Down-regulation Of Metabolism Research Articles

Human nuclear hormone receptor activity contributes to malaria parasite liver stage development

Chemical genetic approaches have had a transformative impact on discovery of drug targets for malaria but have primarily been used for parasite targets. To identify human pathways required for intrahepatic development of parasite, we implemented multiplex cytological profiling of malaria infected hepatocytes treated with liver stage active compounds. Some compounds, including MMV1088447 and MMV1346624, exhibited profiles similar to cells treated with nuclear hormone receptor (NHR) agonist/antagonists. siRNAs targeting human NHRs, or their signaling partners identified eight genes that were critical for Plasmodium berghei infection. Knockdown of NR1D2, a host NHR, significantly impaired parasite growth by downregulation of host lipid metabolism. Importantly, treatment with MMV1088447 and MMV1346624 but not other antimalarials, phenocopied the lipid metabolism defect of NR1D2 knockdown. Our data underlines the use of high-content imaging for host-cellular pathway deconvolution, highlights host lipid metabolism as a drug-able human pathway and provides new chemical biology tools for studying host-parasite interactions.

Impact of Inflammation on Voriconazole Exposure in Critically ill Patients Affected by Probable COVID-19-Associated Pulmonary Aspergillosis.

(1) Background: To explore the impact of the degree of inflammation on voriconazole exposure in critically ill patients affected by COVID-associated pulmonary aspergillosis (CAPA); (2) Methods: Critically ill patients receiving TDM-guided voriconazole for the management of proven or probable CAPA between January 2021 and December 2022 were included. The concentration/dose ratio (C/D) was used as a surrogate marker of voriconazole total clearance. A receiving operating characteristic (ROC) curve analysis was performed by using C-reactive protein (CRP) or procalcitonin (PCT) values as the test variable and voriconazole C/D ratio > 0.375 (equivalent to a trough concentration [Cmin] value of 3 mg/L normalized to the maintenance dose of 8 mg/kg/day) as the state variable. Area under the curve (AUC) and 95% confidence interval (CI) were calculated; (3) Results: Overall, 50 patients were included. The median average voriconazole Cmin was 2.47 (1.75-3.33) mg/L. The median (IQR) voriconazole concentration/dose ratio (C/D) was 0.29 (0.14-0.46). A CRP value > 11.46 mg/dL was associated with the achievement of voriconazole Cmin > 3 mg/L, with an AUC of 0.667 (95% CI 0.593-0.735; p < 0.001). A PCT value > 0.3 ng/mL was associated with the attainment of voriconazole Cmin > 3 mg/L (AUC 0.651; 95% CI 0.572-0.725; p = 0.0015). (4) Conclusions: Our findings suggest that in critically ill patients with CAPA, CRP and PCT values above the identified thresholds may cause the downregulation of voriconazole metabolism and favor voriconazole overexposure, leading to potentially toxic concentrations.

Abstract 3694: Metabolic response in human cervical cancer cells to modifications in bioavailable ATP

Abstract Introduction: Cancer cells utilize a markedly reduced oxidative phosphorylation (OXPHOS) when experiencing conditions of high oxygen stress (Warburg Effect/aerobic glycolysis), a phenomenon first studied by Otto Warburg. While there have been many discoveries associated with metabolic differences across cancer cells, one of the most common alterations is the primary means of generating ATP. The importance of deciphering these cellular decisions will enable an understanding of the multifaceted role ATP has in cancer proliferation, senescence, and chemotherapeutic resistance. The use of synthetic protein DX, a man-made ATP chelator with high specificity and affinity, is a proposed method of investigating the metabolic response in cancer cells. Hypothesis: Following DX expression, HeLa cells respond to energy stress (reduced intracellular ATP) via metabolic adaptations, specifically inducing the spare respiratory capacity. Methods: The impact of DX on cell viability was determined using a tetrazolium-based colorimetric cell viability assay and a caspase 3/7 assay. To correlate phenotypic/viability change with DX activity, bioavailable ATP levels were measured at specific time points following DX expression. Additionally, the relative contribution of glycolysis and OXPHOS to the total ATP production rate was measured using the label-free XF Real Time ATP Rate Assay and XF Cell Mito Stress Test (XFe96 Seahorse, Agilent Technologies) over time post DX expression. To determine the impact of ATP stress on mitochondrial and nuclear content, both were quantified following DX-expression. Results: In a time- and dose- dependent manner, DX negatively impacted cell growth and induced cell death via apoptosis, at a time concomitant with a decrease in bioavailable ATP. In response to DX over time, the total ATP production rates in HeLa cells significantly decreased. Importantly, this reduction in the rate of ATP production was associated with a significant downregulation in both OXPHOS and glycolysis. Conclusion: Advances in synthetic biology have allowed for the intentional design of artificial proteins that maintain function in vivo. These proteins can be developed into powerful investigative tools to study biological questions, such as cellular decisions involved in cancer cell metabolism. In response to DX-potentiated ATP stress, the significant reduction in both glycolysis and oxidative phosphorylation suggests metabolic downregulation is required to maintain HeLa cell viability. Citation Format: Parth K. Jayaswal, Taha Muhammad, Ashley Brown, Jeffrey Norris, Shaleen B. Korch. Metabolic response in human cervical cancer cells to modifications in bioavailable ATP. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3694.

Metabolomic analysis of bone-derived exosomes in osteonecrosis of the femoral head based on UPLC–MS/MS

Osteonecrosis of the femoral head (ONFH) is a disorder that causes a collapse of the femoral head, requiring subsequent total hip replacement. However, the pathogenesis of ONFH remains largely unclear. Herein, exosome metabolomics analyses were conducted to explore the pathophysiology of ONFH. This study aimed to conduct metabolic profiling of bone-derived exosomes of ONFH. 30 ONFH patients and 30 femoral neck fracture (FNF) patients were included in this study. Exosomes were harvested from the femoral head by using ultracentrifugation. Ultraperformance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) was performed in combination with multivariate statistical analysis to reveal and provided new insight into identify the global metabolic profile of ONFH. The results of transmission electron microscope (TEM), nanoparticle tracking analysis (NTA), and Western blots indicated that the microvesicles isolated from the femoral head were exosomes. Several compounds were identified, including lipids and lipid-like molecules, amino acids, peptides, organooxygen compounds. 44 differential metabolites were screened between ONFH and FNF patients. The up-and down-regulation of Riboflavin metabolism, Pantothenate and CoA biosynthesis, Glycerophospholipid metabolism, and Sphingolipid metabolism were associated with ONFH pathophysiology. Our results suggest that metabolomics has huge prospects for elucidating pathophysiology of ONFH.

Relationship between disorders of the intestinal microbiota and heart failure in infants with congenital heart disease.

There is a close relationship between the intestinal microbiota and heart failure, but no study has assessed this relationship in infants with congenital heart disease. This study aimed to explore the relationship between heart failure and intestinal microbiota in infants with congenital heart disease. Twenty-eight infants with congenital heart disease with heart failure admitted to a provincial children's hospital from September 2021 to December 2021 were enrolled in this study. A total of 22 infants without heart disease and matched for age, sex, and weight were selected as controls. Faecal samples were collected from every participant and subjected to 16S rDNA gene sequencing. The composition of the intestinal microbiota was significantly disordered in infants with heart failure caused by congenital heart disease compared with that in infants without heart disease. At the phylum level, the most abundant bacteria in the heart failure group were Firmicutes, Actinobacteria, Proteobacteria, and Bacteroidetes, and the most abundant bacteria in the control group were Firmicutes, Proteobacteria, Actinobacteria, and Bacteroidetes. At the genus level, the most abundant bacteria in the heart failure group were Enterococcus, Bifidobacterium, Subdoligranulum, Shigella, and Streptococcus, and the most abundant bacteria in the control group were Bifidobacterium, Blautia, Bacteroides, Streptococcus, and Ruminococcus. The alpha and beta diversities of the gut bacterial community in the heart failure group were significantly lower than those in the control group (p<0.05). Compared with the control group, retinol metabolism was significantly downregulated in the heart failure group. Heart failure in infants with congenital heart disease caused intestinal microbiota disorder, which was characterised by an increase in pathogenic bacteria, a decrease in beneficial bacteria, and decreases in diversity and richness. The significant downregulation of retinol metabolism in the intestinal microbiota of infants with heart failure may be related to the progression of heart failure, and further study of the underlying mechanism is needed.

Glyoxylate cycle maintains the metabolic homeostasis of Pseudomonas aeruginosa in viable but nonculturable state induced by chlorine stress

Bacteria enter a viable but non-culturable (VBNC) state with low metabolic activity to cope with environmental stress (e.g., chlorine disinfection). Elucidating the mechanism and key pathway of VBNC bacteria maintaining low metabolic competence is of great significance to realize their effective control and reduce their environmental and health risks. This study discovered that the glyoxylate cycle is a key metabolic pathway for VBNC bacteria, but not for culturable bacteria. And blocking the glyoxylate cycle pathway inhibited the reactivation and led to the death of VBNC bacteria. The main mechanisms involved the breakdown of material and energy metabolism and the antioxidant system. Gas chromatography-tandem mass spectrometry analysis showed that blocking the glyoxylate cycle led to a disruption of carbohydrate metabolism and fatty acid catabolism in VBNC bacteria. As a result, the energy metabolism system of VBNC bacteria collapsed and the abundance of energy metabolites (ATP, NAD+ and NADP+) decreased significantly. Moreover, the decrease in the level of quorum sensing signaling molecules (quinolinone and N-Butanoyl-D-homoserine lactone) inhibited the synthesis of extracellular polymeric substances (EPSs) and biofilm formation. And the downregulation of glycerophospholipid metabolic competence increased the permeability of cell membranes, leading to the entry of large amounts of hypochlorous acid (HClO) into the bacteria. In addition, the down-regulation of nucleotide metabolism, glutathione metabolism, and the reduction of antioxidant enzyme content resulted in the inability to scavenge reactive oxygen species (ROS) generated by chlorine stress. The large production of ROS and the reduction of antioxidants together led to the breakdown of the antioxidant system of VBNC bacteria. In short, the glyoxylate cycle is the key metabolism pathway of VBNC bacteria for stress resistance and maintaining cellular metabolic balance, and targeting the glyoxylate cycle represents an attractive strategy for developing new and efficient disinfection methods for the control of VBNC bacteria.

Transcriptomic analysis reveals the inhibition mechanism of pulsed light on fungal growth and ochratoxin A biosynthesis in Aspergillus carbonarius

Pulsed light (PL) technology has a good effect on the control of fungi in postharvest fruit. In this present work, PL inhibited the growth of Aspergillus carbonarius in a dose-dependent manner, the mycelial growth decreased by 4.83 %, 13.91 % and 30.01 % at a fluence of 4.5 J·cm−2 (PL5), 9 J·cm−2 (PL10) and 13.5 J·cm2 (PL15), respectively. When inoculated with PL15 treated A. carbonarius, the scab diameter of the pears, ergosterol and OTA content was reduced by 23.2 %, 27.9 % and 80.7 % after 7 days, respectively. The third-generation sequencing technique was applied to study the transcriptome response of A. carbonarius treated with PL. Compared with the blank control, a total number of 268 and 963 differentially expressed genes (DEGs) were discovered in the group of PL10 and PL15, respectively. To be specific, a large amount of DEGs involved in DNA metabolism were up-regulated, while most of DEGs related to cell integrity, energy and glucose metabolism, ochratoxin A (OTA) biosynthesis and transport were down-regulated. In addition, the stress response of A. carbonarius was imbalanced, including up-regulation of Catalase and PEX12 and down-regulation of taurine and subtaurine metabolism, alcohol dehydrogenase and glutathione metabolism. Meanwhile, the results of transmission electron microscopy, mycelium cellular leakage and DNA electrophoresis indicated that PL15 treatment caused mitochondrial swelling, the destroyed cell membrane permeability and imbalance of DNA metabolism. The expression of P450 and Hal involved in OTA biosynthesis pathway were down-regulated in PL treated samples detected by qRT-PCR. In conclusion, this study reveals the molecular mechanism of pulsed light on inhibiting the growth, development and toxin production of A. carbonarius.

Inhibition of carnitine palmitoyl-transferase 1 is a potential target in a mouse model of Parkinson’s disease

Glucose metabolism is dysregulated in Parkinson’s disease (PD) causing a shift toward the metabolism of lipids. Carnitine palmitoyl-transferase 1A (CPT1A) regulates the key step in the metabolism of long-chain fatty acids. The aim of this study is to evaluate the effect of downregulating CPT1, either genetically with a Cpt1a P479L mutation or medicinally on PD using chronic rotenone mouse models using C57Bl/6J and Park2 knockout mice. We show that Cpt1a P479L mutant mice are resistant to rotenone-induced PD, and that inhibition of CPT1 is capable of restoring neurological function, normal glucose metabolism, and alleviate markers of PD in the midbrain. Furthermore, we show that downregulation of lipid metabolism via CPT1 alleviates pathological motor and non-motor behavior, oxidative stress, and disrupted glucose homeostasis in Park2 knockout mice. Finally, we confirm that rotenone induces gut dysbiosis in C57Bl/6J and, for the first time, in Park2 knockout mice. We show that this dysbiosis is alleviated by the downregulation of the lipid metabolism via CPT1.

Integrated metabolomics and transcriptomics reveal the neuroprotective effect of nervonic acid on LPS-induced AD model mice

Nervonic acid (NA) is one of the long-chain fatty acids with significant biological activity that has been widely studied in recent years. It is believed that NA may play a crucial role in the recovery of human cognitive disorders. Although many literatures have shown that NA has some neuroprotective effect in experimental animal models, the detailed neuroprotective mechanism of NA is still poorly understood. In this study, we applied behavioral, transcriptomic and metabolomic approaches to analyze the neuroprotective effect of NA and its molecular mechanism in AD (Alzheimer’s disease) model mice. We demonstrated that NA improved motor skills and learning and memory abilities of mice at the behavioral level. To further understand the specific pathways involved in this protective effect, we applied the metabolomics and transcriptomics profilings and focused on the expression patterns of genes that NA might alter, particularly those related to the accumulation of metabolites in the brain. According to the results, pathways related to neuroinflammation were significantly increased in LPS (lipopolysaccharide)-induced AD mice compared with the normal control, and pathways related to neuronal growth and synaptic plasticity were significantly downregulated. When NA was used for protection, these signaling pathways induced by LPS were partially reversed. At the same time, compared with the AD model group, upregulation of arachidonic acid metabolism, purine metabolism, and primary bile acid biosynthesis and downregulation of amino acid metabolic pathways were particularly pronounced in the NA treatment group. We also verified the enzymes of some metabolic pathways were consistent with transcriptome result. In summary, our results show that NA can significantly ameliorate LPS-induced neuroinflammation and deterioration of learning and memory, and exerts a neuroprotective function through regulation of multiple gene transcription and metabolism pathways. In particular, the arachidonic acid metabolism which related to inflammation and the amino acids metabolism which related to the synthesis of neurotransmitters were most significant response to NA treatment. Our results provided the first preliminary evidences for molecular mechanism investigation of NA from a combined transcriptome and metabolome perspective.

Zinc deficiency disrupts pain signaling promoting nociceptive but not inflammatory pain in mice.

Zinc (Zn) is an essential micronutrient involved in the physiology of nervous system and pain modulation. There is little evidence for the role of nutritional Zn alternations to the onset and progression of neuropathic (NP) and inflammatory pain. The study investigated the effects of a zinc restricted diet on the development of pain. Weaned mice were submitted to a regular (38 mg/kg of Zn) or Zn deficient (11 mg/kg of Zn) diets for four weeks, pain responses evaluated (mechanical, cold and heat allodynia; formalin- and carrageenan-induced inflammatory hypernociception), plasma and tissues collected for biochemical and metabolomic analysis. Zn deficient diet inhibited animal growth (37%) and changed mice sensitivity pattern, inducing an intense allodynia evoked by mechanical, cold and heat stimulus for four weeks. The inflammatory pain behavior of formalin test was drastically reduced or absent when challenged by an inflammatory stimulus. Zn restriction also reduce plasma TNF, increase neuronal activation, oxidative stress, indicating a disruption of the immune response. Liver metabolomic analyses suggest a downregulation of lipid metabolism of arachidonic acid. Zn restriction since weaned disrupts pain signaling considerably and reduce inflammatory pain. Zn could be considered a predisposing factor for the onset of chronic pain such as painful neuropathies.

Non-bioenergetic roles of mitochondrial GPD2 promote tumor progression.

Rationale: Despite growing evidence for mitochondria's involvement in cancer, the roles of specific metabolic components outside the respiratory complex have been little explored. We conducted metabolomic studies on mitochondrial DNA (mtDNA)-deficient (ρ0) cancer cells with lower proliferation rates to clarify the undefined roles of mitochondria in cancer growth. Methods and results: Despite extensive metabolic downregulation, ρ0 cells exhibited high glycerol-3-phosphate (G3P) level, due to low activity of mitochondrial glycerol-3-phosphate dehydrogenase (GPD2). Knockout (KO) of GPD2 resulted in cell growth suppression as well as inhibition of tumor progression in vivo. Surprisingly, this was unrelated to the conventional bioenergetic function of GPD2. Instead, multi-omics results suggested major changes in ether lipid metabolism, for which GPD2 provides dihydroxyacetone phosphate (DHAP) in ether lipid biosynthesis. GPD2 KO cells exhibited significantly lower ether lipid level, and their slower growth was rescued by supplementation of a DHAP precursor or ether lipids. Mechanistically, ether lipid metabolism was associated with Akt pathway, and the downregulation of Akt/mTORC1 pathway due to GPD2 KO was rescued by DHAP supplementation. Conclusion: Overall, the GPD2-ether lipid-Akt axis is newly described for the control of cancer growth. DHAP supply, a non-bioenergetic process, may constitute an important role of mitochondria in cancer.

Combining Molecular Subtypes with Multivariable Clinical Models Has the Potential to Improve Prediction of Treatment Outcomes in Prostate Cancer at Diagnosis.

Clinical management of prostate cancer is challenging because of its highly variable natural history and so there is a need for improved predictors of outcome in non-metastatic men at the time of diagnosis. In this study we calculated the model score from the leading clinical multivariable model, PREDICT prostate, and the poor prognosis DESNT molecular subtype, in a combined expression and clinical dataset that were taken from malignant tissue at prostatectomy (n = 359). Both PREDICT score (p < 0.0001, IQR HR = 1.59) and DESNT score (p < 0.0001, IQR HR = 2.08) were significant predictors for time to biochemical recurrence. A joint model combining the continuous PREDICT and DESNT score (p < 0.0001, IQR HR = 1.53 and 1.79, respectively) produced a significantly improved predictor than either model alone (p < 0.001). An increased probability of mortality after diagnosis, as estimated by PREDICT, was characterised by upregulation of cell-cycle related pathways and the downregulation of metabolism and cholesterol biosynthesis. The DESNT molecular subtype has distinct biological characteristics to those associated with the PREDICT model. We conclude that the inclusion of biological information alongside current clinical prognostic tools has the potential to improve the ability to choose the optimal treatment pathway for a patient.

Impacts of a bacterial algicide on metabolic pathways in Chlorella vulgaris

Chlorella is a dominant species during harmful algal blooms (HABs) worldwide, which bring about great environmental problems and are also a serious threat to drinking water safety. Application of bacterial algicides is a promising way to control HABs. However, the identified bacterial algicides against Chlorella and the understanding of their effects on algal metabolism are very limited. Here, we isolated a novel bacterium Microbacterium paraoxydans strain M1 that has significant algicidal activities against Chlorella vulgaris (algicidal rate 64.38 %, at 120 h). Atrazine-desethyl (AD) was then identified from strain M1 as an effective bacterial algicide, with inhibition or algae-lysing concentration values (EC50) of 1.64 μg/mL and 1.38 μg/mL, at 72 h and 120 h, respectively. LAD (2 μg/mL AD) or HAD (20 μg/mL AD) causes morphology alteration and ultrastructure damage, chlorophyll a reduction, gene expression regulation (for example, psbA, 0.05 fold at 24 h, 2.97 fold at 72 h, and 0.23 fold of the control in HAD), oxidative stress, lipid oxidation (MDA, 2.09 and 3.08 fold of the control in LAD and HAD, respectively, at 120 h) and DNA damage (average percentage of tail DNA 6.23 % at 120 h in HAD, slight damage: 5∼20 %) in the algal cells. The impacts of AD on algal metabolites and metabolic pathways, as well as the algal response to the adverse effects were investigated. The results revealed that amino acids, amines, glycosides and urea decreased significantly compared to the control after 24 h exposure to AD (p < 0.05). The main up-regulated metabolic pathways implied metabonomic resistance and defense against osmotic pressure, oxidative stress, photosynthesis inhibition or partial cellular structure damage, such as phenylalanine metabolism, arginine biosynthesis. The down-regulated glycine, serine and threonine metabolism is a major lead in the algicidal mechanism according to the value of pathway impact. The down-regulated glycine, and serine are responsible for the downregulation of glyoxylate and dicarboxylate metabolism, aminoacyl-tRNA biosynthesis, glutathione metabolism, and sulfur metabolism, which strengthen the algae-lysing effect. It is the first time to highlight the pivotal role of glycine, serine and threonine metabolism in algicidal activities, which provided a new perspective for understanding the mechanism of bacterial algicides exerting on algal cells at the metabolic level.

In silico transcriptional analysis of asymptomatic and severe COVID-19 patients reveals the susceptibility of severe patients to other comorbidities and non-viral pathological conditions

COVID-19 is a severe respiratory disease caused by SARS-CoV-2, a novel human coronavirus. Patients infected with SARS-CoV-2 exhibit heterogeneous symptoms that pose pragmatic hurdles for implementing appropriate therapy and management of the COVID-19 patients and their post-COVID complications. Thus, understanding the impact of infection severity at the molecular level in the host is vital to understand the host response and accordingly it's precise management. In the current study, we performed a comparative transcriptomics analysis of publicly available seven asymptomatic and eight severe COVID-19 patients. Exploratory data analysis employing Principal Component Analysis (PCA) showed the distinct clusters of asymptomatic and severe patients. Subsequently, the differential gene expression analysis using DESeq2 identified 1224 significantly upregulated genes (logFC≥ 1.5, p-adjusted value <0.05) and 268 significantly downregulated genes (logFC≤ −1.5, p-adjusted value <0.05) in severe samples in comparison to asymptomatic samples. Eventually, Gene Set Enrichment Analysis (GSEA) revealed the upregulation of anti-viral and anti-inflammatory pathways, secondary infections, Iron homeostasis, anemia, cardiac-related, etc.; while, downregulation of lipid metabolism, adaptive immune response, translation, recurrent respiratory infections, heme-biosynthetic pathways, etc. Conclusively, these findings provide insight into the enhanced susceptibility of severe COVID-19 patients to other health comorbidities including non-viral pathogenic infections, atherosclerosis, autoinflammatory diseases, anemia, male infertility, etc. owing to the activation of biological processes, pathways and molecular functions associated with them. We anticipate this study will facilitate the researchers in finding efficient therapeutic targets and eventually the clinicians in management of COVID-19 patients and post-COVID-19 effects in them.

Congenital heart disease-associated pulmonary dysplasia and its underlying mechanisms.

Clinical observation indicates that exercise capacity, an important determinant of survival in patients with congenital heart disease (CHD), is most decreased in children with reduced pulmonary blood flow (RPF). However, the underlying mechanism remains unclear. Here, we obtained human RPF lung samples from children with tetralogy of Fallot as well as piglet and rat RPF lung samples from animals with pulmonary artery banding surgery. We observed impaired alveolarization and vascularization, the main characteristics of pulmonary dysplasia, in the lungs of RPF infants, piglets, and rats. RPF caused smaller lungs, cyanosis, and body weight loss in neonatal rats and reduced the number of alveolar type 2 cells. RNA sequencing demonstrated that RPF induced the downregulation of metabolism and migration, a key biological process of late alveolar development, and the upregulation of immune response, which was confirmed by flow cytometry and cytokine detection. In addition, the immunosuppressant cyclosporine A rescued pulmonary dysplasia and increased the expression of the Wnt signaling pathway, which is the driver of postnatal lung development. We concluded that RPF results in pulmonary dysplasia, which may account for the reduced exercise capacity of patients with CHD with RPF. The underlying mechanism is associated with immune response activation, and immunosuppressants have a therapeutic effect in CHD-associated pulmonary dysplasia.

Deletion of tetrahydrobiopterin synthesis in cardiomyocytes causes downregulation of fatty acid metabolism whilst protected against cardiac ischemia reperfusion injury

Deletion of tetrahydrobiopterin synthesis in cardiomyocytes causes downregulation of fatty acid metabolism whilst protected against cardiac ischemia reperfusion injury

Dysfunctional intercellular communication and metabolic signaling pathways in thin endometrium.

Background: The endometrial thickness is a key factor for successful implantation. Thin endometrium is associated with lower implantation rate and pregnancy rate. Lacking of a better understanding for the cellular and molecular mechanisms of thin endometrium, managing patients with thin endometrium still represents a major challenge for clinicians. Methods: In this study, we combined four single-cell RNA sequencing (scRNA-seq) and one bulk sequencing (bulk-seq) data for thin endometrium to perform an integrated analysis for endometrial cells in proliferating phase. Cell proportion and differentially expressed genes (DEGs) were analyzed to determine the disease-specific cell type and signaling pathways. The cell-cell communication among cell types were inferred by "CellChat" to illustrate the differential intercellular communication under normal and thin endometrium conditions. GSEA and GSVA were applied to identify dysfunctional signals and metabolic pathways before and after thin endometrium. Results: Integration of scRNA-seq identified eight cell types. The proportion of stromal cells showed a significant difference between normal and thin endometrial tissue. The DEGs in diverse cell types revealed enriched pathways in a cell-specific manner. Aberrant cell-cell signaling transduction was found in almost all cell types, especially in immune cells and epithelial cells. Furthermore, dysfunctional metabolic signaling pathways were induced in a cell-type dependent way. The down-regulation of carbohydrate metabolism and nucleotide metabolism was observed and the energy metabolism switch was indicated. Conclusion: Conclusively, we discover dysfunctional signals and metabolic pathways in thin endometrium, providing insight into mechanisms and therapeutic strategies for the atrophic endometrium.

Glycemic control releases regenerative potential of pancreatic beta cells blocked by severe hyperglycemia.

Diabetogenic ablation of beta cells in mice triggers a regenerative response whereby surviving beta cells proliferate and euglycemia is regained. Here, we identify and characterize heterogeneity in response to beta cell ablation. Efficient beta cell elimination leading to severe hyperglycemia (>28mmol/L), causes permanent diabetes with failed regeneration despite cell cycle engagement of surviving beta cells. Strikingly,correction of glycemia via insulin, SGLT2 inhibition, or a ketogenic diet for about 3weeks allows partial regeneration of beta cell mass and recovery from diabetes, demonstrating regenerative potential masked by extreme glucotoxicity. We identify gene expression changes in beta cells exposed to extremely high glucose levels, pointing to metabolic stress and downregulation of key cell cycle genes, suggesting failure of cell cycle completion. These findings reconcile conflicting data on the impact of glucose on beta cell regeneration and identify a glucose threshold converting glycemic load from pro-regenerative to anti-regenerative.

Effects of low salinities on growth, fatty acid composition, and transcriptome in Florida pompano (Trachinotus carolinus) at early developmental stages

The Florida pompano, Trachinotus carolinus, is a prime marine finfish candidate for commercial production in the United States (U.S.). Low salinity conditions (i.e., < 30 parts per thousand, ppt) can affect the early development of T. carolinus by increasing osmoregulatory stress. To address the knowledge gap regarding the impact of low salinity on Florida pompano health, we conducted an experiment to determine the optimal salinity for the culture of fingerlings. Larvae were reared in three salinities (10, 20, and 30 ppt) at local producers' farms and growth, fatty acid profiles, and transcriptome responses were quantified every three days after hatching (3, 6, 9, 12, 15, 18, and 24 days post hatch) and results were compared across salinities. Larvae reared at 10 ppt grew at a normal rate and the developmental stage had a greater impact than salinity on fatty acid composition and larval gene expression. Although there were few differentially expressed genes between salinities (n = 17), there was an upregulation of gene sets associated with ribosomes and oxidative phosphorylation and a downregulation of glycerophospholipid and carbon metabolism at lower salinities in comparison to higher salinities. In the early days of development, the fatty acids linoleic acid (LA), alpha linoleic acid (LNA), and 18:3 n-6 were proven to be important as potential energy fuels and precursors for long-chain polyunsaturated fatty acids (LC-PUFA) biosynthesis, which was supported by the whole transcriptomics analysis. The gene expression of fatty acid synthesis genes coincided with changes in the fatty acid levels suggesting the ability of Florida pompano larvae to biosynthesize LC-PUFAs from LA and LNA precursors. Overall, this study suggests that it is possible to raise Florida pompano larvae for 24 DPH under low salinity conditions as low as 10 ppt. However, it is important to run this study for a longer period to investigate the long-term effects of low salinity on larval health and development. Importantly, this research serves as a model study for future on-farm collaborations and helps build a bridge between scientists and farmers in aquaculture.

Gut Microbiota Differentially Mediated by Qingmao Tea and Qingzhuan Tea Alleviated High-Fat-Induced Obesity and Associated Metabolic Disorders: The Impact of Microbial Fermentation

Although dark tea is a unique microbial-fermented tea with a high reputation for having an antiobesity effect, little is known about the effect of microbial fermentation on tea leaves’ antiobesity properties. This study compared the antiobesity effects of microbial-fermented Qingzhuan tea (QZT) and unfermented Qingmao tea (QMT), providing insight into their underlying mechanisms associated with gut microbiota. Our results indicated that the supplementation of QMT extract (QMTe) and QZT extract (QZTe) displayed similar antiobesity effects in high-fat diet (HFD)-fed mice, but the hypolipidemic effect of QZTe was significantly stronger than that of QMTe. The microbiomic analysis indicated that QZTe was more effective than QMTe at regulating HFD-caused gut microbiota dysbiosis. Akkermansiaceae and Bifidobacteriaceae, which have negative correlations with obesity, were enhanced notably by QZTe, whereas Faecalibaculum and Erysipelotrichaceae, which are positively correlated with obesity, were decreased dramatically by QMTe and QZTe. A Tax4Fun analysis of QMTe/QZTe-mediated gut microbiota revealed that QMTe supplementation drastically reversed the HFD-induced upregulation of glycolysis and energy metabolism, whereas QZTe supplementation significantly restored the HFD-caused downregulation of pyruvate metabolism. Our findings suggested that microbial fermentation showed a limited effect on tea leaves’ antiobesity, but enhanced their hypolipidemic activity, and QZT could attenuate obesity and associated metabolic disorders by favorably modulating gut microbiota.