Modulation Of Metabolism Research Articles

The hypolipidemic effect of MI-883, the combined CAR agonist/ PXR antagonist, in diet-induced hypercholesterolemia model

Abstract Constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are closely related nuclear receptors with overlapping regulatory functions in xenobiotic clearance but distinct roles in endobiotic metabolism. Car activation has been demonstrated to ameliorate hypercholesterolemia by regulating cholesterol metabolism and bile acid elimination, whereas PXR activation is associated with hypercholesterolemia and liver steatosis. Here we show a human CAR agonist/PXR antagonist, MI-883, which effectively regulates genes related to xenobiotic metabolism and cholesterol/bile acid homeostasis by leveraging CAR and PXR interactions in gene regulation. Through comprehensive analyses utilizing lipidomics, bile acid metabolomics, and transcriptomics in humanized PXR-CAR-CYP3A4/3A7 mice fed high-fat and high-cholesterol diets, we demonstrate that MI-883 significantly reduces plasma cholesterol levels and enhances fecal bile acid excretion. This work paves the way for the development of ligands targeting multiple xenobiotic nuclear receptors. Such ligands hold the potential for precise modulation of liver metabolism, offering new therapeutic strategies for metabolic disorders.

Nitidine chloride inhibits the progression of hepatocellular carcinoma by suppressing IGF2BP3 and modulates metabolic pathways in an m6A-dependent manner

BackgroundHepatocellular carcinoma (HCC) stands as a major health concern due to its significant morbidity and mortality. Among potential botanical therapeutics, nitidine chloride (NC) has garnered attention for its potential anti-HCC properties. However, the underlying mechanisms, especially the possible involvement of the m6A pathway, remain to be elucidated.MethodsHCC cell and zebrafish xenograft models were utilized to validate the anti-HCC effects of NC. RNA-seq and MeRIP-seq analyses were performed to explore the potential targets and mechanisms of NC against HCC. The target effect of NC on IGF2BP3 was verified through RT-qPCR, WB, molecular docking, molecular dynamics (MD) simulation, surface plasmon resonance (SPR), and CCK8 off-target assays. Downstream target genes were confirmed using RNA stability assays.ResultsIn this study, utilizing HCC cell and zebrafish xenograft models, we validated NC’s ability to inhibit the growth, metastasis, and angiogenesis of HCC. Subsequently, employing RNA sequencing, RT-qPCR, WB, molecular docking, MD simulation, SPR, and CCK8 off-target assays, we pinpointed IGF2BP3 as a direct target of NC. IGF2BP3 is highly expressed in HCC, and IGF2BP3 knockdown significantly inhibited the proliferation, migration and invasion of HCC cells. Further MeRIP-seq and RIP-seq revealed 197 genes interacting with IGF2BP3, downregulated at mRNA and m6A levels after NC treatment, primarily associated with multiple metabolism-related pathways. Through intersection analysis, we pinpointed 30 potential metabolic target genes regulated by NC through IGF2BP3. Based on the expression of these genes, the metabolic scores for each HCC patient were calculated. Our findings suggest that patients with high metabolic scores have poorer prognoses, and the metabolic score serves as an independent prognostic factor. Finally, RNA stability experiments confirmed CKB, RRM2, NME1, PKM, and UXS1 as specific metabolic target genes affected by NC/IGF2BP3, displaying reduced RNA half-life post IGF2BP3 downregulation.ConclusionOur study suggest that NC may exert its anti-HCC effects by downregulating IGF2BP3, inhibiting the m6A modification levels of metabolic-related genes, thereby reducing their stability and expression. Such insights provide a new direction in the study of NC’s anti-HCC mechanisms and offer novel perspectives for the treatment of HCC patients, focusing on both metabolic levels and m6A modification levels.

Modification of intracellular metabolism by expression of a C-terminal variant of phosphoribulokinase from Synechocystis sp. PCC 6803.

Phosphoribulokinase (PRK) is a key enzyme in the Calvin cycle of cyanobacteria required for CO2 fixation and enhancing intracellular PRK activity will contribute to altering the metabolic state. In Synechocystis sp. PCC 6803, PRK activity is inhibited by the small protein CP12 and intramolecular disulfide bonds in its C-terminal loop. This study aimed to increase PRK activity by expressing a mutant PRK that inhibitory Cys residues (positions 229 and 235) in the C-terminal loop were replaced with Ser. The engineered strain showed increased PRK activity under photomixotrophic conditions. Metabolomic analysis revealed that this strain accumulates organic acids downstream of glycolysis and the tricarboxylic acids cycle, highlighting its potential for producing chemicals using these metabolites as precursors. These findings suggest that preventing disulfide bond formation in the PRK C-terminal loop enhances its activity, providing a promising approach for metabolic engineering in cyanobacteria.

Tetrastigma hemsleyanum polysaccharide protects against "two-hit" induced severe pneumonia via TLR4/NF-κB signaling pathway.

Severe pneumonia, frequently accompanied by cytokine storms, stands as a perilous respiratory condition with alarmingly high mortality rates. Tetrastigma hemsleyanum polysaccharide (THP), a pivotal constituent derived from Tetrastigma hemsleyanum Diels et Gilg (TH), has demonstrated efficacy in treating lung inflammation. However, its precise efficacy and underlying mechanisms in the context of severe pneumonia remain elusive. Our research aims to elucidate THP's protective effects in a "two-hit" severe pneumonia model. Our observations indicate that THP administration markedly shields the lungs from injury, reduces pulmonary apoptosis, balances the formation of immune thrombus and alleviates oxidative stress in pneumonia-induced mice. Furthermore, THP significantly decreases the levels of pro-inflammatory cytokines, suggesting its robust anti-inflammatory capabilities. Notably, THP also plays a crucial role in normalizing gut microbiota imbalance, which is vital in the pathogenesis of severe pneumonia. Metabolomic analysis further validates THP's restorative effects on plasma metabolites, indicating its involvement in regulating energy metabolism and immune homeostasis. Mechanistically, THP targets the TLR4/NF-κB signaling pathway, a core mediator of inflammation, thereby dampening the inflammatory cascade. In summary, our findings underscore that THP, through its multifaceted actions targeting inflammation, oxidative stress, immune thrombus formation, gut microbiota regulation, and metabolic modulation, emerges as a promising therapeutic approach for severe pneumonia. This study provides invaluable insights into the potential applications of natural polysaccharides in treating severe pneumonia and highlights the significance of the TLR4/NF-κB pathway in the disease's progression.

FGF21 affects the glycolysis process via mTOR-HIF1α axis in hepatocellular carcinoma.

Metabolic reprogramming, particularly glycolysis, is essential in processes like cancer and immune response. While FGF21's role in hepatocyte glucose metabolism has been linked to glucose transporters and its impact on aerobic glycolysis and cellular growth in HCC remain unclear. In this study, we investigated FGF21-mediated modulation of glucose metabolism in HCC through mTOR and HIF1α axis in HCC. The study evaluated the dysregulation of FGF21 and its prognostic impact in HCC using various datasets. The literature review was done to identify glycolysis related genes to find significant interaction with FGF21 using stringdb and their correlation in datasets. The regulation of FGF21 was validated in HepG2 cell lines by transfecting FGF21 and measuring its effects on glycolysis, including glucose uptake, lactate levels, and key glycolytic enzymes using rt-PCR. Additionally, the effect of FGF21 transfection on mTOR and HIF1α was also evaluated using rt-PCR. The insilico analysis indicates that the FGF21-mTOR-HIF1α signaling axis regulates glucose metabolism, with mTOR as a central integrator of signals from FGF21 and HIF1α. Invitro experiments showed that silencing FGF21 expression via siRNA reduced glycolytic enzyme expression, glucose uptake, lactate levels, and cell proliferation in HepG2 cells. Conversely, recombinant FGF21 treatment has a reverse effect in HepG2 cells. Additionally, FGF21 treatment also affected mTOR and HIF1α expression, highlighting its role in metabolic regulation and disease through the mTOR-HIF1α axis. The regulation of FGF21 influences glycolysis via the mTOR-HIF1α axis, highlighting its critical role in glucose metabolism and metabolic adaptation in response to energy availability.

BXQ-350, a novel sphingolipid metabolism modulator, in combination with mFOLFOX7 and bevacizumab in newly diagnosed metastatic colorectal cancer (mCRC) patients: A phase 1b/2 randomized study.

TPS320 Background: Ceramides and sphingosine-1-phosphate (S1P) are key bioactive signaling molecules. Ceramides are proapoptotic and mitigate chemoresistance. Conversely, S1P promotes cancer cell proliferation, activates multiple oncogenic pathways, and stimulates immuno-suppressor cell populations promoting a pro-tumoral microenvironment. Several studies in colorectal cancer patients have shown high levels of ceramides are associated with improved survival, while high S1P levels are associated with a poor prognosis. Hence, modulation of sphingolipid metabolism could be a promising therapeutic approach. BXQ-350 is a nanovesicle of Saposin C, an allosteric activator of sphingolipid metabolism, that lowers systemic S1P and increases C18 ceramide. BXQ-350 was investigated in a Phase 1 dose-escalation safety study in cancer patients with advanced solid malignancies (NCT02859857). BXQ-350 was safe and well-tolerated (no DLT, no MTD). Also, 13 patients (~17.8% of evaluable patients) had a clinical benefit up to cycle 6 and beyond (PR, SD). Among patients with PFS > 6 months, there were 4 recurrent CRC patients: 1 patient had a PFS of ~12 months, 2 of ~18 months, and 1 is still on study after 7 years suggesting potential long-term benefit. Furthermore, there were signs that BXQ-350 may alleviate symptoms of CIPN as 4 out of 10 patients with chronic CIPN at time of enrollment experienced an improvement of their symptoms. Methods: BXQ-350 is being investigated in a Phase 1b/2 study in combination with mFOLFOX7 and Bevacizumab in newly diagnosed mCRC patients (NCT05322590) to assess the efficacy and safety of BXQ-350. Design of the Phase 1b (open label study): 1) A safety dose escalation part to establish the RP2D: patients will initially receive 1.8 mg/kg BXQ-350 in combination with mFOLFOX7 and Bevacizumab. If safe (no MTD), dose of BXQ-350 will be increased to 2.4 mg/kg and 9 additional patients will be entered at this dose level. If safe, then this dose will be the RP2D and 21 additional patients will be enrolled, completing a 30 patient expansion cohort 2) Efficacy will then be evaluated for all patients entered at the RP2D. Primary objectives of the Phase 1b are to assess safety, identify RP2D, and assess preliminary efficacy of BXQ-350 in this combination. A secondary objective is to determine if BXQ-350 decreases CIPN. Enrollment in the expansion cohort of 30 patients is nearly complete, with 26 patients enrolled as of September 2024. Clinical trial information: NCT05322590 .

Envisioning Glucose Transporters (GLUTs and SGLTs) as Novel Intervention against Cancer: Drug Discovery Perspective and Targeting Approach.

Metabolic reprogramming and altered cellular energetics have been recently established as an important cancer hallmark. The modulation of glucose metabolism is one of the important characteristic features of metabolic reprogramming in cancer. It contributes to oncogenic progression by supporting the increased biosynthetic and bio-energetic demands of tumor cells. This oncogenic transformation consequently results in elevated expression of glucose transporters in these cells. Moreover, various cancers exhibit abnormal transporter expression patterns compared to normal tissues. Recent investigations have underlined the significance of glucose transporters in regulating cancer cell survival, proliferation, and metastasis. Abnormal regulation of these transporters, which exhibit varying affinities for hexoses, could enable cancer cells to efficiently manage their energy supply, offering a crucial edge for proliferation. Exploiting the upregulated expression of glucose transporters, GLUTs, and Sodium Linked Glucose Transporters (SGLTs), could serve as a novel therapeutic intervention for anti-cancer drug discovery as well as provide a unique targeting approach for drug delivery to specific tumor tissues. This review aims to discussthe previous and emerging research on the expression of various types of glucose transporters in tumor tissues, the role of glucose transport inhibitors as a cancer therapy intervention as well as emerging GLUT/SGLT-mediated drug delivery strategies that can be therapeutically employed to target various cancers.

Advances in Cysteine Protease B Inhibitors for Leishmaniasis Treatment.

The expression and release of cysteine proteases by Leishmania spp. and their virulence factors significantly influence the modulation of host immune responses and metabolism, rendering cysteine proteases intriguing targets for drug development. This review article explores the substantial role of cysteine protease B (CPB) in medicinal chemistry from 2001 to 2024, particularly concerning combatting Leishmania parasites. We delve into contemporary advancements and potential prospects associated with targeting cysteine proteases for therapeutic interventions against leishmaniasis, emphasizing drug discovery in this context. Computational analysis using the pkCSM tool assessed the physicochemical properties of compounds, providing valuable insights into their molecular characteristics and drug-like potential, enriching our understanding of the pharmacological profiles, and aiding rational inhibitor design. Our investigation highlights that while nonpeptidic compounds constitute the majority (69.2%, 36 compounds) of the dataset, peptidomimetic- based derivatives (30.8%, 16 compounds) also hold promise in medicinal chemistry. Evaluating the most promising compounds based on dissociation constant (Ki) and half maximal inhibitory concentration (IC50) values revealed notable potency, with 41.7% and 80.0% of nonpeptidic compounds exhibiting values < 1 μM, respectively. On the other hand, all peptidic compounds evaluated for Ki (43.8%) and IC50 (31.3%) obtained values < 1 μM, respectively. Further analysis identified specific compounds within both categories (nonpeptidic: 1, 2, and 4; peptidic: 48-52) as particularly promising, warranting deeper investigation into their structure-activity relationships. These findings underscore the diverse landscape of inhibitors in medicinal chemistry and highlight the potential of both nonpeptidic and peptide-based compounds as valuable assets in therapeutic development against leishmaniasis.

Effects of targeting CTMP on immunogenicity of MSI-L colon adenocarcinoma cells by metabolism and cell cycle modulation.

246 Background: Regimen of metastatic colon cancer (mCOAD) is moving towards combination of immune checkpoint inhibitors (ICBs) and targeted therapy, however ICBs are rarely effective in MSI-L metastatic colon cancers, limiting options for backline treatments, new targeted therapy is on demand to improve immunogenicity of MSI-L mCOAD. As targeting fatty acid metabolism or cell cycle has shown potential in improving the efficacy of ICBs, our team focused on CTMP, a thioesterase (ACOT) family member, mainly modulates fatty acid β oxidation, meanwhile it binds to phosphorylation sites of AKT thus intervenes cell cycle, currently its role on immunogenicity of COAD is not clear. Methods: Correlation between CTMP and OS in MSI-L colon cancer patients was assessed by KM plotter in GEO database.11 Clinical samples of MSI-L colon cancer, who received a third-line treatment regimen of anti-PD-1 and fruquintinib, were collected then applied in immunofluorescence and western blot analyses to evaluate CTMP and MHC-I expression. In vitro, Lentiviral transfection of targeted genes were stably established,then applied in RNA-seq and metabolic assays. Proteomic analysis and co-IP were applied to explore CTMP-modulating pathway. In vitro, IFNγ was intratumorally injected. Results: KM curve showed CTMP was negatively correlated with OS in MSI-L COAD in GEO database. In clinical samples, lower CTMP expression and higher MHC-I expression were observed in partial response (PR) than progressive disease (PD) group. In vitro, CTMP-OE reduced MHC-I, increased AKT phosphorylation and immune checkpoints (PD-L1, IDO-1), promoted clone formation. Seahorse assay showed increased capacity of glycolysis and oxidative phosphorylation in CTMP-OE than vector. RNA-seq showed CTMP-OE reduced MHC-I augmentation under IFN-γ treatment, meanwhile glucose metabolism genes, ACOT family ,immune checkpoints were also up-regulated, indicating ACOT family related metabolism promotion and immunogenicity suppression of COAD. Proteomic analysis and co-IP assay indicated CTMP interacts REV7, a key mitotic regulatory protein. Enzyme activity assay showed REV7 negatively regulates CDK1. Furthermore, REV7-OE alone is capable to induce MHC I augmentation and G2 arrest, accordingly CTMP-KD enhanced REV7's negative modulation on CDK1,contributing to G2 arrest, that also augmented MHC I . In homologous mice tumor-bearing model, tumor shrinkage was observed in CTMP-KD/ REV7-OE group. CTMP-KD/ REV7-OE increases MHC I expression,CD8+ T cell infiltration under IFN γ intra-tumoral injection. Conclusions: In summary, our studies suggested that CTMP regulates the metabolism of colorectal cancer and intervenes MHC-I molecules expression, and targeting CTMP is potential in suppressing tumor cell cycle and promoting immunogenicity through its modulation on REV7.

Physiological and pathological roles of PGAM5: An update and future trend.

PGAM5, a phosphatase found in mitochondria, is crucial for mitochondrial quality control (MQC) through its regulation on mitochondrial dynamics, biogenesis, and mitophagy. Previous studies have shown its involvement in multiple regulated cell deaths (RCDs), including apoptosis, necroptosis, and pyroptosis. The objective of this review is to enhance our comprehension of the involvement of PGAM5 in MQC and RCDs. Additionally, we summarize some novel roles of PGAM5 in cellular senescence, lipid metabolism, and immune response modulation in recent studies. Finally, we discuss PGAM5's contribution to the pathological state of cardiovascular, hepatic, neurological, and neoplastic diseases, offering potential perspectives for future research.

Genetic and neurochemical profiles underlying cortical morphometric vulnerability to Parkinson's disease.

Increasing evidence has documented cortical involvement at all stages of PD. The local vulnerabilities within certain brain regions in PD have been previously demonstrated, whereas its underlying genetic and neurochemical factors remain unclear. This study aims to investigate the spatial spectrum of cortical atrophy in Parkinson's disease (PD) and link these variances in gray matter properties and curvature respectively to putative molecular pathways and neurotransmitter factors. We recruited 141 clinically diagnosed PD patients and 70 healthy controls. Cortical morphological abnormalities of PD were obtained by intergroup comparisons in gray matter properties metrics and curvature measurements. Then we performed gene-category enrichment and spatial correlation analyses to evaluate the specific correspondence between cortical alteration in PD and genetic expression from the Allen Human Brain Atlas and normative neurotransmitter atlases from Neuromaps. We found decreased gray matter properties in temporal, somatomotor, cingulate and occipital cortices, decreased curvature measures in occipital, temporal and orbitofrontal cortices, and increased curvature measures in somatomotor, prefrontal and posterior parietal cortices for PD patients. The related genes were enriched for the glucose metabolism, mitochondrial function, and post-translational histone modifications processes. In addition, the serotonin and norepinephrine transporter devoted more to gray matter properties alterations while the dopamine, gamma-aminobutyric acid receptors, and norepinephrine transporter were strong contributors of curvature abnormalities in PD. Collectively, the present study offered interpretation of cortical morphological alterations and the cortical pathogenic theory in PD from genetic and neurochemical perspectives, which inspire further research on new pharmacotherapeutic approaches.

Signaling molecule alleviates inhibitory impacts of surfactant on methane production during sludge and food waste co-digestion: Insights of electron bifurcation and quorum sensing.

Anaerobic co-digestion of food waste (FW) and waste-activated sludge (WAS) is increasingly recognized as a viable solution for managing organic wastes. However, emerging contaminants (ECs), such as surfactant like sodium dodecylbenzene sulfonate (SDBS), can severely inhibit methane production. This study explores the potential of C6-HSL, a quorum sensing (QS) signaling molecule, to mitigate inhibitory effects of SDBS during FW and WAS co-digestion. Results demonstrated that SDBS reduced methane yields from 122.2 mL/g VSS in the control to 18.5 mL/g VSS, but supplementation with C6-HSL alleviated this inhibition, increasing yields to 115.4 mL/g VSS. C6-HSL not only restored suppressed methanogen populations but also promoted bacteria-archaea mutualisms, enhancing system resilience and stability. Additionally, C6-HSL enhanced key electron bifurcation pathways critical for overcoming thermodynamic barriers in methane metabolism, increasing the relative abundance of functional genes involved in four methane metabolism modules. Moreover, C6-HSL enhanced QS system (e.g., SecY and trpE), prompting microorganisms to activate adaptive mechanisms, such as DNA replication (e.g., rfcL and rfcS), efflux pumps (e.g., mdlA and mdlB), and bacterial chemotaxis (e.g., cheB and cheD), to counter SDBS toxicity. Correspondingly, TCA cycle (e.g., fumA and fumB) was also upregulated to ensure sufficient energy and electrons for methane production and microbial adaptation.

Unlocking new electron transport routes: Insights into enhanced long-chain fatty acid conversion in valorization of lipid-rich waste.

In this study, the alkaline fermentation of combined lipid-rich waste (LRW) was explored to produce volatile fatty acids (VFAs). By introducing sulfate as an external electron acceptor, the long-chain fatty acid (LCFA) metabolic pathway was enhanced, achieving a VFA yield of 671.1 ± 21.9 mg COD/g VSS-an increase of 4.7 times compared to the control-under conditions of high lipid content (10 g/L). Significant conversion of long-chain fatty acids (LCFAs), such as oleic and linolenic acids, was achieved via the β-oxidation pathway, which also led to a synergistic enhancement of the fermentation of non-lipidic organic matter. Key functional genes from five LCFA metabolic modules were identified, revealing diverse electron transport routes, including non-syntrophic and syntrophic LCFA oxidation mediated by differentiated microbial function groups. Genome-centric metagenomics analysis further identified microbial functional groups responsible for the reconstructed pathways, offering new insights into optimizing LRW recycling and VFA production in anaerobic fermentation systems.

Exertional Exhaustion (Post-Exertional Malaise, PEM) Evaluated by the Effects of Exercise on Cerebrospinal Fluid Metabolomics–Lipidomics and Serine Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Post-exertional malaise (PEM) is a defining condition of myalgic encephalomyelitis (ME/CFS). The concept requires that a provocation causes disabling limitation of cognitive and functional effort (“fatigue”) that does not respond to rest. Cerebrospinal fluid was examined as a proxy for brain metabolite and lipid flux and to provide objective evidence of pathophysiological dysfunction. Two cohorts of ME/CFS and sedentary control subjects had lumbar punctures at baseline (non-exercise) or after submaximal exercise (post-exercise). Cerebrospinal fluid metabolites and lipids were quantified by targeted Biocrates mass spectrometry methods. Significant differences between ME/CFS and control, non-exercise vs. post-exercise, and by gender were examined by multivariate general linear regression and Bayesian regression methods. Differences were found at baseline between ME/CFS and control groups indicating disease-related pathologies, and between non-exercise and post-exercise groups implicating PEM-related pathologies. A new, novel finding was elevated serine and its derivatives sarcosine and phospholipids with a decrease in 5-methyltetrahydrofolate (5MTHF), which suggests general dysfunction of folate and one-carbon metabolism in ME/CFS. Exercise led to consumption of lipids in ME/CFS and controls while metabolites were consumed in ME/CFS but generated in controls. In general, the frequentist and Bayesian analyses generated complementary but not identical sets of analytes that matched the metabolic modules and pathway analysis. Cerebrospinal fluid is unique because it samples the choroid plexus, brain interstitial fluid, and cells of the brain parenchyma. The quantitative outcomes were placed into the context of the cell danger response hypothesis to explain shifts in serine and phospholipid synthesis; folate and one-carbon metabolism that affect sarcosine, creatine, purines, and thymidylate; aromatic and anaplerotic amino acids; glucose, TCA cycle, trans-aconitate, and coenzyme A in energy metabolism; and vitamin activities that may be altered by exertion. The metabolic and phospholipid profiles suggest the additional hypothesis that white matter dysfunction may contribute to the cognitive dysfunction in ME/CFS.

Melatonin induces fiber switching by improvement of mitochondrial oxidative capacity and function via NRF2/RCAN/MEF2 in the vastus lateralis muscle from both sex Zücker diabetic fatty rats.

The positive role of melatonin in obesity control and skeletal muscle (SKM) preservation is well known. We recently showed that melatonin improves vastus lateralis muscle (VL) fiber oxidative phenotype. However, fiber type characterization, mitochondrial function, and molecular mechanisms that underlie VL fiber switching by melatonin are still undefined. Our study aims to investigate whether melatonin induces fiber switching by NRF2/RCAN/MEF2 pathway activation and mitochondrial oxidative metabolism modulation in the VL of both sex Zücker diabetic fatty (ZDF) rats. 5-Weeks-old male and female ZDF rats (N=16) and their age-matched lean littermates (ZL) were subdivided into two subgroups: control (C) and orally treated with melatonin (M) (10mg/kg/day) for 12 weeks. Interestingly, melatonin increased oxidative fibers amounts (Types I and IIa) counteracting the decreased levels found in the VL of obese-diabetic rats, and upregulated NRF2, calcineurin and MEF2 expression. Melatonin also restored the mitochondrial oxidative capacity increasing the respiratory control ratio (RCR) in both sex and phenotype rats through the reduction of the proton leak component of respiration (state 4). Melatonin also improved the VL mitochondrial phosphorylation coefficient and modulated the total oxygen consumption by enhancing complex I, III and IV activity, and fatty acid oxidation (FAO) in both sex obese-diabetic rats, decreasing in male and increasing in female the complex II oxygen consumption. These findings suggest that melatonin treatment induces fiber switching in SKM improving mitochondrial functionality by NRF2/RCAN/MEF2 pathway activation.

Glycolytic metabolism modulation on spinal neuroinflammation and vital functions following cervical spinal cord injury.

High spinal cord injuries (SCIs) often result in persistent diaphragm paralysis and respiratory dysfunction. Chronic neuroinflammation within the damaged spinal cord after injury plays a prominent role in limiting functional recovery by impeding neuroplasticity. In this study, we aimed to reduce glucose metabolism that supports neuroinflammatory processes in an acute preclinical model of C2 spinal cord lateral hemisection in rats. We administered 2-deoxy-D-glucose (2-DG; 200 mg/kg/day s.c., for 7 days) and evaluated the effect on respiratory function and chondroitin sulfate proteoglycans (CSPGs) production around spinal phrenic motoneurons. Contrary to our initial hypothesis, our 2-DG treatment did not have any effect on diaphragm activity and CSPGs production in injured rats, although slight increases in tidal volume were observed. Unexpectedly, it led to deleterious effects in uninjured (sham) animals, characterized by increased ventilation and CSPGs production. Ultimately, our results seem to indicate that this 2-DG treatment paradigm may create a neuroinflammatory state in healthy animals, without affecting the already established spinal inflammation in injured rats.

Photosynthesis in Synechocystis sp. PCC 6803 is not optimally regulated under very high CO2

One strategy for CO2 mitigation is using photosynthetic microorganisms to sequester CO2 under high concentrations, such as in flue gases. While elevated CO2 levels generally promote growth, excessively high levels inhibit growth through uncertain mechanisms. This study investigated the physiology of the cyanobacterium Synechocystis sp. PCC 6803 under very high CO2 concentrations and yet stable pH around 7.5. The growth rate of the wild type (WT) at 200 µmol photons m−2 s−1 and a gas phase containing 30% CO2 was 2.7-fold lower compared to 4% CO2. Using a CRISPR interference mutant library, we identified genes that, when repressed, either enhanced or impaired growth under 30% or 4% CO2. Repression of genes involved in light harvesting (cpc and apc), photochemical electron transfer (cytM, psbJ, and petE), and several genes with little or unknown functions promoted growth under 30% CO2, while repression of key regulators of photosynthesis (pmgA) and CO2 capture and fixation (ccmR, cp12, and yfr1) increased growth inhibition under 30% CO2. Experiments confirmed that WT cells were more susceptible to light inhibition under 30% than under 4% CO2 and that a light-harvesting-impaired ΔcpcG mutant showed improved growth under 30% CO2 compared to the WT. These findings suggest that enhanced fitness under very high CO2 involves modifications in light harvesting, electron transfer, and carbon metabolism, and that the native regulatory machinery is insufficient, and in some cases obstructive, for optimal growth under 30% CO2. This genetic profiling provides potential targets for engineering cyanobacteria with improved photosynthetic efficiency and stress resilience for biotechnological applications.Key points• Synechocystis growth was inhibited under very high CO2.• Inhibition of growth under very high CO2 was light dependent.• Repression of photosynthesis genes improved growth under very high CO2.Graphical

Apolipoprotein B100 acts as a tumor suppressor in ovarian cancer via lipid/ER stress axis-induced blockade of autophagy.

Ovarian cancer presents a significant treatment challenge due to its insidious nature and high malignancy. As autophagy is a vital cellular process for maintaining homeostasis, targeting the autophagic pathway has emerged as an avenue for cancer therapy. In the present study, we identify apolipoprotein B100 (ApoB100), a key modulator of lipid metabolism, as a potential prognostic biomarker of ovarian cancer. ApoB100 functioned as a tumor suppressor in ovarian cancer, and the knockdown of ApoB100 promoted ovarian cancer progression in vivo. Moreover, ApoB100 blocked autophagic flux, which was dependent on interfering with the lipid accumulation/endoplasmic reticulum (ER) stress axis. The effects of LFG-500, a novel synthetic flavonoid, on ApoB100 induction were confirmed using proteomics and lipidomics analyses. Herein, LFG-500 induced lipid accumulation and ER stress and subsequently blocked autophagy by upregulating ApoB100. Moreover, data from in vivo experiments further demonstrated that ApoB100, as well as the induction of the lipid/ER stress axis and subsequent blockade of autophagy, were responsible for the anti-tumor effects of LFG-500 on ovarian cancer. Hence, our findings support that ApoB100 is a feasible target of ovarian cancer associated with lipid-regulated autophagy and provide evidence for using LFG-500 for ovarian cancer treatment.

Dietary Modulation of Fatty Acid Oxidation Imparts Stem Cell Protection in Bone Marrow

Hematopoietic stem cells (HSCs) maintain production of all functional blood cells and are located within the bone marrow. In pathological conditions, such as obesity or leukemia, changes in these cells contribute to disease pathophysiology. In this study, we examined the impact of metabolic modulation of stem and progenitor cells within the bone marrow during diet-induced obesity (DIO) and leukemia relapse. Avocatin B (Avo), an inhibitor of fatty acid oxidation (FAO), was provided in the diet and its impact on stem cells using two disease models was tested. In DIO, high fat diet(HFD)-induced alterations in HSC number and function were attenuated with Avo (HFD: 46.9% decrease compared to control; p < 0.001; whereas DIO + Avo: 58.8% recovery; p < 0.05). In leukemia relapse, dietary Avo delayed disease reoccurrence. Taken together, addition of Avo into the diet imparts protection in the bone marrow.

Bioenergetic trade-offs can reveal the path to superior microbial CO2 fixation pathways.

A comprehensive optimization of known prokaryotic autotrophic carbon dioxide (CO2) fixation pathways is presented that evaluates all their possible variants under different environmental conditions. This was achieved through a computational methodology recently developed that considers the trade-offs between energy efficiency (yield) and growth rate, allowing us to evaluate candidate metabolic modifications in silico for microbial conversions. The results revealed the superior configurations in terms of both yield (efficiency) and rate (driving force). The pathways from anaerobic organisms appear to fix carbon at lower net ATP cost than those found in aerobic organisms, and the reverse TCA cycle pathway shows the lowest overall energy cost and maximum adaptability across a broad range of CO2 and electron donor (H2) concentrations. The reverse tricarboxylic acid cycle and Wood-Ljungdahl pathways appear highly efficient under a broad range of conditions, while the 3-hydroxypropionate 4-hydroxybutyrate cycle and the 3-hydroxypropionate bicycle appear capable of generating large thermodynamic driving forces at only moderate ATP yield losses.IMPORTANCEBiotechnology can lead to cost-effective processes for capturing carbon dioxide using the natural or genetically engineered metabolic capabilities of microorganisms. However, introducing desirable genetic modifications into microbial strains without compromising their fitness (growth yield and rate) during industrial-scale cultivation remains a challenge. The approach and results presented can guide optimal pathway configurations for enhanced prokaryotic carbon fixation through metabolic engineering. By aligning strain modifications with these theoretically revealed near-optimal pathway configurations, we can optimally engineer strains of good fitness under open culture industrial-scale conditions.