Substitution of chemical nitrogen (N) with organic fertilizers in agricultural ecosystems has been promoted to sustain crop yield and soil quality. Soil microbes play key roles in soil nutrient ...cycling after organic matter addition. However, there is limited information about the effect of the organic substitution ratio (OSR) on soil bacterial communities, which are considered as a good indicator of soil quality in a tea plantation. In this study, a long-term field experiment with six treatments was established to study the effect of different OSRs of N, from pure synthetic fertilization (NPK) to 100% N substituted with organic fertilizer (OM100), on tea yield and soil bacterial communities. The soil bacterial community composition was measured using a high-throughput sequencing technique. The results showed that as the OSR increased, the soil bacterial diversity increased and the community structure shifted significantly. However, 25% N substituted with organic fertilizer (OM25) produced the highest yield. Additionally, the soil pH and organic carbon (SOC) were the predominant soil characteristics that accounted for the soil bacterial community structural change. With more chemical N being substituted with organic fertilizer, the soil pH, available potassium, SOC, total N, and microbial biomass C and N, were elevated; however, the yield of fresh tea leaves decreased. These results indicated the trade-off effect between tea yield and soil bacterial diversity under different OSRs, which could also alter the soil bacterial communities by changing soil characteristics.
Partial substitution of chemical fertilizers by organic amendments is essential for improving the soil quality without yield loss. Fungi play an important role in soil quality because they decompose ...organic matter and cycle nutrients in the soil. However, there is limited information regarding the effect of different organic substitution rates (OSRs) on the soil quality and fungal community. This study investigated the relationship between the soil quality index and fungal community in a tea plantation under different OSRs of N, from a single application of synthetic fertilizer (NPK) to 100% N substitution with organic fertilizer (OM100). The OSRs were positively correlated with the soil physicochemical and biological soil quality index (SQI), but only the physicochemical SQI exhibited a significant relationship with tea production. The OSR also shifted the soil fungal community composition. Soil pH, soil organic C (SOC), microbial biomass C (MBC), and available potassium (AK) were the key characteristics that were significantly correlated with the variation of soil fungal community. Network analysis indicated that additional organic substitution can enhance the soil fungal network complexity, which also showed a positive correlation with the SQI. These results confirmed the feasibility of organic substitution for soil quality improvement, and implied that the soil fungal network complexity could be a new indicator for soil quality assessment.
Fibroblast growth factor 21 (FGF21) has been identified as a potent metabolic regulator. Administration of recombinant FGF21 protein to rodents and rhesus monkeys with diet-induced or genetic obesity ...and diabetes exerts strong antihyperglycemic and triglyceride-lowering effects and reduction of body weight. Despite the importance of FGF21 in the regulation of glucose, lipid, and energy homeostasis, the mechanisms by which FGF21 functions as a metabolic regulator remain largely unknown. Here we demonstrate that FGF21 regulates energy homeostasis in adipocytes through activation of AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1), resulting in enhanced mitochondrial oxidative function. AMPK phosphorylation levels were increased by FGF21 treatment in adipocytes as well as in white adipose tissue from ob/ob mice. FGF21 treatment increased cellular NAD⁺ levels, leading to activation of SIRT1 and deacetylation of its downstream targets, peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and histone 3. Activation of AMPK and SIRT1 by FGF21 in adipocytes enhanced mitochondrial oxidative capacity as demonstrated by increases in oxygen consumption, citrate synthase activity, and induction of key metabolic genes. The effects of FGF21 on mitochondrial function require serine/threonine kinase 11 (STK11/LKB1), which activates AMPK. Inhibition of AMPK, SIRT1, and PGC-1α activities attenuated the effects of FGF21 on oxygen consumption and gene expression, indicating that FGF21 regulates mitochondrial activity and enhances oxidative capacity through an AMPK-SIRT1-PGC1α-dependent mechanism in adipocytes.
Platinum-based cancer therapy is restricted by dose-limiting side effects and is associated with elevation of growth differentiation factor 15 (GDF-15). But whether this elevation contributes to such ...side effects has been unclear. Here, we explored the effects of GDF-15 blockade on platinum-based chemotherapy-induced emesis, anorexia, and weight loss in mice and/or nonhuman primate models. We found that circulating GDF-15 is higher in subjects with cancer receiving platinum-based chemotherapy and is positively associated with weight loss in colorectal cancer (NCT00609622). Further, chemotherapy agents associated with high clinical emetic score induce circulating GDF-15 and weight loss in mice. Platinum-based treatment-induced anorexia and weight loss are attenuated in GDF-15 knockout mice, while GDF-15 neutralization with the monoclonal antibody mAB1 improves survival. In nonhuman primates, mAB1 treatment attenuates anorexia and emesis. These results suggest that GDF-15 neutralization is a potential therapeutic approach to alleviate chemotherapy-induced side effects and improve the quality of life.
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•Plasma GDF-15 is higher in subjects with cancer receiving platinum-based chemotherapy•GDF-15 deletion attenuates anorexia and weight loss induced by platinum-based agents•GDF-15 neutralization lowered cisplatin-induced emesis/anorexia in nonhuman primates•GDF-15 neutralization + cisplatin treatment promotes survival in a mouse tumor model
In this work, circulating GDF-15 is higher in subjects with cancer receiving platinum-based chemotherapy. In mice and/or nonhuman primates, GDF-15 neutralization with a novel antibody (mAB1) alleviates emesis, anorexia, and weight loss induced by platinum-based chemotherapies, and mAB1 treatment improves survival in tumor-bearing mice when given in combination with cisplatin.
SIRT4, a member of the sirtuin family, has been implicated in the regulation of insulin secretion by modulation of glutamate dehydrogenase. However, the role of this enzyme in the regulation of ...metabolism in other tissues is unknown. In this study we investigated whether depletion of SIRT4 would enhance liver and muscle metabolic functions. To do this SIRT4 was knocked down using an adenoviral shRNA in mouse primary hepatocytes and myotubes. We observed a significant increase in gene expression of mitochondrial and fatty acid metabolism enzymes in hepatocytes with reduced SIRT4 levels. SIRT4 knockdown also increased SIRT1 mRNA and protein levels both in vitro and in vivo. In agreement with the increased fatty acid oxidation (FAO) gene expression, we showed a significant increase in FAO in SIRT4 knockdown primary hepatocytes compared with control, and this effect was dependent on SIRT1. In primary myotubes, knockdown of SIRT4 resulted in increased FAO, cellular respiration, and pAMPK levels. When SIRT4 was knocked down in vivo by tail vein injection of a shRNA adenovirus, we observed a significant increase in hepatic mitochondrial and FAO gene expression consistent with the findings in primary hepatocytes. Taken together these findings demonstrate that SIRT4 inhibition increases fat oxidative capacity in liver and mitochondrial function in muscle, which might provide therapeutic benefits for diseases associated with ectopic lipid storage such as type 2 diabetes.
Chronic noise exposure is correlated with gut microbiota dysbiosis and glucose and lipid metabolism disorders. However, evidence on the mechanisms underlying of gut microbiota alterations in chronic ...noise induced glucose and lipid metabolism disorders is limited, and the potential aftereffects of chronic noise exposure on metabolic disorders remain unclear. In present study, we established chronic daytime and nighttime noise exposure mice models to explore the effects and underlying mechanism of gut microbiota on chronic noise-induced glucose and lipid metabolism disorders. The results showed that exposure to chronic daytime or nighttime noise significantly increased the fasting blood glucose, serum and liver TG levels, impaired glucose tolerance, and decreased serum HDL-C levels and liver TC levels in mice. However, after 4 weeks of recovery, only serum TG of mice in nighttime noise recovery group remained elevated. Besides, exposure to chronic noise reduced the intestinal tight junction protein levels and increased intestinal permeability, while this effect did not completely dissipate even after the recovery period. Moreover, chronic noise exposure changed the gut microbiota and significantly regulated metabolites and metabolic pathways, and further activate hepatic gluconeogenesis CRTC2/CREB-PCK1 signaling pathway and lipid synthesis SREBP1/SCD signaling pathway through intestinal hepatic axis. Together, our findings demonstrated that chronic daytime and nighttime noise exposure could cause the glucose and lipid metabolism disorder by modulating the gut microbiota and serum metabolites, and activating hepatic gluconeogenic CREB/CRTC2-PCK1 signaling and lipid synthesis SREBP1/SCD signaling pathway. The potential aftereffects of noise exposure during wakefulness on metabolic disorders are more significant than that of noise exposure during sleep.
The anorectic and weight-suppressive effects of growth differentiation factor-15 (GDF15) are attracting considerable attention for treating obesity. Current experiments in rats investigate whether ...GDF15 induces an aversive visceral malaise-based state that mediates its acute anorectic effect and, through aversion conditioning, exerts longer-term anorexia. Visceral malaise, conditioned affective food responses (taste reactivity), gastric emptying (GE), food intake, and body weight are evaluated after acute and chronic systemic dosing of GDF15 or long-acting Fc-GDF15. Pica, a marker of visceral malaise, is present at all anorectic GDF15 doses. Moreover, malaise induced by GDF15 does not decline over time, suggesting the lack of an improved tolerance after prolonged exposure. One association between GDF15 and novel food conditions a disgust/aversive response that persists beyond GDF15 acute action. Delayed GE is not a requirement for GDF15-induced anorexia. Clinical studies are required to evaluate whether GDF15’s aversive-state-based anorexia will be contraindicated as an obesity treatment.
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•Acute GDF15 systemic delivery induces visceral malaise, anorexia, and body weight loss•Chronic GDF15 exposure triggers visceral malaise that does not decline over time•GDF15 conditions food-aversive responses persisting beyond its acute anorectic action•GDF15’s visceral malaise and anorectic effects do not require slowed gastric emptying
Borner et al. show that the visceral malaise (i.e., pica) that accompanies GDF15-induced anorexia persists after prolonged exposure, denoting the lack of improved tolerance. Further, the food-GDF15 pairing conditions a disgust/aversive response that contributes to anorexia and lasts beyond GDF15’s acute action. Reduced gastric emptying is not required for GDF15-induced anorexia/malaise.
GDF15 is a distant TGF-β family member that induces anorexia and weight loss. Due to its function, GDF15 has attracted attention as a potential therapeutic for the treatment of obesity and its ...associated metabolic diseases. However, the pharmacokinetic and physicochemical properties of GDF15 present several challenges for its development as a therapeutic, including a short half-life, high aggregation propensity, and protease susceptibility in serum. Here, we report the design, characterization and optimization of GDF15 in an Fc-fusion protein format with improved therapeutic properties. Using a structure-based engineering approach, we combined knob-into-hole Fc technology and N-linked glycosylation site mutagenesis for half-life extension, improved solubility and protease resistance. In addition, we identified a set of mutations at the receptor binding site of GDF15 that show increased GFRAL binding affinity and led to significant half-life extension. We also identified a single point mutation that increases p-ERK signaling activity and results in improved weight loss efficacy in vivo. Taken together, our findings allowed us to develop GDF15 in a new therapeutic format that demonstrates better efficacy and potential for improved manufacturability.
为深入推进化肥减量行动，需要对已研发出的茶园化肥减施增效技术模式进行社会经济效果评价，筛选出适宜当地优先推广的技术模式。本研究采用文献综合研究法和专家咨询法，构建了一套适宜茶园化肥减施增效技术模式社会经济效果评价的指标体系，并运用基于专家意见多重相关性的灰色关联分析模型，对福建省闽东绿茶区5种化肥减施增效技术模式（模式1：施用专用肥模式；模式2：有机肥料替代部分化肥模式；模式3：施用脲甲醛复合肥新型肥料模式；模式4：施用生物炭基肥模式；模式5：地力改良与施生物炭结合模式）进行实证评价。结果表明：采用专家组多重相关性赋权法得到的最终权重中，技术特征指标权重最高，为36.52%，经济效益指标权重次之，为26.95%，社会效益指标权重为21.24%，管理指标权重最低，为15.29%； 5项技术模式的综合评价得分排序为模式2 （0.798 6） >模式1 （0.744 4） >模式4 （0.560 0） >模式3 （0.482 4） >模式5 （0.467 6）。研究表明，福建省闽东绿茶区适合优先推广有机肥料替代部分化肥技术模式，其次是专用肥模式，而其他三项技术模式有待进一步研究优化。To further promote the action of chemical fertilizer reduction, it is necessary to evaluate the socio-economic effects of the developed chemical fertilizer application reduction and efficiency improvement technical modes in tea gardens and select the appropriate and prioritized technical modes for application. The index system was constructed by comprehensive literature research and expert consultation method to evaluate the socio-economic effects of chemical fertilizer application reduction and efficiency improvement tech
Muscle wasting is one of the main characteristics of cachexia associated with cancer and other chronic diseases and is often exacerbated by antineoplastic agents. Increased oxidative stress is ...associated with muscle wasting, along with depletion of glutathione, the most abundant endogenous antioxidant. Therefore, boosting endogenous glutathione has been proposed as a therapeutic strategy to prevent muscle wasting. Here, we tested this hypothesis by inactivating CHAC1, an intracellular glutathione degradation enzyme. We found CHAC1 expression is increased under multiple muscle wasting conditions in animal models, including fasting, cancer cachexia, and chemotherapy. The elevation of muscle Chac1 expression is associated with reduced glutathione level. CHAC1 inhibition via CRSPR/Cas9 mediated knock-in of an enzyme inactivating mutation demonstrates a novel strategy to preserve muscle glutathione levels under wasting conditions but fails to prevent muscle wasting in mice. These results suggest that preserving intracellular glutathione level alone may not be sufficient to prevent cancer or chemotherapy induced muscle wasting.
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