Biochimica Et Biophysica Acta[JOURNAL]
Sun
200 papers
Cepharanthine-mediated PD-L1 autophagic degradation via regulation of TSPO and RILP boosts anti-lung cancer chemo-immunotherapy efficacy.
Gao YJ, Chen SY, Li LG … +8 more , Bai XF, Han N, You H, Kong C, Hu J, Wang MF, Li TF, Ren T
Biochim Biophys Acta Mol Basis Dis · 2026 Aug · PMID 42191265 · Publisher ↗
Non-small cell lung cancer (NSCLC) accounts for the second highest incidence and highest mortality rates globally, wherein immune checkpoint molecules such as PD-L1, highly-expressed in malignant cells bind to PD-1 locat...
Non-small cell lung cancer (NSCLC) accounts for the second highest incidence and highest mortality rates globally, wherein immune checkpoint molecules such as PD-L1, highly-expressed in malignant cells bind to PD-1 located in immunocytes, leading to immune escape. We hereby investigate the role of phytomedicine Cepharanthine (CEP) in the regulation of PD-L1 in NSCLC and elucidate the involved mechanism. CEP showed robust cytotoxicity against lung cancer cells, as demonstrated by reduced cell viability and elevated apoptosis. Furthermore, the tumor grafts in mice were significantly suppressed by CEP. Importantly, CEP down-regulated PD-L1 at the mRNA, protein, and membrane levels, thereby arousing the immune microenvironment of lung adenocarcinoma. Further exploration presented that CEP induced autophagy, which specifically accelerated the fusion of lysosomes with autophagosomes, ultimately leading to the degradation of PD-L1 in lung cancer cells. Mechanistically, TSPO and RILP were critical molecules through which CEP accelerated autophagic flux, as validated by drug target techniques and genetic perturbation. Finally, the findings supported the clinical translational potential of CEP plus anti-PD-L1 as a novel chemo-immunotherapy regimen. Taken together, CEP accelerates autophagy through direct inhibition of TSPO and activation of RILP, leading to PD-L1 autophagic degradation, which arouses immune microenvironment of lung adenocarcinoma. The immune regulation effects mediated by CEP prove to be a novel combination chemo-immunotherapy strategy for lung cancer treatment.
Expression of concern for "Carcinogen-induced early molecular events and its implication in the initiation of chemical hepatocarcinogenesis in rats: Chemopreventive role of vanadium on this process' by Malay Chatterjee" [Biochim. Biophys. Acta (BBA) Mol. Basis Dis. 1772 (1) (January 2007) 48-59 https://doi.org/10.1016/j.bbadis.2006.10.019].
Biochim Biophys Acta Mol Basis Dis · 2026 Aug · PMID 42191264 · Publisher ↗
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HN1/CEBPB/CCL2 signaling shapes VSIG4 tumor-associated macrophages in anaplastic thyroid carcinoma.
Fang Z, Li Y, Hu X … +9 more , Chen J, Xuan Z, Wang S, Zhao R, Zhang R, Wang Y, Huang P, Wang J, Pan Z
Biochim Biophys Acta Mol Basis Dis · 2026 May · PMID 42191099 · Publisher ↗
V-set and immunoglobulin domain-containing protein 4 (VSIG4) positive tumor-associated macrophage (VSIG4 TAM) is an immunosuppressive subpopulation specifically infiltrates anaplastic thyroid carcinoma (ATC) tissues and...
V-set and immunoglobulin domain-containing protein 4 (VSIG4) positive tumor-associated macrophage (VSIG4 TAM) is an immunosuppressive subpopulation specifically infiltrates anaplastic thyroid carcinoma (ATC) tissues and drives tumor growth. However, the mechanisms by which ATC cells shape the VSIG4 TAM immunophenotype remain unclear. We screen for the cytokine essential for inducing VSIG4 TAMs using cytokine array screening and coculture validation. This reveals that CC motif chemokine ligand 2 (CCL2) is highly expressed in ATC cells and promotes VSIG4 macrophage differentiation. Both CCL2-neutralizing antibody and CCL2 knockdown significantly inhibits macrophage migration and the proportion of VSIG4 macrophages induced by ATC cells. Notably, the combination of CCL2 and VSIG4 blockade synergistically alleviates the growth of subcutaneously transplanted tumors in mice and reshaped the immunosuppressive microenvironment of ATC tumors. Further study showed that the expression of CCL2 is regulated by hematological and neurological expressed 1 (HN1) in ATC cells, and HN1-CCL2 signaling induces VSIG4 macrophage differentiation via activation of the CCR2/PI3K/AKT pathway. HN1 forms complex with transcription factor CCAAT/enhancer binding protein beta (CEBPB) to prevent CEBPB from ubiquitination and degradation, thereby promoting CCL2 transcription. In summary, our findings demonstrate HN1/CCL2/VSIG4 axis is essential for fostering immunosuppressive microenvironment in ATC, shedding light on potential targets concerning cancer cell-TAMs crosstalk.
EA1-linked Kv1.1 dysfunction enhances susceptibility to cerebellar spreading depression and a transient cerebellar refractory state.
Servettini I, Megaro A, Caramia M … +3 more , Sforna L, Michelucci A, Catacuzzeno L
Biochim Biophys Acta Mol Basis Dis · 2026 May · PMID 42191098 · Publisher ↗
Episodic ataxia type 1 (EA1) is a neurological channelopathy caused by loss-of-function mutations in the KCNA1 gene, which encodes the Kv1.1 α-subunit of voltage-gated potassium channels. Clinically, EA1 is characterized...
Episodic ataxia type 1 (EA1) is a neurological channelopathy caused by loss-of-function mutations in the KCNA1 gene, which encodes the Kv1.1 α-subunit of voltage-gated potassium channels. Clinically, EA1 is characterized by interictal myokymia and transient episodes of generalized ataxia. While the molecular basis of the disease is well established, the mechanisms underlying the paroxysmal nature of attacks remains unclear. Drawing parallels with migraine with aura, an episodic disorder in which cortical spreading depression (CSD), a propagating wave of neuronal and glial depolarization followed by prolonged suppression of excitability, triggers symptoms, we hypothesized that EA1 may similarly involve an increased susceptibility to cerebellar spreading depression (CeSD), driven by reduced Kv1.1 channel activity and heightened cerebellar excitability. In mouse cerebellar slices exposed to elevated extracellular K, CeSD displayed several properties distinct from CSD, including sensitivity to AMPA and GABA receptor antagonists, insensitivity to NMDA receptor blockade, and a markedly slower propagation rate. Notably, cerebellar slices from knock-in (KI) mice carrying the EA1-associated Kv1.1 loss-of-function mutation V408A showed significantly accelerated CeSD propagation and greater spatial spread within the molecular layer compared with wild-type counterparts. Furthermore, cerebellar slices from KI mice exhibited increased susceptibility to CeSD when challenged with elevated extracellular K. Extracellular and patch-clamp recordings further demonstrated that CeSD induced a transient suppression of cerebellar excitatory transmission at parallel fiber-Purkinje cell synapses, with a duration resembling the temporal profile of EA1 attacks. Collectively, these findings support a central role for CeSD in the pathophysiology of EA1.
Spatial gradients of lipase activity govern lipid droplet remodeling in the zebrafish embryo.
Sarkar S, Haldar S, Mandal S … +4 more , Nanda N, Karmakar S, Sen P, Sinha DK
Biochim Biophys Acta Mol Cell Biol Lipids · 2026 Jun · PMID 42190981 · Publisher ↗
Early zebrafish embryos rely on maternally supplied yolk lipids to fuel growth before the onset of feeding; yet, how these lipids are mobilized and redistributed remains poorly understood. Here, we combine live imaging w...
Early zebrafish embryos rely on maternally supplied yolk lipids to fuel growth before the onset of feeding; yet, how these lipids are mobilized and redistributed remains poorly understood. Here, we combine live imaging with the solvatochromic dye Nile Red to map lipid composition in space and time through changes in the emission peak, a readout of local polarity. We show that lipid droplets (LDs) in the blastodisc are highly heterogeneous in size and polarity at the "one-cell stage" but progressively homogenize as development proceeds. LDs originate at the yolk-blastodisc interface, where localized lipase activity drives their biogenesis and initial composition. As LDs migrate toward the animal pole, their polarity increases, reflecting continuous lipolysis within a spatially confined metabolic zone. Smaller LDs display greater lipolytic efficiency than larger ones, linking droplet geometry to metabolic turnover. Inhibition of lipase activity disrupts both LD formation and lipid cycling, demonstrating that shared enzymatic machinery underlies droplet synthesis and degradation. Together, our findings reveal a spatially organized and developmentally regulated lipid metabolism in the zebrafish blastodisc, where local enzyme activity, droplet mechanics, and lipid composition are dynamically coupled. This live-imaging approach establishes a framework for studying lipid regulation in vertebrate development and disease. DIGEST SUMMARY: By visualizing lipids in living zebrafish embryos, this study reveals that lipid droplets are not passive fat stores but dynamic organelles whose size, composition, and behavior are shaped by local enzyme activity at the yolk-blastodisc interface, offering new insight into how developing cells control their energy reserves.
The molecular language: decoding exosomal cargoes in macrophage-gastric cancer dialogue.
Wang J, Sun Y, Su X … +6 more , Xie Y, Ye B, Wang X, Mao L, SongGong, Qian H
Biochim Biophys Acta Rev Cancer · 2026 May · PMID 42184896 · Publisher ↗
Exosomes mediate a two-way signaling between gastric cancer (GC) cells and macrophages in the tumor microenvironment (TME) and have significant effects on tumor progression, immune suppression, and treatment outcomes. Th...
Exosomes mediate a two-way signaling between gastric cancer (GC) cells and macrophages in the tumor microenvironment (TME) and have significant effects on tumor progression, immune suppression, and treatment outcomes. This paper will bring together existing literature on the vesicular cargo of macrophage-derived and GC-derived exosomes, such as non-coding RNAs (ncRNAs), and proteins, and their contribution to the re-polarization of macrophages, as well as the behavior of GC cells. The cargo contained in macrophage-derived exosomes biases signaling pathways associated with macrophage polarization, tumor-promoting phenotype, and helping GC proliferation, invasion, metastasis, and chemoresistance. Conversely, macrophage exosomal messages may complement anti-tumor immunity through the regulation of PD-L1 and augmentation of T cells. The exosomes of GC also remodel the macrophage phenotype in favor of immunosuppression by delivering cargoes, facilitating metabolic reprogramming, and tumor-associated macrophages (TAMs) polarization. This crosstalk is generalized to more widespread tumor stroma interactions, which involve cancer-associated fibroblasts (CAFs) and angiogenesis. The resulting therapeutic implications are engineered exosomes and cargo-modified vesicles to tip the balance towards anti-tumor immunity and overcome chemoresistance, where a high efficiency of loading and precision of targeting remain problematic, and the translation of preclinical research findings to the clinic.
GALNT6 coordinates glycolysis and α-KG-dependent DNA methylation to promote TNBC progression.
Bian Z, Liu Y, Guo S … +4 more , Hu D, Liu D, Fan S, Chen X
Biochim Biophys Acta Mol Basis Dis · 2026 May · PMID 42173327 · Publisher ↗
BACKGROUND: As the most aggressive form of breast cancer, triple-negative breast cancer (TNBC) is associated with poor prognosis and a lack of effective therapeutic options. Glycosylation has been linked to metabolic rep...
BACKGROUND: As the most aggressive form of breast cancer, triple-negative breast cancer (TNBC) is associated with poor prognosis and a lack of effective therapeutic options. Glycosylation has been linked to metabolic reprogramming in various cancers, and therapies targeting glycosylation-mediated metabolic reprogramming have been found to be effective. However, the role of the glycosyltransferase GALNT6 in TNBC metabolic reprogramming has not been examined. METHODS: Our approach involved analyzing clinical data to assess the association between GALNT6 levels and patient outcomes. We employed gene knockdown techniques to silence GALNT6 expression in TNBC models. To investigate the underlying mechanisms, we utilized methods to measure glycolytic activity, metabolite levels, protein stability assays, transcriptional analysis, and assessment of DNA methylation status. RESULTS: Our results revealed that high level of GALNT6 were associated with poor clinical outcomes in TNBC. GALNT6 knockdown inhibited glycolytic and enhanced α-KG accumulation. Mechanistically, GALNT6 stabilizes HIF-1α through O-glycosylation, thereby enhancing the transcriptional levels of glycolytic enzymes. Meanwhile, GALNT6 stabilizes PFKM and PKM2 via O-glycosylation to protect them from proteasomal degradation. In parallel, GALNT6 promotes α-KG depletion by upregulating IDH2 and α-KGDH while suppressing GPT2. This depletion inhibits TET3-mediated DNA demethylation, thereby elevating 5mC levels, which in turn activates genes such as KIF14 to promote TNBC progression. Notably, silencing glycosylation-dependent glycolytic pathways or inhibiting α-KG-dependent processes markedly suppressed TNBC proliferation. CONCLUSION: Our study uncovers GALNT6 as a key regulator of metabolic reprogramming (glycolysis/TCA cycle) and epigenetic remodeling (5mC/TET3) to accelerate TNBC progression, suggesting that targeting the GALNT6-mediated metabolic-epigenetic axis may provide a novel therapeutic strategy for TNBC.
Sixty years of discoveries in glycoprotein biosynthesis and functions.
Brockhausen I, Neelamegham S, Matta K
Biochim Biophys Acta Gen Subj · 2026 Aug · PMID 42172741 · Publisher ↗
Harry Schachter was at the forefront of glycobiology research for more than 60 years. His work led to the discovery of novel enzymes and pathways critical for glycoprotein biosynthesis, exploring glycan functions across...
Harry Schachter was at the forefront of glycobiology research for more than 60 years. His work led to the discovery of novel enzymes and pathways critical for glycoprotein biosynthesis, exploring glycan functions across various model systems and uncovering the biochemical basis of abnormal glycosylation in human disease. A dedicated mentor and role model, Schachter made groundbreaking contributions that shaped the modern glycoscience field. Central to his success were strategic collaborations with chemists who developed the specialized acceptor substrates necessary to validate his findings. These efforts notably catalyzed the creation of companies that now provide essential reference compounds to the global research community. Beyond driving biosynthetic discovery, this library of compounds enabled the synthesis of decoy molecules designed to disrupt biosynthetic processes, including potential membrane-permeable compounds with therapeutic potential. Furthermore, the development of robust glycosyltransferase assays initiated a new era of screening for core enzymes and their biosynthetic pathways. As large-scale data collection and computational modeling tools come online, the fundamental biochemical knowledge is being translated and integrated into cellular biochemical networks. This review details Schachter' s seminal work on N-glycans and mucin-type O-glycans, which established the foundation for contemporary studies of glycan function in both health and disease.
Bigger isn't always better: Comparing system size, hydration, and software for lipid membrane analysis.
Carvalho F, Maximiano P, Simões PN … +1 more , Hashemi M
Biochim Biophys Acta Biomembr · 2026 May · PMID 42167506 · Publisher ↗
The structural and dynamic properties of lipid membranes vary with bilayer size and hydration. While Molecular Dynamics (MD) simulations are a powerful tool for studying cellular membranes, results can be sensitive to th...
The structural and dynamic properties of lipid membranes vary with bilayer size and hydration. While Molecular Dynamics (MD) simulations are a powerful tool for studying cellular membranes, results can be sensitive to the analysis workflow and software. In this study, all-atom MD simulations were conducted on 128, 256, 512, and 1024 POPC lipids at 40, 80, and 160 water molecules per lipid. A two-fold study was performed: (1) to assess the convergence of structural and dynamic properties of POPC bilayers as a function of membrane size and hydration level, including area per lipid (APL), bilayer thickness, order parameter, headgroup orientation, and lateral diffusion, and (2) to compare the performance of four software packages: CPPTRAJ (CPP), GROMACS (GRO), MDAnalysis (MDA), and LiPyphilic (LiP). For the first objective, the average APL, bilayer thickness, order parameter, and headgroup orientation were largely independent of size and hydration, whereas the lateral diffusion coefficient was sensitive to both. Notably, 128-lipid systems were susceptible to artificially inflated lateral diffusion due to finite-size artifacts at higher hydration levels. Increasing system size primarily decreased the statistical variance of APL and thickness. For the second objective, all four packages produced consistent results for APL and thickness, with the main discrepancy being a known artifact of the gmx order tool applied to unsaturated carbons. CPP was the fastest serial tool, whereas parallelization benefited MDA and LiP for some metrics. These findings demonstrate that moderately sized systems (e.g., 256L), combined with CPP, offer an efficient workflow for membrane structural property analysis.
Nanoclusters of small amphiphilic molecules in a raft-mimicking model membrane.
Kashnik AS, Baranov DS, Dzuba SA
Biochim Biophys Acta Biomembr · 2026 May · PMID 42167505 · Publisher ↗
Biological membranes are considered as laterally heterogeneous, containing disordered and ordered regions ranging in size from a few nanometers to micrometers. Pulsed dipolar EPR spectroscopy (PDS) is specifically design...
Biological membranes are considered as laterally heterogeneous, containing disordered and ordered regions ranging in size from a few nanometers to micrometers. Pulsed dipolar EPR spectroscopy (PDS) is specifically designed to determine distances between spin-labeled molecules in the range from 1.5 to typically 8 nm. A non-steroidal anti-inflammatory drug ibuprofen, due to its amphiphilic nature, is integrated into the cell membrane. In this study, we investigated spin-labeled ibuprofen (ibuprofen-SL) in a lipid raft-mimicking bilayer formed by a mixture of dioleoyl-glycero-phosphocholine (DOPC), dipalmitoyl-glycero-phosphocholine (DPPC) and cholesterol (35:35:30 mol%). Two variants of PDS were used: double electron-electron resonance (DEER, also known as PELDOR) and the simple 2-pulse electron spin echo (2p ESE) method. Analysis of PDS data in the time and frequency domains shows that ibuprofen-SL molecules at a threshold concentration of about 1 mol% form 6-membered clusters in the membrane. The clusters apparently have a prismatic structure oriented along the normal to the membrane, with a maximum diagonal of about 4 nm, and are most likely located in cavities formed between nanodomains approximately 30 nm in diameter.
Structure-guided engineering of serratiopeptidase using constant-pH molecular dynamics and site-directed mutagenesis to improve pH-dependent functional resilience.
Dhiman A, Singh R, Chauhan M … +3 more , Himanshu, Kumar A, Purohit R
Biochim Biophys Acta Proteins Proteom · 2026 Jul · PMID 42167470 · Publisher ↗
Serratiopeptidase is a metalloprotease enzyme mainly used for its anti-inflammatory and therapeutic applications. The functional performance of serratiopeptidase is compromised by the reduced enzymatic activity at extrem...
Serratiopeptidase is a metalloprotease enzyme mainly used for its anti-inflammatory and therapeutic applications. The functional performance of serratiopeptidase is compromised by the reduced enzymatic activity at extreme pH levels especially in oral administration. To address the problem, the present research employed the structure-based rational design strategy to assess the possibility of modifying the functional performance of serratiopeptidase by introducing a point mutation, N412D, which might improve the functional performance of the metalloprotease under extreme pH levels. Constant pH molecular dynamics simulations were used as an in-silico tool for the qualitative analysis of the wild type (WT) and the mutated serratiopeptidase under variable pH environments. To perform the functional evaluation, the mutated serratiopeptidase was expressed, refolded, and purified using the Escherichia coli expression host. Retained caseinolytic activity was analyzed at different pH levels ranging from 3.0 to 11.0 to evaluate the functional property of serratiopeptidase. It has been noted that the functional activity of mutated serratiopeptidase is slightly changed with respect to an optimal pH, coupled with high retained caseinolytic activity at variable pH levels. The highest improvement in the retained caseinolytic activity was observed under alkaline pH. A small improvement in the retained caseinolytic activity was also observed under acidic pH levels. This research demonstrated the importance of rational design strategies in the selection of the mutation site which might influence the functional resilience of serratiopeptidase under different pH levels.
Strategy for probing the functionality and stereoselectivity of enzyme active sites: Single sites, multiple sites versus multiple molecular forms, conformations, allozymes and isozymes.
Masson P, Shaihutdinova Z, Pashirova T
Biochim Biophys Acta Proteins Proteom · 2026 Jul · PMID 42162638 · Publisher ↗
The existence of multiple molecular forms of enzymes, genetic polymorphism and functional promiscuity raise the question of the identity of active center(s) responsible for several activities. In the present review, we r...
The existence of multiple molecular forms of enzymes, genetic polymorphism and functional promiscuity raise the question of the identity of active center(s) responsible for several activities. In the present review, we recapitulate the general strategy, implementing the simple and rigorous inhibition kinetic method for probing the existence of single or multiple active sites on enzyme molecules. The model enzyme we chose to illustrate this approach is human butyrylcholinesterase, an enzyme that shows a complex functional (promiscuity), structural (multiple oligomeric forms) and genetic polymorphisms (numerous allelozymes and isoenzymes). This classical active site discrimination method is based on the analysis of enzyme irreversible inhibition profiles of enzymes under first-order conditions by monitoring the progressive enzyme activity decay with two reporter substrates of different specificity. The use of chiral irreversible inhibitors and/or chiral reporter substrates provides additional kinetic information about preferential enantioselectivity or binding complementarity of the target enzyme, allowing selection of the best inhibitors or substrates. Then, additional investigations, using structural methods (X-ray structure analysis, mass spectrometry), in silico simulations and classical biochemical methods (electrophoresis, PCR) provide definitive answers.
A CDR1 aggregation hotspot controls unfolding kinetics and multimolecular aggregation in IGLV2 light chains.
Gulyásová T, Šipošová K, Džupponová V
Biochim Biophys Acta Proteins Proteom · 2026 Jul · PMID 42162637 · Publisher ↗
Immunoglobulin light chains (LCs) exhibit diverse aggregation behaviours that depend sensitively on sequence composition and intermolecular interactions. Understanding how specific residues modulate aggregation kinetics...
Immunoglobulin light chains (LCs) exhibit diverse aggregation behaviours that depend sensitively on sequence composition and intermolecular interactions. Understanding how specific residues modulate aggregation kinetics remains a key challenge in elucidating the molecular basis of light-chain amyloidosis. Here, we investigate sequence-dependent aggregation using recombinant λ LCs derived from the IGLV2 gene family. Comparison of two closely related LCs differing by only 16 amino acids revealed striking differences in aggregation behaviour under thermal stress. Bioinformatic analysis identified an additional aggregation-prone segment in the CDR1 region of the aggregation-prone M10 variant, associated with residues Ser33 and Tyr34. Rational substitution of these residues (S33D/Y34S) markedly reduced aggregation while leaving the thermal transition temperature largely unchanged (∼53 °C). Differential scanning calorimetry revealed that the wild-type M10 LC unfolds with a significantly lower apparent activation energy (∼290 kJ/mol) compared with the non-aggregating H9 (∼605 kJ/mol) and the stabilised double mutant (∼560 kJ/mol), indicating reduced kinetic stability. Aggregation of unfolded species showed much weaker temperature dependence (E ≈ 10-70 kJ/mol) and exhibited strong concentration dependence consistent with a multimolecular association process. Additional experiments suggest that aromatic interactions involving Tyr34 contribute to the stabilisation of intermolecular assemblies. Together, these results establish a quantitative link between local sequence variation in the CDR1 region, kinetic stability of the LC fold, and aggregation propensity, highlighting how targeted mutations can modulate aggregation behaviour in immunoglobulin light chains.
Emerging roles of S100 proteins in podocyte biology and disease: A mini review.
Lam S, Trentin-Sonoda M, Cooper TT … +1 more , Myette RL
Biochim Biophys Acta Proteins Proteom · 2026 Jul · PMID 42162636 · Publisher ↗
The glomerular podocyte is the final barrier preventing urinary protein loss, relying on a resilient ultrastructure exposed to shear stress and hydrostatic forces. While often affected secondarily by systemic disease, po...
The glomerular podocyte is the final barrier preventing urinary protein loss, relying on a resilient ultrastructure exposed to shear stress and hydrostatic forces. While often affected secondarily by systemic disease, podocytes are primary targets in conditions such as nephrotic syndrome. S100 proteins, involved in diverse intra- and extracellular functions, are linked to several diseases, yet their roles in podocytes remain poorly defined. The available podocyte-specific literature remains sparse, but emerging studies suggest that selected S100 proteins may be associated with podocyte injury and disease. Here, we review the limited current knowledge on S100 proteins in podocytes and outline focused future approaches to clarify their mechanistic relevance.
Membrane structural properties in Staphylococcus aureus are tuned by the carotenoid 4,4'-diaponeurosporenoic acid.
Múnera-Jaramillo J, López GD, Suesca E … +5 more , Ibáñez E, Cifuentes A, Carazzone C, Leidy C, Manrique-Moreno M
Biochim Biophys Acta Biomembr · 2026 Jul · PMID 42155832 · Publisher ↗
Staphylococcus aureus (S. aureus) is a clinically relevant pathogen capable of adapting its membrane composition in response to environmental stress. In this adaptive process, bacterial carotenoids play a crucial role. A...
Staphylococcus aureus (S. aureus) is a clinically relevant pathogen capable of adapting its membrane composition in response to environmental stress. In this adaptive process, bacterial carotenoids play a crucial role. Although staphyloxanthin (STX) is the main carotenoid produced by the bacterium, S. aureus also synthesizes other pigmented intermediates that play an unknown role in regulating membrane biophysical properties. In this study, we purified 4,4'-diaponeurosporenoic acid (4,4'-DNPA) from S. aureus carotenoid extracts and evaluated its effect on the thermotropic and biophysical properties of representative membrane models. The highly rigid triterpenoid 4,4'-DNPA is one of the last precursors in the biosynthesis of STX and is found in high concentrations in the stationary phase of S. aureus. Phase transition temperatures were determined using infrared spectroscopy, while interfacial hydration and hydrophobic core dynamics were investigated using fluorescence spectroscopy through Laurdan generalized polarization and DPH anisotropy. The results show that 4,4'-DNPA increases the main phase transition temperature of lipid bilayers in a concentration-dependent manner. This is in contrast to STX that decreases the transition temperature. This difference is consistent with the additional fatty acid present in STX that changes its effect on the phase behavior. Furthermore, 4,4'-DNPA reduced the interfacial hydration levels and restricted hydrophobic-core dynamics at higher concentrations, consistent with increased molecular order and stability. 4,4'-DNPA therefore complements STX in increasing membrane order and lipid packing. These findings support the notion that the production of bacterial carotenoids functions as a biophysical regulatory mechanism of lipid packing in S. aureus membranes.
p300/Ahnak1 promotes the depression of I of atrial myocytes induced by aging.
Peng DW, Li QQ, Liu HY … +12 more , Zhou HS, Lai YY, Gao XY, Yan GF, Zhang XR, Yang H, Zhang MZ, Liu PY, Deng CY, Wu SL, Rao F, Xue YM
Biochim Biophys Acta Mol Basis Dis · 2026 May · PMID 42155816 · Publisher ↗
Atrial electrical remodeling induced by aging, characterized by decreased L-type calcium channel current (I) and shortened action potential duration (APD), contributes to the onset of atrial fibrillation (AF). Our previo...
Atrial electrical remodeling induced by aging, characterized by decreased L-type calcium channel current (I) and shortened action potential duration (APD), contributes to the onset of atrial fibrillation (AF). Our previous study revealed that acetyltransferase p300 contributed to the aging-related atrial fibrosis. However, the role of p300 in aging-related atrial electrical remodeling is still unknown. In the present study, biochemical assays, whole-cell patch-clamp, and in vivo electrophysiological examination were performed on atrial tissues and atrial myocytes isolated from aged mice, and senescent atrium-derived cells (HL-1 cells). The results showed that: 1) Increased protein levels of p300, p53, p21 and p16, decreased Cav1.2/I, and shortened APD were found in the atrial tissues and atrial myocytes from aged mice, as well as senescent HL-1 cells. 2) In aged mice and senescent HL-1 cells, p300 knockdown and p300 inhibitor curcumin reduced the aging degree of atrial tissues, ameliorated the atrial electrical remodeling and decreased the inducibility of AF. 3) The expression of Ahnak1 and the association of Ahnak1 and Cavβ2 were increased in aged mice and senescent HL-1 cells, which could be reversed by p300 inhibition. Moreover, Ahnak1 directly regulated the expression of p21 and p16 in HL-1 cells. 4) Stability and conformational analyses indicated that the direct interaction between Ahnak1 and Cavβ2 is strong and stable. Our findings demonstrate that p300 contributes to atrial electrical remodeling induced by aging through regulation of the Ahnak1/Cavβ2 and Ahnak1/p21/p16 pathway, representing a potential pathogenic mechanism in AF.
MARCHF6 regulates ferroptosis in myocardial ischemia-reperfusion injury via the ADAMTS4/SDC-1 pathway.
Lou Q, Bai R, Liu Y … +3 more , Li B, Zhu H, Liu G
Biochim Biophys Acta Mol Basis Dis · 2026 May · PMID 42155815 · Publisher ↗
Myocardial ischemia-reperfusion injury is a key factor affecting prognosis after acute myocardial infarction. MARCHF6, as an E3 ubiquitin ligase, is closely implicated in the ferroptosis process. The role of MARCHF6 in M...
Myocardial ischemia-reperfusion injury is a key factor affecting prognosis after acute myocardial infarction. MARCHF6, as an E3 ubiquitin ligase, is closely implicated in the ferroptosis process. The role of MARCHF6 in MIRI and its mechanism for regulating myocardial cell ferroptosis remained unclear. A mouse model of MIRI overexpressing MARCHF6 was established by tail vein injection of MARCHF6-overexpressing AAV9 virus, followed by left anterior descending coronary artery ligation surgery in mice. High expression of MARCHF6 significantly improved cardiac function and reduced myocardial injury in MIRI mice. Compared with the MIRI mice, the MARCHF6 overexpression mice exhibited a reduction of approximately 14% in myocardial infarction area. Histological damage in the cardiac ischemic penumbra region was markedly alleviated, and the number of cell deaths was significantly decreased. Concurrently, MARCHF6 overexpression substantially reduced serum levels of myocardial injury markers CK-MB, cTnI, and LDH. Mitochondrial morphological alterations and expression of ferroptosis-related indicators in the ischemic penumbra of the heart indicated that MARCHF6 overexpression alleviated ferroptosis in MIRI hearts. In an OGD/R-induced cardiomyocyte microvascular endothelial cell (CMEC) model, MARCHF6 overexpression alleviated lipid peroxidation and inhibited ferroptosis. MARCHF6 overexpression suppressed the upregulation of ACSL4 and 4-HNE while blocking the downregulation of SLC7A11 and GPX4 in vivo and vitro. Mechanistically, MARCHF6 promoted the ubiquitin-mediated degradation of ADAMTS4, thereby upregulating its downstream target SDC-1. This sequence of events inhibits lipid peroxidation, mitigates mitochondrial damage, and ultimately blocks the ferroptosis process in endothelial cells. These findings unveil a novel regulatory pathway involving MARCHF6/ADAMTS4/SDC-1 against MIRI by inhibiting ferroptosis.
Aromatic interactions surrounding the Asp-X-Glu motif stabilize the active site of HYAL1 and PH20.
Nguyen K, Ho OM, Vu L … +4 more , Nguyen TA, Tran KN, Choi MG, Lee C
Biochim Biophys Acta Proteins Proteom · 2026 Jul · PMID 42155755 · Publisher ↗
Hyaluronidases degrade hyaluronic acid and participate in physiological processes, including tissue remodeling and fertilization. Vertebrate and venom hyaluronidases share a conserved Asp-X-Glu catalytic motif in the β4...
Hyaluronidases degrade hyaluronic acid and participate in physiological processes, including tissue remodeling and fertilization. Vertebrate and venom hyaluronidases share a conserved Asp-X-Glu catalytic motif in the β4 loop (X = Trp or Phe). Here, we investigated HYAL1, a lysosomal enzyme, and compared it with PH20, a sperm surface hyaluronidase, to elucidate how conserved aromatic residues surrounding this motif stabilize the active site, particularly under acidic conditions. In HYAL1, Tyr82 (β3' loop), Trp130 (X residue), and Trp133 form an aromatic cluster adjacent to the active site. Substitutions at these positions reduced activity at pH 4, indicating that this cluster is required to maintain a catalytically competent conformation, with Tyr82 stabilizing the β3'-β4 loops through hydrogen bonding and Trp130 and Trp133 providing aromatic stabilization, with Trp133 playing a dominant role. A Phe-Phe interaction, analogous to that in insect venom hyaluronidases (Y82F/W130F), partially rescued activity and active-site stability compared with single substitutions. In PH20, corresponding substitutions caused greater activity losses at pH 4, indicating increased structural sensitivity to acidic conditions despite its broad pH range. pH-dependent ANS fluorescence revealed more pronounced acid-induced conformational changes at pH 4 than at pH 7 in both enzymes. Molecular dynamics simulations indicated that HYAL1, PH20, and bee venom hyaluronidase retain a rigid catalytic core, with differences arising primarily from loop and domain flexibility. These findings show that aromatic interactions surrounding the Asp-X-Glu motif stabilize the active site, whereas Phe-Phe interactions represent an alternative active-site stabilization strategy in insect venom hyaluronidases.
SFRP2 is involved in hyperoxia-induced bronchopulmonary dysplasia in newborn mice by suppressing Nrf2/HO-1 pathway.
Li J, Feng X, Si R … +4 more , Liu Y, Huo Z, Song H, Zhou C
Biochim Biophys Acta Mol Cell Res · 2026 May · PMID 42155672 · Publisher ↗
Bronchopulmonary dysplasia (BPD), characterized by inflammation, is a severe pulmonary condition of preterm infants. This study aimed to investigate the role of secreted frizzled related protein 2 (SFRP2) in BPD and to e...
Bronchopulmonary dysplasia (BPD), characterized by inflammation, is a severe pulmonary condition of preterm infants. This study aimed to investigate the role of secreted frizzled related protein 2 (SFRP2) in BPD and to elucidated its underlying mechanisms, focusing on inflammation, apoptosis, and the Nrf2/HO-1 signaling pathway. In vivo neonatal mouse models and in vitro murine lung epithelial-12 (MLE-12) models were established by hyperoxia induction. Administration of recombinant SFRP2 (rSFRP2) aggravated hyperoxia-induced lung injury, reduced alveolation, and increased inflammatory cytokines (TNF-α, IL-1β, and IL-6) in both lung tissues and cells (all P < 0.05). This demonstrated that SFRP2 aggravated hyperoxia-induced inflammation. These results were also evidenced by elevated numbers of inflammatory cells in the BALF and increasing counts of MAC-3 positive cells in the lung tissues of rSFRP2-treated BPD mice (all P < 0.05). rSFRP2 treatment promoted hyperoxia-induced apoptosis of lung tissue in mice and MLE-12 cells, reflected in increased count of TUNEL-positive cells. The Nrf2/HO-1 pathway was inhibited in the lung tissues of mice and MLE-12 cells after hyperoxia induction, and rSFRP2 therapy further suppressed its activity. Rescue experiments demonstrated that the activation of Nrf2 expression mitigated rSFRP2-induced inflammation and apoptosis in MLE-12 cells. Mechanically, SFRP2 promoted competitive binding of BACH1 to the ARE sequence of HO-1, impaired Nrf2 binding, and suppressed antioxidant signaling. We concluded that SFRP2 might exacerbate lung inflammation and apoptosis by inhibiting the Nrf2/HO-1 pathway, thus promoting the progression of BPD.
USP1 represses ferroptosis in endometrial carcinoma cells by regulating the ubiquitination and stability of ESR1.
Lin Q, Xiao Y, Liu J … +4 more , Lu R, Chen Y, Li J, Ye X
Biochim Biophys Acta Mol Cell Res · 2026 Jun · PMID 42155671 · Publisher ↗
Endometrial carcinoma (EC) is a prevalent gynecologic malignancy. Ferroptosis, a type of programmed cell death, holds promise as a therapeutic strategy for cancer treatment. However, the specific role of ferroptosis and...
Endometrial carcinoma (EC) is a prevalent gynecologic malignancy. Ferroptosis, a type of programmed cell death, holds promise as a therapeutic strategy for cancer treatment. However, the specific role of ferroptosis and the underlying mechanisms in EC cells remain largely unexplored. In this study, we identified ubiquitin-specific protease 1 (USP1) as a key inhibitor of ferroptosis in EC cells. Our findings show that USP1 expression is reduced in EC cells undergoing ferroptosis but is elevated in EC tissues. Overexpressing USP1 significantly enhanced cell viability, colony formation, cell cycle progression, and migration/invasion capabilities, while strongly suppressing ferroptosis induced by the ferroptosis activator erastin. Through bioinformatic analysis and functional validation, we identified estrogen receptor 1 (ESR1) as a USP1-interacting protein involved in ferroptosis regulation. USP1 was shown to interact with ESR1, reduce its polyubiquitination, and enhance its protein stability. Rescue experiments revealed that ESR1 overexpression counteracted the pro-ferroptotic effects of USP1 depletion in erastin-treated EC cells. Finally, in vivo studies using an EC xenograft model confirmed the anti-ferroptotic and tumor-promoting role of the USP1-ESR1 axis. Together, our findings reveal a novel mechanism by which USP1 promotes EC progression through suppression of ferroptosis via ESR1 stabilization. Thus, targeting the USP1-ESR1 signaling axis may offer a new therapeutic strategy for EC.
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