Critical role of endoplasmic reticulum stress on bisphenol A-induced cytotoxicity in human keratinocyte HaCaT cells.

Bisphenol A (BPA) is widely used in plastic and paper products, and its exposure can occur through skin contact or oral ingestion. The hazardous effects of BPA absorbed through the skin may be more severe; however, few studies have investigated the skin toxicity of BPA. This study investigated the effects of BPA on human epidermal keratinocyte cell lines, which is relevant for skin exposure. BPA treatment reduced cell viability in a time- and concentration-dependent manner and elevated oxidative and endoplasmic reticulum (ER) stress. N-acetylcysteine (NAC), an oxidative stress inhibitor, reduced BPA-induced reactive oxygen species (ROS) levels. However, only 10% of the decreased cell viability was restored at the highest NAC concentration. Treatment with tauroursodeoxycholic acid (TUDCA), which is an ER stress inhibitor, effectively countered the increase in ER stress-related proteins induced by BPA. Moreover, TUDCA treatment led to a reduction in oxidative stress, as demonstrated by the decrease in ROS levels, maintenance of mitochondrial membrane potential, and modulation of stress signaling proteins. Consequently, TUDCA significantly improved BPA-induced cytotoxicity in a concentration-dependent manner. Notably, combined treatment using TUDCA and NAC further reduced the BPA-induced ROS levels; however, no significant difference in cell viability was observed compared with that for TUDCA treatment alone. These findings indicated that the oxidative stress observed following BPA exposure was exacerbated by ER stress. Moreover, the principal factor driving BPA-induced cytotoxicity was indeed ER stress, which has potential implications for developing therapeutic strategies for diseases associated with similar stress responses.

Fasting potentiates diclofenac-induced liver injury via inductions of oxidative/endoplasmic reticulum stresses and apoptosis, and inhibition of autophagy by depleting hepatic glutathione in mice.

Diclofenac, a widely used non-steroidal anti-inflammatory drug, can cause liver damage via its metabolic activation by hepatic CYP450s and UGT2B7. Fasting can affect drug-induced liver injury by modulating the hepatic metabolism, but its influence on diclofenac hepatotoxicity is unknown. Thus, we investigated diclofenac-induced liver damage after fasting in mice, and the cellular events were examined. Male ICR mice fasted for 16 h showed the elevation of CYP3A11, but the decreases of UGT2B7, glutathione (GSH), and GSH S-transferase-µ/-π levels in the livers. Diclofenac (200 mg/kg) injection into the mice after 16-h fasting caused more significant liver damage compared to that in the diclofenac-treated fed mice, as shown by the higher serum ALT and AST activities. Diclofenac-promoted hepatic oxidative stress (oxidized proteins, 4-hydroxynonenal, and malondialdehyde), endoplasmic reticulum (ER) stress (BiP, ATF6, and CHOP), and apoptosis (cleaved caspase-3 and cleaved PARP) were enhanced by fasting. Autophagic degradation was inhibited in the diclofenac-treated fasting mice compared to that of the corresponding fed mice. The results suggest that fasting can make the liver more susceptible to diclofenac toxicity by lowering GSH-mediated detoxification; increased oxidative/ER stresses and apoptosis and suppressed autophagic degradation may be the cellular mechanisms of the aggravated diclofenac hepatotoxicity under fasting conditions.

TM4SF19-mediated control of lysosomal activity in macrophages contributes to obesity-induced inflammation and metabolic dysfunction.

Adipose tissue (AT) adapts to overnutrition in a complex process, wherein specialized immune cells remove and replace dysfunctional and stressed adipocytes with new fat cells. Among immune cells recruited to AT, lipid-associated macrophages (LAMs) have emerged as key players in obesity and in diseases involving lipid stress and inflammation. Here, we show that LAMs selectively express transmembrane 4 L six family member 19 (TM4SF19), a lysosomal protein that represses acidification through its interaction with Vacuolar-ATPase. Inactivation of TM4SF19 elevates lysosomal acidification and accelerates the clearance of dying/dead adipocytes in vitro and in vivo. TM4SF19 deletion reduces the LAM accumulation and increases the proportion of restorative macrophages in AT of male mice fed a high-fat diet. Importantly, male mice lacking TM4SF19 adapt to high-fat feeding through adipocyte hyperplasia, rather than hypertrophy. This adaptation significantly improves local and systemic insulin sensitivity, and energy expenditure, offering a potential avenue to combat obesity-related metabolic dysfunction.

Advantages of Using 3D Spheroid Culture Systems in Toxicological and Pharmacological Assessment for Osteogenesis Research.

Bone differentiation is crucial for skeletal development and maintenance. Its dysfunction can cause various pathological conditions such as rickets, osteoporosis, osteogenesis imperfecta, or Paget's disease. Although traditional two-dimensional cell culture systems have contributed significantly to our understanding of bone biology, they fail to replicate the intricate biotic environment of bone tissue. Three-dimensional (3D) spheroid cell cultures have gained widespread popularity for addressing bone defects. This review highlights the advantages of employing 3D culture systems to investigate bone differentiation. It highlights their capacity to mimic the complex in vivo environment and crucial cellular interactions pivotal to bone homeostasis. The exploration of 3D culture models in bone research offers enhanced physiological relevance, improved predictive capabilities, and reduced reliance on animal models, which have contributed to the advancement of safer and more effective strategies for drug development. Studies have highlighted the transformative potential of 3D culture systems for expanding our understanding of bone biology and developing targeted therapeutic interventions for bone-related disorders. This review explores how 3D culture systems have demonstrated promise in unraveling the intricate mechanisms governing bone homeostasis and responses to pharmacological agents.

Role of autophagy in betaine-promoted hepatoprotection against non-alcoholic fatty liver disease in mice.

Betaine, a compound found in plants and sea foods, is known to be beneficial against non-alcoholic fatty liver disease (NAFLD), but its hepatoprotective and anti-steatogenic mechanisms have been not fully understood. In the present study, we investigated the mechanisms underlying betaine-mediated alleviation of NAFLD induced by a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) in mice, with special focus on the contribution of betaine-stimulated autophagy to NAFLD prevention. Male ICR mice were fed a CDAHFD with or without betaine (0.2-1% in drinking water) for 1 week. Betaine ameliorated the CDAHFD-induced fatty liver by restoring sulfur amino acid (SAA)-related metabolites, such as S-adenosylmethionine and homocysteine, and the phosphorylation of AMPK and ACC. In addition, it reduced the CDAHFD-induced ER stress (BiP, ATF6, and CHOP) and apoptosis (Bax, cleaved caspase-3, and cleaved PARP); however, it induced autophagy (LC3II/I and p62) which was downregulated by CDAHFD. To determine the role of autophagy in the improvement of NAFLD, chloroquine (CQ), an autophagy inhibitor, was injected into the mice fed a CDAHFD and betaine (0.5 % in drinking water). CQ did not affect SAA metabolism but reduced the beneficial effects of betaine as shown by the increases of hepatic lipids, ER stress, and apoptosis. Notably, the betaine-induced improvements in lipid metabolism determined by protein levels of p-AMPK, p-ACC, PPARα, and ACS1, were reversed by CQ. Thus, the results of this study suggest that the activation of autophagy is an important upstream mechanism for the inhibition of steatosis, ER stress, and apoptosis by betaine in NAFLD.

Amelioration of Astrocyte-Mediated Neuroinflammation by EI-16004 Confers Neuroprotection in an MPTP-induced Parkinson's Disease Model.

Parkinson's disease (PD) is a neurodegenerative disorder that results in motor impairment due to dopaminergic neuronal loss. The pathology of PD is closely associated with neuroinflammation, which can be characterized by astrocyte activation. Thus, targeting the inflammatory response in astrocytes might provide a novel therapeutic approach. We conducted a luciferase assay on an in-house chemical library to identify compounds with anti-inflammatory effects capable of reducing MPP+-induced NF-κB activity in astrocytes. Among the compounds identified, EI-16004, a novel 3-benzyl-N-phenyl-1H-pyrazole-5-carboxamides, exhibited a significant anti-inflammatory effect by significantly reducing MPP+-induced astrocyte activation. Biochemical analysis and docking simulation indicated that EI-16004 inhibited the MPP+-induced phosphorylation of p65 by attenuating ERK phosphorylation, and EI-16004 reduced pro-inflammatory cytokine and chemokine levels in astrocytes. In vivo studies on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model in male C57BL/6 mice showed that EI-16004 ameliorated motor impairment and protected against dopaminergic neuronal loss, and EI-16004 effectively mitigated the MPTP-induced astrocyte activation in striatum (STR) and substantia nigra (SN). These results indicate EI-16004 is a potential neuroprotective agent for the prevention and treatment of astrocyte-mediated neuroinflammatory conditions in PD.

Iridoid Glycosides and Coumarin Glycoside Derivatives from the Roots of Nymphoides peltata and Their In Vitro Wound Healing Properties.

Nymphoides peltata has been used as a medicinal herb in traditional medicines to treat strangury, polyuria, and swelling. The phytochemical investigation of the MeOH extract of N. peltata roots led to the isolation of three iridoid glycosides and three coumarin glycoside derivatives, which were characterized as menthiafolin (1), threoninosecologanin (2), callicoside C (3), and scopolin (4), as well as two undescribed peltatamarins A (5) and B (6). The chemical structures of the undescribed compounds were determined by analyzing their 1 dimensional (D) and 2D nuclear magnetic resonance (NMR) spectra and using high-resolution (HR)-electrospray ionization mass spectroscopy (ESI-MS), along with the chemical reaction of acid hydrolysis. The wound healing activities of the isolated compounds 1-6 were evaluated using a HaCaT cell scratch test. Among the isolates, scopolin (4) and peltatamarin A (5) promoted HaCaT cell migration over scratch wounds, and compound 5 was the most effective. Furthermore, compound 5 significantly promoted cell migration without adversely affecting cell proliferation, even when treated at a high dose (100 µM). Our results demonstrate that peltatamarin A (5), isolated from N. peltata roots, has the potential for wound healing effects.

Doxorubicin Attenuates Free Fatty Acid-Induced Lipid Accumulation via Stimulation of p53 in HepG2 Cells.

Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive accumulation of fat in the liver, and there is a global increase in its incidence owing to changes in lifestyle and diet. Recent findings suggest that p53 is involved in the development of non-alcoholic fatty liver disease; however, the association between p53 expression and the disease remains unclear. Doxorubicin, an anticancer agent, increases the expression of p53. Therefore, this study aimed to investigate the role of doxorubicin-induced p53 upregulation in free fatty acid (FFA)-induced intracellular lipid accumulation. HepG2 cells were pretreated with 0.5 µg/mL of doxorubicin for 12 h, followed by treatment with FFA (0.5 mM) for 24 h to induce steatosis. Doxorubicin pretreatment upregulated p53 expression and downregulated the expression of endoplasmic reticulum stress- and lipid synthesis-associated genes in the FFA -treated HepG2 cells. Additionally, doxorubicin treatment upregulated the expression of AMP-activated protein kinase, a key modulator of lipid metabolism. Notably, siRNA-targeted p53 knockdown reversed the effects of doxorubicin in HepG2 cells. Moreover, doxorubicin treatment suppressed FFA -induced lipid accumulation in HepG2 spheroids. Conclusively, these results suggest that doxorubicin possesses potential application for the regulation of lipid metabolism by enhance the expression of p53 an in vitro NAFLD model.

Complement C3-Deficiency-Induced Constipation in FVB/N-C3em1Hlee/Korl Knockout Mice Was Significantly Relieved by Uridine and Liriope platyphylla L. Extracts.

Complement component 3 (C3) deficiency has recently been known as a cause of constipation, without studies on the therapeutic efficacy. To evaluate the therapeutic agents against C3-deficiency-induced constipation, improvements in the constipation-related parameters and the associated molecular mechanisms were examined in FVB/N-C3em1Hlee/Korl knockout (C3 KO) mice treated with uridine (Urd) and the aqueous extract of Liriope platyphylla L. (AEtLP) with laxative activity. The stool parameters and gastrointestinal (GI) transit were increased in Urd- and AEtLP-treated C3 KO mice compared with the vehicle (Veh)-treated C3 KO mice. Urd and AEtLP treatment improved the histological structure, junctional complexes of the intestinal epithelial barrier (IEB), mucin secretion ability, and water retention capacity. Also, an improvement in the composition of neuronal cells, the regulation of excitatory function mediated via the 5-hydroxytryptamine (5-HT) receptors and muscarinic acetylcholine receptors (mAChRs), and the regulation of the inhibitory function mediated via the neuronal nitric oxide synthase (nNOS) and inducible NOS (iNOS) were detected in the enteric nervous system (ENS) of Urd- and AEtLP-treated C3 KO mice. Therefore, the results of the present study suggest that C3-deficiency-induced constipation can improve with treatment with Urd and AEtLP via the regulation of the mucin secretion ability, water retention capacity, and ENS function.

Compositional changes in fecal microbiota in a new Parkinson's disease model: C57BL/6-Tg(NSE-haSyn) mice.

BACKGROUND: The gut-brain axis (GBA) in Parkinson's disease (PD) has only been investigated in limited mice models despite dysbiosis of the gut microbiota being considered one of the major treatment targets for neurodegenerative disease. Therefore, this study examined the compositional changes of fecal microbiota in novel transgenic (Tg) mice overexpressing human α-synuclein (hαSyn) proteins under the neuron-specific enolase (NSE) to analyze the potential as GBA model. RESULTS: The expression level of the αSyn proteins was significantly higher in the substantia nigra and striatum of NSE-hαSyn Tg mice than the Non-Tg mice, while those of tyrosine hydroxylase (TH) were decreased in the same group. In addition, a decrease of 72.7% in the fall times and a 3.8-fold increase in the fall number was detected in NSE-hαSyn Tg mice. The villus thickness and crypt length on the histological structure of the gastrointestinal (GI) tract decreased in NSE-hαSyn Tg mice. Furthermore, the NSE-hαSyn Tg mice exhibited a significant increase in 11 genera, including Scatolibacter, Clostridium, Feifania, Lachnoclostridium, and Acetatifactor population, and a decrease in only two genera in Ligilactobacillus and Sangeribacter population during enhancement of microbiota richness and diversity. CONCLUSIONS: The motor coordination and balance dysfunction of NSE-hαSyn Tg mice may be associated with compositional changes in gut microbiota. In addition, these mice have potential as a GBA model.

Glucocorticoid Receptor Down-Regulation Affects Neural Stem Cell Proliferation and Hippocampal Neurogenesis.

Dysregulation of the hypothalamic-pituitary-adrenal axis and abnormalities in the glucocorticoid receptor (GR) have been linked to major depressive disorder. Given the critical role of GR in stress response regulation, we investigated the impact of GR changes on neural stem cells (NSCs) proliferation and hippocampal neurogenesis. Stress response was induced using dexamethasone (DEX), a GR agonist, which led to reduced proliferation of neural stem cells and neural progenitor cells, as well as decreased expression of GR. Additionally, a reduction of serum concentration within the culture media resulted in suppressed cell proliferation, accompanied by decreased GR expression. The association between GR expression and cell proliferation was further confirmed through GR siRNA knockdown and overexpression experiments. Furthermore, in vivo studies utilizing young male C57BL/6 mice demonstrated that corticosterone (CORT) (35 µg/ml) administered through drinking water for four weeks induced depression-like behavior, as indicated by increased immobility times in forced swimming and tail suspension tests. CORT exposure led to reduced GR and nestin expression levels, along with diminished numbers of BrdU-positive cells in the hippocampi, indicating impaired hippocampal neurogenesis. Taken together, our findings provide the first evidence that stress-induced downregulation of GR negatively affects neurogenesis by inhibiting NSCs proliferation.

MicroRNA 29a therapy for CEACAM6-expressing lung adenocarcinoma.

BACKGROUND: Non-coding microRNAs (miRNAs) play critical roles in tumor progression and hold great promise as therapeutic agents for multiple cancers. MicroRNA 29a (miR-29a) is a tumor suppressor miRNA that inhibits cancer cell growth and tumor progression in non-small cell lung cancer. Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), which plays an important role in lung cancer progression, has been identified as a target of miR-29a. Here, we evaluated the therapeutic efficacy of a peptide vector capable of delivering miR-29a intracellularly using the acidic tumor microenvironment in a lung adenocarcinoma xenograft mouse model. METHODS: A miRNA delivery vector was constructed by tethering the peptide nucleic acid form of miR-29a to a peptide with a low pH-induced transmembrane structure (pHLIP) to enable transport of the miRNAs across the plasma membrane. Tumor suppressive effects of pHLIP-miR29a on lung adenocarcinoma development in vivo were assessed using a BALB/c xenograft model injected with A549 cells. RESULTS: Incubation of A549 cells with pHLIP-miR-29a at an acidic pH downregulated endogenous CEACAM6 expression and reduced cell viability. Intravenous injection of the mice with pHLIP-miR-29a inhibited tumor growth by up to 18.1%. Intraperitoneal injection of cisplatin reduced tumor volume by 29.9%. Combined pHLIP-miR-29a + cisplatin treatment had an additive effect, reducing tumor volume up to 39.7%. CONCLUSIONS: Delivery of miR-29a to lung adenocarcinoma cells using a pHLIP-mediated method has therapeutic potential as a unique cancer treatment approach.

Lipid remodeling of adipose tissue in metabolic health and disease.

Adipose tissue is a dynamic and metabolically active organ that plays a crucial role in energy homeostasis and endocrine function. Recent advancements in lipidomics techniques have enabled the study of the complex lipid composition of adipose tissue and its role in metabolic disorders such as obesity, diabetes, and cardiovascular disease. In addition, adipose tissue lipidomics has emerged as a powerful tool for understanding the molecular mechanisms underlying these disorders and identifying bioactive lipid mediators and potential therapeutic targets. This review aims to summarize recent lipidomics studies that investigated the dynamic remodeling of adipose tissue lipids in response to specific physiological changes, pharmacological interventions, and pathological conditions. We discuss the molecular mechanisms of lipid remodeling in adipose tissue and explore the recent identification of bioactive lipid mediators generated in adipose tissue that regulate adipocytes and systemic metabolism. We propose that manipulating lipid-mediator metabolism could serve as a therapeutic approach for preventing or treating obesity-related metabolic diseases.

Cationic nanoplastic causes mitochondrial dysfunction in neural progenitor cells and impairs hippocampal neurogenesis.

Nanoplastics (NPs) exposure to humans can occur through various routes, including the food chain, drinking water, skin contact, and respiration. NPs are plastics with a diameter of less than 100 nm and have the potential to accumulate in tissues, leading to toxic effects. This study aimed to investigate the neurotoxicity of polystyrene NPs on neural progenitor cells (NPCs) and hippocampal neurogenesis in a rodent model. Toxicity screening of polystyrene NPs based on their charge revealed that cationic amine-modified polystyrene (PS-NH3+) exhibited cytotoxicity, while anionic carboxylate-modified polystyrene (PS-COO-) and neutral NPs (PS) did not. NPCs treated with PS-NH3+ showed a significant reduction in growth rate due to G1 cell cycle arrest. PS-NH3+ increased the expression of cell cycle arrest markers p21 and p27, while decreasing cyclin D expression in NPCs. Interestingly, PS-NH3+ accumulated in mitochondria, leading to mitochondrial dysfunction and energy depletion, which caused G1 cell cycle arrest. Prolonged exposure to PS-NH3+ in C17.2 NPCs increased the expression of p16 and senescence-associated secretory phenotype factors, indicating cellular senescence. In vivo studies using C57BL/6 mice demonstrated impaired hippocampal neurogenesis and memory retention after 10 days of PS-NH3+ administration. This study suggests that NPs could deplete neural stem cell pools in the brain by mitochondrial dysfunction, thereby adversely affecting hippocampal neurogenesis and neurocognitive functions.

Dramatic reduction of toxicity of Poly(hexamethylene guanidine) disinfectant by charge neutralization.

The current study aimed to investigate the toxicity of positively charged polyhexamethylene guanidine (PHMG) polymer and its complexation with different anionic natural polymers such as k-carrageenan (kCG), chondroitin sulfate (CS), sodium alginate (Alg.Na), polystyrene sulfonate sodium (PSS.Na) and hydrolyzed pectin (HP). The physicochemical properties of the synthesized PHMG and its combination with anionic polyelectrolyte complexes (PECs) namely PHMG:PECs were characterized using zeta potential, XPS, FTIR, and TG analysis. Furthermore, cytotoxic behavior of the PHMG and PHMG:PECs, respectively, were evaluated using human liver cancer cell line (HepG2). The study results revealed that the PHMG alone had slightly higher cytotoxicity to the HepG2 cells than the prepared polyelectrolyte complexes such as PHMG:PECs. The PHMG:PECs showed a significant reduction of cytotoxicity to the HepG2 cells than the pristine PHMG alone. A reduction of PHMG toxicity was observed may be due to the facile formation of complexation between the positively charged PHMG and negatively charged anionic natural polymers such as kCG, CS, Alg. Na, PSS.Na and HP, respectively, via charge balance or neutralization. The experimental results indicate that the suggested method might significantly lower PHMG toxicity while improving biocompatibility.

Chitinase 3 like 1 deficiency ameliorates lipopolysaccharide-induced acute liver injury by inhibition of M2 macrophage polarization.

Chitinase 3-like-1 protein (CHI3L1) is involved in various infectious diseases, especially sepsis. Aberrant CHI3L1 expression potentially plays a critical role in chronic inflammation because a considerable number of macrophages are associated with immune/inflammatory diseases. In this study, we examined the effect of CHI3L1 on hepatic sepsis injury using a lipopolysaccharide (LPS)-induced model. LPS-treated CHI3L1 knockout (KO) mice exhibited a higher survival rate than LPS-treated CHI3L1 wild-type (WT) mice. In addition, hepatic injury-related enzyme levels (aspartate transaminase, alanine transaminase, and lactate dehydrogenase) decreased in CHI3L1 KO mice sera, suggesting attenuated LPS-induced septic liver damage in CHI3L1 KO mice. A greater reduction in the mRNA and protein expressions of M2 polarization markers, such as MRC1, ARG1, IL-10, and IL-4, was observed in LPS-induced CHI3L1 KO mice livers than in LPS-induced WT mice livers. Nonetheless, no change in the mRNA and protein expressions of M1 polarization markers, such as INOS, CD86, TNF-α, and IL6, was noted in LPS-induced CHI3L1 KO mice livers compared with those in LPS-induced WT and KO mice. Similar to the in vivo scenario, liver CHI3L1 depletion in LPS-treated HEP3B cells significantly decreased M2 polarization marker protein expression. However, M1 polarization marker protein expression did not differ significantly. These results suggest that CHI3L1 depletion decreases M2 macrophage polarization, and this effect is potentially associated with the alleviation of liver sepsis in CHI3L1 KO mice.

Effect of Isoquercitrin on Free Fatty Acid-Induced Lipid Accumulation in HepG2 Cells.

Liver metabolic disorders and oxidative stress are crucial factors in the development of nonalcoholic fatty liver disease (NAFLD); however, treatment strategies to combat NAFLD remain poorly established, presenting an important challenge that needs to be addressed. Herein, we aimed to examine the effect of isoquercitrin on lipid accumulation induced by exogenous free fatty acids (FFA) using HepG2 cells and elucidate the underlying molecular mechanism. The cells were exposed to 0.5 mM FFA to induce intracellular lipid accumulation, followed by co-treatment with isoquercitrin to confirm the potential inhibitory effect on FFA-induced lipid production. HepG2 cells exposed to FFA alone exhibited intracellular lipid accumulation, compromised endoplasmic reticulum (ER) stress, and enhanced expression of proteins and genes involved in lipid synthesis; however, co-treatment with isoquercitrin decreased the expression of these molecules in a dose-dependent manner. Furthermore, isoquercitrin could activate AMP-activated protein kinase (AMPK), a key regulatory protein of hepatic fatty acid oxidation, suppressing new lipid production by phosphorylating acetyl-CoA carboxylase (ACC) and inhibiting sterol regulatory element-binding transcription factor 1 (SREBP-1)/fatty acid synthase (FAS) signals. Overall, these findings suggest that isoquercitrin can be employed as a therapeutic agent to improve NAFLD via the regulation of lipid metabolism by targeting the AMPK/ACC and SREBP1/FAS pathways.

Comparison of Hepatic Metabolite Profiles between Infant and Adult Male Mice Using 1H-NMR-Based Untargeted Metabolomics.

Although age-related characteristics of hepatic metabolism are reported, those in infants are not fully understood. In the present study, we performed untargeted metabolomic profiling of the livers of infant (3-week-old) and adult (9-week-old) male ICR mice using 1H-NMR spectroscopy and compared 35 abundant hepatic metabolite concentrations between the two groups. The liver/body weight ratio did not differ between the two groups; however, serum glucose, blood urea nitrogen, total cholesterol, and triglyceride concentrations were lower in infants than in adults. Hepatic carbohydrate metabolites (glucose, maltose, and mannose) were higher, whereas amino acids (glutamine, leucine, methionine, phenylalanine, tyrosine, and valine) were lower in infant mice than in adult mice. The concentrations of ascorbate, betaine, sarcosine, and ethanolamine were higher, whereas those of taurine, inosine, and O-phosphocholine were lower in infant mice than in adult mice. The differences in liver metabolites between the two groups could be due to differences in their developmental stages and dietary sources (breast milk for infants and laboratory chow for adults). The above results provide insights into the hepatic metabolism in infants; however, the exact implications of the findings require further investigation.

Adipocyte lysoplasmalogenase TMEM86A regulates plasmalogen homeostasis and protein kinase A-dependent energy metabolism.

Dysregulation of adipose tissue plasmalogen metabolism is associated with obesity-related metabolic diseases. We report that feeding mice a high-fat diet reduces adipose tissue lysoplasmalogen levels and increases transmembrane protein 86 A (TMEM86A), a putative lysoplasmalogenase. Untargeted lipidomic analysis demonstrates that adipocyte-specific TMEM86A-knockout (AKO) increases lysoplasmalogen content in adipose tissue, including plasmenyl lysophosphatidylethanolamine 18:0 (LPE P-18:0). Surprisingly, TMEM86A AKO increases protein kinase A signalling pathways owing to inhibition of phosphodiesterase 3B and elevation of cyclic adenosine monophosphate. TMEM86A AKO upregulates mitochondrial oxidative metabolism, elevates energy expenditure, and protects mice from metabolic dysfunction induced by high-fat feeding. Importantly, the effects of TMEM86A AKO are largely reproduced in vitro and in vivo by LPE P-18:0 supplementation. LPE P-18:0 levels are significantly lower in adipose tissue of human patients with obesity, suggesting that TMEM86A inhibition or lysoplasmalogen supplementation might be therapeutic approaches for preventing or treating obesity-related metabolic diseases.

Effects of dietary restriction on hepatic sulfur-containing amino acid metabolism and its significance in acetaminophen-induced liver injury.

Dietary restriction (DR) has been revealed to have health benefits as it induces reduction in oxidative stress. Glutathione (GSH), an important cellular antioxidant, is increased in rodent livers owing to DR; however, the exact mechanism and clinical relevance of DR are yet to be fully understood. In this study, male C57BL/6 mice were administered a 50% restricted diet for 7 d, and the hepatic sulfur-containing amino acid (SAA) metabolism was determined to assess the biosynthesis of GSH. The hepatic methionine level was found to decrease, while the homocysteine, cysteine, and GSH levels were increased owing to decreased betaine-homocysteine methyltransferase (BHMT) and increased CßS, CγL, and glutamate cysteine ligase catalytic subunit (GCLC) proteins in the livers of mice subjected to DR. To determine the effects of DR on drug-induced oxidative liver injury, mice subjected to DR were injected with a toxic dose (300 mg/kg) of acetaminophen (APAP). DR significantly alleviated APAP-induced liver damage and oxidative stress, which might be attributed to the higher levels of GSH and related antioxidant enzyme (GPx, GSTα, and GSTµ) in the livers. The decrease in the levels of hepatic CYP1A, 2E1, and 3A, which imply the inhibition of APAP metabolic activation, could contribute to the lower hepatotoxicity in mice subjected to DR. Overall, our findings revealed that DR stimulated the hepatic transsulfuration pathway and GSH synthesis. The consequent elevation of GSH could thus serve as an important mechanism of DR-mediated liver protection against APAP intoxication.