RETRACTED: Zhang, E. Hepatic PLIN5 Deficiency Impairs Lipogenesis through Mitochondrial Dysfunction. Int. J. Mol. Sci. 2022, 23, 15598.

The International Journal of Molecular Sciences retracts the article entitled "Hepatic PLIN5 Deficiency Impairs Lipogenesis through Mitochondrial Dysfunction" [...].

Hepatic PLIN5 Deficiency Impairs Lipogenesis through Mitochondrial Dysfunction.

Regulation of lipid droplets (LDs) metabolism is the core of controlling intracellular fatty acids (FAs) fluxes, and perilipin 5 (PLIN5) plays a key role in this process. Our previous studies have found that hepatic PLIN5 deficiency reduces LDs accumulation, but the trafficking of FAs produced from this pathway and the interaction between mitochondria and LDs in this process are largely unknown. Here, we found that the deficiency of PLIN5 decreases LDs accumulation by increasing FAs efflux. In addition, the decreased lipogenesis of PLIN5-deficient hepatocytes is accompanied by mitochondrial dysfunction, suggesting that PLIN5 plays an important role in mediating the interaction between LDs and mitochondria. Importantly, PLIN5 ablation negates oxidative capacity differences of peri-droplet and cytosolic mitochondria. In summary, these data indicate that PLIN5 plays a vital role in maintaining mitochondrial-mediated lipogenesis, which provides an important new perspective on the regulation of liver lipid storage and the relationship between PLIN5 and mitochondria.

A case study on the bearing characteristics of a bottom uplift pile in a layered foundation.

The bottom uplift pile, which has been applied in practical projects, has the following advantages: the pile body is not easy to crack, good bearing characteristics, and small displacement of the pile top. Based on the bearing capacity test of foundation piles in the third stage expansion project of Lanzhou Zhongchuan International Airport, the upper part pile of the self-balancing test method was used to simulate the bottom uplift pile, and the anchor piles in the anchor pile method were regarded as normal uplift piles. The bearing characteristics of the bottom uplift pile in a layered foundation were studied by comparing these two kinds of piles. The results show that under the same displacement of the pile top, the ultimate uplift bearing capacity of the bottom uplift pile can be more than twice that of the normal uplift pile because of the fully exerted frictional resistance of the soil at the bottom of the pile, the Poisson effect of the pile body and the avoidance of the influence of pile body deformation on the pile top displacement. The maximum axial force of the bottom uplift pile appears at the bottom of the pile and gradually decreases from the bottom to the top, which is opposite to that of the normal uplift pile. The properties and thickness of the soil layers around the pile have a great influence on the distribution curves of the frictional resistance along the pile length of the two kinds of uplift piles. With changing soil layer conditions, the distribution curve may be a "parabola", a "straight line" or a "double line". The soil property plays a decisive role in the frictional resistance, which may cause softening. The influence of the pile diameter on the ultimate uplift bearing capacity is greater than that of the pile length, while the elastic modulus of the pile has little influence.

Role of Ferroptosis in Non-Alcoholic Fatty Liver Disease and Its Implications for Therapeutic Strategies.

Non-alcoholic fatty liver disease (NAFLD) has become the chronic liver disease with the highest incidence throughout the world, but its pathogenesis has not been fully elucidated. Ferroptosis is a novel form of programmed cell death caused by iron-dependent lipid peroxidation. Abnormal iron metabolism, lipid peroxidation, and accumulation of polyunsaturated fatty acid phospholipids (PUFA-PLs) can all trigger ferroptosis. Emerging evidence indicates that ferroptosis plays a critical role in the pathological progression of NAFLD. Because the liver is the main organ for iron storage and lipid metabolism, ferroptosis is an ideal target for liver diseases. Inhibiting ferroptosis may become a new therapeutic strategy for the treatment of NAFLD. In this article, we describe the role of ferroptosis in the progression of NAFLD and its related mechanisms. This review will highlight further directions for the treatment of NAFLD and the selection of corresponding drugs that target ferroptosis.

Impact of Sodium Glucose Cotransporter 2 Inhibitors on Nonalcoholic Fatty Liver Disease Complicated by Diabetes Mellitus.

Sodium glucose cotransporter 2 (SGLT2), a type of membrane protein highly expressed in the kidney, can regulate plasma glucose through the glomerular filtration process by reabsorption from the kidney. SGLT2 inhibitors, which are newly developed oral antidiabetic drugs, can play a role in liver diseases by inhibiting SGLT2-mediated renal glucose reabsorption and inducing glycosuria. Nonalcoholic fatty liver disease (NAFLD) is the most common type of liver disease, resulting in severe liver dysfunction. During the progression of NAFLD, there are some hallmark complications, including lipid metabolism disorders, inflammation induction, and hepatocyte death. Herein, we review several SGLT2 inhibitors that are capable of protecting individuals with NAFLD from severe complications by inhibiting de novo lipogenesis, oxidative responses, inflammation induction, and hepatocyte death.

Involvement of activation of PLIN5-Sirt1 axis in protective effect of glycycoumarin on hepatic lipotoxicity.

Licorice is a popular medicinal plant, and it has been used to treat various diseases, including liver diseases. Glycycoumarin (GCM) is a major coumarin compound isolated from licorice with favorable bioavailability property. Our previous studies have shown that GCM is capable of inhibiting lipoapoptosis in both cell culture and methionine-choline-defcient (MCD) diet-induced mouse model of non-alcoholic steatohepatitis (NASH) through mechanisms involving suppression of endoplasmic reticulum (ER) stress. Perilipin 5 (PLIN5), a newly identified lipid drop protein in the perilipin family, is highly expressed in oxidative tissues including the liver and is suggested to play an important role in protecting against hepatic lipotoxicity. Give the hepatoprotective role of PLIN5, we hypothesized that induction of PLIN5 might contribute to the hepatoprotective effect of GCM via mitigating ER stress and inflammatory responses. Results showed that PLIN5 and its downstream target Sirt1 were induced by GCM both in vitro and in vivo. Inhibition of either PLIN5 or Sirt1 led to significantly attenuated protective effect of GCM on palmitic acid (PA)-induced lipoapoptosis and inflammatory responses, supporting involvement of PLIN5-Sirt1 axis in the protective effect of GCM on hepatic lipotoxicity. The findings of the present study provide novel insight into the understanding of mechanisms underlying the hepatoprotective effect of GCM.

Activation of the IRE1α Arm, but not the PERK Arm, of the Unfolded Protein Response Contributes to Fumonisin B1-Induced Hepatotoxicity.

Previous studies by us or others have shown that endoplasmic reticulum (ER) stress was activated by fumonisin 1 (FB1) exposure, which is considered to be a critical event in the FB1-induced toxic effect. However, the detailed mechanisms underlying FB1-induced ER stress-mediated liver toxicity remain elusive. The objectives of the present study were designed to address the following issues: (1) the contribution of each arm of the unfolded protein response (UPR); (2) the downstream targets of ER stress that mediated FB1-induced liver toxicity; and (3) the relationship between ER stress and oxidative stress triggered by FB1. We also investigated whether the inhibition of ER stress by its inhibitor could offer protection against FB1-induced hepatotoxicity in vivo, which has not been critically addressed previously. The results showed that the activation of the IRE1α axis, but not of the PERK axis, of UPR contributed to FB1-induced ER stress-mediated hepatocyte toxicity; the activation of the Bax/Bak-mediated mitochondrial pathway lay downstream of IRE1α to trigger mitochondrial-dependent apoptosis in response to FB1; FB1-induced oxidative stress and ER stress augmented each other through a positive feedback mechanism; tauroursodeoxycholic acid (TUDCA)-mediated ER stress inactivation is an effective approach to counteract FB1-induced hepatotoxicity in vivo. The data of the present study allow us to better understand the mechanisms of FB1-induced hepatotoxicity.

Hepatic PLIN5 signals via SIRT1 to promote autophagy and prevent inflammation during fasting.

Lipid droplets (LDs) are energy-storage organelles that are coated with hundreds of proteins, including members of the perilipin (PLIN) family. PLIN5 is highly expressed in oxidative tissues, including the liver, and is thought to play a key role in uncoupling LD accumulation from lipotoxicity; however, the mechanisms behind this action are incompletely defined. We investigated the role of hepatic PLIN5 in inflammation and lipotoxicity in a murine model under both fasting and refeeding conditions and in hepatocyte cultures. PLIN5 ablation with antisense oligonucleotides triggered a pro-inflammatory response in livers from mice only under fasting conditions. Similarly, PLIN5 mitigated lipopolysaccharide- or palmitic acid-induced inflammatory responses in hepatocytes. During fasting, PLIN5 was also required for the induction of autophagy, which contributed to its anti-inflammatory effects. The ability of PLIN5 to promote autophagy and prevent inflammation were dependent upon signaling through sirtuin 1 (SIRT1), which is known to be activated in response to nuclear PLIN5 under fasting conditions. Taken together, these data show that PLIN5 signals via SIRT1 to promote autophagy and prevent FA-induced inflammation as a means to maintain hepatocyte homeostasis during periods of fasting and FA mobilization.

Protective effects of glycycoumarin on liver diseases.

Licorice, an edible and medicinal plant, has long been used to treat various diseases, including liver diseases. Glycycoumarin (GCM) is a representative coumarin compound in licorice with favorable bioavailability feature. Recent studies by us demonstrated that GCM is highly effective against alcoholic liver disease, nonalcoholic fatty liver disease, acetaminophen-induced hepatotoxicity, and liver cancer through mechanisms involved in activation of Nrf2 antioxidant system, stimulation of AMPK-mediated energy homeostasis, induction of autophagy degradation process, and inhibiting oncogenic kinase T-lymphokine-activated killer cell-originated protein kinase activity. In this review, we summarize the findings on the hepatoprotective effect of GCM, discuss the signaling pathways underlying GCM-induced protective effect on liver diseases, and propose the issues that need to be addressed to promote further development of GCM as a clinically useful hepatoprotective agent.

3'-Desmethylarctigenin induces G2/M cell cycle arrest and apoptosis through reactive oxygen species generation in hepatocarcinoma cells.

Previous studies have shown that arctigenin is a promising chemopreventive or therapeutic agent against various cancers. However, less is known about anticancer activity of 3'-desmethylarctigenin (3'-DMAG), which is a biotransformed product from arctigenin or arctin. In this study, we compared the anticancer activity of 3'-DMAG with its parent compound arctigenin and demonstrated that 3'-DMAG exerted a more potent inhibitory effect on HepG2 cells than arctigenin. Mechanistically, reactive oxygen species generation played an apical role in 3'-DMAG-induced G2/M cell cycle arrest and apoptosis in HepG2 cells. Furthermore, the Chk2-Cdc25c-Cdc2-cyclin B1 cascade was found to contribute to the cell cycle arrest, whereas the activation of mitochondrial pathway was involved in the cell apoptosis by 3'-DMAG. Additionally, a mouse xenograft hepatocellular carcinoma model was used to evaluate the antitumor effect of 3'-DMAG in vivo, and the results indicated that 3'-DMAG treatment significantly inhibited tumor growth without apparent toxicity. Taken together, 3'-DMAG is highly effective against liver cancer both in vitro and in vivo. The findings of the present study suggest that this compound deserves to be further investigated for its potential anticancer activity.

The association between orthostatic blood pressure changes and subclinical target organ damage in subjects over 60 years old.

BACKGROUND: Although recent studies have indicated that both orthostatic hypotension and orthostatic hypertension independently predict cardiovascular events, the underlying mechanisms are still controversial. The aim of the study was to investigate the relationships between orthostatic changes and organ damage in subjects over 60 years old. METHODS: This is a prospective observational cohort study. One thousand nine hundred and ninety-seven subjects over 60 years old were enrolled. Participants were grouped according to whether they had a drop ≥ 20 mmHg in systolic or ≥ 10 mmHg in diastolic BP (orthostatic hypotension), an increase in mean orthostatic systolic blood pressure ≥ 20 mm Hg (orthostatic hypertension), or normal changes within 3 min of orthostatism. Multiple regression modeling was used to investigate the relationship between orthostatic hypotension, orthostatic hypertension and subclinical organ damage with adjustment for confounders. RESULTS: Orthostatic hypotension and orthostatic hypertension were found in 461 (23.1%) and 189 (9.5%) participants, respectively. Measurement of carotid intima-media thickness (IMT), brachial-ankle pulse wave velocity (baPWV), clearance of creatinine, and microalbuminuria were associated with orthostatic hypotension; measurement of IMT and baPWV were associated with orthostatic hypertension in a cruse model. After adjustment, IMT [odds ratio (OR), 95% confidence interval (CI) per one-SD increment: 1.385, 1.052-1.823; P = 0.02], baPWV (OR = 1.627, 95% CI: 1.041-2.544; P = 0.033) and microalbuminuria (OR = 1.401, 95% CI: 1.002-1.958; P = 0.049) were still associated with orthostatic hypotension, while orthostatic hypertension was only associated with IMT (OR = 1.730, 95% CI: 1.143-2.618; P = 0.009). CONCLUSIONS: Orthostatic hypotension seems to be independently correlated with increased carotid atherosclerosis, arterial stiffness and renal damage in subjects over 60 years old. Orthostatic hypertension correlates with carotid atherosclerosis only.

The functional role of Bax/Bak in palmitate-induced lipoapoptosis.

Induction of programmed cell death, mainly apoptosis (lipoapoptosis) is a major cellular consequence of the lipotoxicity, a harmful effect resulting from the overload of lipids. Both Endoplasmic reticulum (ER) stress and autophagy have been suggested to play important role in the regulation of lipoapoptosis. However, the exact mechanisms underlying lipoapoptosis remain unclear. In the present study, we aimed to investigate the functional role of Bax/Bak in lipoapoptosis using mouse embryonic fibroblasts (MEFs) cell culture model. Results showed that palmitate induced caspase-dependent apoptosis in wild-type Bax/Bak MEF cells, whereas a caspase-independent cell death was induced by palmitate in Bax/Bak knockout MEF cells, suggesting requirement of Bax/Bak in palmitate-induced caspase activation. More importantly, we found that the status of Bax/Bak is a determinant that governs the decision between the pro-survival or pro-death function of autophagy in response to palmitate exposure, and Bax/Bak is required for palmitate-induced activation of endoplasmic reticulum (ER) stress and subsequently ER stress-mediated apoptosis. The findings of the present study provided novel insights into understanding the mechanisms involved in the regulation of palmitate-induced lipoapoptosis.

Glycycoumarin Sensitizes Liver Cancer Cells to ABT-737 by Targeting De Novo Lipogenesis and TOPK-Survivin Axis.

Glycycoumarin (GCM) is a representative of bioactive coumarin compounds isolated from licorice, an edible and medicinal plant widely used for treating various diseases including liver diseases. The purpose of the present study is to examine the possibility of GCM as a sensitizer to improve the efficacy of BH3 mimetic ABT-737 against liver cancer. Three liver cancer cell lines (HepG2, Huh-7 and SMMC-7721) were used to evaluate the in vitro combinatory effect of ABT-737/GCM. HepG2 xenograft model was employed to assess the in vivo efficacy of ABT-737/GCM combination. Results showed that GCM was able to significantly sensitize liver cancer cells to ABT-737 in both in vitro and in vivo models. The enhanced efficacy by the combination of ABT-737 and GCM was attributed to the inactivation of T-LAK cell-originated protein kinase (TOPK)-survivin axis and inhibition of de novo lipogenesis. Our findings have identified induction of TOPK-survivin axis as a novel mechanism rendering cancer cells resistant to ABT-737. In addition, ABT-737-induced platelet toxicity was attenuated by the combination. The findings of the present study implicate that bioactive coumarin compound GCM holds great potential to be used as a novel chemo-enhancer to improve the efficacy of BH3 mimetic-based therapy.

Role of p62 in the regulation of cell death induction.

p62 is a multifunctional adaptor protein implicated in various cellular processes. It has been found to regulate selective autophagy, cell survival, cell death, oxidative stress, DNA repair and inflammation, and to play a role in a number of diseases, such as tumourigenesis, Paget's disease of bone, neurodegenerative disease, diabetes, and obesity. Cell death induction is an important cellular process. The dysregulation of cell death induction is involved in the pathogenesis of various diseases, such as cancer, neurodegeneration diseases, and diabetes. In this review, we discuss the functional role of p62 in inducing cell death in response to multiple stimuli, and we summarize the potential signaling pathways that contribute to this regulation. Given the important role of p62 in regulating cell death, p62 is considered to be a reasonable target for managing cell death dysregulation-related pathogenic conditions. A better understanding of the role of p62 and its related mechanisms in regulating cell death is necessary for the more precise utilization of p62 as a target for treating relevant diseases.

Methylseleninic Acid Prevents Patulin-Induced Hepatotoxicity and Nephrotoxicity via the Inhibition of Oxidative Stress and Inactivation of p53 and MAPKs.

Patulin is one of the common food-borne mycotoxins. Previous studies have demonstrated that patulin can cause diverse toxic effects in animals including hepatotoxicity and nephrotoxicity. In the present study, we have addressed the protective effect of two forms of selenium compounds methylseleninic acid (MSeA) and sodium selenite on patulin-induced nephrotoxicity and hepatotoxicity using both in vitro and in vivo models. Results showed that MSeA at concentrations of 3-5 µM, not sodium selenite at the same concentrations, is capable of protecting against patulin-induced cytotoxicity in the cell culture model. Moreover, the hepatoprotective and nephroprotective effects of MSeA (2 mg/kg body weight, oral administration) on patulin-induced toxicity (10 mg/kg body weight, intraperitoneal injection) were also achieved in the animal model. A further mechanistic study revealed that the protective effect of MSeA on patulin-mediated toxicity is attributed to its ability to inhibit patulin-mediated ROS generation and inactivate p53 and mitogen-activated protein kinase (MAPK) signaling pathways. Our findings support a possible usefulness of MSeA as a novel detoxicant to mitigate the toxicities of patulin.

Glycycoumarin inhibits hepatocyte lipoapoptosis through activation of autophagy and inhibition of ER stress/GSK-3-mediated mitochondrial pathway.

Herbal medicine as an alternative approach in the treatment of disease has drawn growing attention. Identification of the active ingredient is needed for effective utilization of the herbal medicine. Licorice is a popular herbal plant that is widely used to treat various diseases including liver diseases. Glycycoumarin (GCM) is a representative of courmarin compounds isolated from licorice. In the present study, the protective effect of GCM on hepatocyte lipoapoptosis has been evaluated using both cell culture model of palmitate-induced lipoapoptosis and animal model of non-alcoholic steatohepatitis (NASH). The results demonstrated for the first time that GCM was highly effective in suppressing hepatocyte lipoapoptosis in both in vitro and in vivo. Mechanistically, GCM was able to re-activate the impaired autophagy by lipid metabolic disorders. In line with the activation of autophagy, ER stress-mediated JNK and mitochondrial apoptotic pathway activation was inhibited by GCM both in vitro and in vivo. In addition, inactivation of GSK-3 might also contribute to the protective effect of GCM on hepatocyte lipoapoptosis. Our findings supported GCM as a novel active component of licorice against non-alcoholic fatty liver disease (NAFLD).

Glycycoumarin exerts anti-liver cancer activity by directly targeting T-LAK cell-originated protein kinase.

Glycycoumarin (GCM) is a major bioactive coumarin compound isolated from licorice and the anti-cancer activity of GCM has not been scientifically addressed. In the present study, we have tested the anti-liver cancer activity of GCM using both in vitro and in vivo models and found for the first time that GCM possesses a potent activity against liver cancer evidenced by cell growth inhibition and apoptosis induction in vitro and tumor reduction in vivo. Mechanistically, GCM was able to bind to and inactivate oncogenic kinase T-LAK cell-originated protein kinase (TOPK), which in turn led to activation of p53 pathway. Our findings supported GCM as a novel active compound that contributed to the anti-cancer activity of licorice and TOPK could be an effective target for hepatocellular carcinoma (HCC) treatment.

p53 activation contributes to patulin-induced nephrotoxicity via modulation of reactive oxygen species generation.

Patulin is a major mycotoxin found in fungal contaminated fruits and their derivative products. Previous studies showed that patulin was able to induce increase of reactive oxygen species (ROS) generation and oxidative stress was suggested to play a pivotal role in patulin-induced multiple toxic signaling. The objective of the present study was to investigate the functional role of p53 in patulin-induced oxidative stress. Our study demonstrated that higher levels of ROS generation and DNA damage were induced in wild-type p53 cell lines than that found in either knockdown or knockout p53 cell lines in response to patulin exposure, suggesting p53 activation contributed to patulin-induced ROS generation. Mechanistically, we revealed that the pro-oxidant role of p53 in response to patulin was attributed to its ability to suppress catalase activity through up-regulation of PIG3. Moreover, these in vitro findings were further validated in the p53 wild-type/knockout mouse model. To the best of our knowledge, this is the first report addressing the functional role of p53 in patulin-induced oxidative stress. The findings of the present study provided novel insights into understanding mechanisms behind oxidative stress in response to patulin exposure.