Yogurt Alleviates Cyclophosphamide-Induced Immunosuppression in Mice through D-Lactate.

Numerous studies have investigated the immunomodulatory effects of yogurt, but the underlying mechanism remained elusive. This study aimed to elucidate the alleviating properties of yogurt on immunosuppression and proposed the underlying mechanism was related to the metabolite D-lactate. In the healthy mice, we validated the safety of daily yogurt consumption (600 µL) or D-lactate (300 mg/kg). In immunosuppressed mice induced by cyclophosphamide (CTX), we evaluated the immune regulation of yogurt and D-lactate. The result showed that yogurt restored body weight, boosted immune organ index, repaired splenic tissue, recovered the severity of delayed-type hypersensitivity reactions and increased serum cytokines (IgA, IgG, IL-6, IFN-γ). Additionally, yogurt enhanced intestinal immune function by restoring the intestinal barrier and upregulating the abundance of Bifidobacterium and Lactobacillus. Further studies showed that D-lactate alleviated immunosuppression in mice mainly by promoting cellular immunity. D-lactate recovered body weight and organ development, elevated serum cytokines (IgA, IgG, IL-6, IFN-γ), enhanced splenic lymphocyte proliferation and increased the mRNA level of T-bet in splenic lymphocyte to bolster Th1 differentiation. Finally, CTX is a chemotherapeutic drug, thus, the application of yogurt and D-lactate in the tumor-bearing mouse model was initially explored. The results showed that both yogurt (600 µL) and D-lactate (300 mg/kg) reduced cyclophosphamide-induced immunosuppression without promoting tumor growth. Overall, this study evaluated the safety, immune efficacy and applicability of yogurt and D-lactate in regulating immunosuppression. It emphasized the potential of yogurt as a functional food for immune regulation, with D-lactate playing a crucial role in its immunomodulatory effects.

Yogurt Prevents Colitis-Associated Colorectal Cancer in Mice.

SCOPE: Epidemiological studies indicate an inverse correlation between yogurt consumption and colorectal cancer (CRC), but whether there is a cause-and-effect relationship has not yet been validated. This study aims to investigate the effects and possible mechanisms of yogurt on colitis-associated colorectal cancer (CAC) in mice. METHODS AND RESULTS: Experimental CAC is induced by azoxymethane (AOM, 10 mg kg-1 , ip) followed by three cycles of dextran sulfate sodium (DSS, 3%) treatment. Colitis is induced by adding DSS (3%) in drinking water for 5 days. Primary mouse macrophages are isolated for mechanistic studies. Data clearly show that yogurt (15 g kg-1 body weight) significantly reduces the multiplicity of colonic neoplasms by 38.83% in mice. Yogurt protects mice from colitis dependent on lactate receptor GPR81. The deficiency of Gpr81 exacerbates colitis and CAC in mice. Further investigation reveals that GPR81 may be dispensable for gut barrier function but essential for colonic mucosal repair. d-lactate in yogurt can activate GPR81 to suppress proinflammatory macrophage polarization, thereby facilitating inflammatory resolution after colonic injury and consequently suppressing CAC progression. CONCLUSION: Yogurt effectively protects against colitis-associated colorectal tumorigenesis in mice, and this study provides a rationale for introducing yogurt supplementation to patients with chronic inflammatory bowel diseases.

Thromboxane A2-TP axis promotes adipose tissue macrophages M1 polarization leading to insulin resistance in obesity.

Aberrant arachidonic acid metabolism has been implicated in multiple pathophysiological conditions, and the downstream prostanoids levels are associated with adipocyte dysfunction in obesity. However, the role of thromboxane A2 (TXA2) in obesity remains unclear. We observed that TXA2, through its receptor TP, is a candidate mediator in obesity and metabolic disorders. Obese mice with upregulated TXA2 biosynthesis (TBXAS1) and TXA2 receptor (TP) expression in caused insulin resistance and macrophage M1 polarization in white adipose tissue (WAT), which can be prevented by treatment with aspirin. Mechanistically, the activation of TXA2-TP signaling axis leads to accumulation of protein kinase Cɛ (PKCɛ), thereby enhancing free fat acid (FFA) induced Toll-like receptor4 (TLR4) proinflammatory macrophage activation and the tumor necrosis factor-a (TNF-a) production in adipose tissues. Importantly, TP knockout mice reduced the accumulation of proinflammatory macrophages and adipocyte hypertrophy in WAT. Thus, our findings demonstrate that TXA2-TP axis plays a crucial role in obesity-induced adipose macrophage dysfunction, and rational targeting TXA2 pathway may improve obesity and its associated metabolic disorders in future. In this work, we establish previously unknown role of TXA2-TP axis in WAT. These findings might provide new insight into the molecular pathogenesis of insulin resistance, and indicate rational targeting TXA2 pathway to improve obesity and its associated metabolic disorders in future.

Correlation between bacterial diversity and flavor substances in Longgang soy sauce.

Longgang soy sauce is one of the traditional fermented condiments in China, but its bacterial community succession and its unique flavor development during the fermentation process are not well-investigated. This study evaluated the bacterial diversity, flavor changes, and their correlation during the fermentation of Longgang soy sauce. The results showed that Weissella was the dominant bacterial genus in the fermentation stage of sauce fermented grains. In the first 31 days of the moromi fermentation stage, a variety of bacterial genera such as Weissella, Halomonas, Bacteroides, Pseudomonas, and Tetragenococcus were the dominant bacteria. Our results showed that these bacteria have a significantly positive correlation with phenylethyl alcohol, ethyl acetate, and 3-methyl-1-butanol. As the fermentation progressed, a flora structure with Halomonas as the main bacterial genus was formed. This genus exhibited a significantly positive and positive correlation with 1-octanol, ethyl palmitate, heptanol, and 2-nonanol, which are the unique flavor components of Longgang soy sauce.

Dietary d-Lactate Intake Facilitates Inflammatory Resolution by Modulating M1 Macrophage Polarization.

SCOPE: Given the d-lactate dehydrogenase (D-LDH) deficiency, L- but not d-lactate is assumed to be the physiological isomer in mammals. Paradoxically, many fermented foods (e.g., yogurt, sauerkraut, cheeses) often contain substantial amounts of d-lactate. In the present study, dietary d-lactate may be a previously unrecognized nutrient aiding in inflammatory resolution is hypothesized. METHODS AND RESULTS: The anti-inflammatory properties of d-lactate are evaluated in experimental colitis and endotoxemia. Oral administration of d-lactate favorably affects acute inflammation in two different mouse models. Analysis of lactate-the lactate receptor (the hydroxycarboxylic acid receptor 1 HCA1, formerly GPR81) signal axis in inflammation is performed in primary peritoneal macrophages and wild-type (WT) or GPR81 knockout (KO) mice. GPR81 KO mice are susceptible to endotoxic shock than WT mice, while d-lactate exerts its anti-inflammatory activities in a GPR81-dependent manner. Mechanistically, the activation of lactate-GPR81 axis may suppress LPS-TLR4 signaling to modulate M1 macrophage polarization. Although D-LDH deficiency in mammals impairs d-lactate clearance, it might prolong its plasma terminal half-life, and thus provide a pharmacokinetic advantage of d-lactate over l-lactate. CONCLUSION: This study highlights housekeeping function of the lactate-GPR81 axis in inflammation control, and suggests that dietary intake of d-lactate may underlie Metchnikoff's probiotic yogurt theory of life prolongation.

Comprehensive and clinically accurate head and neck cancer organs-at-risk delineation on a multi-institutional study.

Accurate organ-at-risk (OAR) segmentation is critical to reduce radiotherapy complications. Consensus guidelines recommend delineating over 40 OARs in the head-and-neck (H&N). However, prohibitive labor costs cause most institutions to delineate a substantially smaller subset of OARs, neglecting the dose distributions of other OARs. Here, we present an automated and highly effective stratified OAR segmentation (SOARS) system using deep learning that precisely delineates a comprehensive set of 42 H&N OARs. We train SOARS using 176 patients from an internal institution and independently evaluate it on 1327 external patients across six different institutions. It consistently outperforms other state-of-the-art methods by at least 3-5% in Dice score for each institutional evaluation (up to 36% relative distance error reduction). Crucially, multi-user studies demonstrate that 98% of SOARS predictions need only minor or no revisions to achieve clinical acceptance (reducing workloads by 90%). Moreover, segmentation and dosimetric accuracy are within or smaller than the inter-user variation.

Relationship between flavor compounds and changes of microbial community in the solid fermented vinegar.

The relationship between volatile compounds of vinegar and microorganisms is not clear, especially pyrazine, a trace component. In order to reveal their potential relationship, high throughput sequencing, solid-phase microextraction-gas chromatography-mass spectrometry (SPME-GC-MS) and Spearman's correlation analysis were used. Results showed that Acetobacter and Lactobacillus with opposite abundance trends were the predominant bacteria, and the total abundance of them exceeds 98%, while the predominant fungal genera were Aspergillus and Malassezia, their highest abundances are 75.4% and 81.5%, respectively. In the whole process of microbial community succession, 6 pyrazines were detected including trimethylpyrazine and tetramethylpyrazine, etc., and Spearman's correlation analysis showed that they were positively correlated with the presence of Vibrionimonas, Paraburkholderia, Paucibacter, Komagataeibacter, Acinetobacter, and Slinibacter. In general, this study further revealed more species related to pyrazines, it will be helpful to understand the formation of pyrazines and promote the improvement of vinegar quality.

The lactate receptor GPR81 mediates hepatic lipid metabolism and the therapeutic effect of metformin on experimental NAFLDs.

The lactate receptor G protein-coupled receptor 81 (GPR81) has been recently implicated in lipolysis in adipose tissue. In this study, we accidently discovered the role of GPR81 in hepatic lipid metabolism. Data clearly showed that hepatic GPR81 was markedly up-regulated in fasted mice, whereas it was severely down-regulated in obese mice. Genetic deficiency of GPR81 impaired ketogenic response, enhanced hepatic lipid accumulation, and exacerbated hepatosteatosis under acute fasting conditions. Mechanically, we demonstrated that hepatic GPR81 might function as a modulator of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), activate the downsream transcription of liver carnitine o-palmitoyltransferase 1(L-CPT1), and thereby control the influx of fatty acids into mitochondria for ß-oxidation. Importantly, metformin improved experimental nonalcoholic fatty liver disease (NAFLDs) in a GPR81-dependent manner. Collectively, GPR81 was critical for hepatic lipid homeostasis and activation of hepatic GPR81 might represent a promising strategy for the treatment of obesity and its associated metabolic disorders.

Isolation of lipopeptide antibiotics from Bacillus siamensis: a potential biocontrol agent for Fusarium graminearum.

Fusarium head blight (FHB), a destructive fungal disease that can cause damage to various crops and reduce yield and quality, is primarily caused by several species of the soil-borne fungal genus Fusarium, which produce mycotoxins that contaminate grains and may cause various severe chronic diseases in humans and livestock. In recent years, Bacillus spp. have been reported to be good producers of antifungal antibiotics against FHB. This study aimed to explore the potential role of a newly identified Bacillus strain, designated as CU-XJ-9, against FHB. This strain, which was isolated from traditional Chinese fermented food, was identified as Bacillus siamensis and confirmed to produce lipopeptide biosurfactants, which according to the analysis by quadrupole time-of-flight tandem mass spectrometry (Q-TOF-MS/MS) may belong to the iturin lipopeptide family. At 100 µg/mL, the isolated antifungal compounds completely inhibited conidial germination. Observation of the effects of the isolated antifungal compounds on the mycelia of F. graminearum by scanning electron microscopy revealed obvious nodes in the middle of the mycelia and destroyed mycelial structures, and these changes became more pronounced with increasing dose. Overall, this study provides important information regarding the ability of Bacillus siamensis to produce lipopeptide biosurfactants, which showed significant antagonistic activity against F. graminearum.

Aspirin suppresses breast cancer metastasis to lung by targeting anoikis resistance.

Clinical evidence recently suggests that the regular use of aspirin is associated with a lower risk of breast cancer metastasis, but mechanisms remain unclear. Resistance to anoikis has been implicated in malignant transformation and metastasis. Here, we investigated whether aspirin might prevent breast cancer metastasis to lung by targeting anoikis resistance. Aspirin sensitized breast cancer cells to anoikis in vitro and lowered the circulating tumor cells as well as distant metastasis in vivo. Mechanistically, thromboxane A2 (TXA2) pathway was identified as the relevant molecular target for aspirin in anoikis sensitization. Upon detachment, both thromboxane A2 receptor (TP) and thromboxane A2 synthase 1 (TBXAS1) were up-regulated in metastatic breast cancer cells, conferred anoikis resistance through persistent activation of Akt, thereby facilitated breast cancer metastasis to lung. Consistently, either knockdown of TP in cancer cells or genetic deletion of TP in mice protected against lung metastasis in vivo. Collectively, TXA2 pathway plays a critical role in anoikis resistance and might serve as potential target for chemoprevention of breast cancer metastasis.

Glutamine deficiency links clindamycin-induced dysbiosis and intestinal barrier dysfunction in mice.

Antibiotics rank as the most powerful weapons against bacterial infection, but their use is often limited by antibiotic-associated diarrhoea (AAD). Here, we reported that glutamine deficiency might act as a new link between clindamycin-induced dysbiosis and intestinal barrier dysfunction during AAD progression. Using a mouse model, we demonstrated that glutamine became a conditionally essential amino acid upon persistent therapeutic-dose clindamycin exposure, evidenced by a dramatic decrease in intestinal glutamine level and glutaminase expression. Mechanistically, clindamycin substantially confounded the abundance of butyrate-producing strains, leading to the deficiency of faecal butyrate which is normally a fundamental fuel for enterocytes, and in turn increased the compensatory use of glutamine. In addition to its pivotal roles in colonic epithelial cell turnover, glutamine was required for nitric oxide production in classic macrophage-driven host defence facilitating pathogen removal. Importantly, oral administration of glutamine effectively attenuated clindamycin-induced dysbiosis and restored intestinal barrier dysfunction in mice. Collectively, the present study highlighted the importance of gut microbiota in host energy homoeostasis and provided a rationale for introducing glutamine supplementation to patients receiving long-term antibiotic treatment.

Dietary Lactate Supplementation Protects against Obesity by Promoting Adipose Browning in Mice.

Yogurt has been widely used in weight-loss foods to prevent obesity, but its molecular nature remains unclear. Lactate is a major ingredient of yogurt, while its cognate cell surface receptor GPR81 is highly expressed in adipose tissues in mammals. Here we hypothesized that dietary lactate supplementation might activate GPR81 to promote adipose browning. Studying mouse models, we observed that GPR81 was substantially lowered in adipose tissue of obese mice compared with that for lean ones, whereas its expression was markedly up-regulated by a ß3-adrenergic receptor (ß3-AR) agonist. The deficiency of GPR81 greatly attenuated experimental adipose browning and thermogenesis. Importantly, oral administration of lactate effectively induced adipose browning, enhanced thermogenesis, improved dyslipidemia, and protected mice against high-fat-diet-induced obesity. Mechanistically, p38 mitogen-activated protein kinase might serve as a key downstream effect or of GPR81. Collectively, our findings revealed a critical role of GPR81 in adipose browning and provided a new insight into obesity management by modulating lactate-GPR81 signaling axis.

Nephroprotective effects of diacylglycerol on diabetic nephropathy in type 2 diabetic rats.

Diacylglycerol (DAG) has been reported to reduce the serum lipid and glucose levels more effectively compared with triacylglycerol (TAG). The present study examined the long-term effects of dietary DAG on rats with type 2 diabetic nephropathy (DN). The type 2 DN model was established by administering a high-fat and high-calorie diet along with an intraperitoneal injection of 35 mg/kg body weight streptozocin, and the disease developed over the following 8 weeks. Sprague-Dawley rats were then randomly divided into the control, TAG, low-dose DAG (Low-DAG) and high-dose DAG (High-DAG) groups. Blood glucose (BG), lipid levels and renal function parameters were then measured. The results revealed that the body weight in the High-DAG group was significantly reduced compared with the TAG group, while there was no significant difference in the food intake between TAG and DAG groups. BG, advanced glycation end products (AGEs), TAG, low-density lipoprotein cholesterol, urine protein and urine albumin levels were significantly reduced, while high-density lipoprotein cholesterol levels were significantly increased in the two DAG groups. In addition, hematoxylin-eosin stained glomeruli presented decreased glomerular enlargement and mesangial expansion in the DAG groups. Immunohistochemical detection revealed that the levels of transforming growth factor-ß1 and connective tissue growth factor in renal tissues of the DAG groups were also significantly reduced compared with the TAG group. These findings indicate that DAG oils can significantly reduce BG levels and the deposition of AGEs in renal tissue, as well as regulate the levels of transforming growth factor-ß1 and connective tissue growth factor, thus delaying the progression of nephropathy.