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Glia–neuron interaction is a crucial feature in aged hippocampus during the occurrence of postoperative cognitive impairment. However, the regulatory effects of microglia, astrocytes, and oligodendrocytes in this glia–neuron interaction, the potential mechanisms and gene targets are still to be elucidated. Here, single‐cell RNA sequencing was performed to detect the perioperative genomic expression characteristics of neuroglial system in the hippocampus of aged mice, and to investigate the potential cross‐cellular mechanisms and valuable treatment options for glia–neuron interaction‐related cognitive impairment. We found that postoperative neurons and glia cells exhibited protein dysmetabolism and mitochondrial electron misrouting. Impaired autophagy and circadian rhythm worsened microglia activation/neuroinflammation, and exacerbated these metabolic alterations. Reactive microglia also aggravated astrocyte and oligodendrocyte cytotoxicity through the PGD2/DP and complement pathways, altering glutamate level and synaptic function via the “tripartite synapses” model, and affecting neuronal myelination. Ligand‐receptor communication also indicated these synaptic and axonal dysfunctions via enhanced MDK and PTN pathways. Additionally, we found that anesthetic dexmedetomidine hold therapeutic potential within the disrupted neuroglial system. It enhanced neuronal metabolic rebalance (Atf3‐related) and reduced neuroinflammation from a multicellular perspective, therefore improving postoperative cognitive impairment. Together, our study proposes an aged hippocampal cell atlas and provides insights into the role of disrupted glia–neuron cycle in postoperative cognitive impairment. Our findings also elucidate the therapeutic potential and mechanism of dexmedetomidine intervention. [ABSTRACT FROM AUTHOR]

Post-traumatic stress disorder (PTSD) is a multisystem syndrome. Integration of systems-level multi-modal datasets can provide a molecular understanding of PTSD. Proteomic, metabolomic, and epigenomic assays are conducted on blood samples of two cohorts of well-characterized PTSD cases and controls: 340 veterans and 180 active-duty soldiers. All participants had been deployed to Iraq and/or Afghanistan and exposed to military-service-related criterion A trauma. Molecular signatures are identified from a discovery cohort of 218 veterans (109/109 PTSD+/-). Identified molecular signatures are tested in 122 separate veterans (62/60 PTSD+/-) and in 180 active-duty soldiers (PTSD+/-). Molecular profiles are computationally integrated with upstream regulators (genetic/methylation/microRNAs) and functional units (mRNAs/proteins/metabolites). Reproducible molecular features of PTSD are identified, including activated inflammation, oxidative stress, metabolic dysregulation, and impaired angiogenesis. These processes may play a role in psychiatric and physical comorbidities, including impaired repair/wound healing mechanisms and cardiovascular, metabolic, and psychiatric diseases.

ABSTRACT: Milk composition, particularly milk fatty acids, has been extensively studied as an indicator of the metabolic status of dairy cows during early lactation. In addition to milk biomarkers, on-farm sensor data also hold potential in providing insights into the metabolic health status of cows. While numerous studies have explored the collection of a wide range of sensor data from cows, the combination of milk biomarkers and on-farm sensor data remains relatively underexplored. Therefore, this study aims to identify associations between metabolic blood variables, milk variables, and various on-farm sensor data. Second, it seeks to examine the supplementary or substitutive potential of these data sources. Therefore, data from 85 lactations on metabolic status and on-farm data were collected during 3 wk before calving up to 5 wk after calving. Blood samples were taken on d 3, 6, 9, and 21 after calving for determination of β-hydroxybutyrate (BHB), nonesterified fatty acids (NEFA), glucose, insulin-like growth factor-1 (IGF-1), insulin, and fructosamine. Milk samples were taken during the first 3 wk in lactation and analyzed by mid-infrared for fat, protein, lactose, urea, milk fatty acids, and BHB. Walking activity, feed intake, and body condition score (BCS) were monitored throughout the study. Linear mixed effect models were used to study the association between blood variables and (1) milk variables (i.e., milk models); (2) on-farm data (i.e., on-farm models) consisting of activity and dry matter intake analyzed during the dry period ([D]) and lactation ([L]) and BCS only analyzed during the dry period ([D]); and (3) the combination of both. In addition, to assess whether milk variables can clarify unexplained variation from the on-farm model and vice versa, Pearson marginal residuals from the milk and on-farm models were extracted and related to the on-farm and milk variables, respectively. The milk models had higher coefficient of determination (R2) than the on-farm models, except for IGF-1 and fructosamine. The highest marginal R2 values were found for BHB, glucose, and NEFA (0.508, 0.427, and 0.303 vs. 0.468, 0.358, and 0.225 for the milk models and on-farm models, respectively). Combining milk and on-farm data particularly increased R2 values of models assessing blood BHB, glucose, and NEFA concentrations with the fixed effects of the milk and on-farm variables mutually having marginal R2 values of 0.608, 0.566, and 0.327, respectively. Milk C18:1 was confirmed as an important milk variable in all models, but particularly for blood NEFA prediction. On-farm data were considerably more capable of describing the IGF-1 concentration than milk data (marginal R2 of 0.192 vs. 0.086), mainly due to dry matter intake before calving. The BCS [D] was the most important on-farm variable in relation to blood BHB and NEFA and could explain additional variation in blood BHB concentration compared with models solely based on milk variables. This study has shown that on-farm data combined with milk data can provide additional information concerning the metabolic health status of dairy cows. On-farm data are of interest to be further studied in predictive modeling, particularly because early warning predictions using milk data are highly challenging or even missing.

Milk composition, particularly milk fatty acids, has been extensively studied as an indicator of the metabolic status of dairy cows during early lactation. In addition to milk biomarkers, on-farm sensor data also hold potential in providing insights into the metabolic health status of cows. While numerous studies have explored the collection of a wide range of sensor data from cows, the combination of milk biomarkers and on-farm sensor data remains relatively underexplored. Therefore, this study aims to identify associations between metabolic blood variables, milk variables, and various on-farm sensor data. Second, it seeks to examine the supplementary or substitutive potential of these data sources. Therefore, data from 85 lactations on metabolic status and on-farm data were collected during 3 wk before calving up to 5 wk after calving. Blood samples were taken on d 3, 6, 9, and 21 after calving for determination of β-hydroxybutyrate (BHB), nonesterified fatty acids (NEFA), glucose, insulin-like growth factor-1 (IGF-1), insulin, and fructosamine. Milk samples were taken during the first 3 wk in lactation and analyzed by mid-infrared for fat, protein, lactose, urea, milk fatty acids, and BHB. Walking activity, feed intake, and body condition score (BCS) were monitored throughout the study. Linear mixed effect models were used to study the association between blood variables and (1) milk variables (i.e., milk models); (2) on-farm data (i.e., on-farm models) consisting of activity and dry matter intake analyzed during the dry period ([D]) and lactation ([L]) and BCS only analyzed during the dry period ([D]); and (3) the combination of both. In addition, to assess whether milk variables can clarify unexplained variation from the on-farm model and vice versa, Pearson marginal residuals from the milk and on-farm models were extracted and related to the on-farm and milk variables, respectively. The milk models had higher coefficient of determination (R2) than the on-farm models, except for IGF-1 and fructosamine. The highest marginal R2 values were found for BHB, glucose, and NEFA (0.508, 0.427, and 0.303 vs. 0.468, 0.358, and 0.225 for the milk models and on-farm models, respectively). Combining milk and on-farm data particularly increased R2 values of models assessing blood BHB, glucose, and NEFA concentrations with the fixed effects of the milk and on-farm variables mutually having marginal R2 values of 0.608, 0.566, and 0.327, respectively. Milk C18:1 was confirmed as an important milk variable in all models, but particularly for blood NEFA prediction. On-farm data were considerably more capable of describing the IGF-1 concentration than milk data (marginal R2 of 0.192 vs. 0.086), mainly due to dry matter intake before calving. The BCS [D] was the most important on-farm variable in relation to blood BHB and NEFA and could explain additional variation in blood BHB concentration compared with models solely based on milk variables. This study has shown that on-farm data combined with milk data can provide additional information concerning the metabolic health status of dairy cows. On-farm data are of interest to be further studied in predictive modeling, particularly because early warning predictions using milk data are highly challenging or even missing. [ABSTRACT FROM AUTHOR]

Denervation-induced skeletal muscle atrophy can potentially cause the decline in the quality of life of patients and an increased risk of mortality. Complex pathophysiological mechanisms with dynamic alterations have been documented in skeletal muscle atrophy resulting from innervation loss. Hence, an in-depth comprehension of the key mechanisms and molecules governing skeletal muscle atrophy at varying stages, along with targeted treatment and protection, becomes essential for effective atrophy management. Our preliminary research categorizes the skeletal muscle atrophy process into four stages using microarray analysis. This review extensively discusses the pathways and molecules potentially implicated in regulating the four stages of denervation and muscle atrophy. Notably, drugs targeting the reactivare oxygen species stage and the inflammation stage assume critical roles. Timely intervention during the initial atrophy stages can expedite protection against skeletal muscle atrophy. Additionally, pharmaceutical intervention in the ubiquitin-proteasome pathway associated with atrophy and autophagy lysosomes can effectively slow down skeletal muscle atrophy. Key molecules within this stage encompass MuRF1, MAFbx, LC3II, p62/SQSTM1, etc. This review also compiles a profile of drugs with protective effects against skeletal muscle atrophy at distinct postdenervation stages, thereby augmenting the evidence base for denervation-induced skeletal muscle atrophy treatment. [ABSTRACT FROM AUTHOR]

Olfactory dysfunction, influenced by factors such as aging and environmental stress, is linked to various neurological disorders. The olfactory bulb's connections to brain areas like the hypothalamus, piriform cortex, entorhinal cortex, and limbic system make olfactory dysfunction a contributor to a range of neuropathological conditions. Recent research has underscored that olfactory deficits are prevalent in individuals with both metabolic syndrome and dementia. These systemic metabolic alterations correlate with olfactory impairments, potentially affecting brain regions associated with the olfactory bulb. In cases of metabolic syndrome, phenomena such as insulin resistance and disrupted glucose metabolism may result in compromised olfactory function, leading to multiple neurological issues. This review synthesizes key findings on the interplay between metabolic-induced olfactory dysfunction and neuropathology. It emphasizes the critical role of olfactory assessment in diagnosing and managing neurological diseases related to metabolic syndrome. [Display omitted] • Metabolic imbalance causes olfactory mucosa damage and olfactory neurogenesis. • Metabolic imbalance accelerates amyloid beta accumulation, and insulin resistance, leading to olfactory deficits • Hyperglycemia and insulin resistance increases inflammation, and decreased expression of GLUT 3,4,6,8 in olfactory bulb. • Olfactory dysfunction caused by metabolic imbalance influences various brain regions and multiple functions. [ABSTRACT FROM AUTHOR]

Cerebral ischemia is a major health problem worldwide, that affects millions of people, leaving a major percentage of them with major disabilities, therefore becoming one of the most resource consuming pathology. Beside the blockage of blood supply of the brain that leads to loss of cellular function and neuronal necrosis, metabolic processes are modified in the whole body through mechanisms that are not fully explained yet. The results in the analysis of the 2 groups, one with 70 patients with stroke and another with 68 patients with no cerebral infarction, revealed that brain ischemia is more often found in patients with atrial fibrillation and higher blood pressure values. The metabolic changes, found in the stroke group, are represented by increased values of blood glucose, serum urea and lower levels of creatinine levels. Also, the value of leucocytes count and the erythrocyte sedimentation rate were shown to be increased in stroke patients, indicating that inflammation is highly present in cerebral infarction. In the regard of these findings, cerebral ischemia is associated with major systemic disruptions that could be significant pathogenic factors and also effects of the complex processes that take place in the affected brain region, but further investigation should be done in order to explain all the mechanisms involved and also the possible impact in prophylaxis and acute management of stroke. [ABSTRACT FROM AUTHOR]

Metabolic syndromes (e.g., obesity) are characterized by insulin resistance, chronic inflammation, impaired glucose metabolism, and dyslipidemia. Recently, patients with metabolic syndromes have experienced not only metabolic problems but also neuropathological issues, including cognitive impairment. Several studies have reported blood-brain barrier (BBB) disruption and insulin resistance in the brain of patients with obesity and diabetes. Adenosine, a purine nucleoside, is known to regulate various cellular responses (e.g., the neuroinflammatory response) by binding with adenosine receptors in the central nervous system (CNS). Adenosine has four known receptors: A1R, A2AR, A2BR, and A3R. These receptors play distinct roles in various physiological and pathological processes in the brain, including endothelial cell homeostasis, insulin sensitivity, microglial activation, lipid metabolism, immune cell infiltration, and synaptic plasticity. Here, we review the recent findings on the role of adenosine receptor-mediated signaling in neuropathological issues related to metabolic imbalance. We highlight the importance of adenosine signaling in the development of therapeutic solutions for neuropathological issues in patients with metabolic syndromes. [Display omitted] • Adenosine receptors-mediated signaling improves energy metabolism, glucose metabolism, and lipid metabolism. • Adenosine receptors-mediated signaling attenuates neuroinflammation and immune responses. • Adenosine receptors-mediated signaling inhibits BBB disruption. • Adenosine receptors-mediated signaling improves synaptic plasticity and memory function. [ABSTRACT FROM AUTHOR]

The global prevalence of nonalcoholic fatty liver disease (NAFLD) has reached 30 %, with an annual increase. The incidence of NAFLD-induced cirrhosis is rapidly rising and has become the leading indicator for liver transplantation in the US. However, there are currently no US Food and Drug Administration-approved drugs for NAFLD. Increasing evidence underscores the close association between NAFLD and bile acid metabolism disorder, highlighting the feasibility of targeting the bile acid signaling pathway for NAFLD treatment. The farnesoid X receptor (FXR) is an endogenous receptor for bile acids that exhibits favorable effects in ameliorating the metabolic imbalance of bile acids, lipid disorders, and disruption of intestinal homeostasis, all of which are key characteristics of NAFLD, making FXR a promising therapeutic target for NAFLD. The present review provides a comprehensive overview of the diverse mechanisms through which FXR improves NAFLD, with particular emphasis on its involvement in regulating bile acid homeostasis and the recent advancements in drug development targeting FXR for NAFLD treatment. [Display omitted] • FXR is a crucial therapeutic target for the management of NAFLD. • Dyslipidemia and pruritus remain major challenges in the development of FXR agonists. • Intestinal FXR antagonists represent a promising strategy for NAFLD therapy. [ABSTRACT FROM AUTHOR]

Mounting evidence has linked the metabolic disease to neurovascular disorders and cognitive decline. Using a murine model of a high‐fat high‐sugar diet mimicking obesity‐induced type 2 diabetes mellitus (T2DM) in humans, we show that pro‐inflammatory mediators and altered immune responses damage the blood‐brain barrier (BBB) structure, triggering a proinflammatory metabolic phenotype. We find that disruption to tight junctions and basal lamina due to loss of control in the production of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) causes BBB impairment. Together the disruption to the structural and functional integrity of the BBB results in enhanced transmigration of leukocytes across the BBB that could contribute to an initiation of a neuroinflammatory response through activation of microglia. Using a humanized in vitro model of the BBB and T2DM patient post‐mortem brains, we show the translatable applicability of our results. We find a leaky BBB phenotype in T2DM patients can be attributed to a loss of junctional proteins through changes in inflammatory mediators and MMP/TIMP levels, resulting in increased leukocyte extravasation into the brain parenchyma. We further investigated therapeutic avenues to reduce and restore the BBB damage caused by HFHS‐feeding. Pharmacological treatment with recombinant annexin A1 (hrANXA1) or reversion from a high‐fat high‐sugar diet to a control chow diet (dietary intervention), attenuated T2DM development, reduced inflammation, and restored BBB integrity in the animals. Given the rising incidence of diabetes worldwide, understanding metabolic‐disease‐associated brain microvessel damage is vital and the proposed therapeutic avenues could help alleviate the burden of these diseases. [ABSTRACT FROM AUTHOR]

Magnesium is one of the essential nutrients for plant growth, and plays a pivotal role in plant development and metabolism. Soil magnesium deficiency is evident in citrus production, which ultimately leads to failure of normal plant growth and development, as well as decreased productivity. Citrus is mainly propagated by grafting, so it is necessary to fully understand the different regulatory mechanisms of rootstock and scion response to magnesium deficiency. Here, we characterized the differences in morphological alterations, physiological metabolism and differential gene expression between trifoliate orange rootstocks and lemon scions under normal and magnesium-deficient conditions, revealing the different responses of rootstocks and scions to magnesium deficiency. The transcriptomic data showed that differentially expressed genes were enriched in 14 and 4 metabolic pathways in leaves and roots, respectively, after magnesium deficiency treatment. And the magnesium transport-related genes MHX and MRS2 may respond to magnesium deficiency stress. In addition, magnesium deficiency may affect plant growth by affecting POD, SOD, and CAT enzyme activity, as well as altering the levels of hormones such as IAA, ABA, GA 3 , JA, and SA, and the expression of related responsive genes. In conclusion, our research suggests that the leaves of lemon grafted onto trifoliate orange were more significantly affected than the roots under magnesium-deficient conditions, further indicating that the metabolic imbalance of scion lemon leaves was more severe. • Magnesium-deficient conditions can inhibit the growth of lemon plants and alter their external morphology. • Magnesium deficiency can affect plant physiological metabolism, and the response degree of scion and rootstock of grafted plants to magnesium deficiency is different. • Magnesium transport-related genes MHX and MRS2 may respond to magnesium deficiency stress. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive and selective loss of motor neurons, amyotrophy and skeletal muscle paralysis usually leading to death due to respiratory failure. While generally considered an intrinsic motor neuron disease, data obtained in recent years, including our own, suggest that motor neuron protection is not sufficient to counter the disease. The dismantling of the neuromuscular junction is closely linked to chronic energy deficit found throughout the body. Metabolic (hypermetabolism and dyslipidemia) and mitochondrial alterations described in patients and murine models of ALS are associated with the development and progression of disease pathology and they appear long before motor neurons die. It is clear that these metabolic changes participate in the pathology of the disease. In this review, we summarize these changes seen throughout the course of the disease, and the subsequent impact of glucose–fatty acid oxidation imbalance on disease progression. We also highlight studies that show that correcting this loss of metabolic flexibility should now be considered a major goal for the treatment of ALS.

Hepatocellular carcinoma (HCC) is ranked the third deadliest cancer worldwide whose molecular pathogenesis is not fully understood. Although deregulated metabolic pathways have been implicated in HCC onset and progression, the mechanisms triggering this metabolic imbalance are yet to be explored. Here, we identified a gene signature coding catabolic enzymes (Cat-GS) involved in key metabolic pathways like amino acid, lipid, carbohydrate, drug, and retinol metabolism as suppressed in HCC. A higher expression of deregulated Cat-GS is associated with good survival and less aggressive disease state in HCC patients. On the other hand, we identified mTOR signaling as a key determinant in HCC onset and progression, whose hyperactivation is found associated with poor survival and aggressive disease state in HCC patients. Next, out of Cat-GS, we established two key regulators of alcohol metabolism, alcohol dehydrogenase 1A (ADH1A) and aldehyde dehydrogenase 2 (ALDH2), as being transcriptionally suppressed by histone deacetylase 1 (HDAC1) at the downstream of mTORC1 signaling. Suppressed ADH1A and ALDH2 expression aligns well with HCC-specific molecular profile and can efficiently predict disease onset and progression, whereas higher ADH1A and ALDH2 expression is associated with good survival and less aggressive disease state in HCC patients. Overall, our in silico findings suggest that transcriptional suppression of alcohol metabolism regulators, ADH1A and ALDH2, at the downstream of mTOR signaling is, in part, responsible for triggering oncogenic transformation of hepatocytes resulting in disease onset and progression in HCC.

Hepatocellular carcinoma (HCC) is ranked the third deadliest cancer worldwide whose molecular pathogenesis is not fully understood. Although deregulated metabolic pathways have been implicated in HCC onset and progression, the mechanisms triggering this metabolic imbalance are yet to be explored. Here, we identified a gene signature coding catabolic enzymes (Cat-GS) involved in key metabolic pathways like amino acid, lipid, carbohydrate, drug, and retinol metabolism as suppressed in HCC. A higher expression of deregulated Cat-GS is associated with good survival and less aggressive disease state in HCC patients. On the other hand, we identified mTOR signaling as a key determinant in HCC onset and progression, whose hyperactivation is found associated with poor survival and aggressive disease state in HCC patients. Next, out of Cat-GS, we established two key regulators of alcohol metabolism, alcohol dehydrogenase 1A (ADH1A) and aldehyde dehydrogenase 2 (ALDH2), as being transcriptionally suppressed by histone deacetylase 1 (HDAC1) at the downstream of mTORC1 signaling. Suppressed ADH1A and ALDH2 expression aligns well with HCC-specific molecular profile and can efficiently predict disease onset and progression, whereas higher ADH1A and ALDH2 expression is associated with good survival and less aggressive disease state in HCC patients. Overall, our in silico findings suggest that transcriptional suppression of alcohol metabolism regulators, ADH1A and ALDH2, at the downstream of mTOR signaling is, in part, responsible for triggering oncogenic transformation of hepatocytes resulting in disease onset and progression in HCC. [ABSTRACT FROM AUTHOR]

Background: The gut microbiome interacts with the central nervous system through the gut-brain axis, and this interaction involves neuronal, endocrine, and immune mechanisms, among others, which allow the microbiota to influence and respond to a variety of behavioral and mental conditions., Aim: To explore the correlation between cognitive impairment and gut microbiota imbalance in patients with schizophrenia., Methods: A total of 498 untreated patients with schizophrenia admitted to our hospital from July 2020 to July 2022 were selected as the case group, while 498 healthy volunteers who underwent physical examinations at our hospital during the same period were selected as a control group. Fluorescence in situ hybridization was employed to determine the total number of bacteria in the feces of the two groups. The cognitive function test package was used to assess the score of cognitive function in each dimension. Then, the relationship between gut microbiota and cognitive function was analyzed., Results: There were statistically significant differences in the relative abundance of gut microbiota at both phylum and class levels between the case group and the control group. In addition, the scores of cognitive function, such as atten-tion/alertness and learning ability, were significantly lower in the case group than in the control group (all P < 0.05). The cognitive function was positively correlated with Actinomycetota, Bacteroidota, Euryarchaeota, Fusobacteria, Pseudomonadota, and Saccharibacteria, while negatively correlated with Bacillota, Tenericutes, and Verrucomicrobia at the phylum level. While at the class level, the cognitive function was positively correlated with Class Actinobacteria, Bacteroidia, Betaproteobacteria, Proteobacteria, Blastomycetes, and Gammaproteobacteria, while negatively correlated with Bacilli, Clostridia, Coriobacteriia, and Verrucomicrobiae., Conclusion: There is a relationship between the metabolic results of gut microbiota and cognitive function in patients with schizophrenia. When imbalances occur in the gut microbiota of patients, it leads to more severe cognitive impairment., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to declare., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Insulin is a key hormone with important functions in energy metabolism and is involved in the regulation of reproduction. Hyperinsulinaemia is known to impair fertility (for example, in obese mothers); therefore, we aimed to investigate the impact of elevated insulin concentrations during the sensitive period of oocyte maturation on gene expression and lipid profiles of the bovine Day-8 embryo. Two different insulin concentrations were used during in vitro oocyte maturation (INS10 = 10 µg mL-1 and INS0.1 = 0.1 µg mL-1) in order to observe possible dose-dependent effects or thresholds for hyperinsulinaemia in vitro. By investigating gene expression patterns by an mRNA microarray in combination with lipid profile analysis by desorption electrospray ionisation-mass spectrometry (DESI-MS) of embryos derived from insulin-treated oocytes, we gained further insights regarding molecular responses of embryos to insulin provocation during the first days of development. Lipid metabolism appeared to be influenced on multiple levels according to gene expression results but the profiles collected in positive-ion mode by DESI-MS (showing mostly ubiquinone, cholesteryl esters and triacylglycerols) did not differ significantly from controls. There are parallels in follicular development of ruminants and humans that make this bovine model relevant for comparative research on early human embryonic development during hyperinsulinaemia. [ABSTRACT FROM AUTHOR]

This study examined the effect of two feeding levels during the antepartum and postpartum period on reproductive performance and blood metabolites (glucose, non-esterified fatty acids (NEFA), insulin) in primiparous Holstein and Swedish Red (SRB) cows, in order to identify possible differences in the way these breeds respond to negative energy balance after calving. A total of 44 cows (22 Holstein, 22 SRB) kept in a loose housing system were included in the study. The control group (HE, n = 23) was fed a diet for high-producing cows (target 35 kg/d energycorrected milk, ECM). A lower feeding intensity (LE, n = 21) was achieved by giving -50% concentrate to target 25 kg/d ECM. Diets were implemented 30 days before expected calving and the cows were monitored for 120 days postpartum. Milk yield and composition, dry matter intake (DMI), live body weight and body condition score (BCS) were assessed to calculate the weekly energy balance (residual feed intake). Blood sampling started before diet implementation and was repeated every 2 weeks until Day 60 postpartum and then once monthly until Day 120. Plasma was kept at −20 °C until analysis for glucose, insulin and NEFA concentrations. Mixed linear models were used to analyse data (SAS 9.3; PROC MIXED). Holstein cows had lower mean energy balance than SRB cows (−4.7 ± 1.4 and −0.9 ± 1.4 MJ, respectively; p = 0.05). SRB cows had higher (p<0.001) BCS (3.3 ± 0.1) than Holstein cows (2.7 ± 0.1) and also higher plasma glucose concentrations from Day -30 to Day 120 relative to parturition (4.1 ± 0.1 and 4.2 ± 0.1 log ; mg/100 ml, respectively; p < 0.05). Overall, breed or diet had no effect on NEFA blood plasma concentrations. However, plasma NEFA concentration levels tended to be higher (p = 0.09) in SRB cows than in Holsteins at Day -14 before calving, indicating higher mobilisation of lipid from adipose tissue already before calving. In contrast, Holstein cows had higher NEFA at Day 14 postpartum than SRB cows (p < 0.05). There were no significant effects of diet or breed on reproductive performance (% pregnant at first AI, days open). However, commencement of luteal activity within 21d postpartum was affected (p < 0.05) by the interaction of breed and diet. These results suggest that Holstein cows prioritise milk production to a larger extent than SRB cows, resulting in a less balanced metabolic profile. [ABSTRACT FROM AUTHOR]

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Abstract: The intracellular redox state plays an important role in the cellular physiology that determines the efficiency of chemical and biofuel production by microbial cell factories. However, it is difficult to achieve optimal redox rebalancing of synthetic pathways owing to the sensitive responses of cellular physiology according as the intracellular redox state changes. Here, we demonstrate optimal rebalancing of the intracellular redox state by model-driven control of expression using n-butanol production in Escherichia coli as a model system. The synthetic n-butanol production pathway was constructed by implementing synthetic constitutive promoters and designing synthetic 5′-untranslated regions (5′-UTR) for each gene. Redox rebalancing was achieved by anaerobically activating the pyruvate dehydrogenase (PDH) complex and additionally tuning the expression level of NAD+-dependent formate dehydrogenase (fdh1 from Saccharomyces cerevisiae) through rational UTR engineering. Interestingly, efficient production of n-butanol required different amounts of reducing equivalents depending on whether the substrate was glucose or galactose. One intriguing implication of this work is that additional strain improvement can be achieved, even within given genetic components, through rebalancing intracellular redox state according to target products and substrates. [Copyright &y& Elsevier]

Sodium monofluoroacetate (SMFA; also known as compound 1080) is a highly toxic chemical; therefore, accidental exposure and intentional misuse are of great concern. SMFA intoxication is reportedly caused by the inhibition of aconitase. However, the pathogenesis underlying SMFA intoxication is not clear. This study was conducted to elucidate the acute effects of SMFA on glucose, amino-acid, and fatty-acid metabolism and to assess glucose supplementation as a possible alleviator or aggravator in SMFA intoxication. Rats were assigned to three groups: SMFA+saline, SMFA+glucose, and control (i.e., no SMFA), and blood samples were analyzed at 3 hours after SMFA or saline (control) administration. Additional rats were used for the monitoring of blood-glucose and lactate concentrations for 10 hour- and 14-day survival rates. SMFA increased the serum-citrate, serum-pyruvate, and blood-lactate concentrations. However, despite significant increases in these parameters when SMFA was administered with glucose, the effects on pH values were small and the survival rate was not changed. SMFA also increased the serum concentrations of free fatty acids, branched-chain amino acids, ammonia, urea, and calcium. The presence of glucose enhanced or suppressed these metabolic changes. Amphibolic intermediates in the tricarboxylic acid cycle might be supplied through the catabolism of proteins in SMFA intoxication. We conclude that other factors, in addition to the accumulation of lactate, citrate, and pyruvate, may affect survival rates, and that SMFA induces imbalances in glucose, amino-acid, and, fatty-acid metabolism. All these changes are inter-related and may contribute to SMFA intoxication. [ABSTRACT FROM AUTHOR]

Abstract: We have studied the physicochemical and biological structure of a permanent filament off Cape Ghir (31°N) and estimated the transport of organic matter associated with it. The seaward filament exported coastal upwelled water, with low temperature and salinity and high organic matter, to the open ocean even in the absence of upwelling-favorable conditions. The estimated flux of excess organic carbon (the nonrefractory pool) expressed in annual basis yielded a value of 3.1×109 kg C, from which ∼90% was transported as dissolved organic carbon. This flux represents about 63% of the average annual primary production for the region of study. We conclude that the net-offshore transport may contribute to the enrichment of offshore oligotrophic waters throughout the year, partly explaining the metabolic imbalance found in open ocean waters of the subtropical Northeast Atlantic. [Copyright &y& Elsevier]

The objective of this review was to explore the relationship between lactational performance and health. We focused on lactational incidence rates (LIR) of the production diseases that are of economic importance to the dairy industry. Based on a review of 11 epidemiological and 14 genetic studies we found little evidence that high yielding cows have increased risk of dystocia, retained placenta, metritis and left-displaced abomasum. Results for periparturient paresis were inconsistent. Whilst we found no phenotypical relationship between milk yield and the risk of ketosis and lameness, selection for higher milk yields will probably increase LIR for these diseases. Mastitis was the only disease where there was a clear relationship between milk yield and risk of infection. Continued selection for higher milk yields will worsen this situation. However, our overall conclusion is that reviewing existing literature, even with a structured literature selection, is inadequate to the task of elucidating the relationship between lactational performance and risk of production diseases. There are substantial problems with confounding effects and unaccounted for biological correlations. In the second part of the review we argue towards a common basis for addressing production diseases. We propose abnormal body mobilisation and immune competence as common currencies for metabolic and immune status and argue for the development of indicators of metabolic imbalance and the early development of diseases. Furthermore, we suggest the use of indicators of ‘imbalance’ to guide feeding according to the needs of individual cows with their specific genotype and management history. We believe that this approach has the potential to provide new diagnostic and decision support tools to improve animal health and reproduction, whilst simultaneously maintaining optimal production and efficiency. Further research is needed to identify and validate new indicators and individual feeding strategies. [Copyright &y& Elsevier]

Objective: To explore the mechanism of Buyang Huanwu Decoction (BHD) in treating early cerebral infarction. Methods: Seventy cases with early cerebral infarction were randomly divided into two groups. Chinese medicine group (CMG, n = 35) was treated with BHD; western medicine group (WMG, n = 35) was treated with hydroxyethyl starch injection and enteric coated aspirin tablets. The levels of endothelin (ET) and calcitonin gene related peptide (CGRP) in plasma before and after treatment and the results of clinical treatment were observed. Also healthy subjects were used as the normal control. Results: The levels of ET before treatment in the two treated groups were significantly higher than that of the healthy subjects (P<0. 001), and the levels of CGRP were significantly lower (P < 0.001). After treatment the metabolic imbalance of ET and CGRP improved significantly in the two treated groups (P<0. 001), but the ET and CGRP in CMG improved more obviously than those in WMG (P<0.01, P<0.05). The markedly effective and curative rate of CMG was higher than that of WMG (68. 6 % vs 31.4 %; ϰ = 9. 65, P < 0. 01). Conclusion: BHD could improve the metabolic imbalance of ET and CGRP in patients with early cerebral infarction and on the virtue of this mechanism it could be used to treat cerebral infarction. [ABSTRACT FROM AUTHOR]

Growth hormone (GH) deficiency is a common cause of late sexual maturation and fertility issues. To determine whether GH-induced effects on reproduction are associated with alterations in hypothalamic kisspeptin system, we studied the male reproduction in two distinct GH deficiency mouse models. In the first model, mice present GH deficiency secondary to arcuate nucleus of the hypothalamus (ARH) lesions induced by posnatal monosodium glutamate (MSG) injections. MSG-induced ARH lesions led to significant reductions in hypothalamic Ghrh mRNA expression and consequently growth. Hypothalamic Kiss1 mRNA expression and Kiss1- expressing cells in the ARH were disrupted in the MSG-treated mice. In contrast, kisspeptin immunoreactivity remained preserved in the anteroventral periventricular and rostral periventricular nuclei (AVPV/PeN) of MSG-treated mice. Importantly, ARH lesions caused late sexual maturation and infertility in male mice. In our second mouse model, we studied animals profound GH deficiency due to a loss-of-function mutation in the Ghrhr gene (Ghrhr lit/lit mice). Interestingly, although Ghrhr lit/lit mice exhibited late puberty onset, hypothalamic Kiss1 mRNA expression and hypothalamic kisspeptin fiber density were normal in Ghrhr lit/lit mice. Despite presenting dwarfism, the majority of Ghrhr lit/lit male mice were fertile. These findings suggest that spontaneous GH deficiency during development does not compromise the kisspeptin system. Furthermore, ARH Kiss1- expressing neurons are required for fertility, while AVPV/PeN kisspeptin expression is sufficient to allow maturation of the hypothalamic-pituitary-gonadal axis in male mice. • Neonatal-induced ARH lesions compromise the kisspeptin system and the somatotropic axis. • Kisspeptin expression in the rostral hypothalamus is sufficient for HPG axis maturation. • Kisspeptin expression in the arcuate nucleus of the hypothalamus is essential for male fertility. • Growth hormone deficiency does not compromise the kisspeptin system. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive and selective loss of motor neurons, amyotrophy and skeletal muscle paralysis usually leading to death due to respiratory failure. While generally considered an intrinsic motor neuron disease, data obtained in recent years, including our own, suggest that motor neuron protection is not sufficient to counter the disease. The dismantling of the neuromuscular junction is closely linked to chronic energy deficit found throughout the body. Metabolic (hypermetabolism and dyslipidemia) and mitochondrial alterations described in patients and murine models of ALS are associated with the development and progression of disease pathology and they appear long before motor neurons die. It is clear that these metabolic changes participate in the pathology of the disease. In this review, we summarize these changes seen throughout the course of the disease, and the subsequent impact of glucose–fatty acid oxidation imbalance on disease progression. We also highlight studies that show that correcting this loss of metabolic flexibility should now be considered a major goal for the treatment of ALS. [ABSTRACT FROM AUTHOR]

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• Treatment of thyroid carcinoma with Parthenolide, a traditional Chinese medicine. • In addition to the commonly used cell biological research methods, we mainly use metabonomics to study the anti-thyroid effect of Parthenolide in order to reveal the anticancer mechanism of Parthenolide more comprehensively. • The metabolic differences between the PTL group and the control group were compared by non-targeted metabonomics, and 31 potential biomarkers were identified. They were mainly involved in the metabolism of tricarboxylic acid cycle, amino acid and other significant metabolites. Thyroid cancer is the most common endocrine malignant tumor in the world, and its incidence is increasing. Although the mortality rate of thyroid cancer is low, its persistence/recurrence rate is high. In addition, some patients with thyroid cancer fail to respond to radiation. Therefore, it is urgent need to develop a novel treatment for thyroid cancer. Parthenolide (PTL), a traditional Chinese medicine Tanacetum parthenium extract, has shown encouraging effects in anti-tumor, anti-inflammatory and anti-malaria. However, it is unclear whether PTL has an anti-thyroid cancer effect and its possible mechanism of action. In the recent years, metabonomics has been widely used in tumors research to explore the pharmacological mechanism of drugs, but few studies used metabonomics to investigate the pharmacological effects of PTL in thyroid tumors. In order to comprehensively reveal the mechanism and effects of PTL on anti-thyroid tumors, metabonomics combined cell biological research methods were conducted. The results showed that PTL promote apoptosis of thyroid cancer cells (TPC-1) in a concentration-dependent manner. The metabolic differences between the PTL group and the control group were compared by metabonomics, and 31 potential metabolites were identified. These metabolites were mainly involved in the tricarboxylic acid cycle, amino acid metabolism, choline metabolism and lipid metabolism. These results implied that PTL may inhibit the proliferation and development of thyroid carcinoma by accelerating oxidation emergency response, inhibiting adenosine triphosphate (ATP) synthesis and metabolic imbalance. The results of this study revealed that PTL can be an effective and potential drug for the treatment of thyroid cancer. [ABSTRACT FROM AUTHOR]

Insulin functions as a regulator of metabolism and plays an important role in reproduction. Hyperinsulinemia is often observed in patients with obesity and diabetes type 2 and is known to impair fertility, but the underlying molecular mechanisms are only partly understood. Metabolic programming through epigenetic mechanisms such as DNA methylation during embryonic development can lead to health implications for the offspring later in life. Our aim was to study the potential effect of hyperinsulinemia on gene expression and DNA methylation of embryos by adding insulin (0.1 µg/ml = INS0.1 or 10 µg/ml = INS10) during in vitro oocyte maturation by using the EmbryoGENE DNA methylation array for a study of the bovine epigenome. Our results showed significant differences between blastocysts originating from insulin-treated oocytes compared with untreated control blastocysts. In total, 13,658 and 12,418 probes were differentially methylated (DM) in INS0.1 and INS10, respectively, with an overlap of 3,233 probes in the DM regions (DMR) for both insulin groups. Genes related to pathways such as lipid metabolism, growth and proliferation, mitochondrial function, and oxidative stress responses were influenced at both the epigenetic and transcriptomic levels. In addition, imprinted genes and genes with functions in the epigenetic machinery were among the DMRs. This study identified DMRs correlated to differential expression of genes involved in metabolic regulation and should help to improve our knowledge of the underlying molecular mechanisms of metabolic imbalance., (© 2018 Wiley-Liss, Inc., A Wiley Company.)