Metabolic changes in cells that participate in inflammation, such as activated macrophages and T-helper 17 cells, include a shift towards enhanced glucose uptake, glycolysis and increased activity of ...the pentose phosphate pathway. Opposing roles in these changes for hypoxia-inducible factor 1α and AMP-activated protein kinase have been proposed. By contrast, anti-inflammatory cells, such as M2 macrophages, regulatory T cells and quiescent memory T cells, have lower glycolytic rates and higher levels of oxidative metabolism. Some anti-inflammatory agents might act by inducing, through activation of AMP-activated protein kinase, a state akin to pseudo-starvation. Altered metabolism may thus participate in the signal-directed programs that promote or inhibit inflammation.
Starvation Ketosis and the Kidney Palmer, Biff F.; Clegg, Deborah J.
American journal of nephrology,
08/2021, Letnik:
52, Številka:
6
Journal Article
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Background: The remarkable ability of the body to adapt to long-term starvation has been critical for survival of primitive man. An appreciation of these processes can provide the clinician better ...insight into many clinical conditions characterized by ketoacidosis. Summary: The body adapts to long-term fasting by conserving nitrogen, as the brain increasingly utilizes keto acids, sparing the need for glucose. This shift in fuel utilization decreases the need for mobilization of amino acids from the muscle for purposes of gluconeogenesis. Loss of urinary nitrogen is initially in the form of urea when hepatic gluconeogenesis is dominant and later as ammonia reflecting increased glutamine uptake by the kidney. The carbon skeleton of glutamine is utilized for glucose production and regeneration of consumed HCO 3 − . The replacement of urea with NH 4 + provides the osmoles needed for urine flow and waste product excretion. Over time, the urinary loss of nitrogen is minimized as kidney uptake of filtered ketone bodies becomes more complete. Adjustments in urine Na + serve to minimize kidney K + wasting and, along with changes in urine pH, minimize the likelihood of uric acid precipitation. There is a sexual dimorphism in response to starvation. Key Message: Ketoacidosis is a major feature of common clinical conditions to include diabetic ketoacidosis, alcoholic ketoacidosis, salicylate intoxication, SGLT2 inhibitor therapy, and calorie sufficient but carbohydrate-restricted diets. Familiarity with the pathophysiology and metabolic consequences of ketogenesis is critical, given the potential for the clinician to encounter one of these conditions.
Persistence of infection despite extensive chemotherapy with antibiotics displaying low MICs is a hallmark of lung disease caused by
(Mab). Thus, the classical MIC assay is a poor predictor of ...clinical outcome. Discovery of more efficacious antibiotics requires more predictive
potency assays. As a mycobacterium, Mab is an obligate aerobe and a chemo-organo-heterotroph - it requires oxygen and organic carbon sources for growth. However, bacteria growing in patients can encounter micro-environmental conditions that are different from aerated nutrient-rich broth used to grow planktonic cultures for MIC assays. These
conditions may include oxygen and nutrient limitation which should arrest growth. Furthermore, Mab was shown to grow as biofilms
. Here, we show Mab Bamboo, a clinical isolate we use for Mab drug discovery, can survive oxygen deprivation and nutrient starvation for extended periods of time in non-replicating states and developed an
model where the bacterium grows as biofilm. Using these culture models, we show that non-replicating or biofilm-growing bacteria display tolerance to clinically used anti-Mab antibiotics, consistent with the observed persistence of infection in patients. To demonstrate the utility of the developed "persister" assays for drug discovery, we determined the effect of novel agents targeting membrane functions against these physiological forms of the bacterium and find that these compounds show "anti-persister" activity. In conclusion, we developed
"persister" assays to fill an assay gap in Mab drug discovery compound progression and to enable identification of novel lead compounds showing "anti-persister" activity.
Chemodynamic therapy (CDT) can efficiently destroy tumor cells via Fenton reaction in the presence of H
O
and a robust catalyst. However, it has faced severe challenges including the limited amounts ...of H
O
and inefficiency of catalysts. Here, an adenosine triphosphate (ATP)-responsive autocatalytic Fenton nanosystem (GOx@ZIF@MPN), incorporated with glucose oxidase (GOx) in zeolitic imidazolate framework (ZIF) and then coated with metal polyphenol network (MPN), was designed and synthesized for tumor ablation with self-supplied H
O
and TA-mediated acceleration of Fe(III)/Fe(II) conversion. In the ATP-overexpressed tumor cells, the outer shell MPN of GOx@ZIF@MPN was degraded into Fe(III) and tannic acid (TA) and the internal GOx was exposed. Then, GOx reacted with the endogenous glucose to produce plenty of H
O
, and TA reduced Fe(III) to Fe(II), which is a much more vigorous catalyst for the Fenton reaction. Subsequently, self-produced H
O
was catalyzed by Fe(II) to generate highly toxic hydroxyl radical (•OH) and Fe(III). The produced Fe(III) with low catalytic activity was quickly reduced to reactive Fe(II) mediated by TA, forming an accelerated Fe(III)/Fe(II) conversion to guarantee efficient Fenton reaction-mediated CDT. This autocatalytic Fenton nanosystem might provide a good paradigm for effective tumor treatment.
Although anammox bacteria are commonly exposed to long-term starvation during transportation and preservation process, physiological changes in these organisms during long-term starvation are not ...well understood, nor are the molecular bases of their starvation survival strategies. To reveal survival mechanisms during long-term anaerobic and anoxic starvation (60 days at 20 ± 1 °C), metaproteomic technology was utilized to identify differentially expressed proteins in Candidatus Kuenenia stuttgartiensis. Our results showed that Candidatus Kuenenia stuttgartiensis exhibits a capacity to withstand long-term starvation stress. Although activity decay rates of 0.0129 d−1 and 0.0049 d−1 were observed for anammox sludge in anoxic and anaerobic starvation, the relative abundance of Candidatus Kuenenia stuttgartiensis, the shape of anammox granules, and the fraction of viable cells remained constant under both anaerobic and anoxic starvation conditions. Metaproteomics results illustrated that Candidatus Kuenenia stuttgartiensis maintained stable levels of most intracellular proteins, especially enzymes involved in principal metabolic pathways after 60-d of anaerobic or anoxic starvation, thereby allowing cells to regain metabolic activities once substrates became available. Induction of starvation proteins could be a survival strategy employed by Candidatus Kuenenia stuttgartiensis to resist long-term starvation stresses. During anaerobic starvation, 34 proteins were upregulated, five of which were associated with carbohydrate catabolism and oxidation of organic compounds, thereby increasing potential for utilization of endogenous carbon sources to produce energy. During anoxic starvation, only two proteins were upregulated, which may be attributed to insufficient energy for the synthesis of starvation-induced proteins.
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•Anammox bacteria has a good capacity to resist long-term starvation at 20 ± 1 °C.•Most intracellular proteins remain stable during the 60 days' starvation.•Lower activity decay rate occurred under anaerobic starvation than that of anoxic anaerobic.•The abundance of anammox bacteria remains stable during 60-d starvation.
Multiple definitions for malnutrition syndromes are found in the literature resulting in confusion. Recent evidence suggests that varying degrees of acute or chronic inflammation are key contributing ...factors in the pathophysiology of malnutrition that is associated with disease or injury.
An International Guideline Committee was constituted to develop a consensus approach to defining malnutrition syndromes for adults in the clinical setting. Consensus was achieved through a series of meetings held at the A.S.P.E.N. and ESPEN Congresses.
It was agreed that an etiology-based approach that incorporates a current understanding of inflammatory response would be most appropriate. The Committee proposes the following nomenclature for nutrition diagnosis in adults in the clinical practice setting. "Starvation-related malnutrition", when there is chronic starvation without inflammation, "chronic disease-related malnutrition", when inflammation is chronic and of mild to moderate degree, and "acute disease or injury-related malnutrition", when inflammation is acute and of severe degree.
This commentary is intended to present a simple etiology-based construct for the diagnosis of adult malnutrition in the clinical setting. Development of associated laboratory, functional, food intake, and body weight criteria and their application to routine clinical practice will require validation.
The human organism has tools to cope with metabolic challenges like starvation that are crucial for survival. Lipolysis, lipid oxidation, ketone body synthesis, tailored endogenous glucose production ...and uptake, and decreased glucose oxidation serve to protect against excessive erosion of protein mass, which is the predominant supplier of carbon chains for synthesis of newly formed glucose. The starvation response shows that the adaptation to energy deficit is very effective and coordinated with different adaptations in different organs. From an evolutionary perspective, this lipid-induced effect on glucose oxidation and uptake is very strong and may therefore help to understand why insulin resistance in obesity and type 2 diabetes mellitus is difficult to treat. The importance of reciprocity in lipid and glucose metabolism during human starvation should be taken into account when studying lipid and glucose metabolism in general and in pathophysiological conditions in particular.
In this work, we identified the regulatory mechanism of the key control point of cyanobacterial carbon metabolism, the glycolytic phosphoglycerate mutase (PGAM) reaction, converting 3-PGA into 2-PGA ...and thereby exporting organic carbon from the photosynthetic Calvin cycle. We show that PGAM activity is controlled by a small modulator protein PirC (product of
sll0944
), which inhibits the enzyme through protein–protein interaction. The availability of PirC for PGAM inhibition is controlled by the pervasive carbon/nitrogen balance regulator P
II
, which sequesters PirC at low 2-oxoglutarate levels and releases it at high 2-oxoglutarate levels. PirC-mediated inhibition of PGAM triggers glycogen accumulation, and disrupting this regulation allows the redirection of carbon flux, a decisive requirement for transforming cyanobacteria into green factories.
Nitrogen limitation imposes a major transition in the lifestyle of nondiazotrophic cyanobacteria that is controlled by a complex interplay of regulatory factors involving the pervasive signal processor P
II
. Immediately upon nitrogen limitation, newly fixed carbon is redirected toward glycogen synthesis. How the metabolic switch for diverting fixed carbon toward the synthesis of glycogen or of cellular building blocks is operated was so far poorly understood. Here, using the nondiazotrophic cyanobacterium
Synechocystis
sp. PCC 6803 as model system, we identified a novel P
II
interactor, the product of the
sll0944
gene, which we named PirC. We show that PirC binds to and inhibits the activity of 2,3-phosphoglycerate–independent phosphoglycerate mutase (PGAM), the enzyme that deviates newly fixed CO
2
toward lower glycolysis. The binding of PirC to either P
II
or PGAM is tuned by the metabolite 2-oxoglutarate (2-OG), which accumulates upon nitrogen starvation. In these conditions, the high levels of 2-OG dissociate the PirC–P
II
complex to promote PirC binding to and inhibition of PGAM. Accordingly, a PirC-deficient mutant showed strongly reduced glycogen levels upon nitrogen deprivation, whereas polyhydroxybutyrate granules were overaccumulated compared to wild-type. Metabolome analysis revealed an imbalance in 3-phosphoglycerate to pyruvate levels in the
pirC
mutant, confirming that PirC controls the carbon flux in cyanobacteria via mutually exclusive interaction with either P
II
or PGAM.
To cope with growth in low-phosphate (Pi) soils, plants have evolved adaptive responses that involve both developmental and metabolic changes. PHOSPHATE STARVATION RESPONSE 1 (PHR1) and related ...transcription factors play a central role in the control of Pi starvation responses (PSRs). How Pi levels control PHR1 activity, and thus PSRs, remains to be elucidated. Here, we identify a direct Pi-dependent inhibitor of PHR1 in Arabidopsis , SPX1, a nuclear protein that shares the SPX domain with yeast Pi sensors and with several Pi starvation signaling proteins from plants. Double mutation of SPX1 and of a related gene, SPX2, resulted in molecular and physiological changes indicative of increased PHR1 activity in plants grown in Pi-sufficient conditions or after Pi refeeding of Pi-starved plants but had only a limited effect on PHR1 activity in Pi-starved plants. These data indicate that SPX1 and SPX2 have a cellular Pi-dependent inhibitory effect on PHR1. Coimmunoprecipitation assays showed that the SPX1/PHR1 interaction in planta is highly Pi-dependent. DNA-binding and pull-down assays with bacterially expressed, affinity-purified tagged SPX1 and ΔPHR1 proteins showed that SPX1 is a competitive inhibitor of PHR1 binding to its recognition sequence, and that its efficiency is highly dependent on the presence of Pi or phosphite, a nonmetabolizable Pi analog that can repress PSRs. The relative strength of the SPX1/PHR1 interaction is thus directly influenced by Pi, providing a link between Pi perception and signaling.
Significance When P levels are low, plants activate an array of adaptive responses to increase efficient acquisition and use of phosphate (Pi), the form in which P is preferentially absorbed, and to protect themselves from Pi starvation stress. Considerable progress has been made recently in dissecting the plant Pi starvation signaling pathway. Nonetheless, little is known as to how Pi levels are perceived by plants. Here, we identify the nuclear protein SPX1 as a Pi-dependent inhibitor of DNA binding by PHOSPHATE STARVATION RESPONSE 1 (PHR1), a master regulator of Pi starvation responses. We show that the Pi dependence of SPX1 inhibition of PHR1 activity can be recreated in vitro using purified proteins, which indicates that the SPX1/PHR1 module links Pi sensing and signaling.
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