Impaired Energy Metabolism Research Articles

Cadmium induced time-dependent kidney injury in common carp via mitochondrial pathway: Impaired mitochondrial energy metabolism and mitochondrion-dependent apoptosis

Toxic effect of heavy metal cadmium (Cd) on fish kidneys had been reported. Mitochondrion is an important organelle for maintaining kidney function, while its role in Cd-induced kidney injury in common carp remained unclarified. In this experiment, we established a poisoning model of common carp with Cd exposure (0.26 mg/L) for 15, 30, and 45 days. Serum biochemistry determination, histological observation, TUNEL assay, qRT-PCR, Western blot, and integrated biomarker response (IBR) were applied to assess the nephrotoxicity of Cd to common carp. Our results displayed that Cd exposure increased the levels of serum biochemical indexes (UREA, CRE, and UA), indicating kidney injury. We further revealed via histological observation that Cd damaged structural integrity of kidneys, as evidenced by renal glomerulus and renal tubular injury, hallmark phenotypes of apoptosis, and mitochondrial damage, suggesting that mitochondria damage and apoptosis were involved in Cd-induced kidney injury. Moreover, Cd exposure decreased ATPase (Na+/K+-ATPase, Ca2+-ATPase, Mg2+-ATPase, and Ca2+Mg2+-ATPase) activities as well as PGC-1a and Mfn2 levels, while increased Drp1 and PINK1 levels as well as LC3-II/LC3-I ratio, which indicated that Cd-impaired renal energy metabolism was related to mitochondrial dysfunction. Additionally, we found that Cd induced oxidative stress (abnormal levels of SOD, CAT, GPX, MDA, and H2O2) in kidneys, which was involved in triggering mitochondrial dysfunction and further impairing mitochondrial energy metabolism. Moreover, the occurrence of mitochondria-dependent apoptosis was found after Cd-exposure in common carp kidneys, as indicated by enhanced levels of Bax, CytC, APAF1, Caspase-9, and Caspase-3, while declined level of Bcl-2. Subsequently, we confirmed a time-dependent nephrotoxicity of Cd to common carp via IBR assessment. In conclusion, Cd induced time-dependent nephrotoxicity in common carp via mitochondrial pathway. This mitochondria-oriented study shed light on underlying mechanisms of Cd-induced renal pathologies and provided a theoretical basis for evaluating Cd toxicity to aquatic organisms.

Targeting PDK2 rescues stress-induced impaired brain energy metabolism.

Depression is a mental illness frequently accompanied by disordered energy metabolism. A dysregulated hypothalamus pituitary adrenal axis response with aberrant glucocorticoids (GCs) release is often observed in patients with depression. However, the associated etiology between GCs and brain energy metabolism remains poorly understood. Here, using metabolomic analysis, we showed that the tricarboxylic acid (TCA) cycle was inhibited in chronic social defeat stress (CSDS)-exposed mice and patients with first-episode depression. Decreased mitochondrial oxidative phosphorylation was concomitant with the impairment of the TCA cycle. In parallel, the activity of pyruvate dehydrogenase (PDH), the gatekeeper of mitochondrial TCA flux, was suppressed, which is associated with the CSDS-induced neuronal pyruvate dehydrogenase kinase 2 (PDK2) expression and consequently enhanced PDH phosphorylation. Considering the well-acknowledged role of GCs in energy metabolism, we further demonstrated that glucocorticoid receptors (GR) stimulated PDK2 expression by directly binding to its promoter region. Meanwhile, silencing PDK2 abrogated glucocorticoid-induced PDH inhibition, restored the neuronal oxidative phosphorylation, and improved the flux of isotope-labeled carbon (U-13C] glucose) into the TCA cycle. Additionally, in vivo, pharmacological inhibition and neuron-specific silencing of GR or PDK2 restored CSDS-induced PDH phosphorylation and exerted antidepressant activities against chronic stress exposure. Taken together, our findings reveal a novel mechanism of depression manifestation, whereby elevated GCs levels regulate PDK2 transcription via GR, thereby impairing brain energy metabolism and contributing to the onset of this condition.

Preclinical investigations of the efficacy of the glutaminase inhibitor CB-839 alone and in combinations in chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) cells are metabolically flexible and adapt to modern anticancer treatments. Bruton tyrosine kinase (BTK) and B-cell lymphoma-2 (BCL-2) inhibitors have been widely used to treat CLL, but CLL cells become resistant to these treatments over time. CB-839 is a small-molecule glutaminase-1 (GLS-1) inhibitor that impairs glutamine use, disrupts downstream energy metabolism, and impedes the elimination of reactive oxygen species. To investigate the in vitro effects of CB-839 on CLL cells, we tested CB-839 alone and in combination with ibrutinib, venetoclax, or AZD-5991 on the HG-3 and MEC-1 CLL cell lines and on primary CLL lymphocytes. We found that CB-839 caused dose-dependent decreases in GLS-1 activity and glutathione synthesis. CB-839-treated cells also showed increased mitochondrial superoxide metabolism and impaired energy metabolism, which were reflected in decreases in the oxygen consumption rate and depletion of the adenosine triphosphate pool and led to the inhibition of cell proliferation. In the cell lines, CB-839 combined with venetoclax or AZD-5991, but not with ibrutinib, demonstrated synergism with an increased apoptosis rate and cell proliferation inhibition. In the primary lymphocytes, no significant effects of CB-839 alone or in combination with venetoclax, ibrutinib, or AZD-5991 were observed. Our findings suggest that CB-839 has limited efficacy in CLL treatment and shows limited synergy in combination with widely used CLL drugs.

Adriamycin downregulates the expression of KLF4 in cardiomyocytes in vitro and contributes to impaired cardiac energy metabolism in Adriamycin-induced cardiomyopathy.

Adriamycin is a well-known anthracycline chemotherapeutic agent widely used in treating a variety of malignancies. However, Adriamycin's clinical use is limited due to its adverse side-effects, most importantly cardiomyopathy. Adriamycin-induced cardiotoxicity reportedly includes mitochondrial dysfunction. We hypothesize that modulation of KLF4, a key regulator of cardiac mitochondrial homeostasis might play a role in the development of Adriamycin-induced cardiomyopathy. Therefore, in the current work, we evaluated the interaction of Adriamycin with KLF4 and its subsequent downstream targets. Molecular docking revealed that Adriamycin interacts strongly with KLF4 at residues Thr 448, Arg 452, Ser 444 falls within C2H2 motif which is the active site. Quantitative real-time PCR also revealed that KLF4 is downregulated by Adriamycin in cardiomyocytes in vitro. The expression of KLF4 is downregulated in a dose-dependent manner, with a 0.12 ± 0.09-fold (p ≤ 0.05, n = 3) downregulation at a low dosage and 0.21 ± 0.02-fold (p ≤ 0.05, n = 3) downregulation at high dosage. Deficiency of KLF4 leads to an impairment of PPARγ that consequently supresses the proteins/enzymes involved in the fatty acid metabolism. Adriamycin-mediated suppression of KLF4 also affected the expression of PPARα in vitro. PPARα dysfunction is likely to cause defects in β-oxidation which ultimately results in impaired ATP synthesis. Cardiac cells are thus forced to switch over the substrate from free fatty acid to glucose. Moreover, Adriamycin elevates the expression of PPARβ due to downregulation of KLF4 leads to increased myocardial glucose utilization. Thus, a change in substrate preference affects the flexibility of metabolic network culminating in diminished energy production and other regulatory activities, altogether contributing to the development of cardiomyopathy. Thus, we conclude that the effect of Adriamycin on KLF4 disrupts mitochondrial homeostasis and lipid/glucose homeostasis resulting in a reduction of ATP synthesis which ultimately results in dilated cardiomyopathy.

Mitochondrial ROS Accumulation Contributes to Maternal Hypertension and Impaired Remodeling of Spiral Artery but Not IUGR in a Rat PE Model Caused by Maternal Glucocorticoid Exposure.

Increased maternal glucocorticoid levels have been implicated as a risk factor for preeclampsia (PE) development. We found that pregnant rats exposed to dexamethasone (DEX) showed hallmarks of PE features, impaired spiral artery (SA) remodeling, and elevated circulatory levels of sFlt1, sEng IL-1β, and TNFα. Abnormal mitochondrial morphology and mitochondrial dysfunction in placentas occurred in DEX rats. Omics showed that a large spectrum of placental signaling pathways, including oxidative phosphorylation (OXPHOS), energy metabolism, inflammation, and insulin-like growth factor (IGF) system were affected in DEX rats. MitoTEMPO, a mitochondria-targeted antioxidant, alleviated maternal hypertension and renal damage, and improved SA remodeling, uteroplacental blood flow, and the placental vasculature network. It reversed several pathways, including OXPHOS and glutathione pathways. Moreover, DEX-induced impaired functions of human extravillous trophoblasts were associated with excess ROS caused by mitochondrial dysfunction. However, scavenging excess ROS did not improve intrauterine growth retardation (IUGR), and elevated circulatory sFlt1, sEng, IL-1β, and TNFα levels in DEX rats. Our data indicate that excess mitochondrial ROS contributes to trophoblast dysfunction, impaired SA remodeling, reduced uteroplacental blood flow, and maternal hypertension in the DEX-induced PE model, while increased sFlt1 and sEng levels and IUGR might be associated with inflammation and an impaired energy metabolism and IGF system.

Targeting human mitochondrial NAD(P)+-dependent malic enzyme (ME2) impairs energy metabolism and redox state and exhibits antileukemic activity in acute myeloid leukemia

Acute myeloid leukemia (AML) is a fast-growing and highly fatal blood cancer, and recent research has shown that targeting metabolism may be a promising therapeutic approach for treating AML. One promising target is the human mitochondrial NAD(P)+-dependent malic enzyme (ME2), which is involved in the production of pyruvate and NAD(P)H and the regulation of the NAD+/NADH redox balance. Inhibition of ME2 via silencing ME2 or utilizing its allosteric inhibitor disodium embonate (Na2EA) causes a decrease in pyruvate and NADH, leading to a decrease in producing ATP via cellular respiration and oxidative phosphorylation. ME2 inhibition also decreases NADPH levels, resulting in an increase in reactive oxygen species (ROS) and oxidative stress, which ultimately leads to cellular apoptosis. Additionally, ME2 inhibition reduces pyruvate metabolism and the biosynthetic pathway. ME2 silencing inhibits the growth of xenotransplanted human AML cells, and the allosteric ME2 inhibitor Na2EA demonstrates antileukemic activity against immune-deficient mice with disseminated AML. Both of these effects are a result of impaired energy metabolism in mitochondria. These findings suggest that the targeting ME2 may be an effective strategy for treating AML. Overall, ME2 plays an essential role in energy metabolism of AML cells, and its inhibition may offer a promising approach for AML treatment.

Exercise intolerance associated with impaired oxygen extraction in patients with long COVID

ObjectiveChronic mental and physical fatigue and post-exertional malaise are the more debilitating symptoms of long COVID-19. The study objective was to explore factors contributing to exercise intolerance in long COVID-19 to guide development of new therapies. Exercise capacity data of patients referred for a cardiopulmonary exercise test (CPET) and included in a COVID-19 Survivorship Registry at one urban health center were retrospectively analyzed. Results:Most subjects did not meet normative criteria for a maximal test, consistent with suboptimal effort and early exercise termination. Mean O2 pulse peak % predicted (of 79 ± 12.9) was reduced, supporting impaired energy metabolism as a mechanism of exercise intolerance in long COVID, n = 59. We further identified blunted rise in heart rate peak during maximal CPET. Our preliminary analyses support therapies that optimize bioenergetics and improve oxygen utilization for treating long COVID-19.

Loss of hypothalamic MCH decreases food intake in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is associated with impaired energy metabolism, including weight loss and decreased appetite which are negatively correlated with survival. Neural mechanisms underlying metabolic impairment in ALS remain unknown. ALS patients and presymptomatic gene carriers have early hypothalamic atrophy. The lateral hypothalamic area (LHA) controls metabolic homeostasis through the secretion of neuropeptides such as orexin/hypocretin and melanin-concentrating hormone (MCH). Here, we show loss of MCH-positive neurons in three mouse models of ALS based on SOD1 or FUS mutations. Supplementation with MCH (1.2 µg/d) through continuous intracerebroventricular delivery led to weight gain in male mutant Sod1G86R mice. MCH supplementation increased food intake, rescued expression of the key appetite-related neuropeptide AgRP (agouti-related protein) and modified respiratory exchange ratio, suggesting increased carbohydrate usage during the inactive phase. Importantly, we document pTDP-43 pathology and neurodegeneration in the LHA of sporadic ALS patients. Neuronal cell loss was associated with pTDP-43-positive inclusions and signs of neurodegeneration in MCH-positive neurons. These results suggest that hypothalamic MCH is lost in ALS and contributes to the metabolic changes, including weight loss and decreased appetite.

Performance of Autumn and Spring Calving Holstein Dairy Cows with Different Levels of Environmental Exposure and Feeding Strategies

Environmental exposure during confinement and feeding strategy affects cow behavior, nutrient utilization, and performance. Milk production and composition, body condition score, non-esterified fatty acids, and beta-hydroxybutyrate were determined during a full lactation in cows submitted to (a) grazing + partial confinement in outdoor soil-bedded pens with shade structures (OD-GRZ); (b) grazing + partial confinement in a compost-bedded pack barn with cooling capacity (CB-GRZ); or (c) total confinement (same facilities as CB-GRZ) and fed TMR ad libitum (CB-TMR). Autumn (ACS) and spring (SCS) calving season cows were used for each treatment, except for CB-TMR (only SCS). In ACS, treatments did not differ in any variable, possibly due to mild weather. In SCS, milk production was higher in CB-TMR than CB-GRZ, which in turn produced more milk than OD-GRZ. Differences coincided with heat waves and/or heavy rains (similar grazing conditions and mixed ration DM intake). Milk fat, protein and lactose yield, protein content, and BCS were higher in CB-TMR, without differences between CB-GRZ and OD-GRZ. Cows in OD-GRZ had impaired energy metabolism. Under moderately unfavorable environmental conditions (ACS), when well-managed, OD-GRZ systems could equate to the productive response of CB-GRZ. However, in worse climatic conditions (SCS), performance could be compromised, especially when compared to TMR systems.

Microfluidic/HPLC combination to study carnosine protective activity on challenged human microglia: Focus on oxidative stress and energy metabolism.

Carnosine (β-alanyl-L-histidine) is a naturally occurring endogenous peptide widely distributed in excitable tissues such as the brain. This dipeptide possesses well-demonstrated antioxidant, anti-inflammatory, and anti-aggregation properties, and it may be useful for treatment of pathologies characterized by oxidative stress and energy unbalance such as depression and Alzheimer's disease (AD). Microglia, the brain-resident macrophages, are involved in different physiological brain activities such synaptic plasticity and neurogenesis, but their dysregulation has been linked to the pathogenesis of numerous diseases. In AD brain, the activation of microglia towards a pro-oxidant and pro-inflammatory phenotype has found in an early phase of cognitive decline, reason why new pharmacological targets related to microglia activation are of great importance to develop innovative therapeutic strategies. In particular, microglia represent a common model of lipopolysaccharides (LPS)-induced activation to identify novel pharmacological targets for depression and AD and numerous studies have linked the impairment of energy metabolism, including ATP dyshomeostasis, to the onset of depressive episodes. In the present study, we first investigated the toxic potential of LPS + ATP in the absence or presence of carnosine. Our studies were carried out on human microglia (HMC3 cell line) in which LPS + ATP combination has shown the ability to promote cell death, oxidative stress, and inflammation. Additionally, to shed more light on the molecular mechanisms underlying the protective effect of carnosine, its ability to modulate reactive oxygen species production and the variation of parameters representative of cellular energy metabolism was evaluated by microchip electrophoresis coupled to laser-induced fluorescence and high performance liquid chromatography, respectively. In our experimental conditions, carnosine prevented LPS + ATP-induced cell death and oxidative stress, also completely restoring basal energy metabolism in human HMC3 microglia. Our results suggest a therapeutic potential of carnosine as a new pharmacological tool in the context of multifactorial disorders characterize by neuroinflammatory phenomena including depression and AD.

Metformin mitigates renal dysfunction in obese insulin-resistant rats via activation of the AMPK/PPARα pathway.

Insulin signaling and lipid metabolism are disrupted by long-term consumption of a high-fat diet (HFD). This disruption can lead to insulin resistance, dyslipidemia and subsequently renal dysfunction as a consequence of the inactivation of the AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-α (PPARα) or AMPK/PPARα pathways. We investigated the impact of metformin on the prevention of renal dysfunction through the modulation of AMPK-regulated PPARα-dependent pathways in insulin-resistant rats induced by a HFD. Male Wistar rats were fed a HFD for 16 weeks to induce insulin resistance. After insulin resistance had been confirmed, metformin (30mg/kg) or gemfibrozil (50mg/kg) was given orally for 8 weeks. Evidence of insulin resistance, dyslipidemia, lipid accumulation and kidney injury were observed in HF rats. Impairment of lipid oxidation, energy metabolism and renal organic anion transporter 3 (Oat3) expression and function were demonstrated in HF rats. Metformin can stimulate the AMPK/PPARα pathways and suppress sterol regulatory element-binding transcription factor 1 (SREBP1) and fatty acid synthase (FAS) signaling (SREBP1/FAS) to enable the regulation of lipid metabolism. Renal inflammatory markers and renal fibrosis expression induced by a HFD were more effectively reduced after metformin treatment than after gemfibrozil treatment. Interestingly, renal Oat3 function and expression and kidney injury were improved following metformin and gemfibrozil treatment. Renal cluster of differentiation 36 (CD36) or sodium glucose cotransporter type 2 (SGLT2) expression did not differ after treatment with metformin or gemfibrozil. Metformin and gemfibrozil could reduce the impairment of renal injury in obese conditions induced by a HFD through the AMPK/PPARα-dependent pathway. Interestingly, metformin demonstrated greater efficacy than gemfibrozil in attenuating renal lipotoxicity through the AMPK-regulated SREBP1/FAS signaling pathway.

Increased circulating uric acid aggravates heart failure via impaired fatty acid metabolism

BackgroundIncreased circulating uric acid (UA) concentration may disrupt cardiac function in heart failure patients, but the specific mechanism remains unclear. Here, we postulate that hyperuremia induces sterol regulatory element binding protein 1 (SREBP1), which in turn activate hepatic fatty acid biosynthesis response, leading to cardiac dysfunction.Methods and resultsIncreased circulating uric acid was observed in heart failure patients and inversely correlated to cardiac function. Besides, uric acid correlated to circulating lipids profile based on metabolomics in heart failure patients. Using cultured human hepatoellular carcinomas (HepG2) and Tg(myl7:egfp) zebrafish, we demonstrated that UA regulated fatty acid synthase (FASN) via SREBP1 signaling pathway, leading to FFA accumulation and impaired energy metabolism, which could be rescued via SREBP1 knockdown. In ISO treated zebrafish, UA aggravated heart failure via increased cardiovascular cavity size, decreased heart beats, pericardial edema and long-stretched heart deformation.ConclusionsOur findings suggest that UA-SREBP1-FASN signaling exacerbates cardiac dysfunction during FFA accumulation. Identification of this mechanism may help in treatment and prevention of heart failure.

Carvacrol protects rat liver exposed to formaldehyde by regulating oxidative stress, and asprosin and subfatin hormones

ABSTRACT Toxic doses of formaldehyde (FA) can cause oxidative damage and impair energy metabolism. Asprosin (ASP) and subfatin (SUB) are adipokines produced by adipose tissue that help regulate energy metabolism. We investigated the effects of carvacrol (CAR), an antioxidant with hepatoprotective properties, on ASP and SUB in rats exposed to FA using immunohistochemistry and biochemistry. We used 42 male Wistar albino rats divided into six groups of seven: group 1, untreated control; group 2, FA (10 ppm FA by inhalation 8 h/day, 5 days/week); group 3, CAR-20 (20 mg/kg); group 4, CAR-40; group 5, FA (10 ppm FA by inhalation 8 h/day, 5 days/week) + CAR-20 (20 mg/kg); group 6, FA (10 ppm FA by inhalation 8 h/day, 5 days/week) + CAR-40 (40 mg/kg). Levels of ASP and SUB, and total oxidant status (TOS) and total antioxidant status (TAS) in blood and liver tissue were measured using ELISA. ASP and SUB immunoreactivity was assessed using immunohistochemistry. The number of apoptotic cells was determined using the TUNEL method. The number of apoptotic cells in group 2 was increased compared to group 1. TOS in group 2 was increased compared to group 1. The numbers of apoptotic cells and TOS in group 3 were decreased compared to group 1. TOS was decreased in group 6 compared to group 2, but TOS was increased compared to group 1. We found ASP and SUB immunoreactivity in the liver. All alterations were reversed by addition of CAR. It appears that FA disrupts energy metabolism and CAR ameliorates the destructive effects of FA when used at appropriate doses, although CAR might be harmful at high doses.

Glycopolymer-Based Hydrogels Impair Energy Metabolism via Delivering Mannose and Depleting Glucose for Tumor Suppression

Carbohydrates serve as a key biomacromolecule, not only as the major building blocks in living organisms, but also as intermediates in energy metabolism via glycolysis. The quest for developing a carbohydrate-based macromolecular system to interfere with aberrant energy metabolism of tumors is a challenging topic. Here we report a class of artificial glycopolymers containing phenolic hydroxyl-functionalized segments that can be cross-linked to form hydrogels by the enzymatic cascade reaction using glucose oxidase (GOD) and horseradish peroxidase (HRP). Glycopolymer-based hydrogels can deliver and sustainably release the antiglycolytic agent mannose at the tumor site; meanwhile, glucose is exhausted gradually during the course of gelation. Glucose uptake and hyperactive glycolysis of tumor cells are concurrently blocked by the enzyme cascade and mannose, respectively, as validated by synergistic tumor suppression in vitro. Finally, the superiority of glycopolymer-based hydrogels loading mannose and enzyme cascade is evaluated in a murine tumor model, demonstrating the ability to impair energy metabolism and retard tumor growth. This work allows glycopolymer-based biomaterials to be promising in intervening energy metabolism for tumor eradication.

Oxoglutarate dehydrogenase complex controls glutamate-mediated neuronal death

Brain injury is accompanied by neuroinflammation, accumulation of extracellular glutamate and mitochondrial dysfunction, all of which cause neuronal death. The aim of this study was to investigate the impact of these mechanisms on neuronal death.Patients from the neurosurgical intensive care unit suffering aneurysmal subarachnoid hemorrhage (SAH) were recruited retrospectively from a respective database. In vitro experiments were performed in rat cortex homogenate, primary dissociated neuronal cultures, B35 and NG108-15 cell lines. We employed methods including high resolution respirometry, electron spin resonance, fluorescent microscopy, kinetic determination of enzymatic activities and immunocytochemistry.We found that elevated levels of extracellular glutamate and nitric oxide (NO) metabolites correlated with poor clinical outcome in patients with SAH. In experiments using neuronal cultures we showed that the 2-oxoglutarate dehydrogenase complex (OGDHC), a key enzyme of the glutamate-dependent segment of the tricarboxylic acid (TCA) cycle, is more susceptible to the inhibition by NO than mitochondrial respiration. Inhibition of OGDHC by NO or by succinyl phosphonate (SP), a highly specific OGDHC inhibitor, caused accumulation of extracellular glutamate and neuronal death. Extracellular nitrite did not substantially contribute to this NO action. Reactivation of OGDHC by its cofactor thiamine (TH) reduced extracellular glutamate levels, Ca2+ influx into neurons and cell death rate. Salutary effect of TH against glutamate toxicity was confirmed in three different cell lines.Our data suggest that the loss of control over extracellular glutamate, as described here, rather than commonly assumed impaired energy metabolism, is the critical pathological manifestation of insufficient OGDHC activity, leading to neuronal death.

Diallyl Trisulfide, a Biologically Active Component of Garlic Essential Oil, Decreases Male Fertility in Sitotroga cerealella by Impairing Dimorphic Spermatogenesis, Sperm Motility and Lipid Homeostasis.

Diallyl trisulfide (DAT) is a biologically active component of garlic essential oil and exhibits multi-targeted activity against many organisms. The current study tested the capacity of DAT to decrease the male fertility of Sitotroga cerealella. The effects on testis morphology, sperm number, motility, and lipid homeostasis were observed in adult males fumigated with DAT at a dose of 0.01 μL/L in air. The results indicated that the DAT significantly decreased the dimorphic sperm number. Meanwhile, the ultrastructural analysis of the sperm showed that the DAT caused malformed and aberrant structures of mitochondrial derivatives of dimorphic sperm. Additionally, the lipid homeostasis and ATP contents in the male adults were significantly decreased after treatment. Moreover, the total sperm motility was reduced, while the wave-propagation velocity, amplitude, frequency, and wavelength were significantly decreased compared with the controls. Overall, this study reported, for the first time, that DAT impairs energy metabolism, inhibits dimorphic spermatogenesis, and decreases sperm motility, while these abnormalities in sperm lead to adult-male infertility.

Do not overwork: cellular communication network factor 3 for life in cartilage.

Cellular communication network factor (CCN) 3, which is one of the founding members of the CCN family, displays diverse functions. However, this protein generally represses the proliferation of a variety of cells. Along with skeletal development, CCN3 is produced in cartilaginous anlagen, growth plate cartilage and epiphysial cartilage. Interestingly, CCN3 is drastically induced in the growth plates of mice lacking CCN2, which promotes endochondral ossification. Notably, chondrocytes in these mutant mice with elevated CCN3 production also suffer from impaired glycolysis and energy metabolism, suggesting a critical role of CCN3 in cartilage metabolism. Recently, CCN3 was found to be strongly induced by impaired glycolysis, and in our study, we located an enhancer that mediated CCN3 regulation via starvation. Subsequent investigations specified regulatory factor binding to the X-box 1 (RFX1) as a transcription factor mediating this CCN3 regulation. Impaired glycolysis is a serious problem, resulting in an energy shortage in cartilage without vasculature. CCN3 produced under such starved conditions restricts energy consumption by repressing cell proliferation, leading chondrocytes to quiescence and survival. This CCN3 regulatory system is indicated to play an important role in articular cartilage maintenance, as well as in skeletal development. Furthermore, CCN3 continues to regulate cartilage metabolism even during the aging process, probably utilizing this regulatory system. Altogether, CCN3 seems to prevent "overwork" by chondrocytes to ensure their sustainable life in cartilage by sensing energy metabolism. Similar roles are suspected to exist in relation to systemic metabolism, since CCN3 is found in the bloodstream.

DOP18 Brain structural correlates of fatigue in active and quiescent Crohn’s Disease

Abstract Background Fatigue is a common and debilitating symptom in IBD, affecting the majority of patients with active disease. While impaired energy metabolism may contribute to the development of fatigue during active phases of the disease, the high prevalence of fatigue in remitted IBD is less comprehensible. The underlying mechanisms of fatigue are poorly understood, but a disturbance along the microbiota-gut-brain-axis seems likely. This study examined brain structural correlates of fatigue in patients with Crohn’s Disease (CD) in an active (aCD) or quiescent (qCD) state and healthy controls (HC). Methods Patients with CD (n=45; aCD=22, qCD=23) and HC (n=35) underwent structural MRI at 3T and completed a questionnaire (WEIMuS) to assess somatic (sFat) and cognitive fatigue (cFat). Whole-brain grey matter volume (GMV) was analysed using CAT12 in SPM12. We calculated group differences between HC and CD as well as CD subgroups and extracted raw values of anatomical regions with significant differences between the groups (at p<.005; k=173) for subsequent correlation analyses with sFat and cFat (Spearman’s ρ). Results Patients had significantly higher mean fatigue scores than HC (both sFat and cFat, p<0.001). Patients with aCD had higher mean fatigue scores than qCD, but differences between groups were not significant (p>0.2). Differences in GMV between CD (aCD+qCD) and HC were detected in frontal, temporal, parietal, and occipital cortex, as well as in the putamen and cerebellum (all p<.005). Across the patient group, GMV in the majority of the above mentioned regions was negatively correlated with sFat and cFat (Fig. 1). Subgroup analysis revealed a negative correlation between sFat and GMV in inferior frontal gyrus in aCD, while several other regions were negatively associated with both sFat and cFat in qCD (all p<.05). No positive correlations between GMV and fatigue were observed. Conclusion This study suggests a brain structural involvement in fatigue symptoms in CD. While fatigue is more common in active CD, the symptom correlation with GMV in this study was more widespread in patients with quiescent disease. The results indicate possible differences in the development and/or processing of fatigue in different disease states and may reflect disturbed brain-gut-interactions in quiescent CD with fatigue. These findings can help to increase our understanding of fatigue in CD and indicate that different therapeutic approaches targeting fatigue in CD may need to be considered depending on the state of disease activity.

Gp130 Activates Mitochondrial Dynamics for Hepatocyte Survival in a Model of Steatohepatitis

Obesity is the main cause of metabolic complications. Fatty liver infiltration is a companion of obesity. NAFLD is associated with impaired energy metabolism with an excess of nutrients. Mitochondrial dynamics are important for the regulation of energy balance, which regulates mitochondrial function, apoptosis, and mitophagy. The aim of this study was to investigate the effect of gp130 on the components of mitochondrial dynamics in a cellular model of steatohepatitis. Addition of IL-6/gp130 contributed to an increase in the percentage of live cells and a decrease in the percentage of dead and apoptotic cells. Addition of IL-6/gp130 increased the expression of NF-kB1 gene and mitochondrial dynamics markers (MFN2 and TFAM) in HepG2 with tBHP/Oleic. Addition of IL-6 or gp130 reduced the expression of cytoprotector genes (HSF1 and HSP70) in HepG2 cell cultures with tBHP/Oleic. Increased mitochondrial dynamics gene activity protected against HepG2 cell death in the steatohepatitis model. Trans-signaling resulted in increased TFAM and MAPLC3B, and decreased DNM1L gene expression in HepG2 with tBHP/Oleic.

Transcriptomic and proteomic investigation of metabolic disruption in Listeria monocytogenes triggered by linalool and its application in chicken breast preservation

Linalool has outstanding antibacterial activity, while few studies have elucidated its inhibitory mechanism based on omics combination techniques. This study aimed to investigate the antibacterial mechanism of linalool toward L. monocytogenes after subjected to transcriptomics and proteomics, and its application in chicken breast preservation. Significant change in transcription and protein levels were verified with linalool, among which, 248 genes were upregulated and 23 were suppressed, while 74 proteins were significantly expressed, and 25 were down. The metabolic network implied that the differentially expressed genes and proteins were mainly involved in DNA replication and repair, energy-related pathways, amino acid and protein metabolism, environmental stimulus responses. Overall, all results above confirmed that linalool exerted antibacterial effect by damaging cellular structure, impairing energy metabolism, activating specific amino acid metabolism and DNA repair for emergency energy supply and coping with DNA damage. In particular, linalool can effectively prevent the growth of L. monocytogenes in chicken breast during the storage at 4 °C for 9 days without affecting the sensory acceptability based on pH, total volatile basic nitrogen, total viable counts and sensory evaluation. This study lays theoretical foundations for the antibacterial mechanism of linalool and its application as novel natural antibacterial agents in foods.