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.

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.

Monosaccharide Composition and In Vitro Activity to HCT-116 Cells of Purslane Polysaccharides after a Covalent Chemical Selenylation.

The anti-cancer effects of selenylated plant polysaccharides are a focus of research. As a natural plant with extensive biological effects, there have been few studies related to edible purslane (Portulaca oleracea L.). Thus, in this study, soluble P. oleracea polysaccharides (PPS) were extracted from the dried P. oleracea and then selenylated chemically using the HNO3-Na2SeO3 method to obtain two selenylated products, namely, SePPS1 and SePPS2. Compared with the extracted PPS, SePPS1 and SePPS2 had much higher Se contents (840.3 and 1770.5 versus 66.0 mg/kg) while also showing lower contents in three saccharides-arabinose, fucose, and ribose-and higher contents in seven saccharides including galactose, glucose, fructose, mannose, rhamnose, galacturonic acid, and glucuronic acid, but a stable xylose content demonstrated that the performed chemical selenylation of PPS led to changes in monosaccharide composition. Moreover, SePPS1 and SePPS2 shared similar features with respect to monosaccharide composition and possessed higher bioactivity than PPS in human colon cancer HCT-116 cells. Generally, SePPS1 and SePPS2 were more active than PPS with respect to cell growth inhibition, the alteration of cell morphology, disruption of mitochondrial membrane potential, intracellular reactive oxygen species (ROS) generation, the induction of cell apoptosis, and upregulation or downregulation of five apoptosis-related genes and proteins such as Bax, Bcl-2, caspases-3/-9, and cytochrome C, that cause cell apoptosis and growth suppression via the ROS-mediated mitochondrial pathway. SePPS2 consistently showed the highest capacity to exert these observed effects on the targeted cells, suggesting that the performed chemical selenylation of PPS (in particular when higher degrees of selenylation are reached) resulted in an increase in activity in the cells. It can thus be concluded that the performed selenylation of PPS was able to incorporate inorganic Se into the final PPS products, changing their monosaccharide composition and endowing them with enhanced nutraceutical and anti-cancer effects in the colon.

Monochromatic Light Pollution Exacerbates High-Fat Diet-Induced Adipocytic Hypertrophy in Mice.

Light pollution worldwide promotes the progression of obesity, which is widely considered a consequence of circadian rhythm disruptions. However, the role of environmental light wavelength in mammalian obesity is not fully understood. Herein, mice fed a normal chow diet (NCD) or a high-fat diet (HFD) were exposed to daytime white (WL), blue (BL), green (GL), and red light (RL) for 8 weeks. Compared with WL and RL, BL significantly increased weight gain and white adipose tissue (WAT) weight, and it disrupted glucose homeostasis in mice fed with HFD but not NCD. The analysis of WAT found that BL significantly aggravated HFD-induced WAT hypertrophy, with a decrease in IL-10 and an increase in NLRP3, p-P65, p-IκB, TLR4, Cd36, Chrebp, Srebp-1c, Fasn, and Cpt1ß relative to WL or RL. More interestingly, BL upregulated the expression of circadian clocks in the WAT, including Clock, Bmal1, Per1, Cry1, Cry2, Rorα, Rev-erbα, and Rev-erbß compared with WL or RL. However, most of the changes had no statistical difference between BL and GL. Mechanistically, BL significantly increased plasma corticosterone (CORT) levels and glucocorticoid receptors in the WAT, which may account for the changes in circadian clocks. Further, in vitro study confirmed that CORT treatment did promote the expression of circadian clocks in 3T3-L1 cells, accompanied by an increase in Chrebp, Cd36, Hsp90, P23, NLRP3, and p-P65. Thus, daily BL, rather than RL exposure-induced CORT elevation, may drive changes in the WAT circadian clocks, ultimately exacerbating lipid dysmetabolism and adipocytic hypertrophy in the HFD-fed mice.

The role of light pollution in mammalian metabolic homeostasis and its potential interventions: A critical review.

Irregular or unnatural artificial light causes severe environmental stress on the survival and health of organisms, which is rapidly becoming a widespread new type of environmental pollution. A series of disruptive behaviors to body homeostasis brought about by light pollution, including metabolic abnormalities, are likely to be the result of circadian rhythm disturbances. Recently, the proposed role of light pollution in metabolic dysregulation has accelerated it into an emerging field. Hence, the regulatory role of light pollution in mammalian metabolic homeostasis is reviewed in this contribution. Light at night is the most widely affected type of light pollution, which disrupts metabolic homeostasis largely due to its disruption of daily food intake patterns, alterations of hormone levels such as melatonin and glucocorticoids, and changes in the rhythm of inflammatory factor production. Besides, light pollution impairs mammalian metabolic processes in an intensity-, photoperiod-, and wavelength-dependent manner, and is also affected by species, gender, and diets. Nevertheless, metabolic disorders triggered by light pollution are not irreversible to some extent. Potential interventions such as melatonin supplementation, recovery to the LD cycle, time-restricted feeding, voluntary exercise, wearing blue light-shied goggles, and bright morning light therapy open a bright avenue to prevent light pollution. This work will help strengthen the relationship between light information and metabolic homeostasis and provide new insights for the better prevention of metabolic disorders and light pollution.

Monosaccharide composition and in vivo immuno-stimulatory potential of soluble yam (Dioscorea opposita Thunb.) polysaccharides in response to a covalent Se incorporation.

The present study aimed to investigate whether selenylation modification could affect compositional features and in vivo immuno-stimulatory potential of yam polysaccharides. In this study, the soluble yam mucilage polysaccharides (YPS) were prepared and selenylated in the HNO3-Na2SeO3 system, and two selenylated polysaccharide products, namely SeYPS-1 and SeYPS-2 with respective Se contents of 719 and 1585 mg/kg, were thus obtained. GC-MS analysis demonstrated that the compositional features of SeYPS-1 and SeYPS-2 were similar to those of YPS. Meanwhile, the immuno-stimulatory potential of the selenylated products, especially SeYPS-2, in the BALB/c mice model was higher than that of YPS, reflected by the elevated contents of serum immunoglobins and increased percentage of CD4+ splenic lymphocytes. It was thus confirmed that the selenylation did not change the composition of monosaccharides but endowed YPS with greater immuno-stimulation in the mice, while the higher extent of selenylation also caused a much enhanced immuno-stimulatory potential of SeYPS-2.

Monochromatic blue light not green light exposure is associated with continuous light-induced hepatic steatosis in high fat diet fed-mice via oxidative stress.

Irregular light exposure is a newly identified environmental factor for the progression of lipid metabolism; however, the specific effect of light color exposure on lipid homeostasis remains unknown. Herein, 4-week-old male C57BL/6 J mice (n = 12) fed a high-fat diet (HFD) were exposed to a standard 12-h light: 12-h dark cycle (LD-WF) and a 24-h continuous monochromatic blue light (LL-BF), green light (LL-GF), or white light (LL-WF) condition for 12 weeks. LL-BF interfered with the expression of circadian genes in the hypothalamus and upregulated the plasma corticosterone (CORT) levels (p < 0.05) compared with LD-WF. Along with elevation of the CORT level, LL-BF enhanced glucocorticoid receptor synthesis, increased the Hsp90 mRNA level, reduced the antioxidant capacity, increased the production of ROS and MDA, and reduced the Pgc-1α mRNA level in the liver (p < 0.05). Furthermore, LL-BF disrupted the hepatic expression levels of genes involved in lipid metabolism, Acc and Hl, which further aggravated the hepatic steatosis status and significantly increased the liver pathological scores, TG, TC, IL-6, and TNF-α levels (p < 0.05). LL-BF consistently increased the body weight and incidence of dyslipidemia and lipid deposition. However, no difference was observed between LL-BF and LL-WF (p > 0.05). Surprisingly, LL-GF did not show any changes induced by LL-BF and LL-WF, and contrary to LL-BF, LL-GF and LD-WF showed no significantly differing changes (p > 0.05). Taken together, exposure to monochromatic blue light but not green light is associated with continuous light-aggravated hepatic steatosis in HFD-fed mice. The effect of continuous blue light exposure may be attributed to the disturbance of biological rhythm, increase in CORT secretion, induction of oxidative stress, and interference of the Acc and Hl levels in the liver.

In Vitro Immunomodulation of the Polysaccharides from Yam (Dioscorea opposita Thunb.) in Response to a Selenylation of Lower Extent.

The immunomodulation of chemically selenylated polysaccharides has been attracting more attention recently, but the corresponding performance of the yam polysaccharides (YPS) with lower selenylation extent remains, thus far, unsolved. In this study, the YPS was selenylated with Na2SeO3 under acidic conditions generated by HNO3 to reach two lower selenylation extents, yielding two selenylated YPSs, namely SeYPS-1 and SeYPS-2 with selenium contents of 715 and 1545 mg/kg, respectively. The results indicated that YPS, SeYPS-1, and SeYPS-2 all had in vitro immuno-modulation when using RAW 264.7 macrophages and murine splenocytes as cell models. In detail, the three polysaccharide samples at dose levels of 5-160 µg/mL showed insignificant cytotoxicity to the macrophages and splenocytes with cell exposure times of 12-24 h, because of the measured values of cell viability larger than 100%. However, Na2SeO3 at dose levels of 1.3-3.25 µg/mL mostly caused obvious cytotoxic effects on the cells, resulting in reduced cell viability values or cell death, efficiently. The results demonstrated that, compared with YPS, both SeYPS-1 and SeYPS-2 at a lower dose level (5 µg/mL) were more active at promoting phagocytosis activity, increasing the CD4+/CD8+ ratio of the T-lymphocyte sub-population in the murine splenocyte, improving cytokine secretion, including interleukin-6 (IL-6), IL-1ß, and tumor necrosis factor-α in the macrophages, or increasing interferon-γ secretion, but suppressing IL-4 production in the splenocytes. Consistently, SeYPS-2 has more potential than SeYPS-1 at exerting these assessed bioactivities in the cells. Thus, we conclude that a chemical modification of YPS using trace element Se at a lower selenylation extent could bring about higher immunomodulatory activity towards macrophages and splenocytes, while selenylation extent of YPS is a critical factor used to govern the assessed activity changes of YPS.

Mechanisms of Melatonin in Obesity: A Review.

Obesity and its complications have become a prominent global public health problem that severely threatens human health. Melatonin, originally known as an effective antioxidant, is an endogenous hormone found throughout the body that serves various physiological functions. In recent decades, increasing attention has been paid to its unique function in regulating energy metabolism, especially in glucose and lipid metabolism. Accumulating evidence has established the relationship between melatonin and obesity; nevertheless, not all preclinical and clinical evidence indicates the anti-obesity effect of melatonin, which makes it remain to conclude the clinical effect of melatonin in the fight against obesity. In this review, we have summarized the current knowledge of melatonin in regulating obesity-related symptoms, with emphasis on its underlying mechanisms. The role of melatonin in regulating the lipid profile, adipose tissue, oxidative stress, and inflammation, as well as the interactions of melatonin with the circadian rhythm, gut microbiota, sleep disorder, as well as the α7nAChR, the opioidergic system, and exosomes, make melatonin a promising agent to open new avenues in the intervention of obesity.

In Vitro Immuno-Modulatory Potentials of Purslane (Portulaca oleracea L.) Polysaccharides with a Chemical Selenylation.

The soluble polysaccharides from a non-conventional and edible plant purslane (Portulaca oleracea L.), namely PSPO, were prepared by the water extraction and ethanol precipitation methods in this study. The obtained PSPO were selenylated using the Na2SeO3-HNO3 method to successfully prepare two selenylated products, namely SePSPO-1 and SePSPO-2, with different selenylation extents. The assay results confirmed that SePSPO-1 and SePSPO-2 had respective Se contents of 753.8 and 1325.1 mg/kg, while PSPO only contained Se element about 80.6 mg/kg. The results demonstrated that SePSPO-1 and SePSPO-2 had higher immune modulation than PSPO (p < 0.05), when using the two immune cells (murine splenocytes and RAW 264.7 macrophages) as two cell models. Specifically, SePSPO-1 and SePSPO-2 were more active than PSPO in the macrophages, resulting in higher cell proliferation, greater macrophage phagocytosis, and higher secretion of the immune-related three cytokines, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1ß. Meanwhile, SePSPO-1 and SePSPO-2 were more potent than PSPO in the concanavalin A- or lipopolysaccharide-stimulated splenocytes in cell proliferation, or more able than PSPO in the splenocytes to promote interferon-γ secretion but suppress IL-4 secretion, or more capable of enhancing the ratio of T-helper (CD4+) cells to T-cytotoxic (CD8+) cells for the T lymphocytes than PSPO. Overall, the higher selenylation extent of the selenylated PSPO mostly caused higher immune modulation in the model cells, while a higher polysaccharide dose consistently led to the greater regulation effect. Thus, it is concluded that the employed chemical selenylation could be used in the chemical modification of purslane or other plant polysaccharides, when aiming to endow the polysaccharides with higher immuno-modulatory effect on the two immune cells.