Saikosaponin-d regulates angiogenesis in idiopathic pulmonary fibrosis through angiopoietin/Tie-2 pathway.

OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is considered as a chronic interstitial lung disease with underlying mechanism of IPF remaining unclear, while there are no definitive treatment options. In recent years, scientists have gradually paid attention to the influence of angiogenesis on IPF. Because IPF is a progressive with microvascular remodeling disorder, scientists have postulated that angiogenesis may also be one of the initiating and contributing factors of the disease. Bupleurum is a common natural Chinese herbal medicine with antibacterial, anti-inflammatory, anti-tumor and other pharmacological effects. As the most important active monomer of Bupleurum, Saikosaponin-d (SSd) is a new discovery with anti-pulmonary fibrosis (PF) activity. This study attempts to investigate the role of SSd in the interference of PF through regulation of angiogenesis in IPF through Angiopoietin (Angpt) /Tie receptor 2 (Tie2) pathway. METHODS: Randomly, we allocated C57BL/6 mice into four groups (n = 20 in each group). Afterwards, establishment of IPF model was accomplished via intratracheal administration of bleomycin (BLM, 5 mg/kg), while corresponding drug intervention was given accordingly. On 3rd, 7th, 14th and 28th days after modeling, we performed histopathological examination through staining. Meanwhile, immunohistochemistry (IHC) of PF and the expression of related factors were observed, while Ang/Tie2 pathway was assessed by ELISA with the effect of SSd on angiogenesis related proteins in IPF being explored with IHC and Western Blot technique. RESULTS: Our results showed that SSd could reduce inflammation and PF levels in lung tissue of experimental mice, while levels of angiogenesis-related factors, namely Tie-2, Ang-1 and ANGPT2 (Ang-2), fibrosis- associated factors like Alpha-smooth muscle actin (α-SMA), collagen-I and hydroxyproline in SSd and dexamethasone (DXM) mice were significantly reduced at each time point compared to BLM (p < 0.01). Additionally, we discovered substantial decreased expressions of Ang-1, Ang-2, Tie-2, α-SMA and collagen-I at protein level in SSd and DXM mice at each time point compared to BLM (p < 0.05). Besides, insignificant differences were observed between SSd and DXM groups (p > 0.05). CONCLUSION: This study has demonstrated that SSd could down-regulate the expression of ANG-1, Ang-2 and Tie2 in the Ang/Tie2 pathway, and may reduce lung inflammation and PF in BLM-induced mice via inhibition of angiogenesis.

SIgA in various pulmonary diseases.

Secretory immunoglobulin A (SIgA) is one of the most abundant immunoglobulin subtypes among mucosa, which plays an indispensable role in the first-line protection against invading pathogens and antigens. Therefore, the role of respiratory SIgA in respiratory mucosal immune diseases has attracted more and more attention. Although the role of SIgA in intestinal mucosal immunity has been widely studied, the cell types responsible for SIgA and the interactions between cells are still unclear. Here, we conducted a wide search of relevant studies and sorted out the relationship between SIgA and some pulmonary diseases (COPD, asthma, tuberculosis, idiopathic pulmonary fibrosis, COVID-19, lung cancer), which found SIgA is involved in the pathogenesis and progression of various lung diseases, intending to provide new ideas for the prevention, diagnosis, and treatment of related lung diseases.

Design of a chimeric glycosyltransferase OleD for the site-specific O-monoglycosylation of 3-hydroxypyridine in nosiheptide.

To identify the potential role of the 3-hydroxyl group of the pyridine ring in nosiheptide (NOS) for its antibacterial activity against Gram-positive pathogens, enzymatic glycosylation was utilized to regio-selectively create a monoglycosyl NOS derivative, NOS-G. For this purpose, we selected OleD, a UDP glycosyltransferase from Streptomyces antibioticus that has a low productivity for NOS-G. Activity of the enzyme was increased by swapping domains derived from OleI, both single and in combination. Activity enhancement was best in mutant OleD-10 that contained four OleI domains. This chimer was engineered by site-directed mutagenesis (single and in combination) to increase its activity further, whereby variants were screened using a newly-established colorimetric assay. OleD-10 with I117F and T118G substitutions (FG) had an increased NOS-G productivity of 56%, approximately 70 times higher than that of wild-type OleD. The reason for improved activity of FG towards NOS was structurally attributed to a closer distance (<3 Å) between NOS/sugar donor and the catalytic amino acid H25. The engineered enzyme allowed sufficient activity to demonstrate that the produced NOS-G had enhanced stability and aqueous solubility compared to NOS. Using a murine MRSA infection model, it was established that NOS-G resulted in partial protection within 20 h of administration and delayed the death of infected mice. We conclude that 3-hydroxypyridine is a promising site for structural modification of NOS, which may pave the way for producing nosiheptide derivatives as a potential antibiotic for application in clinical treatment.

Tamarind Xyloglucan Oligosaccharides Attenuate Metabolic Disorders via the Gut-Liver Axis in Mice with High-Fat-Diet-Induced Obesity.

Functional oligosaccharides exert obesity-reducing effects by acting at various pathological sites responsible for the development of obesity. In this study, tamarind xyloglucan oligosaccharides (TXOS) were used to attenuate metabolic disorders via the gut-liver axis in mice with high-fat-diet (HFD)-induced obesity, as determined through LC/MS-MS and 16S rRNA sequencing technology. A TXOS dose equivalent to 0.39 g/kg/day in humans restored the gut microbiota in obese mice, which was in part supported by the key microflora, particularly Bifidobacterium pseudolongum. Moreover, TXOS reduced the abundance of opportunistic pathogen species, such as Klebsiella variicola and Romboutsia ilealis. The bodyweight and weight gain of TXOS-treated (4.8 g/kg per day) mice began to decrease at the 14th week, decreasing by 12.8% and 23.3%, respectively. Sixteen fatty acids were identified as potential biomarkers in the liver, and B. pseudolongum and caprylic acid were found to tightly regulate each other. This was associated with reduced inflammation in the liver, circulation, and adipose tissue and protection from metabolic disorders. The findings of this study indicate that TXOS can significantly increase the gut microbiota diversity of obese mice and restore the HFD-induced dysbiosis of gut microbiota.

Dietary Methionine Restriction Alleviates Choline-Induced Tri-Methylamine-N-Oxide (TMAO) Elevation by Manipulating Gut Microbiota in Mice.

Dietary methionine restriction (MR) has been shown to decrease plasma trimethylamine-N-oxide (TMAO) levels in high-fat diet mice; however, the specific mechanism used is unknown. We speculated that the underlying mechanism is related with the gut microbiota, and this study aimed to confirm the hypothesis. In this study, we initially carried out an in vitro fermentation experiment and found that MR could reduce the ability of gut microbiota found in the contents of healthy mice and the feces of healthy humans to produce trimethylamine (TMA). Subsequently, mice were fed a normal diet (CON, 0.20% choline + 0.86% methionine), high-choline diet (H-CHO, 1.20% choline + 0.86% methionine), or high-choline + methionine-restricted diet (H-CHO+MR, 1.20% choline + 0.17% methionine) for 3 months. Our results revealed that MR decreased plasma TMA and TMAO levels in H-CHO-diet-fed mice without changing hepatic FMO3 gene expression and enzyme activity, significantly decreased TMA levels and expression of choline TMA-lyase (CutC) and its activator CutD, and decreased CutC activity in the intestine. Moreover, MR significantly decreased the abundance of TMA-producing bacteria, including Escherichia-Shigella (Proteobacteria phylum) and Anaerococcus (Firmicutes phylum), and significantly increased the abundance of short-chain fatty acid (SCFA)-producing bacteria and SCFA levels. Furthermore, both MR and sodium butyrate supplementation significantly inhibited bacterial growth, down-regulated CutC gene expression levels in TMA-producing bacteria, including Escherichia fergusonii ATCC 35469 and Anaerococcus hydrogenalis DSM 7454 and decreased TMA production from bacterial growth under in vitro anaerobic fermentation conditions. In conclusion, dietary MR alleviates choline-induced TMAO elevation by manipulating gut microbiota in mice and may be a promising approach to reducing circulating TMAO levels and TMAO-induced atherosclerosis.

Dietary Methionine Restriction Promotes Fat Browning and Attenuates Hepatic Lipid Accumulation in High-Choline-Fed Mice Associated with the Improvement of Thyroid Function.

This study aims to explore the influences of a methionine-restricted diet (MRD) on fat browning and hepatic lipid accumulation in mice fed with a high-choline diet (HCD) and their possible mechanisms. ICR mice were randomly divided into three groups and fed with a normal diet (0.86% methionine + 0.20% choline, ND), HCD (0.86% methionine + 1.20% choline), or MRD (0.17% methionine + 1.20% choline) for 90 consecutive days. We found that MRD reduced body weight and fat mass; increased heat production and ambulatory locomotor activity; reduced hepatic and plasma lipid levels, hepatic fatty infiltration area, and adipocyte volume in white and brown adipose tissue; promoted fat browning, especially upregulated gene and protein expression levels of uncoupling protein 1 (UCP1); and promoted fat catabolism and inhibited fat anabolism in the liver and adipose tissue. Moreover, MRD increased antioxidant defenses and reduced inflammatory cytokine levels in the thyroid, blood, and liver. Furthermore, MRD improved thyroid morphological structure, promoted the synthesis and secretion of thyroid hormones, and enhanced the actions of thyroid hormones on its receptor organs (liver and adipose tissue). These findings suggested that MRD promoted fat browning and attenuated hepatic lipid accumulation in HCD mice associated with the improvement of thyroid function.

Dityrosine in food: A review of its occurrence, health effects, detection methods, and mitigation strategies.

Protein and amino acid oxidation in food products produce many new compounds, of which the reactive and toxic compound dityrosine, derived from oxidized tyrosine, is the most widely studied. The high reactivity of dityrosine enables this compound to induce oxidative stress and disrupt thyroid hormone function, contributing to the pathological processes of several diseases, such as obesity, diabetes, cognitive dysfunction, aging, and age-related diseases. From the perspective of food safety and human health, protein-oxidation products in food are the main concern of consumers, health management departments, and the food industry. This review highlights the latest research on the formation pathways, toxicity, detection methods, occurrence in food, and mitigation strategies for dityrosine. Furthermore, the control of dityrosine in family cooking and food-processing industry has been discussed. Food-derived dityrosine primarily originates from high-protein foods, such as meat and dairy products. Considering its toxicity, combining rapid high sensitivity dityrosine detection techniques with feasible control methods could be an effective strategy to ensure food safety and maintain human health. However, the current dityrosine detection and mitigation strategies exhibit some inherent characteristics and limitations. Therefore, developing technologies for rapid and effective dityrosine detection and control at the industrial level is necessary.

Dietary Methionine via Dose-Dependent Inhibition of Short-Chain Fatty Acid Production Capacity Contributed to a Potential Risk of Cognitive Dysfunction in Mice.

High-methionine diets induce impaired learning and memory function, dementia-like neurodegeneration, and Alzheimer's disease, while low-methionine diets improve learning and memory function. We speculated that variations in intestinal microbiota may mediate these diametrically opposed effects; thus, this study aimed to verify this hypothesis. The ICR mice were fed either a low-methionine diet (LM, 0.17% methionine), normal methionine diet (NM, 0.86% methionine), or high-methionine diet (HM, 2.58% methionine) for 11 weeks. We found that HM diets damaged nonspatial recognition memory, working memory, and hippocampus-dependent spatial memory and induced anxiety-like behaviors in mice. LM diets improved nonspatial recognition memory and hippocampus-dependent spatial memory and ameliorated anxiety-like behavior, but the differences did not reach a significant level. Moreover, HM diets significantly decreased the abundance of putative short-chain fatty acid (SCFA)-producing bacteria (Roseburia, Blautia, Faecalibaculum, and Bifidobacterium) and serotonin-producing bacteria (Turicibacter) and significantly increased the abundance of proinflammatory bacteria Escherichia-Shigella. Of note, LM diets reversed the results. Consequently, the SCFA and serotonin levels were significantly decreased with HM diets and significantly increased with LM diets. Furthermore, HM diets induced hippocampal oxidative stress and inflammation and selectively downregulated the hippocampus-dependent memory-related gene expression, whereas LM diets selectively upregulated the hippocampus-dependent memory-related gene expression. In conclusion, dietary methionine via dose-dependent inhibition of SCFA production capacity contributed to a potential risk of cognitive dysfunction in mice.

Dietary methionine restriction improves gut microbiota composition and prevents cognitive impairment in D-galactose-induced aging mice.

Dietary methionine restriction (MR) has been shown to delay aging and ameliorate age-related cognitive impairments. We hypothesized that changes in the gut microbiota may mediate these effects. To test this hypothesis, ICR mice subcutaneously injected with 150 mg kg-1 day-1D-galactose were fed a normal (0.86% methionine) or an MR (0.17% methionine) diet for 2 months. Multiple behavioral experiments were performed, and the gut microbiota composition, metabolite profiles related to short-chain fatty acids (SCFAs) in the feces, and indicators related to the redox and inflammatory states in the hippocampus were further analyzed. Our results indicated that MR alleviated cognitive impairment (including non-spatial memory deficits, working memory deficits, and hippocampus-dependent spatial memory deficits) and anxiety-like behavior in D-Gal-induced aging mice. Furthermore, MR increased the abundance of putative SCFA-producing bacteria such as Lachnospiraceae, Turicibacter, Roseburia, Ruminococcaceae_UCG-014, Intestinimonas, Rikenellaceae, Tyzzerella, and H2S-producing bacteria such as Desulfovibrio in feces. Moreover, MR reversed and normalized the levels of intestinal SCFAs (acetate, propionate, and butyrate) and important intermediate metabolites of the SCFAs (pyruvate, lactate, malate, fumarate, and succinate), abolished aging-induced oxidative stress and inflammatory responses, increased the levels of H2S in the plasma and hippocampus, and selectively modulated the expression of multiple learning- and memory-related genes in the hippocampus. These findings suggest that MR improved the gut microbiota composition and SCFA production and alleviated oxidative stress and inflammatory responses in the hippocampus, which might prevent cognitive impairment in D-galactose-induced aging mice.

High dietary methionine intake may contribute to the risk of nonalcoholic fatty liver disease by inhibiting hepatic H2S production.

Methionine, an essential sulfur-containing amino acid, is associated with hepatic lipid accumulation; however, the underlying mechanism is unknown. This study aimed to investigate the effects of different dietary methionine levels on hepatic lipid accumulation in mice and clarify the possible mechanisms involved. The Institute of Cancer Research (ICR) mice were fed a normal diet (ND, 0.86% methionine), high-methionine diet (HMD, 2.58% methionine), or methionine-restricted diet (MRD, 0.17% methionine) for 11 consecutive weeks. Our results showed that HMD increased the liver weight and liver index, plasma and hepatic lipid profiles, and hepatic fatty infiltration area and perirenal fat volume. In addition, HMD promoted lipid synthesis, inhibited lipid catabolism and glycolysis metabolism, reduced the activities of mitochondrial respiratory chain enzyme complexes (Ⅰ and Ⅴ) and adenosine triphosphate (ATP) production, and elevated oxidative stress and inflammation in the liver. Moreover, HMD inhibited homocysteine metabolism and significantly decreased the expression and activity of cystathionine γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST), thereby reducing endogenous H2S production in the liver. Interestingly, MRD reversed these adverse effects, and promoted endogenous H2S production. In conclusion, inhibition of hepatic H2S production may be the mechanism behind an increased risk of nonalcoholic fatty liver disease (NAFLD) associated with high dietary methionine intake. Therefore, it is necessary to reduce methionine intake in the daily diet to prevent NAFLD and maintain good physical health.

Engineering of a UDP-Glycosyltransferase for the Efficient Whole-Cell Biosynthesis of Siamenoside I in Escherichia coli.

The combination of the insufficient availability and the complex structure of siamenoside I (SI), the sweetest glucoside isolated from Siraitia grosvenorii to date, limited its use as a natural sweetener. To solve this problem, an improved biocatalyst, UGT-M2, was semi-rationally created by engineering the uridine diphosphate glycosyltransferase UGT94-289-2 from S. grosvenorii for the monoglucosylation of mogroside IIIE (MG IIIE) to SI. Subsequently, an engineered Escherichia coli cell was constructed, which combined UGT-M2 with a UDP-glucose regeneration system to circumvent the need for expensive UDP-glucose to produce SI. After optimization, high-purity SI (>96.4%) was efficiently prepared from MG IIIE at a 1 L scale with a productivity of 29.78 g/(L day) and a molar yield of 76.5% and without using exogenous UDP-glucose. This study not only developed a whole-cell approach for the preparation of SI but also provided an alternative glycosyltransferase variant for SI biosynthesis with synthetic biology in the future.

Selective enzymatic α-1,6- monoglucosylation of mogroside IIIE for the bio-creation of α-siamenoside I, a potential high-intensity sweetener.

A new compound, α-siamenoside I (α-SI), with a glucose unit selectively bound to the 6-hydroxyl group of the 24-O-ß-glucosyl moiety of mogroside IIIE by α-1,6-glucosidic bond, was bio-created by two screened cyclodextrin glycosyltransferases with a maximum yield of 59.3%. Compared to mogroside IIIE, α-SI showed a significantly increased sweetness intensity (508 times sweeter than 5% sucrose), which is superior to siamenoside I (SI), the sweetest triterpenoid saponin isolated from Siraitia grosvenorii to date. Sensory evaluation showed that the taste quality of α-SI also was obviously better than mogroside IIIE. In addition to α-SI possessing a good stability similar to that of SI, it also did not cause a significant decrease in cell viability at a concentration of 200 µg/mL and had a negative influence on islets function at 1 µM. All of these preliminarily results pave the way for promoting α-SI as a potential low-calorie sweetener.

Dietary methionine restriction improves the gut microbiota and reduces intestinal permeability and inflammation in high-fat-fed mice.

Methionine-restricted diets (MRD) have been shown to prevent high fat diet (HFD) induced complications including fat accumulation, insulin sensitivity decrease, oxidative stress and inflammation increase. We hypothesized that intestinal microbiota changes may mediate these effects, and this study aims to prove this hypothesis. Mice were fed a normal diet (ND, 0.86% methionine + 4% fat), a HF diet (HFD, 0.86% methionine + 20% fat), or a MRD (0.17% methionine + 20% fat) and euthanized at week 22. Our results showed that the HFD induced fat accumulation and gut microbiota dysbiosis; reduced short-chain fatty acid (SCFA) production; and increased intestinal permeability, inflammatory response, and oxidative stress. The MRD decreased the body weight, body fat rate, and blood glucose and plasma lipid levels; increased the abundance of putative SCFA-producing bacteria Bifidobacterium, Lactobacillus, Bacteroides, Roseburia, Coprococcus, and Ruminococcus and inflammation-inhibiting bacteria Oscillospira and Corynebacterium; and decreased the abundance of inflammation-producing bacteria Desulfovibrio in colonic contents. Moreover, the MRD improved intestinal barrier function, inflammatory response, and oxidative stress, and altered the metabolite levels of colonic contents (such as increasing SCFA and bile acid concentrations); the latter may have contributed to the prevention of HFD-induced obesity. In conclusion, the MRD can improve gut health by regulating the intestinal microbiota and its metabolite profiles in the HFD mice. Reducing methionine intake by simple dietary adjustment may be an effective method to improve intestinal health in animals and humans.

Spatial Learning and Memory Impairment in Growing Mice Induced by Major Oxidized Tyrosine Product Dityrosine.

This study focused on the effects of oxidized tyrosine products (OTPs) and major component dityrosine (DT) on the brain and behavior of growing mice. Male and female mice were treated with daily intragastric administration of either tyrosine (Tyr; 420 µg/kg body weight), DT (420 µg/kg body weight), or OTPs (1909 µg/kg body weight) for 35 days. We found that pure DT and OTPs caused redox state imbalance, elevated levels of inflammatory factors, hippocampal oxidative damage, and neurotransmitter disorders while activating the mitochondrial apoptosis pathway in the hippocampus and downregulating the genes associated with learning and memory. These events eventually led to growing mice learning and memory impairment, lagging responses, and anxiety-like behaviors. Furthermore, the male mice exhibited slightly more oxidative damage than the females. These findings imply that contemporary diets and food-processing strategies of the modern world should be modified to reduce oxidized protein intake.

[γ-aminobutyric acid fortified rice alleviated oxidative stress and pancreatic injury in type 2 diabetic mice].

OBJECTIVE: To investigate the effects of gamma aminobutyric acid(GABA) fortified rice diet intervention on oxidative stress and pancreatic injury in type 2 diabetes mellitus(T2 DM) mice. METHODS: Of the 70 male ICR mice, 10 were randomly selected as blank control group and they were always fed with the normal white rice feed. The remaining 60 mice were fed with high-fat white rice for 9 weeks. They were fasted for 12 h and injected intraperitoneally with streptozocin(STZ) at a dose of 50 mg/kg body weigh for two consecutive days. The control group was injected with the corresponding volume of normal saline. Subsequently, 50 T2 DM mice with successful modeling were randomly divided into 5 groups according to blood glucose, 10 in each group: T2 DM model control group, germinated brown rice positive control group(GABA content is 0. 2 g/kg feed), GABA-fortified rice low, medium and high dose group(GABA content was 0. 02, 0. 1 and 0. 2 g/kg feed respectively) and each target diet was fed for 6 weeks. Oral glucose tolerance test was performed one week before the end of the experiment to observe the hypoglycemic effect of different doses of GABA fortified rice. After the end of the experiment, HE staining was used to observe the morphology of pancreas. At the same time, the redox indicators from plasma and pancreas of reactive oxygen species(ROS), malondialdehyde(MDA), total antioxidant capacity(T-AOC), glutathione peroxidase(GSH-Px), superoxide dismutase(SOD) were examined in each group; The mRNA expressions of oxidative stress-related genes including glycogen synthase kinase-3ß(GSK-3ß), nuclear transcription factor 2(Nrf2), heme oxygenase 1(HO-1) and NAD(P)H: quinone oxidoreductase1(NQO1), insulin secretion related genes including pancreatic and duodenal homeobox 1(PDX-1), mus musculus v-maf musculoaponeurotic fibrosarcoma oncogene family, protein A(MafA), glucokinase(GCK), glucose transporter 2(GLUT2) and the apoptosis associated genes including b-cell lymphoma-2(Bcl-2), Bcl-2-associated X protein(Bax) and caspase-3 in pancreas were assayed by real-time fluorescent quantitative PCR. RESULTS: The intervention of GABA fortified rice could alleviate the improvement of the blood glucose level and the lack of insulin secretion in T2 DM mice and relieve plasma and pancreatic oxidative stress. besides, The intervention of GABA fortified rice could up-regulate the expression of insulin secretion-related genes PDX-1, GCK, GLUT2, inhibit the expression of pro-apoptotic gene caspase-3 and promote the expression of anti-apoptosis gene Bcl-2. There was a dose-response relationship between the above result and the 0. 2 g/kg dose group was the most significant, which achieved similar result to germinated brown rice. CONCLUSION: GABA-fortified rice can significantly improve the plasma and pancreatic redox status of STZ-induced T2 DM mice, regulate the expression levels of oxidative stress-related genes and apoptosis-related genes, thereby protect pancreatic tissue morphology, improve pancreatic insulin secretion and thereby alleviate glucose metabolism.

Dietary methionine restriction improves glucose metabolism in the skeletal muscle of obese mice.

Dietary methionine restriction (MR) has many positive effects on metabolic health. Recent studies have indicated that overall insulin sensitivity is improved by dietary MR. This study aimed to determine the effects of MR on insulin signalling and glucose utilisation in the skeletal muscle of obese mice. First, male C57BL/6J mice in the CON group were fed a control diet (0.86% methionine + 4% fat) for 34 weeks, and others were fed a high-fat (HF) diet (0.86% methionine + 20% fat) for 10 weeks to induce obesity. Then, the mice were divided into four dietary groups: the HF group (maintained on the HF diet), HF + MR group (0.17% methionine + 20% fat), C* group (changed to a control diet, 0.86% methionine + 4% fat), and C* + MR group (0.17% methionine + 4% fat) for 24 weeks. Mice were euthanised at 8, 16 or 24 weeks. The results indicated that MR ameliorated obesity-induced hyperglycaemia and hyperinsulinemia. Moreover, MR up-regulated the gene expression of disulfide-bond A oxidoreductase-like protein and cystathionine-γ-lyase and promoted adiponectin and H2S production in inguinal white adipose tissue. Furthermore, MR activated AMP-activated protein kinase and inhibited its downstream signalling and up-regulated insulin signalling-related molecules in gastrocnemius muscle. Overall, MR improved glucose metabolism via increasing glycogen synthesis, glycolysis, and aerobic oxidation. Interestingly, most parameters were equivalent between the HF + MR group and C* + MR group. These findings suggest that dietary MR can improve glucose metabolism in obese mice.

Dietary methionine restriction ameliorates the impairment of learning and memory function induced by obesity in mice.

Dietary methionine restriction (MR) has been reported to extend lifespan, improve insulin sensitivity, reduce adiposity and inflammation response, and in particular, increase endogenous hydrogen sulfide (H2S) production. H2S is a critical anti-inflammatory molecule in the central nervous system and a gaseous signal molecule that mediates learning and memory function. Hence, the present study aimed to investigate whether MR can ameliorate the impairment of learning and memory function induced by obesity, and to clarify its possible mechanisms. C57BL/6J mice were fed a control diet or a high-fat (HF) diet to induce obesity, and were then fed a control diet (CON group, 4.2% fat, 0.86% methionine), a HF diet (HF group, 24% fat, 0.86% methionine), or an MR diet (MR group, 24% fat, 0.17% methionine) for 16 consecutive weeks. Our results showed that HF-induced obesity impaired learning and memory function, reduced H2S production in the hippocampus, cortex, and plasma, and increased plasma and hippocampal inflammation response in the mice. MR improved the impairment of learning and memory function accompanied by selective modulation of the expression of multiple related genes, reduced plasma and hippocampal inflammatory response, normalized H2S levels in the hippocampus, cortex, and plasma, up-regulated the mRNA and protein expression levels of cystathionine ß-synthase in the hippocampus, and reduced hippocampal homocysteine level. These findings suggest that MR can ameliorate the impairment of learning and memory function, likely by increasing H2S production in the hippocampus.

Processing milk causes the formation of protein oxidation products which impair spatial learning and memory in rats.

This study explored the effects of protein oxidation during milk processing on spatial learning and memory in rats. Increasing the heating time, fat content, and inlet air temperature during processing by boiling, microwave heating, spray-drying, or freeze-drying increases milk protein oxidation. Oxidative damage done to milk proteins by microwave heating is greater than that caused by boiling. Dityrosine (DT), as a kind of tyrosine oxidation product, is the most important marker of this process, especially during spray-drying. Rats received diets containing either SWM (spray-dried milk powder diet), FWM (freeze-dried milk powder diet), FWM + LDT (freeze-dried milk powder + low dityrosine diet, DT: 1.4 mg kg-1), or FWM + HDT (freeze-dried milk powder + high dityrosine diet, DT: 2.8 mg kg-1) for 6 weeks. We found that the SWM group, the FWM + LDT group, and the FWM + HDT group appeared to have various degrees of redox state imbalance and oxidative damage in plasma, liver, and brain tissues. Further, hippocampal inflammatory and apoptosis genes were significantly up-regulated in such groups, while learning and memory genes were significantly down-regulated. Eventually, varying degrees of spatial learning and memory impairment were demonstrated in those groups in the Morris water maze. This means that humans should control milk protein oxidation and improve the processing methods applied to food.