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MBio Jun 2024Loss of the inner membrane protein YhcB results in pleomorphic cell morphology and clear growth defects. Prior work suggested that YhcB was directly involved in cell...
Loss of the inner membrane protein YhcB results in pleomorphic cell morphology and clear growth defects. Prior work suggested that YhcB was directly involved in cell division or peptidoglycan assembly. We found that loss of YhcB is detrimental in genetic backgrounds in which lipopolysaccharide (LPS) or glycerophospholipid (GPL) synthesis is altered. The growth defect of Δ could be rescued through inactivation of the Mla pathway, a system responsible for the retrograde transport of GPLs that are mislocalized to the outer leaflet of the outer membrane. Interestingly, this rescue was dependent upon the outer membrane phospholipase PldA that cleaves GPLs at the bacterial surface. Since the freed fatty acids resulting from PldA activity serve as a signal to the cell to increase LPS synthesis, this result suggested that outer membrane lipids are imbalanced in Δ. Mutations that arose in Δ populations during two independent suppressor screens were in genes encoding subunits of the acetyl coenzyme A carboxylase complex, which initiates fatty acid biosynthesis (FAB). These mutations fully restored cell morphology and reduced GPL levels, which were increased compared to wild-type bacteria. Growth of Δ with the FAB-targeting antibiotic cerulenin also increased cellular fitness. Furthermore, genetic manipulation of FAB and lipid biosynthesis showed that decreasing FAB rescued Δ filamentation, whereas increasing LPS alone could not. Altogether, these results suggest that YhcB may play a pivotal role in regulating FAB and, in turn, impact cell envelope assembly and cell division.IMPORTANCESynthesis of the Gram-negative cell envelope is a dynamic and complex process that entails careful coordination of many biosynthetic pathways. The inner and outer membranes are composed of molecules that are energy intensive to synthesize, and, accordingly, these synthetic pathways are under tight regulation. The robust nature of the Gram-negative outer membrane renders it naturally impermeable to many antibiotics and therefore a target of interest for antimicrobial design. Our data indicate that when the inner membrane protein YhcB is absent in , the pathway for generating fatty acid substrates needed for all membrane lipid synthesis is dysregulated which leads to increased membrane material. These findings suggest a potentially novel regulatory mechanism for controlling the rate of fatty acid biosynthesis.
Topics: Escherichia coli; Escherichia coli Proteins; Fatty Acids; Glycerophospholipids; Lipopolysaccharides; Membrane Proteins
PubMed: 38742872
DOI: 10.1128/mbio.00790-24 -
BMC Psychiatry May 2024Sleep disturbances are a common occurrence in patients with schizophrenia, yet the underlying pathogenesis remain poorly understood. Here, we performed a targeted...
BACKGROUND
Sleep disturbances are a common occurrence in patients with schizophrenia, yet the underlying pathogenesis remain poorly understood. Here, we performed a targeted metabolomics-based approach to explore the potential biological mechanisms contributing to sleep disturbances in schizophrenia.
METHODS
Plasma samples from 59 drug-naïve patients with schizophrenia and 36 healthy controls were subjected to liquid chromatography-mass spectrometry (LC-MS) targeted metabolomics analysis, allowing for the quantification and profiling of 271 metabolites. Sleep quality and clinical symptoms were assessed using the Pittsburgh Sleep Quality Index (PSQI) and the Positive and Negative Symptom Scale (PANSS), respectively. Partial correlation analysis and orthogonal partial least squares discriminant analysis (OPLS-DA) model were used to identify metabolites specifically associated with sleep disturbances in drug-naïve schizophrenia.
RESULTS
16 characteristic metabolites were observed significantly associated with sleep disturbances in drug-naïve patients with schizophrenia. Furthermore, the glycerophospholipid metabolism (Impact: 0.138, p<0.001), the butanoate metabolism (Impact: 0.032, p=0.008), and the sphingolipid metabolism (Impact: 0.270, p=0.104) were identified as metabolic pathways associated with sleep disturbances in drug-naïve patients with schizophrenia.
CONCLUSIONS
Our study identified 16 characteristic metabolites (mainly lipids) and 3 metabolic pathways related to sleep disturbances in drug-naïve schizophrenia. The detection of these distinct metabolites provide valuable insights into the underlying biological mechanisms associated with sleep disturbances in schizophrenia.
Topics: Humans; Schizophrenia; Metabolomics; Female; Male; Adult; Sleep Wake Disorders; Chromatography, Liquid; Mass Spectrometry; Sphingolipids; Case-Control Studies; Young Adult; Glycerophospholipids
PubMed: 38741058
DOI: 10.1186/s12888-024-05805-0 -
Journal of Pharmaceutical Health Care... May 2024Coronary heart disease, also known as ischemic heart disease, is induced by atherosclerosis, which is initiated by subendothelial retention of lipoproteins. Plasma... (Review)
Review
Coronary heart disease, also known as ischemic heart disease, is induced by atherosclerosis, which is initiated by subendothelial retention of lipoproteins. Plasma lipoproteins, including high density lipoprotein, low density lipoprotein (LDL), very low density lipoprotein, and chylomicron, are composed of a surface monolayer containing phospholipids and cholesterol and a hydrophobic core containing triglycerides and cholesteryl esters. Phospholipids play a crucial role in the binding of apolipoproteins and enzymes to lipoprotein surfaces, thereby regulating lipoprotein metabolism. High LDL-cholesterol is a well-known risk factor for coronary heart disease, and statins reduce the risk of coronary heart disease by lowering LDL-cholesterol levels. In contrast, the relationships of phospholipids in plasma lipoproteins with coronary heart disease have not yet been established. To further clarify the physiological and pathological roles of phospholipids, we have developed the simple high-throughput assays for quantifying all major phospholipid classes, namely phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, phosphatidylinositol, phosphatidylglycerol + cardiolipin, and sphingomyelin, using combinations of specific enzymes and a fluorogenic probe. These enzymatic fluorometric assays will be helpful in elucidating the associations between phospholipid classes in plasma lipoproteins and coronary heart disease and in identifying phospholipid biomarkers. This review describes recent progress in the identification of phospholipid biomarkers of coronary heart disease.
PubMed: 38734675
DOI: 10.1186/s40780-024-00344-y -
Lipids in Health and Disease May 2024Skin barrier alterations play a crucial function in melasma development. Past researches have demonstrated variations in lipid content between the epidermis of melasma... (Comparative Study)
Comparative Study
BACKGROUND
Skin barrier alterations play a crucial function in melasma development. Past researches have demonstrated variations in lipid content between the epidermis of melasma lesions and normal tissues, along with the varied expression of lipid-related genes in melasma. This study aimed to analyze the lipidome profiles of skin surface lipids (SSL) in patients with melasma before and after treatment to understand associated abnormalities.
METHODS
Melasma was treated with tranexamic acid orally and hydroquinone cream topically. Disease was assessed using the Melasma Area and Severity Index (MASI), and the impact to life was evaluated with Melasma Quality of Life (MELASQoL) score. Epidermal melanin particles were observed using reflection confocal microscopy (RCM), whereas epidermal pigment and blood vessel morphology were observed using dermoscopy, and SSL samples were collected. Specific information regarding alterations in lipid composition was obtained through multivariate analysis of the liquid chromatography-mass spectrometry data.
RESULTS
After treatment, patients with melasma exhibited decreased MASI and MELASQoL scores (P < 0.001); RCM revealed reduced melanin content in the lesions, and dermoscopy revealed fewer blood vessels. Fifteen lipid subclasses and 382 lipid molecules were identified using lipidomic assays. The expression levels of total lipids, phosphatidylcholine, and phosphatidylethanolamine in the melasma lesions decreased after treatment (P < 0.05).
CONCLUSION
This study revealed alterations in the SSL composition after effective melasma treatment, suggesting a compensatory role for lipids in melasma barrier function. The mechanism involving SSL and the lipid barrier, which influences melasma's occurrence, needs further elucidation.
Topics: Humans; Melanosis; Female; Adult; Lipidomics; Quality of Life; Hydroquinones; Tranexamic Acid; Middle Aged; Melanins; Male; Lipids; Epidermis; Phosphatidylethanolamines; Phosphatidylcholines; Skin; Lipid Metabolism
PubMed: 38734619
DOI: 10.1186/s12944-024-02130-z -
Nutrients Apr 2024Non-invasive diagnostics are crucial for the timely detection of renal cell carcinoma (RCC), significantly improving survival rates. Despite advancements, specific lipid...
Non-invasive diagnostics are crucial for the timely detection of renal cell carcinoma (RCC), significantly improving survival rates. Despite advancements, specific lipid markers for RCC remain unidentified. We aimed to discover and validate potent plasma markers and their association with dietary fats. Using lipid metabolite quantification, machine-learning algorithms, and marker validation, we identified RCC diagnostic markers in studies involving 60 RCC and 167 healthy controls (HC), as well as 27 RCC and 74 HC, by analyzing their correlation with dietary fats. RCC was associated with altered metabolism in amino acids, glycerophospholipids, and glutathione. We validated seven markers (l-tryptophan, various lysophosphatidylcholines [LysoPCs], decanoylcarnitine, and l-glutamic acid), achieving a 96.9% AUC, effectively distinguishing RCC from HC. Decreased decanoylcarnitine, due to reduced carnitine palmitoyltransferase 1 (CPT1) activity, was identified as affecting RCC risk. High intake of polyunsaturated fatty acids (PUFAs) was negatively correlated with LysoPC (18:1) and LysoPC (18:2), influencing RCC risk. We validated seven potential markers for RCC diagnosis, highlighting the influence of high PUFA intake on LysoPC levels and its impact on RCC occurrence via CPT1 downregulation. These insights support the efficient and accurate diagnosis of RCC, thereby facilitating risk mitigation and improving patient outcomes.
Topics: Humans; Carcinoma, Renal Cell; Kidney Neoplasms; Case-Control Studies; Male; Female; Middle Aged; Biomarkers, Tumor; Aged; Fatty Acids, Unsaturated; Carnitine O-Palmitoyltransferase; Adult; Lysophosphatidylcholines; Carnitine; Machine Learning; Lipid Metabolism; Tryptophan
PubMed: 38732512
DOI: 10.3390/nu16091265 -
International Journal of Molecular... Apr 2024The human brain possesses three predominate phospholipids, phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylserine (PS), which account for... (Review)
Review
The human brain possesses three predominate phospholipids, phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylserine (PS), which account for approximately 35-40%, 35-40%, and 20% of the brain's phospholipids, respectively. Mitochondrial membranes are relatively diverse, containing the aforementioned PC, PE, and PS, as well as phosphatidylinositol (PI) and phosphatidic acid (PA); however, cardiolipin (CL) and phosphatidylglycerol (PG) are exclusively present in mitochondrial membranes. These phospholipid interactions play an essential role in mitochondrial fusion and fission dynamics, leading to the maintenance of mitochondrial structural and signaling pathways. The essential nature of these phospholipids is demonstrated through the inability of mitochondria to tolerate alteration in these specific phospholipids, with changes leading to mitochondrial damage resulting in neural degeneration. This review will emphasize how the structure of phospholipids relates to their physiologic function, how their metabolism facilitates signaling, and the role of organ- and mitochondria-specific phospholipid compositions. Finally, we will discuss the effects of global ischemia and reperfusion on organ- and mitochondria-specific phospholipids alongside the novel therapeutics that may protect against injury.
Topics: Humans; Phospholipids; Mitochondria; Animals; Brain; Heart Arrest; Signal Transduction; Mitochondrial Membranes; Mitochondrial Dynamics
PubMed: 38731864
DOI: 10.3390/ijms25094645 -
Journal of Colloid and Interface Science Sep 2024Infectious diseases, particularly those associated with biofilms, are challenging to treat due to an increased tolerance to commonly used antibiotics. This underscores...
Infectious diseases, particularly those associated with biofilms, are challenging to treat due to an increased tolerance to commonly used antibiotics. This underscores the urgent need for innovative antimicrobial strategies. Here, we present an alternative simple-by-design approach focusing on the development of biocompatible and antibiotic-free nanocarriers from docosahexaenoic acid (DHA) that has the potential to combat microbial infections and phosphatidylglycerol (DOPG), which is attractive for use as a biocompatible prominent amphiphilic component of Gram-positive bacterial cell membranes. We assessed the anti-bacterial and anti-biofilm activities of these nanoformulations (hexosomes and vesicles) against S. aureus and S. epidermidis, which are the most common causes of infections on catheters and medical devices by different methods (including resazurin assay, time-kill assay, and confocal laser scanning microscopy on an in vitro catheter biofilm model). In a DHA-concentration-dependent manner, these nano-self-assemblies demonstrated strong anti-bacterial and anti-biofilm activities, particularly against S. aureus. A five-fold reduction of the planktonic and a four-fold reduction of biofilm populations of S. aureus were observed after treatment with hexosomes. The nanoparticles had a bacteriostatic effect against S. epidermidis planktonic cells but no anti-biofilm activity was detected. We discuss the findings in terms of nanoparticle-bacterial cell interactions, plausible alterations in the phospholipid membrane composition, and potential penetration of DHA into these membranes, leading to changes in their structural and biophysical properties. The implications for the future development of biocompatible nanocarriers for the delivery of DHA alone or in combination with other anti-bacterial agents are discussed, as novel treatment strategies of Gram-positive infections, including biofilm-associated infections.
Topics: Biofilms; Anti-Bacterial Agents; Phosphatidylglycerols; Staphylococcus aureus; Nanoparticles; Docosahexaenoic Acids; Staphylococcus epidermidis; Microbial Sensitivity Tests; Liquid Crystals; Particle Size
PubMed: 38729002
DOI: 10.1016/j.jcis.2024.04.186 -
Cells Apr 2024Impaired neuronal plasticity and cognitive decline are cardinal features of Alzheimer's disease and related Tauopathies. Aberrantly modified Tau protein and...
Impaired neuronal plasticity and cognitive decline are cardinal features of Alzheimer's disease and related Tauopathies. Aberrantly modified Tau protein and neurotransmitter imbalance, predominantly involving acetylcholine, have been linked to these symptoms. In Drosophila, we have shown that dTau loss specifically enhances associative long-term olfactory memory, impairs foot shock habituation, and deregulates proteins involved in the regulation of neurotransmitter levels, particularly acetylcholine. Interestingly, upon choline treatment, the habituation and memory performance of mutants are restored to that of control flies. Based on these surprising results, we decided to use our well-established genetic model to understand how habituation deficits and memory performance correlate with different aspects of choline physiology as an essential component of the neurotransmitter acetylcholine, the lipid phosphatidylcholine, and the osmoregulator betaine. The results revealed that the two observed phenotypes are reversed by different choline metabolites, implying that they are governed by different underlying mechanisms. This work can contribute to a broader knowledge about the physiologic function of Tau, which may be translated into understanding the mechanisms of Tauopathies.
Topics: Animals; Acetylcholine; Choline; Drosophila; Drosophila melanogaster; Drosophila Proteins; Habituation, Psychophysiologic; Memory; tau Proteins; Phosphatidylcholines
PubMed: 38727282
DOI: 10.3390/cells13090746 -
Cells Apr 2024The histone deacetylase inhibitor (HDACi) valproic acid (VPA) has neuroprotective and anti-inflammatory effects in experimental traumatic brain injury (TBI), which have...
The histone deacetylase inhibitor (HDACi) valproic acid (VPA) has neuroprotective and anti-inflammatory effects in experimental traumatic brain injury (TBI), which have been partially attributed to the epigenetic disinhibition of the transcription repressor RE1-Silencing Transcription Factor/Neuron-Restrictive Silencer Factor (REST/NRSF). Additionally, VPA changes post-traumatic brain injury (TBI) brain metabolism to create a neuroprotective environment. To address the interconnection of neuroprotection, metabolism, inflammation and REST/NRSF after TBI, we subjected C57BL/6N mice to experimental TBI and intraperitoneal VPA administration or vehicle solution at 15 min, 1, 2, and 3 days post-injury (dpi). At 7 dpi, TBI-induced an up-regulation of REST/NRSF gene expression and HDACi function of VPA on histone H3 acetylation were confirmed. Neurological deficits, brain lesion size, blood-brain barrier permeability, or astrogliosis were not affected, and REST/NRSF target genes were only marginally influenced by VPA. However, VPA attenuated structural damage in the hippocampus, microgliosis and expression of the pro-inflammatory marker genes. Analyses of plasma lipidomic and polar metabolomic patterns revealed that VPA treatment increased lysophosphatidylcholines (LPCs), which were inversely associated with interleukin 1 beta () and tumor necrosis factor () gene expression in the brain. The results show that VPA has mild neuroprotective and anti-inflammatory effects likely originating from favorable systemic metabolic changes resulting in increased plasma LPCs that are known to be actively taken up by the brain and function as carriers for neuroprotective polyunsaturated fatty acids.
Topics: Animals; Brain Injuries, Traumatic; Valproic Acid; Mice; Mice, Inbred C57BL; Male; Neurons; Inflammation; Lysophosphatidylcholines; Cell Death; Disease Models, Animal; Histone Deacetylase Inhibitors; Neuroprotective Agents; Repressor Proteins
PubMed: 38727269
DOI: 10.3390/cells13090734 -
Virulence Dec 2024() is the causative agent of Q fever, a zoonotic disease. Intracellular replication of requires the maturation of a phagolysosome-like compartment known as the...
() is the causative agent of Q fever, a zoonotic disease. Intracellular replication of requires the maturation of a phagolysosome-like compartment known as the replication permissive -containing vacuole (CCV). Effector proteins secreted by the Dot/Icm secretion system are indispensable for maturation of a single large CCV by facilitating the fusion of promiscuous vesicles. However, the mechanisms of CCV maintenance and evasion of host cell clearance remain to be defined. Here, we show that secreted vacuolar protein E (CvpE) contributes to CCV biogenesis by inducing lysosome-like vacuole (LLV) enlargement. LLV fission by tubulation and autolysosome degradation is impaired in CvpE-expressing cells. Subsequently, we found that CvpE suppresses lysosomal Ca channel transient receptor potential channel mucolipin 1 (TRPML1) activity in an indirect manner, in which CvpE binds phosphatidylinositol 3-phosphate [PI(3)P] and perturbs PIKfyve activity in lysosomes. Finally, the agonist of TRPML1, ML-SA5, inhibits CCV biogenesis and replication. These results provide insight into the mechanisms of CCV maintenance by CvpE and suggest that the agonist of TRPML1 can be a novel potential treatment that does not rely on antibiotics for Q fever by enhancing Coxiella-containing vacuoles (CCVs) fission.
Topics: Animals; Humans; Bacterial Proteins; Coxiella burnetii; HeLa Cells; Host-Pathogen Interactions; Lysosomes; Phosphatidylinositol 3-Kinases; Phosphatidylinositol Phosphates; Q Fever; Transient Receptor Potential Channels; Vacuoles
PubMed: 38725096
DOI: 10.1080/21505594.2024.2350893