| 1. |
- Begum, Neelu, et al.
(författare)
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Host-mycobiome metabolic interactions in health and disease
- 2022
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Ingår i: Gut microbes. - : Informa UK Limited. - 1949-0976 .- 1949-0984. ; 14:1
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Forskningsöversikt (refereegranskat)abstract
- Fungal communities (mycobiome) have an important role in sustaining the resilience of complex microbial communities and maintenance of homeostasis. The mycobiome remains relatively unexplored compared to the bacteriome despite increasing evidence highlighting their contribution to host-microbiome interactions in health and disease. Despite being a small proportion of the total species, fungi constitute a large proportion of the biomass within the human microbiome and thus serve as a potential target for metabolic reprogramming in pathogenesis and disease mechanism. Metabolites produced by fungi shape host niches, induce immune tolerance and changes in their levels prelude changes associated with metabolic diseases and cancer. Given the complexity of microbial interactions, studying the metabolic interplay of the mycobiome with both host and microbiome is a demanding but crucial task. However, genome-scale modelling and synthetic biology can provide an integrative platform that allows elucidation of the multifaceted interactions between mycobiome, microbiome and host. The inferences gained from understanding mycobiome interplay with other organisms can delineate the key role of the mycobiome in pathophysiology and reveal its role in human disease.
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| 2. |
- Harzandi, Azadeh, et al.
(författare)
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Acute kidney injury leading to CKD is associated with a persistence of metabolic dysfunction and hypertriglyceridemia
- 2021
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Ingår i: iScience. - : Elsevier BV. - 2589-0042. ; 24:2
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Tidskriftsartikel (refereegranskat)abstract
- Fibrosis is the pathophysiological hallmark of progressive chronic kidney disease (CKD). The kidney is a highly metabolically active organ, and it has been suggested that disruption in its metabolism leads to renal fibrosis. We developed a longitudinal mouse model of acute kidney injury leading to CKD and an in vitro model of epithelial to mesenchymal transition to study changes in metabolism, inflammation, and fibrosis. Using transcriptomics, metabolic modeling, and serum metabolomics, we observed sustained fatty acid metabolic dysfunction in the mouse model from early to late stages of CKD. Increased fatty acid biosynthesis and downregulation of catabolic pathways for triglycerides and diacylglycerides were associated with a marked increase in these lipids in the serum. We therefore suggest that the kidney may be the source of the abnormal lipid profile seen in patients with CKD, which may provide insights into the association between CKD and cardiovascular disease.
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| 3. |
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| 4. |
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| 5. |
- Lee, SangWook, et al.
(författare)
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Network analyses identify liver-specific targets for treating liver diseases
- 2017
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Ingår i: Molecular Systems Biology. - : EMBO. - 1744-4292. ; 13:8
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Tidskriftsartikel (refereegranskat)abstract
- We performed integrative network analyses to identify targets that can be used for effectively treating liver diseases with minimal side effects. We first generated co-expression networks (CNs) for 46 human tissues and liver cancer to explore the functional relationships between genes and examined the overlap between functional and physical interactions. Since increased de novo lipogenesis is a characteristic of nonalcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC), we investigated the liver-specific genes co-expressed with fatty acid synthase (FASN). CN analyses predicted that inhibition of these liver-specific genes decreases FASN expression. Experiments in human cancer cell lines, mouse liver samples, and primary human hepatocytes validated our predictions by demonstrating functional relationships between these liver genes, and showing that their inhibition decreases cell growth and liver fat content. In conclusion, we identified liver-specific genes linked to NAFLD pathogenesis, such as pyruvate kinase liver and red blood cell (PKLR), or to HCC pathogenesis, such as PKLR, patatin-like phospholipase domain containing 3 (PNPLA3), and proprotein convertase subtilisin/kexin type 9 (PCSK9), all of which are potential targets for drug development.
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| 6. |
- Liu, Zhengtao, et al.
(författare)
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Pyruvate kinase L/R is a regulator of lipid metabolism and mitochondrial function
- 2019
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Ingår i: Metabolic Engineering. - : Elsevier BV. - 1096-7176 .- 1096-7184. ; 52, s. 263-272
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Tidskriftsartikel (refereegranskat)abstract
- The pathogenesis of non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) has been associated with altered expression of liver-specific genes including pyruvate kinase liver and red blood cell (PKLR), patatin-like phospholipase domain containing 3 (PNPLA3) and proprotein convertase subtilisin/kexin type 9 (PCSK9). Here, we inhibited and overexpressed the expression of these three genes in HepG2 cells, generated RNA-seq data before and after perturbation and revealed the altered global biological functions with the modulation of these genes using integrated network (IN) analysis. We found that modulation of these genes effects the total triglycerides levels within the cells and viability of the cells. Next, we generated IN for HepG2 cells, identified reporter transcription factors based on IN and found that the modulation of these genes affects key metabolic pathways associated with lipid metabolism (steroid biosynthesis, PPAR signalling pathway, fatty acid synthesis and oxidation) and cancer development (DNA replication, cell cycle and p53 signalling) involved in the progression of NAFLD and HCC. Finally, we observed that inhibition of PKLR lead to decreased glucose uptake and decreased mitochondrial activity in HepG2 cells. Hence, our systems level analysis indicated that PKLR can be targeted for development efficient treatment strategy for NAFLD and HCC.
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| 7. |
- Pellon, Aize, et al.
(författare)
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Role of Cellular Metabolism during Candida-Host Interactions
- 2022
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Ingår i: Pathogens. - : MDPI AG. - 2076-0817. ; 11:2
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Tidskriftsartikel (refereegranskat)abstract
- Microscopic fungi are widely present in the environment and, more importantly, are also an essential part of the human healthy mycobiota. However, many species can become pathogenic under certain circumstances, with Candida spp. being the most clinically relevant fungi. In recent years, the importance of metabolism and nutrient availability for fungi-host interactions have been highlighted. Upon activation, immune and other host cells reshape their metabolism to fulfil the energy-demanding process of generating an immune response. This includes macrophage upregulation of glucose uptake and processing via aerobic glycolysis. On the other side, Candida modulates its metabolic pathways to adapt to the usually hostile environment in the host, such as the lumen of phagolysosomes. Further understanding on metabolic interactions between host and fungal cells would potentially lead to novel/enhanced antifungal therapies to fight these infections. Therefore, this review paper focuses on how cellular metabolism, of both host cells and Candida, and the nutritional environment impact on the interplay between host and fungal cells.
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