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The ISME Journal Jul 2023Methyl groups are abundant in anoxic environments and their utilization as carbon and energy sources by microorganisms involves oxidation of the methyl groups to CO,...
Methyl groups are abundant in anoxic environments and their utilization as carbon and energy sources by microorganisms involves oxidation of the methyl groups to CO, followed by transfer of the electrons to an acceptor. In acetogenic bacteria, the electron acceptor is CO that is reduced to enzyme bound carbon monoxide, the precursor of the carboxyl group in acetate. Here, we describe the generation of a mutant of the acetogen Acetobacterium woodii in which the last step in methyl group oxidation, formate oxidation to CO catalyzed by the HDCR enzyme, has been genetically deleted. The mutant grew on glycine betaine as methyl group donor, and in contrast to the wild type, formed formate alongside acetate, in a 1:2 ratio, demonstrating that methyl group oxidation stopped at the level of formate and reduced electron carriers were reoxidized by CO reduction to acetate. In the presence of the alternative electron acceptor caffeate, CO was no longer reduced to acetate, formate was the only product and all the carbon went to formate. Apparently, acetogenesis was not required to sustain formatogenic growth. This is the first demonstration of a genetic reprogramming of an acetogen into a formatogen that grows by homoformatogenesis from methyl groups. Formate production from methyl groups is not only of biotechnological interest but also for the mechanism of electron transfer in syntrophic interactions in anoxic environments.
Topics: Carbon Dioxide; Oxidation-Reduction; Acetates; Bacteria; Formates; Acetobacterium
PubMed: 37061584
DOI: 10.1038/s41396-023-01411-2 -
Environmental Science & Technology Oct 2023It is known that the presence of sulfate decreases the methane yield in the anaerobic digestion systems. Sulfate-reducing bacteria can convert sulfate to hydrogen...
It is known that the presence of sulfate decreases the methane yield in the anaerobic digestion systems. Sulfate-reducing bacteria can convert sulfate to hydrogen sulfide competing with methanogens for substrates such as H and acetate. The present work aims to elucidate the microbial interactions in biogas production and assess the effectiveness of electron-conductive materials in restoring methane production after exposure to high sulfate concentrations. The addition of magnetite led to a higher methane content in the biogas and a sharp decrease in the level of hydrogen sulfide, indicating its beneficial effects. Furthermore, the rate of volatile fatty acid consumption increased, especially for butyrate, propionate, and acetate. Genome-centric metagenomics was performed to explore the main microbial interactions. The interaction between methanogens and sulfate-reducing bacteria was found to be both competitive and cooperative, depending on the methanogenic class. Microbial species assigned to the genus increased in relative abundance after magnetite addition together with the butyrate oxidizing syntrophic partners, in particular belonging to the genus. Additionally, sp. DTU98 and other species assigned to the Chloroflexi phylum were positively correlated to the presence of sulfate-reducing bacteria, suggesting DIET-based interactions. In conclusion, this study provides new insights into the application of magnetite to enhance the anaerobic digestion performance by removing hydrogen sulfide, fostering DIET-based syntrophic microbial interactions, and unraveling the intricate interplay of competitive and cooperative interactions between methanogens and sulfate-reducing bacteria, influenced by the specific methanogenic group.
Topics: Ferrosoferric Oxide; Biofuels; Hydrogen Sulfide; Euryarchaeota; Anaerobiosis; Bacteria; Acetates; Butyrates; Methane; Sulfates; Bioreactors
PubMed: 37862709
DOI: 10.1021/acs.est.3c05948 -
Acta Biochimica Et Biophysica Sinica Dec 2023Cancer cachexia (CAC) is a debilitating condition that often arises from noncachexia cancer (NCAC), with distinct metabolic characteristics and medical treatments....
Cancer cachexia (CAC) is a debilitating condition that often arises from noncachexia cancer (NCAC), with distinct metabolic characteristics and medical treatments. However, the metabolic changes and underlying molecular mechanisms during cachexia progression remain poorly understood. Understanding the progression of CAC is crucial for developing diagnostic approaches to distinguish between CAC and NCAC stages, facilitating appropriate treatment for cancer patients. In this study, we establish a mouse model of colon CAC and categorize the mice into three groups: CAC, NCAC and normal control (NOR). By performing nuclear magnetic resonance (NMR)-based metabolomic profiling on mouse sera, we elucidate the metabolic properties of these groups. Our findings unveil significant differences in the metabolic profiles among the CAC, NCAC and NOR groups, highlighting significant impairments in energy metabolism and amino acid metabolism during cachexia progression. Additionally, we observe the elevated serum levels of lysine and acetate during the transition from the NCAC to CAC stages. Using multivariate ROC analysis, we identify lysine and acetate as potential biomarkers for distinguishing between CAC and NCAC stages. These biomarkers hold promise for the diagnosis of CAC from noncachexia cancer. Our study provides novel insights into the metabolic mechanisms underlying cachexia progression and offers valuable avenues for the diagnosis and treatment of CAC in clinical settings.
Topics: Humans; Animals; Mice; Cachexia; Lysine; Metabolomics; Colonic Neoplasms; Biomarkers; Acetates
PubMed: 37705348
DOI: 10.3724/abbs.2023151 -
BMJ Global Health Jul 2023Cervical cancer accounts for 21.7% of all cancer deaths in the sub-Saharan Africa with a case fatality rate of 68%. Nigeria's Federal Ministry of Health has adopted...
Cervical cancer accounts for 21.7% of all cancer deaths in the sub-Saharan Africa with a case fatality rate of 68%. Nigeria's Federal Ministry of Health has adopted cervical cancer screening (CCS) using visual inspection with acetic acid or Lugol's iodine (VIA/VILI) and cryotherapy treatment for precancerous lesions as the preferred screening and treatment strategy. Using the Exploration, Preparation, Implementation and Sustainment Framework, our study documents our experience during the development, piloting and roll-out of the APIN Public Health Initiatives (APIN)-developed VIA Visual Application (AVIVA) for CCS using the VIA method in 86 APIN-supported health facilities across 7 states in Nigeria. Between December 2019 and June 2022, with the aid of 9 gynaecologists and 133 case finders, a total of 29 262 women living with HIV received VIA-based CCS and 1609 of them were VIA-positive, corresponding to VIA positivity rate of 5.5%. Over the 30 months duration and the 5 phases of CCS scale-up, AVIVA development and expansion, a total of 1247 cases were shared via the AVIVA App (3741 pictures), with 1058 of such cases undergoing expert review, corresponding to a reviewer rate of 84.8%. Overall, the use of the AVIVA App improved both the VIA-positive and VIA-negative concordance rates by 16 percentage points each (26%-42% and 80%-96%, respectively) from baseline to the end of the study. We concluded that the AVIVA App is an innovative tool to improve CCS rates and diagnostic precision by connecting health facility staff and expert reviewers in resource-limited settings.
Topics: Humans; Female; Early Detection of Cancer; Uterine Cervical Neoplasms; Telemedicine; Acetic Acid; Gynecologists
PubMed: 37433694
DOI: 10.1136/bmjgh-2023-012311 -
FASEB Journal : Official Publication of... Nov 2023The roles of DGAT1 and DGAT2 in lipid metabolism and insulin responsiveness of human skeletal muscle were studied using cryosections and myotubes prepared from muscle...
The roles of DGAT1 and DGAT2 in lipid metabolism and insulin responsiveness of human skeletal muscle were studied using cryosections and myotubes prepared from muscle biopsies from control, athlete, and impaired glucose regulation (IGR) cohorts of men. The previously observed increases in intramuscular triacylglycerol (IMTG) in athletes and IGR were shown to be related to an increase in lipid droplet (LD) area in type I fibers in athletes but, conversely, in type II fibers in IGR subjects. Specific inhibition of both diacylglycerol acyltransferase (DGAT) 1 and 2 decreased fatty acid (FA) uptake by myotubes, whereas only DGAT2 inhibition also decreased fatty acid oxidation. Fatty acid uptake in myotubes was negatively correlated with the lactate thresholds of the respective donors. DGAT2 inhibition lowered acetate uptake and oxidation in myotubes from all cohorts whereas DGAT1 inhibition had no effect. A positive correlation between acetate oxidation in myotubes and resting metabolic rate (RMR) from fatty acid oxidation in vivo was observed. Myotubes from athletes and IGR had higher rates of de novo lipogenesis from acetate that were normalized by DGAT2 inhibition. Moreover, DGAT2 inhibition in myotubes also resulted in increased insulin-induced Akt phosphorylation. The differential effects of DGAT1 and DGAT2 inhibition suggest that the specialized role of DGAT2 in esterifying nascent diacylglycerols and de novo synthesized FA is associated with synthesis of a pool of triacylglycerol, which upon hydrolysis results in effectors that promote mitochondrial fatty acid oxidation but decrease insulin signaling in skeletal muscle cells.
Topics: Male; Humans; Diacylglycerol O-Acyltransferase; Muscle Fibers, Skeletal; Glucose; Insulin; Acetates; Triglycerides; Fatty Acids
PubMed: 37779421
DOI: 10.1096/fj.202300960RR -
CPT: Pharmacometrics & Systems... Jul 2023Levetiracetam (LEV) is an anti-epileptic drug approved for use in various populations. The pharmacokinetic (PK) behavior of LEV may be altered in the elderly and...
Levetiracetam (LEV) is an anti-epileptic drug approved for use in various populations. The pharmacokinetic (PK) behavior of LEV may be altered in the elderly and patients with renal and hepatic impairment. Thus, dosage adjustment is required. This study was conducted to investigate how the physiologically-based PK (PBPK) model describes the PKs of LEV in adult and elderly populations, as well as to predict the PKs of LEV in patients with renal and hepatic impairment in both populations. The whole-body PBPK models were developed using the reported physicochemical properties of LEV and clinical data. The models were validated using data from clinical studies with different dose ranges and different routes and intervals of administration. The fit performance of the models was assessed by comparing predicted and observed blood concentration data and PK parameters. It is recommended that the doses be reduced to ~70%, 60%, and 45% of the adult dose for the mild, moderate, and severe renal impairment populations and ~95%, 80%, and 57% of the adult dose for the Child Pugh-A (CP-A), Child Pugh-B (CP-B), and Child Pugh-C (CP-C) hepatic impairment populations, respectively. No dose adjustment is required for the healthy elderly population, but dose reduction is required for the elderly with organ dysfunction accordingly, on a scale similar to that of adults. A PBPK model of LEV was successfully developed to optimize dosing regimens for special populations.
Topics: Adult; Humans; Aged; Levetiracetam; Renal Insufficiency; Kidney; Liver Diseases; Models, Biological
PubMed: 37170680
DOI: 10.1002/psp4.12971 -
Bioorganic Chemistry Nov 20235-Fluorouracil (5-FU) is one of the most widely applied chemotherapeutic agents with a broad spectrum of activity. However, despite this versatile activity, its use...
5-Fluorouracil (5-FU) is one of the most widely applied chemotherapeutic agents with a broad spectrum of activity. However, despite this versatile activity, its use poses many limitations. Herein, novel derivatives of 5-FU and dichloroacetic acid have been designed and synthesized as a new type of codrugs, also known as mutual prodrugs, to overcome the drawbacks of 5-FU and enhance its therapeutic efficiency. The stability of the obtained compounds has been tested at various pH values using different analytical techniques, namely HPLC and potentiometry. The antiproliferative activity of the new 5-FU derivatives was assessed in vitro on SK-MEL-28 and WM793 human melanoma cell lines in 2D culture as well as on A549 human lung carcinoma, MDA-MB-231 breast adenocarcinoma, LL24 normal lung tissue, and HMF normal breast tissue as a multicellular 3D spheroid model cultured in standard (static) conditions and with the use of microfluidic systems, which to a great extent resembles the in vivo environment. In all cases, new mutual prodrugs showed a higher cytotoxic activity toward cancer models and lower to normal cell models than the parent 5-FU itself.
Topics: Humans; Fluorouracil; Prodrugs; Antineoplastic Agents; Acetates; Cell Line; Hydrocarbons, Chlorinated
PubMed: 37639758
DOI: 10.1016/j.bioorg.2023.106784 -
ELife Feb 2024Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. There is growing evidence that dysbiosis of the intestinal...
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. There is growing evidence that dysbiosis of the intestinal microbiota and disruption of microbiota-host interactions contribute to the pathology of NAFLD. We previously demonstrated that gut microbiota-derived tryptophan metabolite indole-3-acetate (I3A) was decreased in both cecum and liver of high-fat diet-fed mice and attenuated the expression of inflammatory cytokines in macrophages and and fatty acid-induced inflammatory responses in an aryl-hydrocarbon receptor (AhR)-dependent manner in hepatocytes. In this study, we investigated the effect of orally administered I3A in a mouse model of diet-induced NAFLD. Western diet (WD)-fed mice given sugar water (SW) with I3A showed dramatically decreased serum ALT, hepatic triglycerides (TG), liver steatosis, hepatocyte ballooning, lobular inflammation, and hepatic production of inflammatory cytokines, compared to WD-fed mice given only SW. Metagenomic analysis show that I3A administration did not significantly modify the intestinal microbiome, suggesting that I3A's beneficial effects likely reflect the metabolite's direct actions on the liver. Administration of I3A partially reversed WD-induced alterations of liver metabolome and proteome, notably, decreasing expression of several enzymes in hepatic lipogenesis and β-oxidation. Mechanistically, we also show that AMP-activated protein kinase (AMPK) mediates the anti-inflammatory effects of I3A in macrophages. The potency of I3A in alleviating liver steatosis and inflammation clearly demonstrates its potential as a therapeutic modality for preventing the progression of steatosis to non-alcoholic steatohepatitis (NASH).
Topics: Animals; Mice; Non-alcoholic Fatty Liver Disease; Gastrointestinal Microbiome; Inflammation; Diet, Western; Cytokines; Dietary Supplements; Acetates; Indoles
PubMed: 38412016
DOI: 10.7554/eLife.87458 -
Nature Communications Apr 2024Beneficial gut bacteria are indispensable for developing colonic mucus and fully establishing its protective function against intestinal microorganisms. Low-fiber diet...
Beneficial gut bacteria are indispensable for developing colonic mucus and fully establishing its protective function against intestinal microorganisms. Low-fiber diet consumption alters the gut bacterial configuration and disturbs this microbe-mucus interaction, but the specific bacteria and microbial metabolites responsible for maintaining mucus function remain poorly understood. By using human-to-mouse microbiota transplantation and ex vivo analysis of colonic mucus function, we here show as a proof-of-concept that individuals who increase their daily dietary fiber intake can improve the capacity of their gut microbiota to prevent diet-mediated mucus defects. Mucus growth, a critical feature of intact colonic mucus, correlated with the abundance of the gut commensal Blautia, and supplementation of Blautia coccoides to mice confirmed its mucus-stimulating capacity. Mechanistically, B. coccoides stimulated mucus growth through the production of the short-chain fatty acids propionate and acetate via activation of the short-chain fatty acid receptor Ffar2, which could serve as a new target to restore mucus growth during mucus-associated lifestyle diseases.
Topics: Animals; Gastrointestinal Microbiome; Dietary Fiber; Fatty Acids, Volatile; Mice; Colon; Humans; Intestinal Mucosa; Male; Receptors, G-Protein-Coupled; Female; Mice, Inbred C57BL; Mucus; Fecal Microbiota Transplantation; Symbiosis; Propionates; Clostridiales; Acetates; Adult; Receptors, Cell Surface
PubMed: 38664378
DOI: 10.1038/s41467-024-47594-w -
CNS Neuroscience & Therapeutics Feb 2024Hepatic ischemia-reperfusion injury (HIRI) resulting from hepatic inflow occlusion, which is a common procedure in liver surgery is inevitable. Previous research has...
AIMS
Hepatic ischemia-reperfusion injury (HIRI) resulting from hepatic inflow occlusion, which is a common procedure in liver surgery is inevitable. Previous research has confirmed that the cognitive dysfunction induced by HIRI is closely related to dysbiosis of the gut microbiota. This research aims to investigate the mechanisms underlying this complication.
METHODS
C57BL/6 mice underwent hepatic ischemia experimentally through the occlusion of the left hepatic artery and portal vein. To assess the HDAC2-ACSS2 axis, gut microbiota transplantation. Enzyme-linked immunosorbent assay and LC/MS short-chain fatty acid detection were utilized.
RESULTS
The findings indicated a notable decline in ACSS2 expression in the hippocampus of mice experiencing hepatic ischemia-reperfusion injury, emphasizing the compromised acetate metabolism in this particular area. Furthermore, the cognitive impairment phenotype and the dysregulation of the HDAC2-ACSS2 axis could also be transmitted to germ-free mice via fecal microbial transplantation. Enzyme-linked immunosorbent assay revealed reduced Acetyl-coenzyme A (acetyl-CoA) and Acetylated lysine levels in the hippocampus.
CONCLUSION
These findings suggest that acetate metabolism is impaired in the hippocampus of HIRI-induced cognitive impairment mice and related to dysbiosis, leading to compromised histone acetylation.
Topics: Animals; Mice; Acetates; Cognitive Dysfunction; Dysbiosis; Gastrointestinal Microbiome; Liver; Mice, Inbred C57BL; Reperfusion Injury
PubMed: 38334013
DOI: 10.1111/cns.14610