Hepatocyte-specific Selenoi deficiency predisposes mice to hepatic steatosis and obesity.

Selenoprotein I (Selenoi) is highly expressed in liver and plays a key role in lipid metabolism as a phosphatidylethanolamine (PE) synthase. However, the precise function of Selenoi in the liver remains elusive. In the study, we generated hepatocyte-specific Selenoi conditional knockout (cKO) mice on a high-fat diet to identify the physiological function of Selenoi. The cKO group exhibited a significant increase in body weight, with a 15.6% and 13.7% increase in fat accumulation in white adipose tissue (WAT) and the liver, respectively. Downregulation of the lipolysis-related protein (p-Hsl) and upregulation of the adipogenesis-related protein (Fasn) were observed in the liver of cKO mice. The cKO group also showed decreased oxygen consumption (VO2), carbon dioxide production (VCO2), and energy expenditure (p < .05). Moreover, various metabolites of the steroid hormone synthesis pathway were affected in the liver of cKO mice. A potential cascade of Selenoi-phosphatidylethanolamine-steroid hormone synthesis might serve as a core mechanism that links hepatocyte-specific Selenoi cKO to biochemical and molecular reactions. In conclusion, we revealed that Selenoi inhibits body fat accumulation and hepatic steatosis and elevates energy consumption; this protein could also be considered a therapeutic target for such related diseases.

Melatonin modulates neuroinflammatory response and microglial activation in mice exposed to dim blue light at night.

Objectives: Dim light at night contributes to neurodegenerative diseases by causing neuroinflammation. In the central nervous system, the activation of microglia is a significant contributor to neuroinflammation. Therefore, there is an urgent need to find an intervention to treat the neuroinflammatory response caused by dim light at night. Melatonin is a rhythmic hormone whose synthesis is suppressed during the day. In this study, we attempt to explore whether and how melatonin improves hippocampal neuroinflammation in mice exposed to dim blue light at night. Materials and Methods: In vivo, a total of 36 male C57BL6/J mice that exposed to no light at night, dim blue light at night, and dim blue light at night with melatonin treatment. In vitro, the corticosterone-induced BV2 cells with or without melatonin treatment were used. Results: Both in vivo and in vitro experiments showed melatonin treatment significantly reduced dim blue light -induced hippocampal microglial activation and the expression of inflammatory factors IL-1ß and TNF-α. This improved effect of melatonin is related to its receptor MT2 rather than MT1. The MT2 blockers significantly increased mRNA levels of M1-type activation marker CD86 and inflammatory cytokines IL-1ß and TNF-α in melatonin-treated BV2 cells. Binding of melatonin to its receptor MT2 downregulated the expression of inflammatory proteins P-P65 and NLRP3, consequently inhibited the CD80 expression and M1-type activation in microglia. Furthermore, consistent with the decrease in microglial activation and inflammatory response after melatonin treatment, we also observed a reduction in hippocampal neuron loss and damage to the HT22 cells. Conclusion: Our findings suggested that melatonin may regulate microglial polarization through MT2/NF-kB-NLRP3 pathway and improves dim blue light -induced hippocampal neuroinflammation in mice.

Neurotoxic mechanisms of mycotoxins: Focus on aflatoxin B1 and T-2 toxin.

Aflatoxin B1 (AFB1) and T-2 toxin are commonly found in animal feed and stored grain, posing a serious threat to human and animal health. Mycotoxins can penetrate brain tissue by compromising the blood-brain barrier, triggering oxidative stress and neuroinflammation, and leading to oxidative damage and apoptosis of brain cells. The potential neurotoxic mechanisms of AFB1 and T-2 toxin were discussed by summarizing the relevant research reports from the past ten years. AFB1 and T-2 toxin cause neuronal damage in the cerebral cortex and hippocampus, leading to synaptic transmission dysfunction, ultimately impairing the nervous system function of the body. The toxic mechanism is related to excessive reactive oxygen species (ROS), oxidative stress, mitochondrial dysfunction, apoptosis, autophagy, and an exaggerated inflammatory response. After passing through the blood-brain barrier, toxins can directly affect glial cells, alter the activation state of microglia and astrocytes, thereby promoting brain inflammation, disrupting the blood-brain barrier, and influencing the synaptic transmission process. We discussed the diverse effects of various concentrations of toxins and different modes of exposure on neurotoxicity. In addition, toxins can also cross the placental barrier, causing neurotoxic symptoms in offspring, as demonstrated in various species. Our goal is to uncover the underlying mechanisms of the neurotoxicity of AFB1 and T-2 toxin and to provide insights for future research, including investigating the impact of mycotoxins on interactions between microglia and astrocytes.

SELENOI Functions as a Key Modulator of Ferroptosis Pathway in Colitis and Colorectal Cancer.

Ferroptosis plays important roles both in normal physiology and multiple human diseases. It is well known that selenoprotein named glutathione peroxidase 4 (GPX4) is a crucial regulator for ferroptosis. However, it remains unknown whether other selenoproteins responsible for the regulation of ferroptosis, particularly in gut diseases. In this study, it is observed that Selenoprotein I (Selenoi) prevents ferroptosis by maintaining ether lipids homeostasis. Specific deletion of Selenoi in intestinal epithelial cells induced the occurrence of ferroptosis, leading to impaired intestinal regeneration and compromised colonic tumor growth. Mechanistically, Selenoi deficiency causes a remarkable decrease in ether-linked phosphatidylethanolamine (ePE) and a marked increase in ether-linked phosphatidylcholine (ePC). The imbalance of ePE and ePC results in the upregulation of phospholipase A2, group IIA (Pla2g2a) and group V (Pla2g5), as well as arachidonate-15-lipoxygenase (Alox15), which give rise to excessive lipid peroxidation. Knockdown of PLA2G2A, PLA2G5, or ALOX15 can reverse the ferroptosis phenotypes, suggesting that they are downstream effectors of SELENOI. Strikingly, GPX4 overexpression cannot rescue the ferroptosis phenotypes of SELENOI-knockdown cells, while SELENOI overexpression can partially rescue GPX4-knockdown-induced ferroptosis. It suggests that SELENOI prevents ferroptosis independent of GPX4. Taken together, these findings strongly support the notion that SELENOI functions as a novel suppressor of ferroptosis during colitis and colon tumorigenesis.

The Effect Mechanism of N6-adenosine Methylation (m6A) in Melatonin Regulated LPS-induced Colon Inflammation.

Colon inflammation is characterized by disturbances in the intestinal microbiota and inflammation. Melatonin (Mel) can improve colon inflammation. However, the underlying mechanism remains unclear. Recent studies suggest that m6A methylation modification may play an important role in inflammatory responses. This study aimed to explore the effects of melatonin and LPS-mediated m6A methylation on colon inflammation. Our study found that melatonin inhibits M1 macrophages, activates M2 macrophages, inhibit the secretion of pro-inflammatory factors, maintain colon homeostasis and improves colon inflammation through MTNR1B. In addition, the increased methylation level of m6A is associated with the occurrence of colon inflammation, and melatonin can also reduce the level of colon methylation to improve colon inflammation. Among them, the main methylated protein METTL3 can be inhibited by melatonin through MTNR1B. In a word, melatonin regulates m6A methylation by improving abnormal METTL3 protein level to reshape the microflora and activate macrophages to improve colon inflammation, mainly through MTNR1B.

Melatonin restores hepatic lipid metabolic homeostasis disrupted by blue light at night in high-fat diet-fed mice.

Artificial light at night (ALAN) is an emerging environmental pollutant that threatens public health. Recently, ALAN has been identified as a risk factor for obesity; however, the role of ALAN and its light wavelength in hepatic lipid metabolic homeostasis remains undetermined. We showed that chronic dim (~5 lx) ALAN (dLAN) exposure significantly promoted hepatic lipid accumulation in obese or diabetic mice, with the most severe effect of blue light and little effect of green or red light. These metabolic phenotypes were attributed to blue rather than green or red dLAN interfering with hepatic lipid metabolism, especially lipogenesis and lipolysis. Further studies found that blue dLAN disrupted hepatic lipogenesis and lipolysis processes by inhibiting hepatic REV-ERBs. Mechanistically, feeding behavior mediated the regulation of dLAN on hepatic REV-ERBs. In addition, different effects of light wavelengths at night on liver REV-ERBs depended on the activation of the corticosterone (CORT)/glucocorticoid receptor (GR) axis. Blue dLAN could activate the CORT/GR axis significantly while other wavelengths could not. Notably, we demonstrated that exogenous melatonin could effectively inhibit hepatic lipid accumulation and restore the hepatic GR/REV-ERBs axis disrupted by blue dLAN. These findings demonstrate that dLAN promotes hepatic lipid accumulation in mice via a short-wavelength-dependent manner, and exogenous melatonin is a potential therapeutic approach. This study strengthens the relationship between ALAN and hepatic lipid metabolism and provides insights into directing ambient light.

Biomimetic MicroRNAs-Selenium-Nanocomposites for Targeted and Combined Hyperlipidemia Therapy.

Hyperlipidemia is considered as a high-risk factor for leading to coronary heart disease. MicroRNA-148a-3p (miR-148a-3p) inhibitor is a potential therapeutic target to bind low-density lipoprotein cholesterol receptors (LDLR) for decreasing the levels of low-density lipoprotein cholesterol in plasma. However, the therapeutic effects are not ideal in the clinical translation of nucleic acids treatment, owing to the short circulation time in vivo. Therefore, a platelet membrane (PM) cloaks Se nanoparticles (SeNPs) delivery system with chitosan (CS) modifies and miR-148a-3p inhibitors encapsulated is designed (PM/CS-SeNPs/miR). The PM/CS-SeNPs/miR shows a uniform shell-core structure with a particle size of ≈90 nm. Co-delivering miR-148a-3p inhibitors and Se effectively alleviate hyperlipidemia via LDLR pathway and Toll-Like Receptor 4 (TLR-4)/NF-κB signaling pathway, respectively. Furthermore, coated by PM, PM/CS-SeNPs/miR successfully prolong circulation time to 48 h in vivo and quickly target to liver with no toxicity. This dual combination therapy with miRNAs and Se based on nanoparticles targeted delivery presents a high-performance strategy for precise hyperlipidemia treatment.

Stabilization by Chaperone GroEL in Biogenic Selenium Nanoparticles Produced from Bifidobacterium animalis H15 for the Treatment of DSS-Induced Colitis.

Inflammatory bowel diseases have a high rate of mortality and pose a serious threat to global public health. Selenium is an essential trace element, which has been shown to play important roles in redox control and antioxidant defense. Microorganisms play important roles in the reduction of toxic inorganic selenium (selenite and selenate) to less-toxic biogenic selenium nanoparticles (Bio-SeNPs), which have higher biocompatibility. In the present study, novel Bio-SeNPs with high stability were synthesized using probiotic Bifidobacterium animalis subsp. lactis H15, which was isolated from breastfed infant feces. The Bio-SeNPs with a size of 122 nm showed stability at various ionic strengths, temperatures, and in simulated gastrointestinal fluid, while chemosynthetic SeNPs underwent aggregation. The main surface protein in the Bio-SeNPs was identified as chaperone GroEL by liquid chromatography-tandem mass spectrometry. The overexpression and purification of GroEL demonstrated that GroEL controlled the assembly of Bio-SeNPs both in vitro and in vivo. In vivo, oral administration of Bio-SeNPs could alleviate dextran sulfate sodium-induced colitis by decreasing cell apoptosis, increasing antioxidant capacity and the number of proliferating cells, and improving the function of the intestinal mucosal barrier. In vitro experiments verified that Bio-SeNPs inhibited lipopolysaccharide-induced toll-like receptor 4/NF-κB signaling pathway activation. These results suggest that the Bio-SeNPs with high stability could have potential as a nutritional supplement for the treatment of colitis in nanomedicine applications.

A ratiometric dual-fluorescent paper-based synthetic biosensor for visual detection of tetracycline on-site.

The excessive use of tetracycline poses a threat to human health, making it essential to monitor and regulate its usage. While whole-cell biosensors offer a simple and cost-effective method, their utility is constrained by limitations in sensitivity, portability, and robustness, hindering real-time measurements within complex environmental contexts. In this study, a ratiometric i/cTetR synthetic biosensing test strip with an engineered modified dual-fluorescence reporting was developed for detecting Tet antibiotics in water and food. First, the standardized unidirectional promoter PtetR by tailoring and screening TetR transcription factor binding sites and verified by molecular docking, shortening the detection time. Secondly, decoupling the sensing and reporting modules enhances the biosensor's performance, eliminating genetic background leakage and tripling the output signal. Thirdly, a ratiometric dual fluorescence signal i/cTetR biosensing test strip was designed. Under the light box LED/UV light source, the dual signal output method significantly reduced false negative results and enhanced the anti-interference capability of the biosensor. The i/cTetR strips can detect Tet in tap water (5-1280 µg/mL) and milk (50-3200 µg/kg) within 45 min in high volume on-site without separation and purification. This study provides a standardized and universal sensing method for the field detection of antibiotic contaminants.

Allosteric strand displacement isothermal amplification for the visual detection of Toxoplasma gondii in 30 minutes.

Early detection of Toxoplasma gondii (T. gondii) is critical due to a lack of effective treatment for toxoplasmosis.This study established a simple, cost-effective, and rapid colorimetric detection method for T. gondii. The entire testing process, from sample collection to results, takes only 0.5 h. These characteristics fulfill the demands of researchers seeking rapid target detection with minimal equipment reliance. For genomic extraction, this study evaluated the ability of two filter papers to capture genomes. A rapid genomic extraction device combined with the two filter papers was designed to simplify the genomic extraction process, which was completed within 10 min and increased the detection sensitivity tenfold. The method utilized a simplified primer design for isothermal amplification, namely allosteric strand displacement (ASD), and employed an underutilized commercial color indicator, Bromothymol Blue (BTB), for signal output. Compared with other reported indicators, BTB exhibited a more pronounced color change, shifting from blue to yellow in positive samples, facilitating easier visual differentiation. The reaction was completed in 20 min with a limit of detection (LOD) as low as 0.014 T. gondii per microliter.

Melatonin Alleviates Lipopolysaccharide-Induced Abnormal Pregnancy through MTNR1B Regulation of m6A.

Pregnancy is a highly intricate and delicate process, where inflammation during early stages may lead to pregnancy loss or defective implantation. Melatonin, primarily produced by the pineal gland, exerts several pharmacological effects. N6-methyladenosine (m6A) is the most prevalent mRNA modification in eukaryotes. This study aimed to investigate the association between melatonin and m6A during pregnancy and elucidate the underlying protective mechanism of melatonin. Melatonin was found to alleviate lipopolysaccharide (LPS)-induced reductions in the number of implantation sites. Additionally, it mitigated the activation of inflammation, autophagy, and apoptosis pathways, thereby protecting the pregnancy process in mice. The study also revealed that melatonin regulates uterine m6A methylation levels and counteracts abnormal changes in m6A modification of various genes following LPS stimulation. Furthermore, melatonin was shown to regulate m6A methylation through melatonin receptor 1B (MTNR1B) and subsequently modulate inflammation, autophagy, and apoptosis through m6A. In conclusion, our study demonstrates that melatonin protects pregnancy by influencing inflammation, autophagy, and apoptosis pathways in an m6A-dependent manner via MTNR1B. These findings provide valuable insights into the mechanisms underlying melatonin's protective effects during pregnancy and may have implications for potential therapeutic strategies in managing pregnancy-related complications.

Extracellular vesicle therapy for obesity-induced NAFLD: a comprehensive review of current evidence.

Non-alcoholic fatty liver disease (NAFLD) as a chronic disease especially in Western countries, is still a tough question in the clinical therapy. With the rising prevalence of various chronic diseases, liver transplantation is expected to be the most common therapy after the next 10 years. However, there is still no approved drug for NAFLD, and targeted therapy for NAFLD is urgent. Exosomes as a kind of extracellular vesicle are cell-derived nanovesicles, which play an essential role in intercellular communication. Due to complex cell-cell interactions in the liver, exosomes as therapeutic drugs or drug delivery vesicles may be involved in physiological or pathological processes in NAFLD. Compared with other nanomaterials, exosomes as a cell-free therapy, are not dependent on cell number limitation, which means can be administered safely in high doses. Apart from this, exosomes with the advantages of being low-toxic, high stability, and low-immunological are chosen for targeted therapy for many diseases. In this review, firstly we introduced the extracellular vesicles, including the biogenesis, composition, isolation and characterization, and fundamental function of extracellular vesicles. And then we discussed the modification of extracellular vesicles, cargo packing, and artificial exosomes. Finally, the extracellular vesicles for the therapies of NAFLD are summarized. Moreover, we highlight therapeutic approaches using exosomes in the clinical treatment of NAFLD, which provide valuable insights into targeting NAFLD in the clinical setting.

A label-free fluorescent magnetic dual-aptasensor based on aptamer allosteric regulation of ß-lactoglobulin.

We presented a label-free fluorescent biosensor based on magnetic dual-aptamer allosteric regulation of ß-lactoglobulin (ß-LG) detection. The bovine serum albumin (BSA) acted as the bridge to connect amino-modified magnetic beads and aptamer, which synthesized pyramid-type probes (MBAP) with high capture and reduced nonspecific adsorption. Moreover, the original aptamer was tailored and then designed as a bivalent aptamer to fabricate allosteric signal probes (ASP). The ASP can both specifically capture ß-LG and output the fluorescence signal. The detection mechanism is as follows. The combination of the dual-aptamer and ß-LG triggered the allosteric change, resulting in the release of SYBR Green (SG I) from the allosteric signal probe and change signals. This method exhibits a broad linear detection range from 10 ng/mL to 1 mg/mL and the limit of detection reaches as low as 8.06 ng/mL. This study provides a highly generalizable strategy for protein biomolecular detection via replacing different target aptamers.

Hesperetin protects hippocampal neurons from the neurotoxicity of Aflatoxin B1 in mice.

Aflatoxin B1 (AFB1) is a major food and feed pollutant that endangers public health. Previous studies have shown that exposure to AFB1 causes neurotoxicity in the body. However, the mechanism of neurotoxicity caused by AFB1 is not well understood, and finding a workable and practical method to safeguard animals from AFB1 toxicity is essential. This study confirmed that AFB1 caused endoplasmic reticulum stress (ER stress) and apoptosis in hippocampal neurons using C57BL/6 J mice and HT22 cells as models. In vitro experiments showed that the aryl hydrocarbon receptor (AHR) plays a significant role in the cytotoxicity of AFB1. Finally, we assessed how hesperetin protecting against the neurotoxicity caused by AFB1. Our findings demonstrated that AFB1 increased the levels of BAX and Cleaved-Caspase3 proteins, while decreasing the levels of BCL2 protein in the CA1 and CA3 regions of the hippocampus. The AFB1 increased the expression of AHR and activated nuclear translocation. It also elevated the expression levels of Chop, GRP78, p-IRE1/ Xbp1s, and p-PERK/p-EIF2a. Importantly, we also discovered for the first time that blocking AHR in HT22 cells dramatically reduced the level of ER stress and apoptosis caused by AFB1. In vivo and in vitro studies, supplementation of hesperetin effectively reversed AFB1-induced cytotoxicity. We have demonstrated that hesperetin effectively restored the imbalance in the GSH/GST system in HT22 cells treated with AFB1. Furthermore, we observed that elevated GSH levels facilitated the formation of AFB1-GSH complexes, which enhanced the excretion of AFB1. Therefore, hesperetin improves ER stress-induced apoptosis by reducing AFB1 activation of AHR.

The signal pathway of melatonin mediates the monochromatic light-induced T-lymphocyte apoptosis in chicken thymus.

Our previous study revealed that under monochromatic red light (RL), the melatonin nuclear receptor reduces the proliferation activity of broiler thymic lymphocytes through the P65 signaling pathway. The main objective of this study was to investigate the signal mechanism by which RL decreases thymic lymphocyte proliferation. Initially, broilers were purchased and randomly assigned to be fed under white light (WL), red light (RL), green light (GL), and blue light (BL). Pinealectomy was performed 3 d later, and the broilers were euthanized after 14 d. The results showed that the expression of the antiapoptotic proteins Bcl-2/Bcl-xl decreased under RL, while the expression of the pro-apoptotic factor Bax/caspase-3 and the pro-inflammatory factors INF-γ/TNF-α/IL-6 increased. After pinealectomy, the expression of Bax/TNF-α/IL-6 increased in conjunction with the decrease in Bcl-2 expression. In vitro experiments demonstrated that exogenous melatonin decreased the expression of Bax/TNF-α/IL-6 in thymic lymphocytes of chicks reared under RL. This melatonin-induced effect was enhanced by SR1078 (RORα/RORγ agonist) but attenuated by SR3335 (RORα antagonist) and BAY (P65 antagonist). These findings revealed that the melatonin nuclear receptor RORα/RORγ promotes the expression of the pro-apoptotic factor Bax/caspase-3 and the pro-inflammatory factors INF-γ/TNF-α/IL-6, while inhibiting the expression of the antiapoptotic factor Bcl-2/Bcl-xl. Our research suggested the signaling pathway of monochromatic red light impacts the apoptosis of thymus lymphocytes in broiler.

Extension characteristics of TdT and its application in biosensors.

The advantages of rapid amplification of nucleic acid without a template based on terminal deoxyribonucleotidyl transferase (TdT) have been widely used in the field of biosensors. However, the catalytic efficiency of TdT is affected by extension conditions. The sensitivity of TdT- mediated biosensors can be improved only under appropriate conditions. Therefore, in this review, we provide a comprehensive overview of TdT extension characteristics and its applications in biosensors. We focus on the relationship between TdT extension conditions and extension efficiency. Furthermore, the construction strategy of TdT-mediated biosensors according to five different recognition types and their applications in targets are discussed and, finally, several current challenges and prospects in the field are taken into consideration.

Brief introduction to terminal deoxyribonucleotidyl transferase (TdT) characteristics.Provided a systematic and comprehensive summary of TdT extension conditions.Summarized the four effect factors of catalytic efficiency based on extension conditions and enzyme conformation.Sensing strategies of TdT-mediated biosensors for five different recognitions were summarized in detail.The applications of TdT-mediated biosensors in six targets were introduced in detail.

Advances in the Study of Selenium-Enriched Probiotics: From the Inorganic Se into Se Nanoparticles.

Selenium (Se) is a momentous metallic element that plays an irreplaceable role in biochemical activities. Se deficiency remains a nutritional challenge across the world. Organic Se supplementation is the most effective treatment means for Se deficiency. Organic Se transformed from Se-enriched probiotics show outstanding excellent properties in antibacteria, anti-oxidation, anti-inflammation, and immunoregulation. Studying the influencing factors for Se enrichment capacity and enrichment mechanisms of Se-enriched probiotics is conducive to the exploit of more potent Se-enriched probiotics. Se-enriched probiotics transform inorganic Se into Se nanoparticles (SeNPs), which have been widely used in animal husbandry and biomedical field. In this paper, the novel development of Se-enriched probiotics is reviewed, and the bioactivities of SeNPs are assessed, so as to display their potential application prospects. The excellent role of SeNPs in anti-oxidation is summarized, and the mechanism by which SeNPs improve Se deficiency and boost animal health is explained.

Chronic Stress That Changed Intestinal Permeability and Induced Inflammation Was Restored by Estrogen.

Chronic psychological stress affects the health of humans and animals (especially females or pregnant bodies). In this study, a stress-induced model was established by placing eight-week-old female and pregnant mice in centrifuge tubes for 4 h to determine whether chronic stress affects the intestinal mucosal barrier and microbiota composition of pregnant mice. Compared with the control group, we found that norepinephrine (NE), corticosterone (CORT), and estradiol (E2) in plasma increased significantly in the stress group. We then observed a decreased down-regulation of anti-inflammatory cytokines and up-regulation of pro-inflammatory cytokines, which resulted in colonic mucosal injury, including a reduced number of goblet cells, proliferating cell nuclear antigen-positive cells, caspase-3, and expression of tight junction mRNA and protein. Moreover, the diversity and richness of the colonic microbiota decreased in pregnant mice. Bacteroidetes decreased, and pernicious bacteria were markedly increased. At last, we found E2 protects the intestinal epithelial cells after H2O2 treatment. Results suggested that 25 pg/mL E2 provides better protection for intestinal barrier after chronic stress, which greatly affected the intestinal mucosal barrier and altered the colonic microbiota composition.

Melatonin Ameliorates Hepatic Ferroptosis in NAFLD by Inhibiting ER Stress via the MT2/cAMP/PKA/IRE1 Signaling Pathway.

Ferroptosis, an iron-dependent cell death form, has recently been observed in the development of non-alcoholic fatty liver disease (NAFLD). Melatonin (Mel) shows potential benefits for preventing and treating liver diseases. Whether and how Mel ameliorates hepatic ferroptosis in NAFLD is not fully understood. Here we established a mouse model of NAFLD induced by long-term high-fat diet (HFD) feeding. We found that Mel treatment ameliorated global metabolic abnormalities and inhibited the progression of NAFLD in mice. Most importantly, Mel supplementation significantly improved HFD-induced iron homeostasis disorders in the liver, including iron overload and ferritin transport disorders. For another, Mel ameliorated HFD-induced hepatic lipid peroxidation. The recuperative role of exogenous Mel on hepatocyte ferroptosis was also observed in PA- or Erastin-treated HepG2 cells. Mechanistically, MT2, but not MT1, was involved in the effect of Mel. Furthermore, Mel treatment inhibited HFD or Erastin-activated ER stress and activated the PKA/IRE1 signaling pathway. Co-expression of p-PKA and p-IRE1 was enhanced by the MT2 antagonist. Inhibitions of PKA and IRE1 respectively improved hepatocyte ferroptosis, and activations of cAMP/PKA reversed Mel's effect on ferroptosis. Collectively, these findings suggest that exogenous Mel inhibits hepatic ferroptosis in NAFLD by ameliorating ER stress through the MT2/cAMP/PKA/IRE1 pathway, proving that Mel is a promising candidate drug for the treatment of hepatic ferroptosis in NAFLD.

Roles of Rac1-Dependent Intrinsic Forgetting in Memory-Related Brain Disorders: Demon or Angel.

Animals are required to handle daily massive amounts of information in an ever-changing environment, and the resulting memories and experiences determine their survival and development, which is critical for adaptive evolution. However, intrinsic forgetting, which actively deletes irrelevant information, is equally important for memory acquisition and consolidation. Recently, it has been shown that Rac1 activity plays a key role in intrinsic forgetting, maintaining the balance of the brain's memory management system in a controlled manner. In addition, dysfunctions of Rac1-dependent intrinsic forgetting may contribute to memory deficits in neurological and neurodegenerative diseases. Here, these new findings will provide insights into the neurobiology of memory and forgetting, pathological mechanisms and potential therapies for brain disorders that alter intrinsic forgetting mechanisms.