (STZ) to induce a diabetes model. H9c2 cardiomyocytes were cultured in high glucose (50 mM) to establish an in vitro model of diabetes. C57BL/6J mice were preinjected with adeno-associated virus 9 (AAV9) intravenously via the tail vein to specifically overexpress myocardial GDF11. GDF11 attenuated pyroptosis in H9c2 cardiomyocytes after high-glucose treatment. In diabetic mice, GDF11 alleviated cardiomyocyte pyroptosis, reduced myocardial fibrosis, and improved cardiac function. Mechanistically, GDF11 inhibited pyroptosis by preventing inflammasome activation. GDF11 achieved this by specifically binding to apoptosis-associated speck-like protein containing a CARD (ASC) and preventing the assembly and activation of the inflammasome. Additionally, the expression of GDF11 during pyroptosis was regulated by peroxisome proliferator-activated receptor α (PPARα). CONCLUSION: These findings demonstrate that GDF11 can treat diabetic cardiomyopathy by alleviating pyroptosis and reveal the role of the PPARα-GDF11-ASC pathway in DCM, providing ideas for new strategies for cardioprotection.

Loss of lncRNA LINC01056 leads to sorafenib resistance in HCC.

BACKGROUND AND AIMS: Sorafenib is a major nonsurgical option for patients with advanced hepatocellular carcinoma (HCC); however, its clinical efficacy is largely undermined by the acquisition of resistance. The aim of this study was to identify the key lncRNA involved in the regulation of the sorafenib response in HCC. MATERIALS AND METHODS: A clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) single-guide RNA (sgRNA) synergistic activation mediator (SAM)-pooled lncRNA library was applied to screen for the key lncRNA regulated by sorafenib treatment. The role of the identified lncRNA in mediating the sorafenib response in HCC was examined in vitro and in vivo. The underlying mechanism was delineated by proteomic analysis. The clinical significance of the expression of the identified lncRNA was evaluated by multiplex immunostaining on a human HCC microtissue array. RESULTS: CRISPR/Cas9 lncRNA library screening revealed that Linc01056 was among the most downregulated lncRNAs in sorafenib-resistant HCC cells. Knockdown of Linc01056 reduced the sensitivity of HCC cells to sorafenib, suppressing apoptosis in vitro and promoting tumour growth in mice in vivo. Proteomic analysis revealed that Linc01056 knockdown in sorafenib-treated HCC cells induced genes related to fatty acid oxidation (FAO) while repressing glycolysis-associated genes, leading to a metabolic switch favouring higher intracellular energy production. FAO inhibition in HCC cells with Linc01056 knockdown significantly restored sensitivity to sorafenib. Mechanistically, we determined that PPARα is the critical molecule governing the metabolic switch upon Linc01056 knockdown in HCC cells and indeed, PPARα inhibition restored the sorafenib response in HCC cells in vitro and HCC tumours in vivo. Clinically, Linc01056 expression predicted optimal overall and progression-free survival outcomes in HCC patients and predicted a better sorafenib response. Linc01056 expression indicated a low FAO level in HCC. CONCLUSION: Our study identified Linc01056 as a critical epigenetic regulator and potential therapeutic target in the regulation of the sorafenib response in HCC.

[High-intensity interval training (HIIT) induces hepatic ketone body production possibly through altering expression of mTORC1, PPARα and FGF21 in mice].

The present study aims to investigate the production of ketone body in the liver of mice after 6 weeks of high-intensity interval training (HIIT) intervention and explore the possible mechanisms. Male C57BL/6J mice (7-week-old) were randomly divided into control and HIIT groups. The control group did not engage in exercise, while the HIIT group underwent a 6-week HIIT (10° slope treadmill exercise). Changes in weight and body composition were recorded, and blood ketone body levels were measured before, immediately after, and 1 h after each HIIT exercise. After 6-week HIIT, the levels of free fatty acids in the liver and serum were detected using reagent kits, and expression levels of regulatory factors and key enzymes of ketone body production in the mouse liver were detected by Western blot and qPCR. The results showed that, the blood ketone body levels in the HIIT group significantly increased immediately after a single HIIT and 1 h after HIIT, compared with that before HIIT. The body weight of the control group gradually increased within 6 weeks, while the HIIT group mice did not show significant weight gain. After 6-week HIIT, compared with the control group, the HIIT group showed decreased body fat ratio, increased lean body weight ratio, and increased free fatty acid levels in liver and serum. Liver carnitine palmitoyl transferase-I (CPT-I), peroxisome proliferator activated receptor α (PPARα), and fibroblast growth factor 21 (FGF21) protein expression levels were up-regulated, whereas mammalian target of rapamycin complex 1 (mTORC1) protein expression level was significantly down-regulated in the HIIT group, compared with those in the control group. These results suggest that HIIT induces hepatic ketone body production through altering mTORC1, PPARα and FGF21 expression in mice.

Protective effect and pharmacokinetics of dihydromyricetin nanoparticles on oxidative damage of myocardium.

PURPOSE: This study aims to investigate the protective mechanism of dihydromyricetin PLGA nanoparticles (DMY-PLGA NPs) against myocardial ischemia-reperfusion injury (MIRI) in vitro and the improvement of oral bioavailability in vivo. METHODS: DMY-PLGA NPs was prepared and characterized by emulsifying solvent volatilization, and the oxidative stress model of rat H9c2 cardiomyocyte induced by H2O2 was established. After administration, cell survival rate, lactate dehydrogenase (LDH), malondialdehyde (MDA) and superoxide dismutase (SOD) were detected, and the expressions of PGC1α and PPARα were detected by western blot (WB). At the same time, the pharmacokinetics in rats were studied to explore the improvement of bioavailability. RESULTS: DMY-PLGA NPs can significantly increase cell survival rate, decrease LDH and MDA content, increase SOD content and PGC1α、PPARα protein expression. Compared with DMY, the peak time of DMY-PLGA NPs was extended (P<0.1), and the bioavailability was increased by 2.04 times. CONCLUSION: DMY-PLGA NPs has a significant protective effect on H9c2 cardiomyocytes, which promotes the absorption of DMY and effectively improves bioavailability.

[Gualou Xiebai Banxia Decoction treats type 2 diabetes mellitus combined with acute myocardial infarction via chemerin/ CMKLR1/PPARα signaling pathway].

This study aims to investigate the effects of Gualou Xiebai Banxia Decoction(GXBD) on type 2 diabetes mellitus(T2DM) combined with acute myocardial infarction(AMI) in rats via chemerin/chemokine-like receptor 1(CMKLR1)/peroxisome proliferator-activated receptor α(PPARα) signaling pathway, and to explore the mechanism of GXBD in alleviating glucose and lipid metabolism disorders. The SD rats were randomized into control, model, positive control, and low-and high-dose GXBD groups. The rat model of T2DM was established by administration with high-fat emulsion(HFE) by gavage and intraperitoneal injection with streptozotocin, and then coronary artery ligation was performed to induce AMI. The control and model groups were administrated with the equal volume of normal saline, and other groups were administrated with corresponding drugs by gavage. Changes in relevant metabolic indicators were assessed by ELISA and biochemical assays, and the protein levels of chemerin, CMKLR1, and PPARα in the liver, abdominal fat, and heart were determined by Western blot. The results showed that GXBD alleviated the myocardial damage and reduced the levels of blood lipids, myocardial enzymes, and inflammatory cytokines, while it did not lead to significant changes in blood glucose. Compared with the model group, GXBD down-regulated the expression of chemerin in peripheral blood and up-regulated the expression of cyclic adenosine monophosphate(cAMP) and protein kinase A(PKA) in the liver. After treatment with GXBD, the protein levels of chemerin and CMKLR1 in the liver, abdominal fat, and heart were down-regulated, while the protein levels of PPARα in the liver and abdominal fat were up-regulated. In conclusion, GXBD significantly ameliorated the disorders of glycolipid metabolism in the T2DM-AMI model by regulating the chemerin/CMKLR1/PPARα signaling pathway to exert a protective effect on the damaged myocardium. This study provides a theoretical basis for further clinical study of GXBD against T2DM-AMI and is a manifestation of TCM treatment of phlegm and turbidity causing obstruction at the protein level.

Staphylococcus aureus oleate hydratase produces ligands that activate host PPARα.

Commensal gut bacteria use oleate hydratase to release a spectrum of hydroxylated fatty acids using host-derived unsaturated fatty acids. These compounds are thought to attenuate the immune response, but the underlying signaling mechanism(s) remain to be established. The pathogen Staphylococcus aureus also expresses an oleate hydratase and 10-hydroxyoctadecanoic acid (h18:0) is the most abundant oleate hydratase metabolite found at Staphylococcal skin infection sites. Here, we show h18:0 stimulates the transcription of a set of lipid metabolism genes associated with the activation of peroxisome proliferator activated receptor (PPAR) in the RAW 264.7 macrophage cell line and mouse primary bone marrow-derived macrophages. Cell-based transcriptional reporter assays show h18:0 selectively activates PPARα. Radiolabeling experiments with bone marrow-derived macrophages show [1-14C]h18:0 is not incorporated into cellular lipids, but is degraded by ß-oxidation, and mass spectrometry detected shortened fragments of h18:0 released into the media. The catabolism of h18:0 was >10-fold lower in bone marrow-derived macrophages isolated from Ppara -/- knockout mice, and we recover 74-fold fewer S. aureus cells from the skin infection site of Ppara -/- knockout mice compared to wildtype mice. These data identify PPARα as a target for oleate hydratase-derived hydroxy fatty acids and support the existence of an oleate hydratase-PPARα signaling axis that functions to suppress the innate immune response to S. aureus.

Oleoylethanolamide and Palmitoylethanolamide Enhance IFNß-Induced Apoptosis in Human Neuroblastoma SH-SY5Y Cells.

Oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) are endogenous lipids that act as agonists of the peroxisome proliferator-activated receptor α (PPARα). Recently, an interest in the role of these lipids in malignant tumors has emerged. Nevertheless, the effects of OEA and PEA on human neuroblastoma cells are still not documented. Type I interferons (IFNs) are immunomodulatory cytokines endowed with antiviral and anti-proliferative actions and are used in the treatment of various pathologies such as different cancer forms (i.e., non-Hodgkin's lymphoma, melanoma, leukemia), hepatitis B, hepatitis C, multiple sclerosis, and many others. In this study, we investigated the effect of OEA and PEA on human neuroblastoma SH-SY5Y cells treated with IFNß. We focused on evaluating cell viability, cell proliferation, and cell signaling. Co-exposure to either OEA or PEA along with IFNß leads to increased apoptotic cell death marked by the cleavage of caspase 3 and poly-(ADP ribose) polymerase (PARP) alongside a decrease in survivin and IKBα levels. Moreover, we found that OEA and PEA did not affect IFNß signaling through the JAK-STAT pathway and the STAT1-inducible protein kinase R (PKR). OEA and PEA also increased the phosphorylation of p38 MAP kinase and programmed death-ligand 1 (PD-L1) expression both in full cell lysate and surface membranes. Furthermore, GW6471, a PPARα inhibitor, and the genetic silencing of the receptor were shown to lower PD-L1 and cleaved PARP levels. These results reveal the presence of a novel mechanism, independent of the IFNß-prompted pathway, by which OEA and PEA can directly impair cell survival, proliferation, and clonogenicity through modulating and potentiating the intrinsic apoptotic pathway in human SH-SY5Y cells.

Molecular Mechanisms of Fucoxanthin in Alleviating Lipid Deposition in Metabolic Associated Fatty Liver Disease.

Metabolic-associated fatty liver disease (MAFLD) is witnessing a global surge; however, it still lacks effective pharmacological interventions. Fucoxanthin, a natural bioactive metabolite derived from marine brown algae, exhibits promising pharmacological functions, particularly in ameliorating metabolic disorders. However, the mechanisms underlying its therapeutic efficacy in addressing MAFLD remain elusive. Our present findings indicated that fucoxanthin significantly alleviated palmitic acid (PA)-induced hepatic lipid deposition in vitro and obesity-induced hepatic steatosis in ob/ob mice. Moreover, at both the protein and transcriptional levels, fucoxanthin effectively increased the expression of PPARα and CPT1 (involved in fatty acid oxidation) and suppressed FASN and SREBP1c (associated with lipogenesis) in both PA-induced HepG2 cells and hepatic tissues in ob/ob mice. This modulation was accompanied by the activation of AMPK. The capacity of fucoxanthin to improve hepatic lipid deposition was significantly attenuated when utilizing the AMPK inhibitor or siRNA-mediated AMPK silencing. Mechanistically, fucoxanthin activates AMPK, subsequently regulating the KEAP1/Nrf2/ARE signaling pathway to exert antioxidative effects and stimulating the PGC1α/NRF1 axis to enhance mitochondrial biogenesis. These collective actions contribute to fucoxanthin's amelioration of hepatic steatosis induced by metabolic perturbations. These findings offer valuable insights into the prospective utilization of fucoxanthin as a therapeutic strategy for managing MAFLD.

4-phenylbutyric acid improves sepsis-induced cardiac dysfunction by modulating amino acid metabolism and lipid metabolism via Comt/Ptgs2/Ppara.

INTRODUCTION: Cardiac dysfunction after sepsis the most common and severe sepsis-related organ failure. The severity of cardiac damage in sepsis patients was positively associated to mortality. It is important to look for drugs targeting sepsis-induced cardiac damage. Our previous studies found that 4-phenylbutyric acid (PBA) was beneficial to septic shock by improving cardiovascular function and survival, while the specific mechanism is unclear. OBJECTIVES: We aimed to explore the specific mechanism and PBA for protecting cardiac function in sepsis. METHODS: The cecal ligation and puncture-induced septic shock models were used to observe the therapeutic effects of PBA on myocardial contractility and the serum levels of cardiac troponin-T. The mechanisms of PBA against sepsis were explored by metabolomics and network pharmacology. RESULTS: The results showed that PBA alleviated the sepsis-induced cardiac damage. The metabolomics results showed that there were 28 metabolites involving in the therapeutic effects of PBA against sepsis. According to network pharmacology, 11 hub genes were found that were involved in lipid metabolism and amino acid transport following PBA treatment. The further integrated analysis focused on 7 key targets, including Comt, Slc6a4, Maoa, Ppara, Pparg, Ptgs2 and Trpv1, as well as their core metabolites and pathways. In an in vitro assay, PBA effectively inhibited sepsis-induced reductions in Comt, Ptgs2 and Ppara after sepsis. CONCLUSIONS: PBA protects sepsis-induced cardiac injury by targeting Comt/Ptgs2/Ppara, which regulates amino acid metabolism and lipid metabolism. The study reveals the complicated mechanisms of PBA against sepsis.

Combining fecal 16 S rRNA sequencing and spinal cord metabolomics analysis to explain the modulatory effect of PPARα on neuropathic pain.

BACKGROUND: Existing evidence suggests that the composition of the gut microbiota is associated with neuropathic pain (NP), but the mechanistic link is elusive. Peroxisome proliferator-activated receptor α (PPARα) has been shown to be a pharmacological target for the treatment of metabolic disorders, and its expression is also involved in inflammatory regulation. The aim of this study was to investigate the important modulatory effects of PPARα on gut microbiota and spinal cord metabolites in mice subjected to chronic constriction injury. METHODS: We analyzed fecal microbiota and spinal cord metabolic alterations in mice from the sham, CCI, GW7647 (PPARα agonist) and GW6471 (PPARα antagonist) groups by 16 S rRNA amplicon sequencing and untargeted metabolomics analysis. On this basis, the intestinal microbiota and metabolites that were significantly altered between treatment groups were analyzed in a combined multiomics analysis. We also investigated the effect of PPARα on the polarization fractionation of spinal microglia. RESULTS: PPARα agonist significantly reduce paw withdrawal threshold and paw withdrawal thermal latency, while PPARα antagonist significantly increase paw withdrawal threshold and paw withdrawal thermal latency. 16 S rRNA gene sequencing showed that intraperitoneal injection of GW7647 or GW6471 significantly altered the abundance, homogeneity and composition of the gut microbiome. Analysis of the spinal cord metabolome showed that the levels of spinal cord metabolites were shifted after exposure to GW7647 or GW6471. Alterations in the composition of gut microbiota were significantly associated with the abundance of various spinal cord metabolites. The abundance of Licheniformes showed a significant positive correlation with nicotinamide, benzimidazole, eicosanoids, and pyridine abundance. Immunofluorescence results showed that intraperitoneal injection of GW7647 or GW6471 altered microglial activation and polarization levels. CONCLUSION: Our study shows that PPARα can promote M2-type microglia polarization, as well as alter gut microbiota and metabolites in CCI mice. This study enhances our understanding of the mechanism of PPARα in the treatment of neuropathic pain.

Propane-2-sulfonic acid octadec-9-enyl-amide, a novel PPARα/γ dual agonist, attenuates molecular pathological alterations in learning memory in AD mice.

OBJECTIVE: Previous studies have revealed that Propane-2-sulfonic acid octadec-9-enyl-amide(N15) exerts a protective role in the inflammatory response after ischemic stroke and in neuronal damage. However, little is known about N15 in Alzheimer's disease (AD). The aim of this study was to investigate the effects of N15 on AD and explore the underlying molecular mechanism. METHODS: AD mice model was established by lateral ventricular injection with Aß25-35. N15 was daily intraperitoneal administered for 28 days. Morris Water Maze was used to evaluate the neurocognitive function of the mice. The expression of PPARα/γ, brain-derived neurotrophic factor (BDNF), Neurotrophin-3 (NT3), ADAM10, PS1 and BACE1 were measured by qPCR. Aß amyloid in the hippocampus was measured by Congo red assay. Toluidine blue staining was used to detect the neuronal apoptosis. Protein levels of ADAM10, PS1 and BACE1 were determined using immunoblotting. RESULTS: N15 treatment significantly reduced neurocognitive dysfunction, which also significantly activated the expression of PPARα/γ at an optimal dose of 200 mg/kg. Administration of N15 alleviated the formation of Aß amyloid in the hippocampus of AD mice, enhanced the BDNF mRNA expression, decreased the mRNA and protein levels of PS1 and BACE1, upregulated ADAM10 mRNA and protein levels. CONCLUSION: N15 exerts its neuroprotective effects through the activation of PPARα/γ and may be a potential drug for the treatment of AD.

The lack of PPARα exacerbated the progression of non-alcoholic steatohepatitis in mice with spleen deficiency syndrome by triggering an inflammatory response.

Background: In addition to abnormal liver inflammation, the main symptoms of non-alcoholic steatohepatitis (NASH) are often accompanied by gastrointestinal digestive dysfunction, consistent with the concept of spleen deficiency (SD) in traditional Chinese medicine. As an important metabolic sensor, whether peroxisome proliferator-activated receptor alpha (PPARα) participates in regulating the occurrence and development of NASH with SD (NASH-SD) remains to be explored. Methods: Clinical liver samples were collected for RNA-seq analysis. C57BL/6J mice induced by folium sennae (SE) were used as an SD model. qPCR analysis was conducted to evaluate the inflammation and metabolic levels of mice. PPARα knockout mice (PPARαko) were subjected to SE and methionine-choline-deficient (MCD) diet to establish the NASH-SD model. The phenotype of NASH and the inflammatory indicators were measured using histopathologic analysis and qPCR as well. Results: The abnormal expression of PPARα signaling, coupled with metabolism and inflammation, was found in the results of RNA-seq analysis from clinical samples. SD mice showed a more severe inflammatory response in the liver evidenced by the increases in macrophage biomarkers, inflammatory factors, and fibrotic indicators in the liver. qPCR results also showed differences in PPARα between SD mice and control mice. In PPARαko mice, further evidence was found that the lack of PPARα exacerbated the inflammatory response phenotype as well as the lipid metabolism disorder in NASH-SD mice. Conclusion: The abnormal NR signaling accelerated the vicious cycle between lipotoxicity and inflammatory response in NAFLD with SD. Our results provide new evidence for nuclear receptors as potential therapeutic targets for NAFLD with spleen deficiency.

MicroRNA-144-3p Inhibits Host Lipid Catabolism and Autophagy by Targeting PPARα and ABCA1 During Mycobacterium Tuberculosis Infection.

MicroRNA-mediated metabolic reprogramming recently has been identified as an important strategy for Mycobacterium tuberculosis (Mtb) to evade host immune responses. However, it is unknown what role microRNA-144-3p (miR-144-3p) plays in cellular metabolism during Mtb infection. Here, we report the meaning of miR-144-3p-mediated lipid accumulation for Mtb-macrophage interplay. Mtb infection was shown to upregulate the expression of miR-144-3p in macrophages. By targeting peroxisome proliferator-activated receptor α (PPARα) and ATP-binding cassette transporter A1 (ABCA1), miR-144-3p overexpression promoted lipid accumulation and bacterial survival in Mtb-infected macrophages, while miR-144-3p inhibition had the opposite effect. Furthermore, reprogramming of host lipid metabolism by miR-144-3p suppressed autophagy in response to Mtb infection. Our findings uncover that miR-144-3p regulates host metabolism and immune responses to Mtb by targeting PPARα and ABCA1, suggesting a potential host-directed tuberculosis therapy by targeting the interface of miRNA and lipid metabolism.

Hepatitis B virus X protein promotes tumor glycolysis by downregulating lncRNA OIP5-AS1/HKDC1 in HCC.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide, with Hepatitis B virus (HBV) infection being the leading cause. This study aims to investigate the role of HBV in HCC pathogenesis involving glucose metabolism. Long non-coding RNA (lncRNA) OIP5-AS1 was significantly downregulated in HBV-positive HCC patients, and its low expression indicated a poor prognosis. This lncRNA was primarily localized in the cytoplasm, acting as a tumor suppressor. HBV protein X (HBx) repressed OIP5-AS1 expression by inhibiting a ligand-activated transcriptional factor peroxisome proliferator-activated receptor α (PPARα). Furthermore, mechanistic studies revealed that OIP5-AS1 inhibited tumor growth by suppressing Hexokinase domain component 1 (HKDC1)-mediated glycolysis. The expression of HKDC1 could be enhanced by transcriptional factor sterol regulatory element-binding protein 1 (SREBP1). OIP5-AS1 facilitated the ubiquitination and degradation of SREBP1 to suppress HKDC1 transcription, which inhibited glycolysis. The results suggest that lncRNA OIP5-AS1 plays an anti-oncogenic role in HBV-positive HCC via the HBx/OIP5-AS1/HKDC1 axis, providing a promising diagnostic marker and therapeutic target for HBV-positive HCC patients.

Azoles display promising anticonvulsant effects through possible PPAR-α activation.

Azoles such as nafimidone, denzimol and loreclezole are known for their clinical efficacy against epilepsy, and loreclezole acts by potentiating γ-aminobutyric acid (GABA)-ergic currents. In the current study, we report a series of azole derivatives in alcohol ester and oxime ester structure showing promising anticonvulsant effects in 6 Hz and maximal electro shock (MES) models with minimal toxicity. The most promising of the series, 5f, was active in both 6 Hz and MES tests with a median effective dose (ED50) of 118.92 mg/kg in 6 Hz test and a median toxic dose (TD50) twice as high in mice. The compounds were predicted druglike and blood-brain barrier (BBB) penetrant in silico. Contrary to what was expected, the compounds showed no in vitro affinity to GABAA receptors (GABAARs) in radioligand binding assays; however, they were found structurally similar to peroxisome proliferator-activated receptors alpha (PPAR-α) agonists and predicted to show high affinity and agonist-like binding to PPAR-α in molecular docking studies. As a result, 5f emerged as a safe azole anticonvulsant with a wide therapeutic window and possible action through PPAR-α activation.

First-in-human Phase I Trial of TPST-1120, an Inhibitor of PPARα, as Monotherapy or in Combination with Nivolumab, in Patients with Advanced Solid Tumors.

PURPOSE: TPST-1120 is a first-in-class oral inhibitor of peroxisome proliferator-activated receptor α (PPARα), a fatty acid ligand-activated transcription factor that regulates genes involved in fatty acid oxidation, angiogenesis, and inflammation, and is a novel target for cancer therapy. TPST-1120 displayed antitumor activity in xenograft models and synergistic tumor reduction in syngeneic tumor models when combined with anti-PD-1 agents. EXPERIMENTAL DESIGN: This phase I, open-label, dose-escalation study (NCT03829436) evaluated TPST-1120 as monotherapy in patients with advanced solid tumors and in combination with nivolumab in patients with renal cell carcinoma (RCC), cholangiocarcinoma (CCA), or hepatocellular carcinoma. Objectives included evaluation of safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity (RECIST v1.1). RESULTS: A total of 39 patients enrolled with 38 treated (20 monotherapy, 18 combination; median 3 prior lines of therapy). The most common treatment-related adverse events (TRAE) were grade 1-2 nausea, fatigue, and diarrhea. No grade 4-5 TRAEs or dose-limiting toxicities were reported. In the monotherapy group, 53% (10/19) of evaluable patients had a best objective response of stable disease. In the combination group, 3 patients had partial responses, for an objective response rate of 20% (3/15) across all doses and 30% (3/10) at TPST-1120 ≥400 mg twice daily. Responses occurred in 2 patients with RCC, both of whom had previously progressed on anti-PD-1 therapy, and 1 patient with late-line CCA. CONCLUSIONS: TPST-1120 was well tolerated as monotherapy and in combination with nivolumab and the combination showed preliminary evidence of clinical activity in PD-1 inhibitor refractory and immune compromised cancers. SIGNIFICANCE: TPST-1120 is a first-in-class oral inhibitor of PPARα, whose roles in metabolic and immune regulation are implicated in tumor proliferation/survival and inhibition of anticancer immunity. This first-in-human study of TPST-1120 alone and in combination with nivolumab supports proof-of-concept of PPARα inhibition as a target of therapeutic intervention in solid tumors.

Tyrosol regulates hepatic lipid metabolism in high-fat diet-induced NAFLD mice.

This study aimed to elucidate the effect of tyrosol (TYR) on the amelioration of nonalcoholic fatty liver disease (NAFLD). Male C57BL/6J mice were fed a low-fat diet (LFD), a high-fat diet (HFD), or a HFD supplemented with 0.025% (w/w) TYR (TYR) for 16 weeks. Following a 16-week intervention, the TYR cohort exhibited diminished final body weight and hepatic lipid accumulation, compared to HFD fed mice. Liver metabolomics analysis revealed that TYR increased the hepatic levels of spermidine, taurine, linoleic acid, malic acid and eicosapentaenoic acid (EPA), indicating the beneficial effect of TYR on lipid homeostasis. Using molecular docking analysis and the luciferase assay, we found that TYR acts as a ligand and binds with peroxisome proliferator-activated receptor-α (PPARα), which plays a pivotal role in the modulation of hepatic lipid metabolism, thereby activating the transcription of downstream genes. Our results suggest that TYR alleviates NAFLD in HFD-fed mice probably by the modulation of the PPARα signaling pathway.

Assessment of the mode of action of perchloroethylene-induced mouse liver tumors.

Perchloroethylene (PCE) is used as a solvent and chemical intermediate. Following chronic inhalation exposure, PCE selectively induced liver tumors in mice. Understanding the mode of action (MOA) for PCE carcinogenesis in mice is important in defining its possible human cancer risk. The proposed MOA is based on the extensive examination of the peer-reviewed studies that have assessed the mouse liver effects of PCE and its major oxidative metabolite trichloroacetic acid (TCA). Similar to PCE, TCA has also been demonstrated to liver tumors selectively in mice following chronic exposure. The Key Events (KE) of the proposed PCE MOA involve oxidative metabolism of PCE to TCA [KE 1]; activation of the peroxisome proliferator-activated receptor alpha (PPARα) [KE 2]; alteration in hepatic gene expression including cell growth pathways [KE 3]; increase in cell proliferation [KE 4]; selective clonal expansion of hepatic preneoplastic foci [KE 5]; and formation of hepatic neoplasms [KE 6]. The scientific evidence supporting the PPARα MOA for PCE is strong and satisfies the requirements for a MOA analysis. The PPARα liver tumor MOA in rodents has been demonstrated not to occur in humans; thus, human liver cancer risk to PCE is not likely.

Disturbed brain energy metabolism in a rodent model of DYT-TOR1A dystonia.

DYT-TOR1A (DYT1) dystonia, characterized by reduced penetrance and suspected environmental triggers, is explored using a "second hit" DYT-TOR1A rat model. We aim to investigate the biological mechanisms driving the conversion into a dystonic phenotype, focusing on the striatum's role in dystonia pathophysiology. Sciatic nerve crush injury was induced in ∆ETorA rats, lacking spontaneous motor abnormalities, and wild-type (wt) rats. Twelve weeks post-injury, unbiased RNA-sequencing was performed on the striatum to identify differentially expressed genes (DEGs) and pathways. Fenofibrate, a PPARα agonist, was introduced to assess its effects on gene expression. 18F-FDG autoradiography explored metabolic alterations in brain networks. Low transcriptomic variability existed between naïve wt and ∆ETorA rats (17 DEGs). Sciatic nerve injury significantly impacted ∆ETorA rats (1009 DEGs) compared to wt rats (216 DEGs). Pathway analyses revealed disruptions in energy metabolism, specifically in fatty acid ß-oxidation and glucose metabolism. Fenofibrate induced gene expression changes in wt rats but failed in ∆ETorA rats. Fenofibrate increased dystonia-like movements in wt rats but reduced them in ∆ETorA rats. 18F-FDG autoradiography indicated modified glucose metabolism in motor and somatosensory cortices and striatum in both ∆ETorA and wt rats post-injury. Our findings highlight perturbed energy metabolism pathways in DYT-TOR1A dystonia, emphasizing compromised PPARα agonist efficacy in the striatum. Furthermore, we identify impaired glucose metabolism in the brain network, suggesting a potential shift in energy substrate utilization in dystonic DYT-TOR1A rats. These results contribute to understanding the pathophysiology and potential therapeutic targets for DYT-TOR1A dystonia.