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Biophysical Reviews Dec 2023Lipid-protein interactions are normally classified as either specific or general. Specific interactions refer to lipid binding to specific binding sites within a... (Review)
Review
Lipid-protein interactions are normally classified as either specific or general. Specific interactions refer to lipid binding to specific binding sites within a membrane protein, thereby modulating the protein's thermal stability or kinetics. General interactions refer to indirect effects whereby lipids affect membrane proteins by modulating the membrane's physical properties, e.g., its fluidity, thickness, or dipole potential. It is not widely recognized that there is a third distinct type of lipid-protein interaction. Intrinsically disordered N- or C-termini of membrane proteins can interact directly but nonspecifically with the surrounding membrane. Many peripheral membrane proteins are held to the cytoplasmic surface of the plasma membrane via a cooperative combination of two forces: hydrophobic anchoring and electrostatic attraction. An acyl chain, e.g., myristoyl, added post-translationally to one of the protein's termini inserts itself into the lipid matrix and helps hold peripheral membrane proteins onto the membrane. Electrostatic attraction occurs between positively charged basic amino acid residues (lysine and arginine) on one of the protein's terminal tails and negatively charged phospholipid head groups, such as phosphatidylserine. Phosphorylation of either serine or tyrosine residues on the terminal tails via regulatory protein kinases allows for an electrostatic switch mechanism to control trafficking of the protein. Kinase action reduces the positive charge on the protein's tail, weakening the electrostatic attraction and releasing the protein from the membrane. A similar mechanism regulates many integral membrane proteins, but here only electrostatic interactions are involved, and the electrostatic switch modulates protein activity by altering the stabilities of different protein conformational states.
PubMed: 38192346
DOI: 10.1007/s12551-023-01166-2 -
Proceedings of the National Academy of... Jul 2023Of the six elements incorporated into the major polymers of life, phosphorus is the least abundant on a global scale [E. Anders, M. Ebihara, 46, 2363-2380 (1982)] and...
Of the six elements incorporated into the major polymers of life, phosphorus is the least abundant on a global scale [E. Anders, M. Ebihara, 46, 2363-2380 (1982)] and has been described as the "ultimate limiting nutrient" [T. Tyrrell, 400, 525-531 (1999)]. In the modern ocean, the supply of dissolved phosphorus is predominantly sustained by the oxidative remineralization/recycling of organic phosphorus in seawater. However, in the Archean Eon (4 to 2.5 Ga), surface waters were anoxic and reducing. Here, we conducted photochemical experiments to test whether photodegradation of ubiquitous dissolved organic phosphorus could facilitate phosphorus recycling under the simulated Archean conditions. Our results strongly suggest that organic phosphorus compounds, which were produced by marine biota (e.g., adenosine monophosphate and phosphatidylserine) or delivered by meteorites (e.g., methyl phosphonate) can undergo rapid photodegradation and release inorganic phosphate into solution under anoxic conditions. Our experimental results and theoretical calculations indicate that photodegradation of organic phosphorus could have been a significant source of bioavailable phosphorus in the early ocean and would have fueled primary production during the Archean eon.
PubMed: 37459508
DOI: 10.1073/pnas.2307524120 -
Frontiers in Medical Technology 2023Cochleates are cylindrical particles composed of dehydrated phospholipid bilayers. They are typically prepared by addition of calcium ions to vesicles composed of...
INTRODUCTION
Cochleates are cylindrical particles composed of dehydrated phospholipid bilayers. They are typically prepared by addition of calcium ions to vesicles composed of negatively charged phospholipids such as phosphatidylserines (PS). Due to their high physical and chemical stability, they provide an interesting alternative over other lipid-based drug formulations for example to improve oral bioavailability or to obtain a parenteral sustained-release formulation.
METHODS
In the present study, the feasibility to prepare cochleate suspensions from soy lecithin-derived phosphatidylserines (SPS) was investigated and compared to the "gold standard" dioleoyl-phosphatidylserine (DOPS) cochleates. The SPS lipids covered a large range of purities between 53 and >96% and computer-controlled mixing was evaluated for the preparation of the cochleate suspensions. Electron microscopic investigations were combined with small-angle x-ray diffraction (SAXD) and Laurdan generalized polarization (GP) analysis to characterize particle structure and lipid organization.
RESULTS
Despite some differences in particle morphology, cochleate suspensions with similar internal lipid structure as DOPS cochleates could be prepared from SPS with high headgroup purity (≥96%). Suspensions prepared from SPS with lower purity still revealed a remarkably high degree of lipid dehydration and well-organized lamellar structure. However, the particle shape was less defined, and the typical cochleate cylinders could only be detected in suspensions prepared with higher amount of calcium ions. Finally, the study proves the feasibility to prepare suspensions of cochleates or cochleate-like particles directly from a calcium salt of soy-PS by dialysis.
PubMed: 37745179
DOI: 10.3389/fmedt.2023.1241368 -
Lipids in Health and Disease May 2024Cancer prognosis remains a critical clinical challenge. Lipidomic analysis via mass spectrometry (MS) offers the potential for objective prognostic prediction,... (Review)
Review
Cancer prognosis remains a critical clinical challenge. Lipidomic analysis via mass spectrometry (MS) offers the potential for objective prognostic prediction, leveraging the distinct lipid profiles of cancer patient-derived specimens. This review aims to systematically summarize the application of MS-based lipidomic analysis in prognostic prediction for cancer patients. Our systematic review summarized 38 studies from the past decade that attempted prognostic prediction of cancer patients through lipidomics. Commonly analyzed cancers included colorectal, prostate, and breast cancers. Liquid (serum and urine) and tissue samples were equally used, with liquid chromatography-tandem MS being the most common analytical platform. The most frequently evaluated prognostic outcomes were overall survival, stage, and recurrence. Thirty-eight lipid markers (including phosphatidylcholine, ceramide, triglyceride, lysophosphatidylcholine, sphingomyelin, phosphatidylethanolamine, diacylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylethanolamine, lysophosphatidic acid, dihydroceramide, prostaglandin, sphingosine-1-phosphate, phosphatidylinosito, fatty acid, glucosylceramide and lactosylceramide) were identified as prognostic factors, demonstrating potential for clinical application. In conclusion, the potential for developing lipidomics in cancer prognostic prediction was demonstrated. However, the field is still nascent, necessitating future studies for validating and establishing lipid markers as reliable prognostic tools in clinical practice.
Topics: Humans; Prognosis; Neoplasms; Lipidomics; Biomarkers, Tumor; Mass Spectrometry; Female; Lipids; Male; Breast Neoplasms; Prostatic Neoplasms; Lysophospholipids; Colorectal Neoplasms
PubMed: 38796445
DOI: 10.1186/s12944-024-02121-0 -
The EMBO Journal May 2024Phosphatidylinositol (PI) is the precursor lipid for the minor phosphoinositides (PPIns), which are critical for multiple functions in all eukaryotic cells. It is poorly...
Phosphatidylinositol (PI) is the precursor lipid for the minor phosphoinositides (PPIns), which are critical for multiple functions in all eukaryotic cells. It is poorly understood how phosphatidylinositol, which is synthesized in the ER, reaches those membranes where PPIns are formed. Here, we used VT01454, a recently identified inhibitor of class I PI transfer proteins (PITPs), to unravel their roles in lipid metabolism, and solved the structure of inhibitor-bound PITPNA to gain insight into the mode of inhibition. We found that class I PITPs not only distribute PI for PPIns production in various organelles such as the plasma membrane (PM) and late endosomes/lysosomes, but that their inhibition also significantly reduced the levels of phosphatidylserine, di- and triacylglycerols, and other lipids, and caused prominent increases in phosphatidic acid. While VT01454 did not inhibit Golgi PI4P formation nor reduce resting PM PI(4,5)P levels, the recovery of the PM pool of PI(4,5)P after receptor-mediated hydrolysis required both class I and class II PITPs. Overall, these studies show that class I PITPs differentially regulate phosphoinositide pools and affect the overall cellular lipid landscape.
Topics: Humans; Phosphatidylinositols; Phospholipid Transfer Proteins; Lipid Metabolism; Cell Membrane; HeLa Cells; Organelles; Endosomes; Animals
PubMed: 38627600
DOI: 10.1038/s44318-024-00096-3 -
Cell Communication and Signaling : CCS Jan 2024Retinal ganglion cell (RGC) degeneration and death cause vision loss in patients with glaucoma. Regulated cell death, once initiated, is generally considered to be an...
BACKGROUND
Retinal ganglion cell (RGC) degeneration and death cause vision loss in patients with glaucoma. Regulated cell death, once initiated, is generally considered to be an irreversible process. Recently, we showed that, by timely removing the cell death stimulus, stressed neuronal PC12 cells can recover from phosphatidylserine (PS) exposure, nuclear shrinkage, DNA damage, mitochondrial fragmentation, mitochondrial membrane potential loss, and retraction of neurites, all hallmarks of an activated cell death program. Whether the cell death process can be reversed in neurons of the central nervous system, like RGCs, is still unknown. Here, we studied reversibility of the activated cell death program in primary rat RGCs (prRGCs).
METHODS
prRGCs were exposed to ethanol (5%, vol/vol) to induce cell death. At different stages of the cell death process, ethanol was removed by washing and injured prRGCs were further cultured in fresh medium to see whether they recovered. The dynamics of single cells were monitored by high-resolution live-cell spinning disk microscopy. PS exposure, mitochondrial structure, membrane potential, and intracellular Ca were revealed by annexin A5-FITC, Mito-tracker, TMRM, and Fluo 8-AM staining, respectively. The distribution of cytochrome c was investigated by immunofluorescence. The ultrastructure of mitochondria was studied by electron microscopy.
RESULTS
Analysis of temporal relationships between mitochondrial changes and PS exposure showed that fragmentation of the mitochondrial network and loss of mitochondrial membrane potential occurred before PS exposure. Mitochondrial changes proceeded caspase-independently, while PS exposure was caspase dependent. Interestingly, prRGCs recovered quickly from these mitochondrial changes but not from PS exposure at the plasma membrane. Correlative light and electron microscopy showed that stress-induced decrease in mitochondrial area, length and cristae number was reversible. Intracellular Ca was elevated during this stage of reversible mitochondrial injury, but there was no sign of mitochondrial cytochrome c release.
CONCLUSIONS
Our study demonstrates that RGCs with impaired mitochondrial structure and function can fully recover if there is no mitochondrial cytochrome c release yet, and no PS is exposed at the plasma membrane. This finding indicates that there is a time window for rescuing dying or injured RGCs, by simply removing the cell death stimulus. Video Abstract.
Topics: Animals; Rats; Apoptosis; Caspases; Cytochromes c; Ethanol; Retinal Ganglion Cells
PubMed: 38297331
DOI: 10.1186/s12964-023-01427-3 -
Cell Communication and Signaling : CCS Dec 2023This study aimed to identify an orcl1 mutation in a patient with Dent-2 Disease and investigate the underlying mechanisms.
BACKGROUND
This study aimed to identify an orcl1 mutation in a patient with Dent-2 Disease and investigate the underlying mechanisms.
METHODS
The ocrl1 mutation was identified through exome sequencing. Knockdown of orcl1 and overexpression of the orcl1 mutant were performed in HK-2 and MPC5 cells to study its function, while flow cytometry measured reactive oxygen species (ROS), phosphatidylserine levels, and cell apoptosis. Scanning electron microscopy observed crystal adhesion, while transmission electron microscopy examined kidney tissue pathology. Laser scanning confocal microscopy was used to examine endocytosis, and immunohistochemical and immunofluorescence assays detected protein expression. Additionally, podocyte-specific orcl1 knockout mice were generated to investigate the role of orcl1 in vivo.
RESULTS
We identified a mutation resulting in the replacement of Histidine with Arginine at position 318 (R318H) in ocrl1 in the proband. orcl1 was widely expressed in the kidney. In vitro experiments showed that knockdown of orcl1 and overexpression of ocrl1 mutant increased ROS, phosphatidylserine exocytosis, crystal adhesion, and cell apoptosis in HK-2 cells. Knockdown of orcl1 in podocytes reduced endocytosis and disrupted the cell cycle while increasing cell migration. In vivo studies in mice showed that conditional deletion of orcl1 in podocytes caused glomerular dysfunction, including proteinuria and fibrosis.
CONCLUSION
This study identified an R318H mutation in orcl1 in a patient with Dent-2 Disease. This mutation may contribute to renal injury by promoting ROS production and inducing cell apoptosis in tubular cells, while disrupting endocytosis and the cell cycle, and promoting cell migration of podocytes. Video Abstract.
Topics: Humans; Animals; Mice; Podocytes; Reactive Oxygen Species; Phosphatidylserines; Oculocerebrorenal Syndrome; Endocytosis; Apoptosis; Cell Cycle
PubMed: 38049819
DOI: 10.1186/s12964-023-01272-4 -
Animals : An Open Access Journal From... Oct 2023Adipose tissue composition contributes greatly to the quality and nutritional value of meat. Transcriptomic and lipidomic techniques were used to investigate the...
Integrative Analysis of Transcriptomic and Lipidomic Profiles Reveals a Differential Subcutaneous Adipose Tissue Mechanism among Ningxiang Pig and Berkshires, and Their Offspring.
Adipose tissue composition contributes greatly to the quality and nutritional value of meat. Transcriptomic and lipidomic techniques were used to investigate the molecular mechanisms of the differences in fat deposition in Ningxiang pigs, Berkshires and F offspring. Transcriptomic analysis identified 680, 592, and 380 DEGs in comparisons of Ningxiang pigs vs. Berkshires, Berkshires vs. F offspring, and Ningxiang pigs vs. F offspring. The lipidomic analysis screened 423, 252, and 50 SCLs in comparisons of Ningxiang pigs vs. Berkshires, Berkshires vs. F offspring, and Ningxiang pigs vs. F offspring. Lycine, serine, and the threonine metabolism pathway, fatty acid biosynthesis and metabolism-related pathways were significantly enriched in comparisons of Berkshires vs. Ningxiang pigs and Berkshires vs. F offspring. The DEGs (, ) and the SCLs (phosphatidylserines) may have a great impact on the glycine, serine, and the threonine metabolism pathway. Moreover, the DEGs (, , , , , , , , , and ) and the SCLs (palmitoleic acid, linoleic acid, arachidonic acid, and icosadienoic acid) play important roles in the fatty acid biosynthesis and metabolism of fatty acids. Thus, the difference in fat deposition among Ningxiang pig, Berkshires, and F offspring may be caused by differences in the expression patterns of key genes in multiple enriched KEGG pathways. This research revealed multiple lipids that are potentially available biological indicators and screened key genes that are potential targets for molecular design breeding. The research also explored the molecular mechanisms of the difference in fat deposition among Ningxiang pig, Berkshires, and F pigs, and provided an insight into selection for backfat thickness and the fat composition of adipose tissue for future breeding strategies.
PubMed: 37958077
DOI: 10.3390/ani13213321 -
Metabolites Sep 2023Parkinson's disease (PD) is a highly prevalent neurodegenerative movement disorder with an unclear etiology and a lack of definite diagnostic tests and effective...
Parkinson's disease (PD) is a highly prevalent neurodegenerative movement disorder with an unclear etiology and a lack of definite diagnostic tests and effective treatments. About 95% of PD cases are idiopathic, in which none of the well-known genes underlying familial parkinsonism are mutated. We used untargeted liquid chromatography-mass spectrometry (LC-MS/MS) to profile the serum lipidome of 50 patients with different stages of idiopathic PD (early, mid, or advanced) and 45 age-matched controls. When comparing the PD patients to the control subjects, 169 lipids were significantly altered in both a univariate analysis and a multivariate partial least-squares discriminant analysis (PLS-DA). Compared to the controls, the patients with PD had higher levels of unsaturated triacylglycerides (e.g., TG O-56:9 and TG 52:3), saturated lysophosphatidylcholines (LPC 17:0, 16:0, and 15:0), and hydroxyeicosatetraenoic acid (12-HETE), while lower levels of phosphatidylserines (e.g., PS 40:4 and PS 16:0_22:4), sphingomyelins (SM 42:1), and ceramides (e.g., Cer 40:0 and 42:0) were found between the PD patients and the controls. A panel of 10 significantly altered lipids (PS 40:0, Cer 40:0, Cer 42:0, LPC 17:0, LPC 15:0, PC 37:7, PE O-40:8, PC O-42:4, FA 23:0, and SM 42:1) resulted in a strong receiver operating characteristic curve with an AUC = 0.974. This panel may, therefore, be useful for diagnosing PD. In addition, lipid panels may prove useful for distinguishing among the progression stages of PD. Using one-way ANOVA, 155 lipid species were significantly altered among the PD stages. Parkinson's disease progressed from the early to advanced stages with decreasing levels of PC 31:1, PC 38:4, and LPE 22:5. Conversely, LPC-O 20:0, PC O-42:3, FA 19:0, and FA 22:2 showed an increase in their levels with disease progression. Overall, this study shows an intriguing number of robust changes in specific serum lipids that may become useful for diagnosing PD and its progression, once panels have been validated in larger clinical trials and prospective studies.
PubMed: 37755270
DOI: 10.3390/metabo13090990 -
Journal of Translational Medicine Aug 2023Bladder cancer is a urological carcinoma with high incidence, among which muscle invasive bladder cancer (MIBC) is a malignant carcinoma with high mortality. There is an...
BACKGROUND
Bladder cancer is a urological carcinoma with high incidence, among which muscle invasive bladder cancer (MIBC) is a malignant carcinoma with high mortality. There is an urgent need to develop new drugs with low toxicity and high efficiency for MIBC because existing medication has defects, such as high toxicity, poor efficacy, and side effects. Jorunnamycin A (JorA), a natural marine compound, has been found to have a high efficiency anticancer effect, but its anticancer function and mechanism on bladder cancer have not been studied.
METHODS
To examine the anticancer effect of JorA on MIBC, Cell Counting Kit 8, EdU staining, and colony formation analyses were performed. Moreover, a xenograft mouse model was used to verify the anticancer effect in vivo. To investigate the pharmacological mechanism of JorA, high-throughput quantitative proteomics, transcriptomics, RT-qPCR, western blotting, immunofluorescence staining, flow cytometry, pulldown assays, and molecular docking were performed.
RESULTS
JorA inhibited the proliferation of MIBC cells, and the IC of T24 and UM-UC-3 was 0.054 and 0.084 μM, respectively. JorA-induced significantly changed proteins were enriched in "cancer-related pathways" and "EGFR-related signaling pathways", which mainly manifested by inhibiting cell proliferation and promoting cell apoptosis. Specifically, JorA dampened the DNA synthesis rate, induced phosphatidylserine eversion, and inhibited cell migration. Furthermore, it was discovered that fatty acid synthase (FASN) and topoisomerase 1 (TOP1) are the JorA interaction proteins. Using DockThor software, the 3D docking structures of JorA binding to FASN and TOP1 were obtained (the binding affinities were - 8.153 and - 7.264 kcal/mol, respectively).
CONCLUSIONS
The marine compound JorA was discovered to have a specific inhibitory effect on MIBC, and its potential pharmacological mechanism was revealed for the first time. This discovery makes an important contribution to the development of new high efficiency and low toxicity drugs for bladder cancer therapy.
Topics: Humans; Animals; Mice; Molecular Docking Simulation; Multiomics; Fatty Acid Synthases; Urinary Bladder Neoplasms; Drug-Related Side Effects and Adverse Reactions; Carcinoma; Muscles; DNA Topoisomerases, Type I; Fatty Acid Synthase, Type I
PubMed: 37587470
DOI: 10.1186/s12967-023-04400-3