RESUMO
Cancer which causes high mortality globally threatens public health seriously. There is an urgent need to develop tumor-specific near-infrared (NIR) imaging agents to achieve precise diagnosis and guide effective treatment. In recent years, imaging probes that respond to acidic environments such as endosomes, lysosomes, or acidic tumor microenvironments (TMEs) are being developed. However, because of their nonspecific internalization by both normal and tumor cells, resulting in a poor signal-to-noise ratio in diagnosis, these pH-sensitive probes fail to be applied to in vivo tumor imaging. To address this issue, a cholecystokinin-2 receptor (CCK2R)-targeted TME-sensitive NIR fluorescent probe R2SM was synthesized by coupling pH-sensitive heptamethine cyanine with a CCK2R ligand, minigastrin analogue 11 (MG11) for in vivo imaging, in which MG11 would target overexpressed CCK2Rs in gastrointestinal stromal tumors (GISTs). Cell uptake assay demonstrated that R2SM exhibited a high affinity for CCK2R, leading to receptor-mediated internalization and making probes finally accumulated in the lysosomes of tumor cells, which suggested in the tumor tissues, the probes were distributed in the extracellular acidic TME and intracellular lysosomes. With a pKa of 6.83, R2SM can be activated at the acidic TME (pH = 6.5-6.8) and lysosomes (pH = 4.5-5.0), exhibiting an apparent pH-dependent behavior and generating more intense fluorescence in these acidic environments. In vivo imaging showed that coupling of MG11 with a pH-sensitive NIR probe facilitated the accumulation of probe and enhanced the fluorescence in CCK2R-overexpressed HT-29 tumor cells. A high signal was observed in the tumor region within 0.5 h postinjection, indicating its potential application in intraoperative imaging. Fluorescence imaging of R2SM exhibited higher tumor-to-liver and tumor-to-kidney ratios (2.1:1 and 2.3:1, respectively), compared separately with the probes that are lipophilic, pH-insensitive, or MG11-free. In vitro and in vivo studies demonstrated that the synergistic effect of tumor targeting with pH sensitivity plays a vital role in the high signal-to-noise ratio of the NIR imaging probe. Moreover, different kinds of tumor-targeting vectors could be conjugated simultaneously with the NIR dye, which would further improve the receptor affinity and targeting efficiency.
Assuntos
Corantes Fluorescentes , Receptor de Colecistocinina B , Linhagem Celular Tumoral , Imagem ÓpticaRESUMO
Inflammatory bowel disease (IBD) is a long-lasting and inflammatory autoimmune condition affecting the gastrointestinal tract, impacting millions of individuals globally. The balance between T helper 17 (Th17) cells and regulatory T cells (Tregs) is pivotal in the pathogenesis and progression of IBD. This review summarizes the pivotal role of Th17/Treg balance in maintaining intestinal homeostasis, elucidating how its dysregulation contributes to the development and exacerbation of IBD. It comprehensively synthesizes the current understanding of how dietary factors regulate the metabolic pathways influencing Th17 and Treg cell differentiation and function. Additionally, this review presents evidence from the literature on the potential of dietary regimens to regulate the Th17/Treg balance as a strategy for the management of IBD. By exploring the intersection between diet, metabolic regulation, and Th17/Treg balance, the review reveals innovative therapeutic approaches for IBD treatment, offering a promising perspective for future research and clinical practice.
Assuntos
Doenças Inflamatórias Intestinais , Linfócitos T Reguladores , Células Th17 , Humanos , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/metabolismo , Células Th17/imunologia , Linfócitos T Reguladores/imunologia , Animais , DietaRESUMO
Antibiotic related intestinal injury in early life affects subsequent health and susceptibility. Here, we employed weaned piglets as a model to investigate the protective effects of baicalin against early-life antibiotic exposure-induced microbial dysbiosis. Piglets exposed to lincomycin showed a marked reduction in body weight (p < 0.05) and deterioration of jejunum intestinal morphology, alongside an increase in antibiotic-resistant bacteria such as Staphylococcus, Dolosicoccus, Escherichia-Shigella, and Raoultella. In contrast, baicalin treatment resulted in body weights, intestinal morphology, and microbial profiles that closely resembled those of the control group (p > 0.05), with a significant increase in norank_f_Muribaculaceae and Prevotellaceae_NK3B31_group colonization compared with lincomycin group (p < 0.05). Further analysis through fecal microbial transplantation into mice revealed that lincomycin exposure led to significant alterations in intestinal morphology and microbial composition, notably increasing harmful microbes and decreasing beneficial ones such as norank_Muribaculaceae and Akkermansia (p < 0.05). This shift was associated with an increase in harmful metabolites and disruption of the calcium signaling pathway gene expression. Conversely, baicalin supplementation not only counteracted these effects but also enhanced beneficial metabolites and regulated genes within the MAPK signaling pathway (MAP3K11, MAP4K2, MAPK7, MAPK13) and calcium channel proteins (ORA13, CACNA1S, CACNA1F and CACNG8), suggesting a mechanism through which baicalin mitigates antibiotic-induced intestinal and microbial disturbances. These findings highlight baicalin's potential as a plant extract-based intervention for preventing antibiotic-related intestinal injury and offer new targets for therapeutic strategies.
Assuntos
Antibacterianos , Flavonoides , Microbioma Gastrointestinal , Lincomicina , Sistema de Sinalização das MAP Quinases , Animais , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Microbioma Gastrointestinal/efeitos dos fármacos , Suínos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Lincomicina/farmacologia , Camundongos , Disbiose/induzido quimicamente , Disbiose/tratamento farmacológico , Masculino , Intestinos/efeitos dos fármacos , Intestinos/patologiaRESUMO
Metrology is the science of measurement and its applications, whereas biometrology is the science of biological measurement and its applications. Biometrology aims to achieve accuracy and consistency of biological measurements by focusing on the development of metrological traceability, biological reference measurement procedures, and reference materials. Irreproducibility of biological and multi-omics research results from different laboratories, platforms, and analysis methods is hampering the translation of research into clinical uses and can often be attributed to the lack of biologists' attention to the general principles of metrology. In this paper, the progresses of biometrology including metrology on nucleic acid, protein, and cell measurements and its impacts on the improvement of reliability and comparability in biological research are reviewed. Challenges in obtaining more reliable biological and multi-omics measurements due to the lack of primary reference measurement procedures and new standards for biological reference materials faced by biometrology are discussed. In the future, in addition to establishing reliable reference measurement procedures, developing reference materials from single or multiple parameters to multi-omics scale should be emphasized. Thinking in way of biometrology is warranted for facilitating the translation of high-throughput omics research into clinical practices.
Assuntos
Proteômica , Humanos , Reprodutibilidade dos Testes , Proteômica/métodos , Padrões de Referência , Animais , Genômica/métodos , MultiômicaRESUMO
Infants and young animals often suffer from intestinal damage caused by oxidative stress, which may adversely affect their overall health. Hydroxytyrosol, a plant polyphenol, has shown potential in decreasing intestinal oxidative stress, but its application and mechanism of action in infants and young animals are still inadequately documented. This study selected piglets as a model to investigate the alleviating effects of hydroxytyrosol on intestinal oxidative stress induced by diquat and its potential mechanism. Hydroxytyrosol improved intestinal morphology, characterized by higher villus height and villus height/crypt depth. Meanwhile, hydroxytyrosol led to higher expression of Occludin, MUC2, Nrf2, and its downstream genes, and lower expression of cytokines IL-1ß, IL-6, and TNF-α. Both oxidative stress and hydroxytyrosol resulted in a higher abundance of Clostridium_sensu_stricto_1, and a lower abundance of Lactobacillus and Streptococcus, without a significant effect on short-chain fatty acids levels. Oxidative stress also led to disorders in bile acid (BA) metabolism, such as the lower levels of primary BAs, hyocholic acid, hyodeoxycholic acid, and tauroursodeoxycholic acid, which were partially restored by hydroxytyrosol. Correlation analysis revealed a positive correlation between these BA levels and the expression of Nrf2 and its downstream genes. Collectively, hydroxytyrosol may reduce oxidative stress-induced intestinal damage by regulating BA metabolism.
Assuntos
Ácidos e Sais Biliares , Mucosa Intestinal , Estresse Oxidativo , Álcool Feniletílico , Animais , Estresse Oxidativo/efeitos dos fármacos , Álcool Feniletílico/análogos & derivados , Álcool Feniletílico/farmacologia , Suínos , Ácidos e Sais Biliares/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Intestinos/efeitos dos fármacos , Intestinos/patologia , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Fator 2 Relacionado a NF-E2/genéticaRESUMO
Alginate oligosaccharides (AOSs), which are an attractive feed additive for animal production, exhibit pleiotropic bioactivities. In the present study, we investigated graded doses of AOS-mediated alterations in the physiological responses of piglets by determining the intestinal architecture, barrier function, and microbiota. A total of 144 weaned piglets were allocated into four dietary treatments in a completely random design, which included a control diet (CON) and three treated diets formulated with 250 mg/kg (AOS250), 500 mg/kg (AOS500), and 1000 mg/kg AOS (AOS1000), respectively. The trial was carried out for 28 days. Our results showed that AOS treatment reinforced the intestinal barrier function by increasing the ileal villus height, density, and fold, as well as the expression of tight junction proteins, especially at the dose of 500 mg/kg AOS. Meanwhile, supplementations with AOSs showed positive effects on enhancing antioxidant capacity and alleviating intestinal inflammation by elevating the levels of antioxidant enzymes and inhibiting excessive inflammatory cytokines. The DESeq2 analysis showed that AOS supplementation inhibited the growth of harmful bacteria Helicobacter and Escherichia_Shigella and enhanced the relative abundance of Faecalibacterium and Veillonella. Collectively, these findings suggested that AOSs have beneficial effects on growth performance, antioxidant capacity, and gut health in piglets.
Assuntos
Alginatos , Antioxidantes , Microbioma Gastrointestinal , Oligossacarídeos , Desmame , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Suínos , Oligossacarídeos/farmacologia , Oligossacarídeos/administração & dosagem , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Alginatos/farmacologia , Suplementos Nutricionais , Ração Animal , Intestinos/microbiologia , Intestinos/efeitos dos fármacos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/microbiologiaRESUMO
BACKGROUND: Dietary fibers with varying physicochemical properties have different fermentation characteristics, which may differently impact host health. The present study aimed to determine the fermentation characteristics including gas production kinetics, short-chain fatty acids (SCFAs) production and microbial composition of different fibrous ingredients using in vitro fermentation by fecal microbiota. RESULTS: Sugar beet pule (SBP), wheat bran (WB), dried corn distillers grains with solubles (DDGS), rice bran (RB) and alfalfa meal (AM) were selected to fermentation in vitro for 36 h. The results showed that SBP had the greatest gas production. SBP had the highest in vitro dry matter fermentability (IVDMF) and production of acetate, propionate and total SCFAs, followed by WB, which were all greater than DDGS, AM and RB. The alpha-diversity was higher in the DDGS, AM and RB groups than in the WB and SBP groups. Differences in microbial community composition were observed among groups. The relative abundance of Treponema was highest in WB group. RB group showed lower Prevotella abundance than other groups but had higher Succinivibrio abundance. Interestingly, the Lactobacillus reached the highest abundances in the DDGS group. Correlation analysis indicated that the relative abundance of Treponema and Prevotella was positively associated with the gas production, IVDMF and SCFAs, whereas norank_f_Muribaculaceae, Rikenellaceae_RC9_gut_group, Lysinibacillus and Succinivibrio were the opposite. CONCLUSION: Collectively, WB and SBP were fermented rapidly by fecal microbiota compared to DDGS, AM and RB. Different fiber sources have different fiber compositions and fermentation properties that affect the microbial compositins and SCFAs production. © 2024 Society of Chemical Industry.
Assuntos
Ração Animal , Bactérias , Fibras na Dieta , Ácidos Graxos Voláteis , Fezes , Fermentação , Microbioma Gastrointestinal , Fibras na Dieta/metabolismo , Fibras na Dieta/análise , Fezes/microbiologia , Animais , Bactérias/metabolismo , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Ácidos Graxos Voláteis/metabolismo , Suínos , Ração Animal/análise , Zea mays/química , Zea mays/metabolismo , Beta vulgaris/química , Beta vulgaris/metabolismo , Beta vulgaris/microbiologia , Medicago sativa/química , Medicago sativa/metabolismo , Medicago sativa/microbiologia , Oryza/metabolismo , Oryza/química , Oryza/microbiologiaRESUMO
Nutrients sensing is crucial for fundamental metabolism and physiological functions, and it is also an essential component for maintaining body homeostasis. Traditionally, basic taste receptors exist in oral cavity to sense sour, sweet, bitter, umami, salty and et al. Recent studies indicate that gut can sense the composition of nutrients by activating relevant taste receptors, thereby exerting specific direct or indirect effects. Gut taste receptors, also named as intestinal nutrition receptors, including at least bitter, sweet and umami receptors, have been considered to be activated by certain nutrients and participate in important intestinal physiological activities such as eating behavior, intestinal motility, nutrient absorption and metabolism. Additionally, gut taste receptors can regulate appetite and body weight, as well as maintain homeostasis via targeting hormone secretion or regulating the gut microbiota. On the other hand, malfunction of gut taste receptors may lead to digestive disorders, and then result in obesity, type 2 diabetes and gastrointestinal diseases. At present, researchers have confirmed that the brain-gut axis may play indispensable roles in these diseases via the secretion of brain-gut peptides, but the mechanism is still not clear. In this review, we summarize the current observation of knowledge in gut taste systems in order to shed light on revealing their important nutritional functions and promoting clinical implications.
Assuntos
Diabetes Mellitus Tipo 2 , Papilas Gustativas , Humanos , Paladar/fisiologia , Diabetes Mellitus Tipo 2/metabolismo , Nutrientes , Dieta , Receptores Acoplados a Proteínas G/fisiologia , Percepção Gustatória/fisiologiaRESUMO
Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver disorders in humans, partly because it is closely related to metabolic disorders of the liver with increasing prevalence. NAFLD begins with hepatic lipid accumulation, which may cause inflammation and eventually lead to fibrosis in the liver. Numerous studies have demonstrated the close relationship between gut dysfunction (especially the gut microbiota and its metabolites) and the occurrence and progression of NAFLD. The bidirectional communication between the gut and liver, named the gut-liver axis, is mainly mediated by the metabolites derived from both the liver and gut through the biliary tract, portal vein, and systemic circulation. Herein, we review the effects of the gut-liver axis on the pathogenesis of NAFLD. We also comprehensively describe the potential molecular mechanisms from the perspective of the role of liver-derived metabolites and gut-related components in hepatic metabolism and inflammation and gut health, respectively. The study provides insights into the mechanisms underlying current summarizations that support the intricate interactions between a disordered gut and NAFLD and can provide novel strategies to lessen the prevalence and consequence of NAFLD.
Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/patologia , Disbiose , Fígado/metabolismo , Fibrose , Inflamação/metabolismoRESUMO
BACKGROUND: Based on our previous research conducted on cinnamaldehyde (CA) exhibiting its ability to improve the growth performance of fattening pigs and the adipogenesis induction model of C2C12 cells constructed in our laboratory, we explored the effects of CA on the generation and development of lipid droplets (LDs) in adipogenic differentiated C2C12 cells. METHODS AND RESULTS: C2C12 cells were treated with either 0.4 mM or 0.8 mM CA. BODIPY staining and triglyceride measurements were conducted to observe the morphology of LDs, and Western blotting was used to measure the expression of their metabolism-related proteins. The results showed that the average number of LDs in the CA treatment groups was more than the control group (P < 0.05), whereas the average LD size and triglyceride content decreased (P < 0.05). Compared with the control group, the expression levels of fusion-related genes in the LDs of the CA treatment group significantly decreased, while decomposition-related genes and autophagy-related genes in the LDs in C2C12 cells significantly increased (P < 0.01). CONCLUSION: Cinnamaldehyde promoted the decomposition and autophagy of lipid droplets in C2C12 cells and inhibited the fusion of lipid droplets.
Assuntos
Acroleína , Adipócitos , Diferenciação Celular , Gotículas Lipídicas , Metabolismo dos Lipídeos , Gotículas Lipídicas/efeitos dos fármacos , Gotículas Lipídicas/metabolismo , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Autofagia/efeitos dos fármacos , Autofagia/genética , Fusão de Membrana/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Carne/normas , Qualidade dos Alimentos , Animais , Camundongos , Linhagem Celular , Acroleína/análogos & derivados , TriglicerídeosRESUMO
This study aimed to explore the protective effects of L-theanine supplementation on the diquat-challenged weaned piglets. A total of 160 weaned piglets were randomly divided into 4 groups using a 2 × 2 two-factor design, there were 4 replicates per group and 10 pigs per replicate. Piglets were fed diets (with 1000 mg/kg L-theanine addition or not), then challenged with diquat or saline on day 7. 21 days after challenge, two pigs from each replicate were selected for sample collection. Results showed that supplement with 1000 mg/kg L-theanine down-regulated the diarrhea rate, serum D-lactate level, tumor necrosis factor-α, and phosphorylation of extracellular regulated protein kinases (ERK1/2), p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK) signaling in pigs without diquat challenge (p < 0.05). While for diquat-challenged piglets, L-theanine addition increased average daily gain, jejunum villus height, and interferon-γ level (p < 0.05). Meanwhile, L-theanine addition decreased the diarrhea rates and mortality, serum D-lactate level, and phosphorylation of ERK and JNK in diquat-challenged pigs (p < 0.05). These results demonstrate that L-theanine pretreatment could alleviate diquat-induced oxidative stress and improve intestinal barrier function in diquat-challenged weaned piglets, which can be attributed to suppression of MAPK phosphorylation signaling pathways.
Assuntos
Diquat , Sistema de Sinalização das MAP Quinases , Suínos , Animais , Diquat/toxicidade , Suplementos Nutricionais , Diarreia/induzido quimicamente , Diarreia/tratamento farmacológico , Diarreia/veterinária , Lactatos , DesmameRESUMO
As an important factor secreted by skeletal muscle, myonectin can regulate lipid metabolism and energy metabolism, but its role in the utilization of peripheral free fatty acids (FFAs) by porcine intramuscular fat cells remains to be further investigated. In this study, porcine intramuscular adipocytes were treated with recombinant myonectin and palmitic acid (PA), either alone or in combination, and then were examined for their uptake of exogenous FFAs, intracellular lipid synthesis and catabolism, and mitochondrial oxidation of fatty acids. The results showed that myonectin decreased the area of lipid droplets in intramuscular adipocytes (p < 0.05) and significantly increased (p < 0.05) the expression levels of hormone-sensitive lipase (HSL) and lipoprotein lipase (LPL). Moreover, myonectin can up-regulate the expression of p38 mitogen-activated protein kinase (p38 MAPK). Myonectin significantly promoted the uptake of peripheral FFAs (p < 0.01), improved (p < 0.05) the expression of fatty transport protein 1 (FATP1) and fatty acid binding protein 4 (FABP4) in intramuscular adipocytes. Myonectin also significantly increased (p < 0.05) the expression levels of fatty acid oxidation markers: transcription factor (TFAM), uncoupling protein-2 (UCP2) and oxidative respiratory chain marker protein complex I (NADH-CoQ) in mitochondria of intramuscular adipocytes. In summary, myonectin promoted the absorption, transport, and oxidative metabolism of exogenous FFAs in mitochondria, thereby inhibiting lipid deposition in porcine intramuscular adipocytes.
Assuntos
Ácidos Graxos não Esterificados , Regulação da Expressão Gênica , Suínos , Animais , Ácidos Graxos não Esterificados/farmacologia , Ácidos Graxos não Esterificados/metabolismo , Adipócitos/metabolismo , Diferenciação Celular , Músculo Esquelético/metabolismo , Ácidos Graxos/farmacologiaRESUMO
Bile acids (BAs) are well known to facilitate the absorption of dietary fat and fat-soluble molecules. These unique steroids also function by binding to the ubiquitous cell membranes and nuclear receptors. As chemical signals in gut-liver axis, the presence of metabolic disorders such as nonalcoholic fatty liver disease (NAFLD), type 2 diabetes mellitus (T2DM), and even tumors have been reported to be closely related to abnormal levels of BAs in the blood and fecal metabolites of patients. Thus, the gut microbiota interacting with BAs and altering BA metabolism are critical in the pathogenesis of numerous chronic diseases. This review intends to summarize the mechanistic links between metabolic disorders and BAs in gut-liver axis, and such stage-specific BA perturbation patterns may provide clues for developing new auxiliary diagnostic means.
Assuntos
Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Humanos , Ácidos e Sais Biliares/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Biomarcadores/metabolismoRESUMO
BACKGROUND: Clinical data suggest that male reproductive dysfunction especially infertility is a critical issue for type 1 diabetic patient (T1D) because most of them are at the reproductive age. Gut dysbiosis is involved in T1D related male infertility. However, the improved gut microbiota can be used to boost spermatogenesis and male fertility in T1D remains incompletely understood. METHODS: T1D was established in ICR (CD1) mice with streptozotocin. Alginate oligosaccharide (AOS) improved gut microbiota (fecal microbiota transplantation (FMT) from AOS improved gut microbiota; A10-FMT) was transplanted into the T1D mice by oral administration. Semen quality, gut microbiota, blood metabolism, liver, and spleen tissues were determined to investigate the beneficial effects of A10-FMT on spermatogenesis and underlying mechanisms. RESULTS: We found that A10-FMT significantly decreased blood glucose and glycogen, and increased semen quality in streptozotocin-induced T1D subjects. A10-FMT improved T1D-disturbed gut microbiota, especially the increase in small intestinal lactobacillus, and blood and testicular metabolome to produce n-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) to ameliorate spermatogenesis and semen quality. Moreover, A10-FMT can improve spleen and liver functions to strengthen the systemic environment for sperm development. FMT from gut microbiota of control animals (Con-FMT) produced some beneficial effects; however, to a smaller extent. CONCLUSIONS: AOS-improved gut microbiota (specific microbes) may serve as a novel, promising therapeutic approach for the improvement of semen quality and male fertility in T1D patients via gut microbiota-testis axis.
Assuntos
Diabetes Mellitus Tipo 1 , Microbioma Gastrointestinal , Animais , Diabetes Mellitus Tipo 1/terapia , Transplante de Microbiota Fecal , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Análise do Sêmen , Estreptozocina , TestículoRESUMO
Mutations in the LDL receptor gene LDLR cause familial hypercholesterolemia (FH); however, the pharmacogenomics of specific LDLR mutations remains poorly understood. The goals of this study were to identify the genetic cause of a three-generation Chinese family affected with autosomal dominant FH, and to investigate the response of FH patients in the family to statin and evolocumab. Whole exome sequencing of the FH family with four patients and six unaffected members identified a heterozygous splicing mutation (c.1187-2A>G) in LDLR. The mutation co-segregated with FH in the family, providing strong genetic evidence to support its pathogenicity. The proband was a 48-year-old male FH patient who had an acute myocardial infarction (MI) and ventricular fibrillation (VF), and showed LDL-C of 5.23 mmol/L. A combination of life style modifications on food and exercise and treatment with rosuvastatin reduced his LDL-C to 2.05-2.80 mmol/L. Addition of ezetimibe did not improve rosuvastatin therapy, but addition of evolocumab further reduced LDL-C by 70% to 0.7 mmol/L at the first time and by 67% to 1.31 mmol/L at the second time. Rosuvastatin also reduced LDL-C for proband's father and sister by 40% and 43-63%, respectively. Lovastatin alone or addition to rosuvastatin treatment did not have any effect on LDL-C for the proband and his son. Both patients carry ApoE 3/4 genotype and SLCO1B1 rs4149056 TT genotype. These results suggest that combined treatment with rosuvastatin (but not lovastatin or ezetimibe) and evolocumab can control LDL-C to meet the LDL-C treatment goal for patients with LDLR splicing mutation c.1187-2A>G.
Assuntos
Hiperlipidemias , Hiperlipoproteinemia Tipo II , Anticorpos Monoclonais Humanizados , LDL-Colesterol/genética , Ezetimiba/uso terapêutico , Humanos , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/genética , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Masculino , Pessoa de Meia-Idade , Mutação , Linhagem , Fenótipo , Pró-Proteína Convertase 9/genética , Receptores de LDL/genética , Receptores de LDL/metabolismo , Rosuvastatina Cálcica/uso terapêuticoRESUMO
AIM: Weaning stress can cause serious damage to piglet's health. Chlortetracycline (CTC) is widely used to ameliorate weaning stress and prevent infectious diseases in weaned piglets. However, antibiotics as growth promoters have to be limited because of increased antimicrobial resistance. In this study, we evaluated the effects of CTC on growth performance and intestinal functions in order to provide evidence for seeking antibiotic substitutes in weaned piglets. METHODS AND RESULTS: A total of 20 weaned piglets were fed a basal diet or a diet supplemented with 75 mg/kg CTC. CTC decreased the crypt depth and increased the ratio of villus height to crypt depth, whilst failing to affect growth performance and serum biochemical parameters and cytokines. 16S rRNA sequencing suggested that CTC supplementation had no effect on the diversity and composition of colonic microbiota. CONCLUSION: We speculated that gut microbiota is no longer sensitive to a low concentration of CTC due to the long-term use and low bioavailability of CTC in weaned piglets.
Assuntos
Clortetraciclina , Animais , Clortetraciclina/farmacologia , Dieta , Suplementos Nutricionais/análise , RNA Ribossômico 16S/genética , Suínos , DesmameRESUMO
Dysregulated lipid metabolism is a key pathology in metabolic diseases and the liver is a critical organ for lipid metabolism. The gut microbiota has been shown to regulate hepatic lipid metabolism in the host. However, the underlying mechanism by which the gut microbiota influences hepatic lipid metabolism has not been elucidated. Here, a gut microbiota depletion mouse model was constructed with an antibiotics cocktail (Abx) to study the mechanism through which intestinal microbiota regulates hepatic lipid metabolism in high-fat diet (HFD)-fed mice. Our results showed that the Abx treatment effectively eradicated the gut microbiota in these mice. Microbiota depletion reduced the body weight and fat deposition both in white adipose tissue and liver. In addition, microbiota depletion reduced serum levels of glucose, total cholesterol (TC), low-density lipoproteins (LDL), insulin, and leptin in HFD-fed mice. Importantly, the depletion of gut microbiota in HFD-fed mice inhibited excessive hepatic lipid accumulation. Mechanistically, RNA-seq results revealed that gut microbiota depletion changed the expression of hepatic genes involved in cholesterol and fatty acid metabolism, such as Cd36, Mogat1, Cyp39a1, Abcc3, and Gpat3. Moreover, gut microbiota depletion reduced the abundance of bacteria associated with abnormal metabolism and inflammation, including Lachnospiraceae, Coriobacteriaceae_UCG-002, Enterorhabdus, Faecalibaculum, and Desulfovibrio. Correlation analysis showed that there was strong association between the altered gut microbiota abundance and the serum cholesterol level. This study indicates that gut microbiota ameliorates HFD-induced hepatic lipid metabolic dysfunction, which might be associated with genes participating in cholesterol and fatty acid metabolism in the liver.
Assuntos
Dieta Hiperlipídica , Microbioma Gastrointestinal , Animais , Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Ácidos Graxos/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BLRESUMO
The adverse effects of short-term megadose of antibiotics exposure on the gastrointestinal and liver tissue reactions in young children have been reported. Antibiotic-induced intestinal and liver reactions are usually unpredictable and present a poorly understood pathogenesis. It is, therefore, necessary to develop strategies for reducing the adverse effects of antibiotics. Studies on the harm and rescue measures of antibiotics from the perspective of the gut-liver system are lacking. Here, we demonstrate that lincomycin exposure reduced body weight, disrupted the composition of gut microbiota and intestinal morphology, triggered immune-mediated injury and inflammation, caused liver dysfunction, and affected lipid metabolism. However, baicalin administration attenuated the lincomycin-induced changes. Transcriptome analysis showed that baicalin improved immunity in mice, as evidenced by the decreased levels of intestinal inflammatory cytokines and expression of genes that regulate Th1, Th2, and Th17 cell differentiation, and inhibited mucin type O-glycan biosynthesis pathways. In addition, baicalin improved liver function by upregulating the expression of genes involved in bile acid secretion and lipid degradation, and downregulating genes involved in lipid synthesis in lincomycin-treated mice. Bile acids can regulate intestinal immunity and strengthen hepatoenteric circulation. In addition, baicalin also improved anti-inflammatory bacteria abundance (Blautia and Coprobacillus) and reduced pathogenic bacteria abundance (Proteobacteria, Klebsiella, and Citrobacter) in lincomycin-treated mice. Thus, baicalin can ameliorate antibiotic-induced injury and its associated complications such as liver disease.
Assuntos
Inflamação , Lincomicina , Animais , Antibacterianos/efeitos adversos , Antibacterianos/metabolismo , Pré-Escolar , Flavonoides , Humanos , Inflamação/patologia , Lincomicina/metabolismo , Lincomicina/farmacologia , Lipídeos/farmacologia , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Although some studies have investigated the DNA methylation modification in goat ovaries, it is not understood DNA methylation related to goat litter size. This investigation was designed to explore the DNA methylation status in the ovaries of high litter size and low litter size groups using whole-genome bisulfite sequencing (WGBS). We found that there was global difference on DNA methylation in high litter size and low litter size goat ovaries. Many differentially methylated region-related genes (DMGs) were found in the ovaries of these two different goat populations. Moreover, enrichment analysis discovered that many DMGs were involved in gamete development, reproductive system development, wingless-type MMTV integration site family (WNT) signalling pathways and mitogen-activated protein kinase 1 (MAPK) signalling pathways. The data indicated that DNA methylation in goat ovaries may play important roles in the folliculogenesis, the oocyte ovulation rate and finally the litter size. This study provides a comprehensive analysis of genome-wide DNA methylation patterns in ovaries of high and low litter size goat which helps the understanding of ovarian DNA methylation in relation to goat fertility capability.
Assuntos
Metilação de DNA , Cabras , Animais , Feminino , Genoma , Cabras/genética , Tamanho da Ninhada de Vivíparos/genética , Ovário/metabolismo , GravidezRESUMO
Muscarinic acetylcholine receptor (mAChR) antagonists have been reported to decrease male fertility; however, the roles of mAChRs in spermatogenesis and the underlying mechanisms are not understood yet. During spermatogenesis, extensive remodeling between Sertoli cells and/or germ cells interfaces takes place to accommodate the transport of developing germ cells across the blood-testis barrier (BTB) and adluminal compartment. The cell-cell junctions play a vital role in the spermatogenesis process. This study used ICR male mice and spermatogonial cells (C18-4) and Sertoli cells (TM-4). shRNA of control or M5 gene was injected into 5-week-old ICR mice testes. Ten days post-viral grafting, mice were deeply anesthetized with pentobarbital and the testes were collected. One testicle was fresh frozen for RNA-seq analysis or Western blotting (WB). The second testicle was fixed for immunofluorescence staining (IHF). C18-4 or TM-4 cells were treated with shRNA of control or M5 gene. Then, the cells were collected for RNA-seq analysis, WB, or IHF. Knockdown of mAChR M5 disrupted mouse spermatogenesis and damaged the actin-based cytoskeleton and many types of junction proteins in both Sertoli cells and germ cells. M5 knockdown decreased Phldb2 expression in both germ cells and Sertoli cells which suggested that Phldb2 may be involved in cytoskeleton and cell-cell junction formation to regulate spermatogenesis. Our investigation has elucidated a novel role for mAChR M5 in the regulation of spermatogenesis through the interactions of Phldb2 and cell-cell junctions. M5 may be an attractive future therapeutic target in the treatment of male reproductive disorders.