Expand available targets for CAR-T therapy to overcome tumor drug resistance based on the "Evolutionary Traps".

Based on the concept of "Evolutionary Traps", targeting survival essential genes obtained during tumor drug resistance can effectively eliminate resistant cells. While, it still faces limitations. In this study, lapatinib-resistant cells were used to test the concept of "Evolutionary Traps" and no suitable target stand out because of the identified genes without accessible drug. However, a membrane protein PDPN, which is low or non-expressed in normal tissues, is identified as highly expressed in lapatinib-resistant tumor cells. PDPN CAR-T cells were developed and showed high cytotoxicity against lapatinib-resistant tumor cells in vitro and in vivo, suggesting that CAR-T may be a feasible route for overcoming drug resistance of tumor based on "Evolutionary Trap". To test whether this concept is cell line or drug dependent, we analyzed 21 drug-resistant tumor cell expression profiles reveal that JAG1, GPC3, and L1CAM, which are suitable targets for CAR-T treatment, are significantly upregulated in various drug-resistant tumor cells. Our findings shed light on the feasibility of utilizing CAR-T therapy to treat drug-resistant tumors and broaden the concept of the "Evolutionary Trap".

Puerarin Delays Mammary Gland Aging by Regulating Gut Microbiota and Inhibiting the p38MAPK Signaling Pathway.

Mammary gland aging is one of the most important problems faced by humans and animals. How to delay mammary gland aging is particularly important. Puerarin is a kind of isoflavone substance extracted from Pueraria lobata, which has anti-inflammatory, antioxidant, and other pharmacological effects. However, the role of puerarin in delaying lipopolysaccharide (LPS)-induced mammary gland aging and its underlying mechanism remains unclear. On the one hand, we found that puerarin could significantly downregulate the expression of senescence-associated secretory phenotype (SASP) and age-related indicators (SA-ß-gal, p53, p21, p16) in mammary glands of mice. In addition, puerarin mainly inhibited the p38MAPK signaling pathway to repair mitochondrial damage and delay mammary gland aging. On the other hand, puerarin could also delay the cellular senescence of mice mammary epithelial cells (mMECs) by targeting gut microbiota and promoting the secretion of gut microbiota metabolites. In conclusion, puerarin could not only directly act on the mMECs but also regulate the gut microbiota, thus, playing a role in delaying the aging of the mammary gland. Based on the above findings, we have discovered a new pathway for puerarin to delay mammary gland aging.

Antibacterial activity of isopropoxy benzene guanidine against Riemerella anatipestifer.

Introduction: Riemerella anatipestifer (R. anatipestifer) is an important pathogen in waterfowl, leading to substantial economic losses. In recent years, there has been a notable escalation in the drug resistance rate of R. anatipestifer. Consequently, there is an imperative need to expedite the development of novel antibacterial medications to effectively manage the infection caused by R. anatipestifer. Methods: This study investigated the in vitro and in vivo antibacterial activities of a novel substituted benzene guanidine analog, namely, isopropoxy benzene guanidine (IBG), against R. anatipestifer by using the microdilution method, time-killing curve, and a pericarditis model. The possible mechanisms of these activities were explored. Results and Discussion: The minimal inhibitory concentration (MIC) range of IBG for R. anatipestifer was 0.5-2 µg/mL. Time-killing curves showed a concentration-dependent antibacterial effect. IBG alone or in combination with gentamicin significantly reduced the bacterial load of R. anatipestifer in the pericarditis model. Serial-passage mutagenicity assays showed a low probability for developing IBG resistance. Mechanistic studies suggested that IBG induced membrane damage by binding to phosphatidylglycerol and cardiolipin, leading to an imbalance in membrane potential and the transmembrane proton gradient, as well as the decreased of intracellular adenosine triphosphate. In summary, IBG is a potential antibacterial for controlling R. anatipestifer infections.

Early supplementation with zinc proteinate does not change rectal microbiota but increases growth performance by improving antioxidant capacity and plasma zinc concentration in preweaned dairy calves.

The present study evaluated the effects of early supplementation with zinc proteinate (ZnP) or zinc oxide (ZnO) for 2 weeks on the growth performance, redox status, plasma trace element concentrations, and rectal microbiota of preweaned dairy calves. A total of 60 newborn healthy female Holstein dairy calves, with initial body weight (BW): 41.33 ± 0.62 kg, were randomly allocated to 5 groups of 12 each: a control group (CON); three groups supplemented with 261 (L-ZnP), 523 (M-ZnP), and 784 (H-ZnP) mg/day ZnP, equivalent to 40, 80, and 120 mg/day zinc, respectively; and one group supplemented with 232 mg/day ZnO, equivalent to 180 mg/day zinc (ZnO). Zinc supplements were administered on days 1-14, and the calves were followed up until day 70. Zinc supplementation increased total dry matter intake (DMI) and starter DMI compared with the CON group (p < 0.01). The final BW, average daily gain, and feed efficiency were higher in the M-ZnP, H-ZnP, and ZnO groups (p < 0.05). The incidence of diarrhea on days 1-28 was reduced by zinc administration (p < 0.01), whereas the incidence on days 29-56 was lower in the M-ZnP and ZnO groups (p < 0.05). Serum glutathione peroxidase activity, total antioxidant capacity, immunoglobulin G and plasma zinc concentrations were increased linearly (p < 0.05), while the serum concentration of malondialdehyde was decreased linearly (p < 0.01), as the dose of ZnP increased. ZnP yielding 80 mg/day zinc had similar effects as ZnO yielding 180 mg/day zinc, except that final BW was higher in the ZnO group (p < 0.05). At the phylum level, ZnO decreased the relative abundance of Firmicutes while increasing the abundance of Bacteroidetes (p < 0.05). At the genus level, ZnO increased the relative abundances of Prevotella, Subdoligranulum, and Odoribacter (p < 0.05). These findings indicated that early supplementation with ZnP did not affect the rectal microbiota of preweaned dairy calves but increased their growth performance, antioxidant capacity, and plasma zinc concentration. In summary, ZnP is an organic zinc source with greater bioavailability than ZnO for preweaned dairy calves. Early dietary supplementation with ZnP yielding 80 mg/day zinc is recommended.

Plasma metabolic profiling reveals that chromium yeast alleviates the negative effects of heat stress in mid-lactation dairy cows.

Chromium yeast (CY) supplementation has the potential to alleviate the negative effects of heat stress in dairy cows, but the mechanism remains elusive. We aimed to identify the metabolic mechanisms whereby CY supplementation alleviates the negative effects of heat stress in mid-lactation dairy cows. Twelve Holstein dairy cows with similar milk yield (24.6 ± 1.5 kg/d), parity (2 or 3) and days in milk (125 ± 8 d) were fed the same basal diet containing 0.09 mg of Cr/kg DM. They were allocated randomly to 2 groups: a control group (CON, without CY supplementation) and a CY group (CY, administered 0.36 mg Cr/kg DM). The experiment was performed over 8 weeks during a hot summer, in which the mean temperature-humidity index was 79.0 ± 3.13 (>72), indicating that the dairy cows were exposed to heat stress. Chromium yeast supplementation reduced rectal temperature (P = 0.032), and increased the lactation performance by increasing the yield of milk (+2.6 kg/d), protein, lactose and total solid, and protein and lactose percentages in the milk of the heat-stressed dairy cows (P < 0.05). Supplementation with CY increased the serum glucose and thyroxine concentrations, but reduced the urea nitrogen, insulin, and triiodothyronine concentrations on d 56 (P < 0.05). Furthermore, plasma metabolomic analysis was performed using liquid chromatography tandem-mass spectrometry, which identified 385 metabolites in the two groups. Subsequently, 16 significantly different metabolites in the plasma, were significantly higher in the CY group (variable importance for the projection >1.0, P < 0.05), and found to be involved in 6 Kyoto Encyclopedia of Genes and Genomes pathways, including those involved in nicotinate and nicotinamide metabolism. Specifically, plasma concentration of nicotinamide was higher after CY supplementation, which might also contribute to the reduction of rectal temperature, the regulation of glucose homeostasis, and an improvement in the lactation performance of heat-stressed dairy cows. In conclusion, CY supplementation reduces rectal temperature, influences metabolism by reducing serum insulin concentration and increasing serum glucose and plasma nicotinamide concentrations, and finally increases lactation performance of heat-stressed dairy cows.

Tartary buckwheat flavonoids alleviates high-fat diet induced kidney fibrosis in mice by inhibiting MAPK and TGF-ß1/Smad signaling pathway.

Tartary buckwheat flavonoids (TBF) are active components extracted from Tartary buckwheat, which have abundant biological effects. According to this study, we investigated the effect of TBF on high-fat diet (HFD)-induced kidney fibrosis and its related mechanisms. In vivo, we established an HFD-induced kidney fibrosis model in mice and administered TBF. The results showed that TBF was able to alleviate kidney injury and inflammatory response. Subsequently, the mRNA levels between the HFD group and the TBF + HFD group were detected using RNA-seq assay. According to the gene set enrichment analysis (GSEA) and Kyoto Encyclopedia of Genes and Genomes (KEGG) results, the differential genes were enriched in lipid metabolism and mitogen-activated protein kinases(MAPK) signaling pathways. We examined the protein expression of lipid metabolism-related pathways and the level of lipid metabolism. The results showed that TBF significantly activated the adenosine monophosphate activated protein kinase/acetyl-CoA carboxylase (AMPK/ACC) pathway and effectively reduced kidney total cholesterol (TC), triglyceride (TG) and low-density lipoproteinc cholesterol (LDL-C) levels and increased high-density lipoprotein cholesterol (HDL-C) levels in mice. TBF also inhibited transforming growth factor-ß1/Smad (TGF-ß1/Smad) and MAPK signaling pathways, thus slowing down the kidney fibrosis process. In vitro, using palmitic acid (PA) to stimulate TCMK-1 cells, the in vivo results similarly demonstrated that TBF could alleviate kidney fibrosis in HFD mice by inhibiting TGF1/Smad signaling pathway and MAPK signaling pathway.

How organizational support can help employees mitigate the effects of distributive injustice: a hierarchical moderated mediation model.

Objectives. At present, the mechanism of distributive justice leading to presenteeism is still unclear. We aim to explore the relationship among distributive justice, organization-based self-esteem, presenteeism and organizational support among Chinese medical workers by building a moderated mediation model. Methods. We employed a cross-level research design that aggregated organizational support to the organizational level. Medical staff from 50 different hospitals in China were invited to participate in the survey, and 1122 valid data questionnaires were obtained. We used hierarchical linear modelling to test this cross-level moderated mediation model. Results. Our results suggest that, at the individual level, organization-based self-esteem partially mediates the distributive justice-presenteeism relationship, and at the individual level, organizational support moderates the relationship between distributive justice and organization-based self-esteem. Conclusions. Distributive justice enhances individuals' organization-based self-esteem, which is associated with a reduction in presenteeism, and underscores the importance of organizations shaping an organizational support climate.

The Road to Unconventional Detections: Paper-Based Microfluidic Chips.

Conventional detectors are mostly made up of complicated structures that are hard to use. A paper-based microfluidic chip, however, combines the advantages of being small, efficient, easy to process, and environmentally friendly. The paper-based microfluidic chips for biomedical applications focus on efficiency, accuracy, integration, and innovation. Therefore, continuous progress is observed in the transition from single-channel detection to multi-channel detection and in the shift from qualitative detection to quantitative detection. These developments improved the efficiency and accuracy of single-cell substance detection. Paper-based microfluidic chips can provide insight into a variety of fields, including biomedicine and other related fields. This review looks at how paper-based microfluidic chips are prepared, analyzed, and used to help with both biomedical development and functional integration, ideally at the same time.

The explorations of dynamic interactions of paxillin at the focal adhesions.

Paxillin is one of the most important adapters in integrin-mediated adhesions that performs numerous crucial functions relying on its dynamic interactions. Its structural behavior serves different purposes, providing a base for several activities. The various domains of paxillin display different functions in the whole process of cell movements and have a significant role in cell adhesion, migration, signal transmission, and protein-protein interactions. On the other hand, some paxillin-associated proteins provide a unique spatiotemporal mechanism for regulating its dynamic characteristics in the tissue homeostasis and make it a more complex and decisive protein at the focal adhesions. This review briefly describes the structural adaptations and molecular mechanisms of recruitment of paxillin into adhesions, explains paxillin's binding dynamics and impact on adhesion stability and turnover, and reveals a variety of paxillin-associated regulatory mechanisms and how paxillin is embedded into the signaling networks.

Supplementation With Zinc Proteinate Increases the Growth Performance by Reducing the Incidence of Diarrhea and Improving the Immune Function of Dairy Calves During the First Month of Life.

Two experiments were conducted to identify the optimal dose of zinc proteinate (ZP) in the diet for dairy calves and then to compare early supplementation with the ZP or zinc methionine (ZM) on the growth performance, incidence of diarrhea, antioxidant status, and immune function of dairy calves during their first month of life. In Experiment 1, forty newborn female Holstein dairy calves were randomly divided into four groups (n = 10): a control group (without ZP supplementation, ZP0) or groups that received ZP supplementation at 40, 80, and 120 mg zinc/day, respectively (ZP40, ZP80, and ZP120). The experiment lasted 14 days, and the growth performance, incidence of diarrhea, and serum zinc concentration were analyzed. In Experiment 2, thirty-six newborn female Holstein dairy calves were randomly allocated to three groups (n = 12): a negative control group (without zinc supplementation, CON), a positive control group (supplemented with 80 mg zinc/day in the form of zinc methionine, ZM), and a ZP group (supplemented with 80 mg zinc/day in the form of ZP). The experiment lasted 28 days, and the growth performance, incidence of diarrhea, serum zinc concentration, serum antioxidant indicators, and concentrations of plasma immunoglobulins and cytokines were determined on days 7, 14, 21, and 28. Results showed that in Experiment 1, supplementation with ZP to yield 80 mg zinc/day increased the ADG (P < 0.01) and serum zinc concentration (P < 0.01), and decreased the F/G (P < 0.01) and the incidence of diarrhea (P < 0.05) during days 1-14. In Experiment 2, compared with the CON group, ZP increased the ADG (P < 0.01), serum zinc concentration (P < 0.01), and plasma immunoglobulin G (IgG; P < 0.01) and IgM (P < 0.01) concentrations, but reduced the incidence of diarrhea (P < 0.01), serum malondialdehyde (P < 0.01), and plasma interleukin-1ß (P < 0.01) concentrations during days 1-28. Overall, ZP supplementation to yield 80 mg zinc/day improves the growth performance and immune function, and decrease the incidence of diarrhea of dairy calves, which was comparable to the same dose of zinc in the form of ZM.

Supplementation with galacto-oligosaccharides in early life persistently facilitates the microbial colonization of the rumen and promotes growth of preweaning Holstein dairy calves.

We aimed to determine the effects of dietary supplementation with galacto-oligosaccharides (GOS) on the growth performance, serum parameters, and the rumen microbial colonization and fermentation of pre-weaning dairy calves. The study comprised 2 phases of 28 and 42 d, respectively. During phase 1, 24 newborn female Holstein dairy calves were randomly allocated to consume a diet supplemented with 10 g/d GOS (GOS, n = 12) or not (CON, n = 12). Thereafter, during phase 2, the GOS group was further divided into 2 groups: one that continued to consume GOS (GOSC, n = 6) and one that no longer consumed GOS (GOSS, n = 6), alongside the CON group. Galacto-oligosaccharides increased the average daily gain (ADG), body weight, feed efficiency, and serum high-density lipoprotein-cholesterol concentration of dairy calves during phase 1 (P < 0.05). Supplementation with GOS for the entire study reduced the incidence of diarrhea and increased the serum total protein and Ca concentrations (P < 0.05) compared with the CON group. The effect of GOS supplementation persisted after it was stopped because the ADG and final body weight of the GOSS group were higher than those of the CON group (P < 0.05). Furthermore, the GOSS group showed a persistently lower incidence of diarrhea and greater colonization of the rumen with probiotics, at the expense of less beneficial bacteria, which would promote ruminal fermentation and microbial protein synthesis. These findings provide a theoretical basis for the rational application of prebiotics and have important practical implications for the design of early life dietary interventions in dairy calf rearing.

Kaempferol attenuates diquat-induced oxidative damage and apoptosis in intestinal porcine epithelial cells.

Kaempferol, a flavonol component of plants, is well-known to exhibit multiple bioactivities, such as anti-oxidative and anti-apoptotic effects. However, the underlying mechanisms responsible for the beneficial effects remain elusive. This study was conducted to test the hypothesis that kaempferol attenuated diquat-induced oxidative damage and intestinal barrier dysfunction by ameliorating oxidative damage and apoptosis in intestinal porcine epithelial cells. Compared with the control group, diquat treatment led to enhanced intracellular ROS production, increased mitochondrial depolarization, and apoptosis, which were accompanied by cell cycle arrest at the G1 phase, reduced cell migration, and disrupted intestinal epithelial barrier function. These effects triggered by diquat were reversed by kaempferol. Further study showed that the protective effect of kaempferol was associated with an enhanced mRNA level of genes related to cell cycle progression (cyclin D1, CDK4, and E2F1) and genes implicated in the anti-oxidant system (GSR, GSTA4, and HO-1), up-regulated abundance of tight junctions (ZO-1, ZO-2, occludin, and claudin-4), as well as enhanced Nrf2, an anti-oxidant transcription factor. In conclusion, we revealed a functional role of kaempferol in the intestinal barrier. Ingestion of kaempferol-rich foods might be a potential strategy to improve the integrity and function of enterocytes.

Amino Acids in Endoplasmic Reticulum Stress and Redox Signaling.

Proteins are the chains of amino acids linked via peptide bonds. In cells, newly synthesized proteins are modified and folded in the endoplasmic reticulum (ER) and matured to be functional proteins before they are transported to other tissues or organs. In addition to protein synthesis, the ER is also a stress-sensing organelle for diverse biological functions, such as calcium storage, lipid synthesis, and cellular metabolism. Nutrient deprivation, accumulation of reactive oxygen species, and other intracellular insults can activate ER stress and unfolded protein response (UPR) to restore homeostasis. Dysfunction of the ER influences cellular physiology and metabolism, and contributes to the pathogenesis of various diseases. Amino acids are the building blocks for proteins of eukaryotic organisms. Both in vivo and in vitro studies have found that amino acids can function as signaling molecules to regulate gene expression, cell proliferation and apoptosis, immune response, and antioxidant capacity in numerous biological processes. Importantly, several lines of studies have indicated that amino acids regulate the abundances of proteins implicated in UPR and the redox state, therefore restoring the intracellular homeostasis. Amino acids play an important role in regulating ER stress and redox homeostasis in animal cells for their survival, growth, and development.

Glycine Attenuates Citrobacter rodentium-Induced Colitis by Regulating ATF6-Mediated Endoplasmic Reticulum Stress in Mice.

SCOPE: Inflammatory bowel disease (IBD) is an inflammatory gastrointestinal disorder in which endoplasmic reticulum (ER) stress and dysbiosis of the intestinal microbiota are implicated. Glycine supplementation is reported to reduce inflammatory responses in experimental colitis. However, the underlying mechanisms responsible for the beneficial effects remain unclear. METHODS AND RESULTS: Female C57BL/6 mice are orally administered with glycine (3.5 or 5.2 g kg-1 body weight) for 14 continuous days. On day 8 post-glycine supplementation, the mice are orally inoculated with 2 × 109 CFU Citrobacter rodentium (C. rodentium). The results show that glycine alleviates C. rodentium-induced body weight loss, increased disease activity index and spleen weight, colon length shortening, and colonic hyperplasia. Glycine suppresses the activation and infiltration of inflammatory cells, and secretion of pro-inflammatory cytokines in the colon tissues. The apoptosis of colon epithelial cells is also abrogated by glycine, which is associated with the inactivation of activating transcription factor 6α (ATF6α)-C/EBP homologous protein (CHOP) signaling. In addition, glycine administration increases α diversity, restores ß diversity, and abolishes the reduction in Lactobacillus, Bifidobacterium, Alistipes, Turicibacter, and Alloprevotella in the colon. CONCLUSIONS: Glycine supplementation is a nutritional strategy that may ameliorate C. rodentium-induced colitis by regulating ATF6α-CHOP-mediated ER stress and enhancing the abundance of Lactobacillus.

Quercetin Alleviates Oxidative Damage by Activating Nuclear Factor Erythroid 2-Related Factor 2 Signaling in Porcine Enterocytes.

Oxidative stress has been implicated in the etiology of multiple gastrointestinal disorders, such as irritable bowel syndrome and inflammatory bowel disease. This study was conducted to evaluate effects of natural product quercetin on diquat-induced oxidative stress in porcine enterocytes and underlying mechanisms. Intestinal porcine epithelial cell line 1 (IPEC-1) cells pretreated with or without quercetin (5 µM, 24 h) were incubated with vehicle or diquat (100 µM) for 6 h. The results showed that diquat treatment induced apoptosis in a caspase-3-dependent manner, as accompanied by elevated reactive oxygen species (ROS) production, increased mitochondrial depolarization, and reduced the abundance of tight junction proteins. These adverse effects of diquat were remarkably abrogated by quercetin administration. Further study indicated that the protective effect of quercetin was associated with elevated protein abundance of nuclear factor erythroid 2-related factor 2 (Nrf2) and increased intracellular glutathione (GSH) content. Interestingly, the beneficial effects of quercetin on diquat-induced oxidative damage were abolished by all-trans-retinoic acid (Atra), a specific inhibitor of Nrf2, indicating a Nrf2-dependent regulation manner. The results show that quercetin attenuates diquat-induced cell injury by promoting protein abundance of Nrf2 and regulating GSH-related redox homeostasis in enterocytes. These findings provide new insights into a function role of quercetin in maintaining intestinal homeostasis.

Epithelial Dysfunction in Lung Diseases: Effects of Amino Acids and Potential Mechanisms.

Lung diseases affect millions of individuals all over the world. Various environmental factors, such as toxins, chemical pollutants, detergents, viruses, bacteria, microbial dysbiosis, and allergens, contribute to the development of respiratory disorders. Exposure to these factors activates stress responses in host cells and disrupt lung homeostasis, therefore leading to dysfunctional epithelial barriers. Despite significant advances in therapeutic treatments for lung diseases in the last two decades, novel interventional targets are imperative, considering the side effects and limited efficacy in patients treated with currently available drugs. Nutrients, such as amino acids (e.g., arginine, glutamine, glycine, proline, taurine, and tryptophan), peptides, and bioactive molecules, have attracted more and more attention due to their abilities to reduce oxidative stress, inhibit apoptosis, and regulate immune responses, thereby improving epithelial barriers. In this review, we summarize recent advances in amino acid metabolism in the lungs, as well as multifaceted functions of amino acids in attenuating inflammatory lung diseases based on data from studies with both human patients and animal models. The underlying mechanisms for the effects of physiological amino acids are likely complex and involve cell signaling, gene expression, and anti-oxidative reactions. The beneficial effects of amino acids are expected to improve the respiratory health and well-being of humans and other animals. Because viruses (e.g., coronavirus) and environmental pollutants (e.g., PM2.5 particles) induce severe damage to the lungs, it is important to determine whether dietary supplementation or intravenous administration of individual functional amino acids (e.g., arginine-HCl, citrulline, N-acetylcysteine, glutamine, glycine, proline and tryptophan) or their combinations to affected subjects may alleviate injury and dysfunction in this vital organ.

Melatonin Modulates Lactation by Regulating Prolactin Secretion Via Tuberoinfundibular Dopaminergic Neurons in the Hypothalamus- Pituitary System.

In-depth studies have identified many hormones important for controlling mammary growth and maintaining lactation. One of these is melatonin, which is synthesized and secreted by the pineal gland to regulate circadian rhythms, improve antioxidant capacity, and enhance immunity. Prolactin is secreted by the pituitary gland and is associated with the growth and development of mammary glands as well as initiation and maintenance of lactation. The hypothalamus-pituitary system, the most important endocrine system in the body, regulates prolactin secretion mainly through dopamine released from tuberoinfundibular dopaminergic neurons. This review provides a reference for further study and describes the regulation of lactation and prolactin secretion by melatonin, primarily via the protection and stimulation of tuberoinfundibular dopaminergic neurons.

Glycine Attenuates LPS-Induced Apoptosis and Inflammatory Cell Infiltration in Mouse Liver.

BACKGROUND: Liver dysfunction impairs immunological homeostasis. Glycine (Gly) has been reported to have antioxidative and anti-inflammatory effects and to regulate apoptosis in various models. OBJECTIVES: The aim of the present study was to determine whether Gly could attenuate LPS-induced liver injury. METHODS: In Experiment 1, 48 6-week-old male C57BL/6 mice were randomly assigned into one of 4 groups: CON (control), GLY [orally administered Gly, 5 g · kg body weight (BW)-1 · d-1 for 6 d], LPS (5 mg/kg BW, intraperitoneally administered), and GLY + LPS (Gly supplementation, and on day 7 LPS treatment). In Experiment 2, mice were untreated, pretreated with Gly as above, or pretreated with Gly + l-buthionine sulfoximine (BSO) (0.5 g/kg BW, intraperitoneally administered every other day) for 6 d. On day 7, mice were injected with LPS as above. Histological alterations, activities of antioxidative enzymes, apoptosis, and immune cell infiltration were analyzed. RESULTS: In Experiment 1, compared with CON, LPS administration resulted in increased karyolysis and karyopyknosis in the liver by 8- to 10-fold, enhanced serum activities of alanine transaminase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH) by 1- to 1.8-fold, and increased hepatic apoptosis by 5.5-fold. Furthermore, LPS exposure resulted in increased infiltration of macrophages and neutrophils in the liver by 3.2- to 7.5-fold, elevated hepatic concentrations of malondialdehyde and hydrogen peroxide (H2O2), and elevated myeloperoxidase (MPO) activity by 1.5- to 6.3-fold. In Experiment 2, compared with the LPS group, mice in the GLY + LPS group had fewer histological alterations (68.5%-75.9%); lower serum ALT, AST, and LDH activities (24.3%-64.7%); and lower hepatic malondialdehyde and H2O2 concentrations (46.1%-80.2%), lower MPO activity (39.2%), immune cell infiltration (52.3%-85.3%), and apoptosis (69.6%), which were abrogated by BSO. Compared with the GLY + LPS group, mice in the GLY + BSO + LPS group had lower hepatic activities of catalase, superoxide dismutase, and glutathione peroxidase by 33.5%-48.5%; increased activation of NF-κB by 2.3-fold; and impaired nuclear factor (erythroid-derived 2)-like 2 signaling by 38.9%. CONCLUSIONS: Gly is a functional amino acid with an ability to protect the liver against LPS-induced injury in mice.

Bioactive Proteins and their Physiological Functions in Milk.

Milk is the basic food for infants and newborn animals, providing a rich source of proteins, carbohydrates, minerals, and vitamins. Milk also provides nourishment for people of all ages due to its abundant nutrients, and it is used in the manufacture of numerous health-related products. Milk contains caseins and whey proteins as the two major protein classes. Caseins fall into four major types known as αs1-, αs2-, ß- and κ-casein, whereas whey proteins comprise a mixture of globular proteins including ß-lactoglobulin, α-lactalbumin, serum albumin, lactoferrin, and other bioactivators. The various biological activities of these proteins are involved in preventing and treating numerous nutritional, physiological and metabolic diseases. This article reviews the bioactivities and functions of milk proteins, which may shed light on future application of milk bioactive substances.