Biochimica Et Biophysica Acta[JOURNAL]
Sun
200 papers
Programming regulated cell death to engineer whole-tumor-cell vaccines for cancer immunotherapy.
Guan Y, Bai D, Bu N … +2 more , Hao W, Maimaitiyiming Y
Biochim Biophys Acta Rev Cancer · 2026 Jun · PMID 42320845 · Publisher ↗
Regulated cell death (RCD) encompasses a variety of genetically controlled cell death programs that are essential for maintaining tissue homeostasis and have emerged as promising therapeutic targets in oncology. When use...
Regulated cell death (RCD) encompasses a variety of genetically controlled cell death programs that are essential for maintaining tissue homeostasis and have emerged as promising therapeutic targets in oncology. When used to prepare whole-tumor-cell (WTC) vaccines, dying cancer cells provide broad tumor-antigen repertoires together with damage-associated molecular patterns (DAMPs) that can function as endogenous adjuvants. This review examines how distinct RCD pathways shape antitumor immunity and how they can be exploited to engineer next-generation WTC vaccines. We summarize the molecular and immunological features of major RCD modalities, including apoptosis, necroptosis, pyroptosis, ferroptosis, cuproptosis, and emerging forms of regulated death, emphasizing their divergent capacities to promote antigen uptake, dendritic-cell activation, cross-presentation, and T-cell priming. We also discuss key translational barriers, including tumor heterogeneity, immunosuppressive tumor microenvironments, variable sensitivity to RCD induction, empirical inactivation methods, and the lack of mechanism-informed potency assays. Particular attention is given to the safety challenge posed by highly inflammatory modalities such as necroptosis and pyroptosis, which require careful control to balance immunogenic potency with hyperinflammation or systemic toxicity. Future development should shift from procedure-defined tumor-cell killing toward precision RCD programming, quantitative validation of immunogenic "death fingerprints," rational combinations with immune-checkpoint blockade or microenvironment modulating therapies, and individualized optimization guided by dynamic immune monitoring. By clarifying the interplay between RCD and antitumor immunity, this review provides a framework for designing reproducible, mechanism-guided, and clinically translatable WTC vaccines.
Key module genes in proximal tubular cells drive microenvironmental chronic inflammation and fibrosis in diabetic kidney disease: A single-cell transcriptomic study.
Zhou W, Chen Z, Ying G … +6 more , Liu L, Xiao W, Liu J, Xia M, Zhang Q, He X
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42320643 · Publisher ↗
Diabetic kidney disease (DKD) is one of the most severe microvascular complications of diabetes, with proximal tubular (PT) epithelial cells playing a pivotal role in its progression, yet the underlying dynamic molecular...
Diabetic kidney disease (DKD) is one of the most severe microvascular complications of diabetes, with proximal tubular (PT) epithelial cells playing a pivotal role in its progression, yet the underlying dynamic molecular mechanisms remain unclear. In this study, single-cell transcriptomic dataset GSE183276 and bulk RNA-seq dataset GSE30122 were integrated to systematically analyze the heterogeneity and functional alterations of PT epithelial cells in DKD. PT epithelial cells were classified into three subpopulations: PT-Homeostatic, PT-Transitional and PT-Stressed. In DKD, the PT-Homeostatic subpopulation decreased markedly, whereas PT-Transitional and PT-Stressed subpopulations increased significantly. Functional enrichment analyses revealed that PT-Homeostatic cells mainly participated in amino acid and fatty acid metabolism; PT-Transitional cells were enriched in wound repair, Wnt signaling and oxidative stress response; PT-Stressed cells were associated with fibroblast proliferation, anti-apoptosis and chemotaxis regulation. Pseudotime analysis indicated that PTECs gradually shift from a homeostatic to a stressed phenotype during DKD progression. Eight core downregulated genes were further screened, among which HPGD and G6PC were specifically highly expressed in PT-Homeostatic cells and significantly downregulated in DKD. In vitro experiments demonstrated that high glucose repressed transcription factor RXRA expression to further reduce G6PC transcription. RXRA overexpression restored G6PC levels, inhibited pro-inflammatory and fibrotic markers, and upregulated E-cadherin, while G6PC knockdown reversed these protective effects. Collectively, this study uncovered the dynamic phenotypic transition of PTECs in DKD and identified the RXRA-G6PC axis as a potential therapeutic target.
Corrigendum to "Inducible beige adipocytes improve impaired glucose metabolism in interscapular BAT-removal mice" [Biochim. Biophys. Acta Mol. Cell Biol. Lipids 1866 (2021) 158871].
Jia XW, Fang DL, Shi XY … +3 more , Lu T, Yang C, Gao Y
Biochim Biophys Acta Mol Cell Biol Lipids · 2026 Jun · PMID 42315402 · Publisher ↗
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The CFIm25/FDPs axis orchestrates protective mitophagy in macrophages to attenuate myocardial infarction.
Zhou Y, Li Y, Liu M … +8 more , Chen M, Guo H, Qi J, Han S, Yu T, Cao Y, Chen Y, Hong M
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42314996 · Publisher ↗
Alternative cleavage and polyadenylation (APA) is a major post-transcriptional regulatory mechanism that is frequently dysregulated following myocardial infarction (MI). To investigate its role in post-infarction remodel...
Alternative cleavage and polyadenylation (APA) is a major post-transcriptional regulatory mechanism that is frequently dysregulated following myocardial infarction (MI). To investigate its role in post-infarction remodeling, we focused on the APA factor cleavage factor Im 25 kDa subunit (CFIm25). We identified macrophage CFIm25 as a pathological regulator of MI and explored its association with mitochondrial quality control. CFIm25 expression was markedly reduced in macrophages during the early stage of MI. Myeloid-specific CFIm25 knockdown significantly reduced infarct size, attenuated cardiac fibrosis, and improved cardiac function after MI. In vitro, CFIm25 deficiency suppressed pro-inflammatory responses and enhanced mitophagic flux, whereas CFIm25 overexpression abolished these protective effects. Transcriptomic analysis identified farnesyl diphosphate synthase (FDPS) as a key downstream effector associated with CFIm25 deficiency. Although FDPS was not established as a direct APA target, our data support its functional role in mediating the downstream effects of CFIm25 loss. Quantitative proteomic profiling revealed significant enrichment of mitochondria-related pathways, indicating extensive mitochondrial remodeling following CFIm25 depletion. Pharmacological inhibition of FDPS using ibandronate attenuated PINK1/Parkin pathway activation, reduced LC3-II accumulation, and suppressed mitophagy, demonstrating that FDPS is functionally required for CFIm25 deficiency-induced mitophagic responses. Collectively, these findings support a model in which CFIm25 deficiency promotes FDPS-dependent activation of PINK1/Parkin-mediated mitophagy, thereby enhancing mitochondrial quality control and limiting inflammation. This study identifies a previously unrecognized CFIm25/FDPS signaling axis regulating macrophage mitophagy following MI and highlights its potential therapeutic relevance in ischemic heart injury.
The human adenosine A receptor co-isolates with anionic phospholipids in SMALPs from Pichia pastoris membranes.
Company-Marín I, Pitt AR, Spickett CM
Biochim Biophys Acta Biomembr · 2026 Jun · PMID 42314793 · Publisher ↗
The adenosine A receptor (AR) is a GPCR that binds adenosine, leading to modulation of inflammation, platelet aggregation and vasodilation of coronary arteries. It is known that phospholipids surrounding GPCRs affect the...
The adenosine A receptor (AR) is a GPCR that binds adenosine, leading to modulation of inflammation, platelet aggregation and vasodilation of coronary arteries. It is known that phospholipids surrounding GPCRs affect their activity but these effects have largely been determined by studies in reconstituted liposomes or by molecular dynamics simulations. Therefore, the aim was to investigate the phospholipid composition of the AR in a native-like environment to determine its preference for specific phospholipids. Recombinant human truncated AR (A316) was overexpressed in Pichia pastoris and solubilized by SMA2000 into SMA lipid particles (SMALPs). Phospholipids in the AR-SMALP were characterised and compared to those in bulk membranes and SMA-solubilized lipids by LC-MS/MS. In all samples, species of phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), phosphatidylglycerol (PG), phosphatidylinositol (PI), lysophosphatidylcholine (LPC), and lysophosphatidylethanolamine (LPE) were detected. Principal component analysis showed clear differences in the lipid profiles of P. pastoris bulk membranes, SMA-solubilized fraction, and purified A2AR-SMALP. Bulk membranes were enriched in PC and LPE, whereas the SMA-solubilized fraction was enriched in PE, PS, and PG. In contrast, the AR-SMALP was enriched in the anionic lipids, especially PG and PA but contained lower intensities of PE. The data provides the first practical evidence suggesting that the AR co-isolates with anionic lipids that are positive regulators for GPCRs and has lower levels of the negative regulator PE than non-specific SMA-solubilized membrane. The study also provides evidence that SMA2000 does preferentially solubilize membrane regions containing certain phospholipids.
Collective lipid dynamics in biomembranes.
Brown MF
Biochim Biophys Acta Biomembr · 2026 Jun · PMID 42314792 · Publisher ↗
Cellular lipids are wonders of biomolecular self-organization whose structure and dynamics are intimately connected with their functionality. Here we review the development and use of NMR spectroscopy in the study of lip...
Cellular lipids are wonders of biomolecular self-organization whose structure and dynamics are intimately connected with their functionality. Here we review the development and use of NMR spectroscopy in the study of lipid membranes. For liquid-crystalline bilayers, the structure is described by orientational order parameters, while the dynamics entail fluctuations about the mean geometry. Addressing the information gap between molecular structure, dynamics, and function involves magnetic resonance spectroscopy combined with X-ray and neutron scattering approaches. Cholesterol gives a crucial test in liquid-ordered (l) membranes, where the bending rigidity oppositely affects solid-state NMR observables-the order parameters increase yet the relaxation rates decrease. By contrast, nonionic surfactants in the liquid-disordered (l) state soften the bilayer and decrease the order parameters, thereby enhancing the spin relaxation. This enigma is explained by a model-free power-law that combines the mean-squared amplitudes and fluctuation rates. Collective modes appear on the mesoscale of the bilayer thickness and less, indicating how membrane elasticity emerges from atomistic-level interactions that drive the response to external forces. The unified power-law scaling shows how the bilayer fluidity corresponds to a hydrocarbon liquid of similar chain length. Magnetic resonance spectroscopy thus yields insights into properties that underlie bilayer phase transitions, curvature, and protein-lipid interactions.
Exposure to the antimicrobial peptides LL-37 and ATRA-1 induces a lipidome response in Staphylococcus aureus that alters membrane biophysical properties.
Fuertes-Chaves C, Gonzalez JE, Suesca E … +5 more , Guzmán-Sastoque P, Muñoz-Camargo C, Manrique-Moreno M, Carazzone C, Leidy C
Biochim Biophys Acta Biomembr · 2026 Jun · PMID 42303202 · Publisher ↗
Staphylococcus aureus (S. aureus) is an opportunistic pathogen that is a global health concern for its ability to cause a wide spectrum of clinical infections ranging from minor skin abscesses to systemic conditions such...
Staphylococcus aureus (S. aureus) is an opportunistic pathogen that is a global health concern for its ability to cause a wide spectrum of clinical infections ranging from minor skin abscesses to systemic conditions such as sepsis and pneumonia. Due to the emergence of resistance to commonly used antibiotics, there has been interest in exploring the use of antimicrobial peptides to treat S. aureus infections. However, changes in the lipid composition of the lipid bilayer membrane can alter the activity of peptides, and S. aureus is able to induce variations in lipid composition in response to environmental stress. Here, we explore how the main lipid components in S. aureus are altered when exposed to LL-37, a human cathelicidin involved in primary immune response, and ATRA-1, a short antimicrobial peptide derived from the snake Naja atra venom. A lipidomic study is conducted through HPLC-MS-MS (LC-ESI-MS/MS) to quantify phosphatidylglycerol, cardiolipin, lysyl-phosphatidylglycerol, monogalacto- and digalacto-diacylglycerol, and carotenoids. In addition, menaquinones, responsible for electron transport during oxidative phosphorylation, were also quantified. Biophysical properties such as membrane electric surface potential and lipid packing were assessed. We find that lipid adaptation is specific to the type of antimicrobial peptide, where ATRA-1 mainly induces changes in the electric surface potential through variations in Lysyl-PG, while exposure to LL-37 changes carotenoid levels, inducing an increase in membrane rigidity as measured by FTIR. In addition, both peptides induce a reduction in menaquinone and DGDG levels. These findings highlight the role of membrane lipid remodeling as a peptide-specific response mechanism in S. aureus, with implications for the development of AMP-based therapies.
The bench-to-bedside journey of circular RNAs in cancer: Status, challenges and future prospects.
Lin H, Tu Y, Wang P … +2 more , Wang T, Long F
Biochim Biophys Acta Rev Cancer · 2026 Jun · PMID 42303186 · Publisher ↗
Cancer remains a major global health challenge, with its heterogeneity and complexity posing significant obstacles to accurate diagnosis and effective treatment. Therefore, it is imperative to find new biomarkers and the...
Cancer remains a major global health challenge, with its heterogeneity and complexity posing significant obstacles to accurate diagnosis and effective treatment. Therefore, it is imperative to find new biomarkers and therapeutic targets to develop more precise and effective strategies. Over the past decade, circular RNAs (circRNAs), a class of covalently closed RNA molecules, have emerged as promising candidates because of their stability, specific expression, and functional roles in cancer. Growing evidence suggests their potential clinical relevance and utility. In particular, owing to their stable presence and detectability in body fluids, circRNAs possess considerable potential to serve as diagnostic, prognostic, and predictive biomarkers. Additionally, promising advances have been made in the development of circRNA-based therapeutic strategies that involve both targeting endogenous circRNAs and delivering synthetic ones. In this review, we delineate the biogenesis, characteristics, and functional involvement of circRNAs in cancer and further summarize their potential as liquid biopsy biomarkers and for the development of circRNA-based therapeutic strategies. We also discuss challenges that must be overcome to unlock the full potential of circRNAs and address future directions.
Perineural invasion in gastrointestinal malignancies: From neurotrophic signaling to targetable tumor-microenvironment crosstalk.
Li Q, Xu J, Hu C … +1 more , Xu Z
Biochim Biophys Acta Rev Cancer · 2026 Jun · PMID 42303185 · Publisher ↗
Perineural invasion (PNI) is increasingly recognized as a distinct metastatic route and a hallmark of aggressive behavior in gastrointestinal (GI) malignancies. This review synthesizes current evidence on the epidemiolog...
Perineural invasion (PNI) is increasingly recognized as a distinct metastatic route and a hallmark of aggressive behavior in gastrointestinal (GI) malignancies. This review synthesizes current evidence on the epidemiology, pathobiology, and clinical translation of PNI in digestive system tumors. We first summarize the incidence and prognostic impact of PNI across major GI cancer subtypes. We then delineate the multilayered molecular network that orchestrates PNI. Particular emphasis is placed on the tumor microenvironment as an active driver of PNI. Clinically, we discuss how tumor-nerve crosstalk underlies cancer-induced neuroinflammation and pain, and outline emerging tools and candidate biomarkers for PNI detection. Finally, we review potential therapeutic strategies aimed at disrupting the tumor-nerve axis. A deeper, spatially resolved understanding of the tumor-nerve interface is expected to enable rational biomarker development and dual-function interventions that simultaneously alleviate pain and restrain PNI -driven progression in GI cancers.
Thermodynamic distinction between hydrophobic anesthetic association and site-specific fatty acid binding in serum albumin.
Nishimoto M, Tsudura K, Goto M … +3 more , Tamai N, Yamanaka M, Matsuki H
Biochim Biophys Acta Gen Subj · 2026 Jun · PMID 42303184 · Publisher ↗
Interactions between volatile anesthetics and bovine serum albumin (BSA) were thermodynamically characterized using isothermal titration calorimetry (ITC). Because weak ligand binding requires appropriately matched prote...
Interactions between volatile anesthetics and bovine serum albumin (BSA) were thermodynamically characterized using isothermal titration calorimetry (ITC). Because weak ligand binding requires appropriately matched protein and ligand concentrations for reliable thermodynamic analysis, measurements were performed at several protein concentrations to characterize the concentration-dependent titration behavior. Binding constants and thermodynamic parameters were evaluated by enthalpy-based analysis combined with Scatchard analysis of the resulting ITC data. For comparison, the binding of medium-chain fatty acids to BSA was analyzed using the same approach to contrast the thermodynamic behavior of weak- and strong-binding ligands. Fatty acid binding exhibited clear saturation behavior and could be described as finite-site binding with a well-defined number of binding sites (approximately 7-9) and relatively high binding constants (on the order of 10-10). In contrast, anesthetic binding showed pronounced protein concentration dependence, and the resulting Scatchard plots were nonlinear, indicating that the interaction cannot be explained by a simple finite-site binding model. The apparent binding constants and binding numbers were broadly consistent with trends in anesthetic hydrophobicity and potency. Although the binding enthalpy changed sign depending on the anesthetic species, this sign did not determine the essential binding mode and likely reflects solvent reorganization and hydrophobic interactions. These results indicate that fatty acids bind to serum albumin through site-specific interactions at a finite number of binding sites, whereas anesthetic interactions are better described as hydrophobic, partition-like multi-site associations on the protein surface. The present study provides a thermodynamic framework for distinguishing site-specific binding from hydrophobic association in protein-ligand interactions.
Extracellular vesicles derived from Lactobacillus rhamnosus GG inhibit lung cancer cell invasion and metastasis by regulating ADHFE1 expression to modulate metabolic reprogramming.
Wang Y, Shen S, Chen N … +4 more , Li J, Su Y, Chen Y, Xu Z
Biochim Biophys Acta Gen Subj · 2026 Jun · PMID 42303183 · Publisher ↗
Non-Small Cell Lung Cancer (NSCLC) remains a leading cause of cancer-related deaths worldwide, creating an urgent need to explore new drugs and clarify their mechanisms of action. In recent years, lactic acid bacteria-de...
Non-Small Cell Lung Cancer (NSCLC) remains a leading cause of cancer-related deaths worldwide, creating an urgent need to explore new drugs and clarify their mechanisms of action. In recent years, lactic acid bacteria-derived extracellular vesicles (EVs) have shown great potential in anti-tumor therapy; however, research on their role in lung cancer remains limited. In this study, EVs from three common Lactobacillus species were isolated to verify their anti-tumor effects on lung cancer. Among these, the extracellular vesicles derived from Lactobacillus rhamnosus GG (LGG-EVs) exhibited the most significant anti-cancer activity. A549 and H1299 cells were treated with LGG-EVs, and transcriptome sequencing analysis was performed. The results revealed that Alcohol Dehydrogenase Iron-Containing 1 (ADHFE1)- a differentially expressed gene with notable changes before and after treatment- displayed the same expression pattern in both cell lines. Further verification was conducted using methods including Western Blotting, Transwell, wound healing, and flow cytometry. Compared with the control group, treatment with LGG-EVs led to downregulated ADHFE1 expression in both cell lines, along with inhibited malignant cellular behaviors and glycolysis capacity. Notably, overexpression of ADHFE1 significantly reversed these effects. These findings indicate that the anti-tumor effect of LGG-EVs on lung cancer may be achieved through ADHFE1-mediated metabolic reprogramming. This study is the first to identify that ADHFE1-mediated metabolic reprogramming could be a key mechanism by which LGG-EVs inhibit lung cancer, providing a new target and strategy for lung cancer treatment.
Overexpression of an engineered artificial nuclease L29E myoglobin in breast cancer cells and its functional consequences.
He ZL, Sun LJ, Gao SQ … +1 more , Lin YW
Biochim Biophys Acta Gen Subj · 2026 Jun · PMID 42303182 · Publisher ↗
Triple-negative breast cancer (TNBC) has a poor prognosis due to the lack of effective therapeutic targets, highlighting the urgent need for new intervention strategies. This study focuses on an engineered artificial nuc...
Triple-negative breast cancer (TNBC) has a poor prognosis due to the lack of effective therapeutic targets, highlighting the urgent need for new intervention strategies. This study focuses on an engineered artificial nuclease, L29E myoglobin, which forms a heterodinuclear Mg-HO-heme center upon Mg binding and exhibits DNA cleavage activity. We overexpressed L29E Mb in the TNBC cell line MDAMB231 and systematically evaluated its effects on cellular physiology. The results showed that, in the presence of Mg, the overexpression of L29E Mb significantly induced DNA damage and loss of mitochondrial membrane potential, leading to G1-phase cell cycle arrest and activation of the caspase-9/caspase-3 cascade, and ultimately promoting apoptosis. These findings establish a proof-of-concept that the complex of Mg-L29E Mb may function as an artificial nuclease and trigger the mitochondrial apoptotic pathway, which provides a foundation for protein-based anticancer strategies.
DLGAP5-induced glycolysis reprogramming reinforces macrophage M2 polarization to impact BC progression.
Lin Y, Wu J, Zhang S … +5 more , Yan Z, Li J, Cheng Z, Wu Q, Yang Z
Biochim Biophys Acta Gen Subj · 2026 Jun · PMID 42297309 · Publisher ↗
BACKGROUND: Breast cancer (BC) is ranked among the most prevalent malignant tumors in the global female population. DLGAP5 is implicated in the progression of various tumors. However, the molecular mechanisms of DLGAP5 i...
BACKGROUND: Breast cancer (BC) is ranked among the most prevalent malignant tumors in the global female population. DLGAP5 is implicated in the progression of various tumors. However, the molecular mechanisms of DLGAP5 involved in BC and TAM interactions remain unclear. METHODS: We investigated the expression and prognostic significance of DLGAP5 in breast cancer (BC) and its association with M2 macrophage infiltration using bioinformatics and experimental methods. DLGAP5 expression was higher in BC cells (MCF-7, MDA-MB-231) than in normal breast epithelial cells (MCF-10 A), as confirmed by qRT-PCR and Western blot. Functional assays showed that DLGAP5 promoted BC cell proliferation, migration, invasion, and anti-apoptotic ability, and increased levels of PCNA, Ki67, and Bax. DLGAP5 also elevated M2 macrophage markers (Arg1, IL-10) and glycolytic enzymes (PGK1, LDHA, PKM2, HK2), and enhanced glycolysis, as indicated by ECAR and OCR measurements. Bioinformatics analysis further supported the link between DLGAP5, glycolysis, and M2 macrophage infiltration. Finally, by establishing an allograft tumor model, the regulatory effect of DLGAP5 knockdown on the malignant progression of BC was validated in vivo. RESULTS: Bioinformatics analysis revealed that the upregulation of DLGAP5, which is linked to poor prognosis in breast cancer (BC), promotes glycolytic reprogramming. This metabolic shift drives macrophage M2 polarization, thereby facilitating BC progression. CONCLUSION: Our work demonstrated that DLGAP5-induced glycolysis reinforces the progression of BC by promoting the polarization of macrophages towards an M2 phenotype. The study can provide a theoretical foundation for BC treatment, pinpointing DLGAP5 as a promising biomarker.
Assessment of toxicity and anticancer activity of attenuatumione D from Hypericum sampsonii hance against hepatocellular carcinoma.
Saeed Y, Sun Z, Zhong R … +2 more , Zhu J, Zhang T
Biochim Biophys Acta Gen Subj · 2026 Jun · PMID 42297308 · Publisher ↗
This study investigates the anticancer effects of attenuatumione D, a bioactive compound derived from Hypericum sampsonii Hance, and its potential to inhibit the proliferation of hepatocellular carcinoma (HCC). For this...
This study investigates the anticancer effects of attenuatumione D, a bioactive compound derived from Hypericum sampsonii Hance, and its potential to inhibit the proliferation of hepatocellular carcinoma (HCC). For this purpose, we employed an in vitro study to assess the cytotoxicity of attenutumione D by measuring cell viability, oxidative stress, and pro-inflammatory cytokine levels using ELISA, as well as apoptosis using flow cytometry and Western blot in HepG2 cells. While in vivo analysis was carried out using H22-tumor-bearing nude Balb/C mice model. Our data from an in vitro study showed cytotoxicity of attenuatumione D, exhibiting time & dose-dependent variation in cell morphology and a reduction in viability of HepG2 cells, with an IC50 value of 25 μM. It was found that the anti-proliferative effects of attenuatumione D were associated with apoptotic cell death, indicated by increased early apoptosis and up-regulation of cleaved caspase-3, with increased ratios of Bax/Bcl-2. Moreover, attenuatumione D treatment reduced the pro-tumorigenic cytokines, i.e., IL-1β, IL-6, and TNF-α in HepG2 cells. These findings were concomitant with increased oxidative stress. In vivo, attenuatumione D demonstrated therapeutic capacity in H22-tumor-bearing mice by inhibiting the tumor growth and protecting the liver histology with minimal hepatic alterations. Metabolomic analysis of H22-tumor-bearing mice serum and its mechanistic validation demonstrated that attenuatumione D treatment reduced the elevated levels of inosine, hypoxanthine, and guanine (key metabolites in purine metabolism) and modulated the expression of key apoptotic proteins, i.e., JNK, ERK, and p38 associated with MAPK signaling. Collectively, this study provides pioneering evidence of the anticancer potential of attenuatumione D against HCC.
The discriminating role of extracellular vesicles in HPV-dependent and HPV-independent head and neck cancer.
Ważny Ł, Rutkowski T, Whiteside TL … +2 more , Gramatyka M, Pietrowska M
Biochim Biophys Acta Rev Cancer · 2026 Jun · PMID 42297221 · Publisher ↗
Head and neck squamous cell carcinoma (HNSCC) is the seventh most frequently diagnosed cancer worldwide, contributing to approximately 400,000 deaths annually. Recently, the involvement of human papillomavirus (HPV) in t...
Head and neck squamous cell carcinoma (HNSCC) is the seventh most frequently diagnosed cancer worldwide, contributing to approximately 400,000 deaths annually. Recently, the involvement of human papillomavirus (HPV) in the etiopathogenesis of this malignancy, particularly in oropharyngeal squamous cell carcinoma (OPSCC), has been emphasized. In parallel, the potential role of extracellular vesicles (EVs) in the initiation and progression of HNSCCassociated with HPV infection has emerged. EVs are small, membrane-bound vesicles secreted by all cell types, that transport biologically significant cargo, including proteins and nucleic acids. EVs produced by tumor cells interact with non-malignant cells and reprogram the tumor microenvironment, inducing immune suppression, promoting angiogenesis, and facilitating tumor metastasis. Tumor-derived EVs carry DNA and may be responsible for the horizontal transfer of viral structural and functional components, including the E6 and E7 oncoproteins to other cells. The interplay between the mechanisms associated with the HPV replication cycle, EV biogenesis and release, and carcinogenesis represents a novel and still poorly understood area in the investigation of HNSCC development and progression. This review synthesizes recent findings on the distinct roles tumor-derived EVs appear to play in both HPV-dependent and HPV-independent HNSCC.
Roles of cholesteryl α-glucosides produced by Helicobacter pylori in the interactions with the host immune system.
Shimamura M
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42297119 · Publisher ↗
Helicobacter pylori extracts cholesterol from the host epithelial cells during infection for nutrition and lipid raft formation. However, the presence of cholesterol in invading bacteria facilitates phagocytosis and subs...
Helicobacter pylori extracts cholesterol from the host epithelial cells during infection for nutrition and lipid raft formation. However, the presence of cholesterol in invading bacteria facilitates phagocytosis and subsequent immune responses by the host. To evade immune surveillance, H. pylori immediately converts cholesterol to cholesteryl 6'-O-acyl α-glucosides (αCAGs) to prevent phagocytosis by the host. In addition, a part of αCAGs translocate to phagosome membranes where they retard the phagosome maturation and the fusion with lysosomes, thereby prolonging survival in phagocytes. On the other hand, H. pylori αCAGs are possible targets of the host immune system because they are recognized by both invariant Vα14 TCR-bearing NKT (iNKT) cells and the C-type lectin receptor Mincle or Clec4e. iNKT cells produce proinflammatory cytokines when activated by the cytokines secreted by antigen-presenting cells (APCs) recognizing αCAGs via Mincle, while iNKT cells directly recognizing αCAGs with CD1d using invariant Vα14 TCR in a Mincle-independent manner produce both pro- and anti-inflammatory cytokines, suggesting their involvement in the regulation of the immune responses against H. pylori infection. This review classifies and discusses the interactions of H. pylori and the host mediated by cholesterol and its glycoside, αCAG, during infection, focusing on the possible ambivalent roles of iNKT cells in the control of the immune responses to the pathogen producing αCAG.
Synergistic apoptosis-sensitizing effect of PD-L1 inhibitor ARB-272572 encapsulated in TRAIL-expressing extracellular vesicles for renal cell carcinoma therapy.
Sun R, Li Q, Peng J … +10 more , Kuang X, Xie B, Kang Y, Jiang J, Wu Z, Huang R, Xu N, Lin X, Hai M, Yuan Z
Biochim Biophys Acta Mol Basis Dis · 2026 Jun · PMID 42297118 · Publisher ↗
Renal cell carcinoma(RCC) is a therapy-resistant malignancy with rising global incidence, highlighting an urgent need for innovative treatments. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively...
Renal cell carcinoma(RCC) is a therapy-resistant malignancy with rising global incidence, highlighting an urgent need for innovative treatments. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in cancer cells, but its clinical translation is hindered by cancer resistance. Extracellular vesicle-delivery of TRAIL (EV-T) has enhanced TRAIL activity. Recent studies reveal that programmed death-ligand 1(PD-L1), beyond its established role in immune evasion, exerts pro-survival functions and mediates TRAIL resistance. Accordingly, we propose the hypothesis that PD-L1 inhibition combined with EV-T may synergistically induce apoptosis in RCC cells. Moreover, we propose EV-based co-delivery of TRAIL and PD-L1 inhibitors could offer a highly efficient therapeutic strategy. First, TRAIL-transduced cells were cultured to prepare EV-Ts. Subsequently, the PD-L1 inhibitor ARB-272572 (ARB) was efficiently encapsulated into EV-Ts via sonication, fabricating a composite nanodrug ARB@EV-T. This formulation demonstrated improved ARB stability, cellular endocytosis, and controlled release kinetics. Importantly, ARB@EV-T overcame TRAIL resistance and showed synergistically enhanced cytotoxicity and apoptosis induction in resistant RCC lines. Mechanistically, the synergistic effect was attributed to upregulation of DR5 and concurrent suppression of anti-apoptotic factors, including cFLIP, MCL-1, BCL-2, XIAP, and Survivin, as well as inhibition of NF-kappaB pathway. In vivo, ARB@EV-T treatment resulted in significant inhibition of tumor proliferation, intense apoptosis, and robust recruitment of natural killer (NK) cells in a subcutaneous RCC xenograft mice model. These effects culminated in substantial tumor regression without any evident adverse events. Collectively, our results demonstrate ARB@EV-T represents an innovative and highly effective therapy against RCC, offering a potential breakthrough for overcoming treatment resistance in RCC.
Impact of ventricular pressure load changes on cardiomyocyte proliferation: the role of ALDH2 and GRAF1.
Cheng P, Wu J, Hao X … +4 more , Gan L, Zhou Y, Li Q, Chen L
Biochim Biophys Acta Mol Cell Res · 2026 Jun · PMID 42297117 · Publisher ↗
Heart failure is a major clinical challenge, posing a significant health threat due to its high mortality rate. The lack of regenerative capacity in the adult mammalian heart remains a core issue in heart failure treatme...
Heart failure is a major clinical challenge, posing a significant health threat due to its high mortality rate. The lack of regenerative capacity in the adult mammalian heart remains a core issue in heart failure treatment. Our previous studies have identified that ALDH2 regulates cardiomyocyte proliferation, and ventricular pressure overload significantly affects cardiomyocyte proliferative capacity. GRAF1 has been reported to be a molecule sensitive to ventricular pressure load. However, the potential roles of ALDH2 and GRAF1 in regulating cardiomyocyte proliferation in response to changes in ventricular pressure overload have not been reported. After pressure overload, cardiomyocyte proliferation peaked on the seventh day post-surgery and gradually declined over time, coinciding with a decrease in ALDH2 expression and activity in the left ventricle. Additionally, pressure overload significantly reduced GRAF1 expression in the left ventricle. GRAF1 knockdown led to enhanced primary cardiomyocyte proliferation, increased YAP nuclear translocation, and decreased p-YAP expression. Inhibition of YAP with Verteporfin significantly reversed cardiomyocyte proliferation. After unloading the heart, cardiomyocyte proliferation further increased, ALDH2 expression returned to baseline levels, and its activity was restored. However, GRAF1 continued to decrease after ventricular pressure overload unloading, promoting YAP expression and nuclear translocation to enhance cardiomyocyte proliferative capacity. Altered ventricular loading conditions were associated with dynamic changes in cardiomyocyte proliferative capacity, accompanied by corresponding alterations in ALDH2 expression and activity in mice. These findings suggest that the ALDH2 and the GRAF1/YAP axis may represent a potential mechanisms underlying changes in cardiomyocyte proliferative activity in response to altered cardiac loading conditions.
Pivotal role of PD-1/PD-L1 as an immune checkpoint in lymphoma and solid tumor: Cellular organization, clinical implications & the potential of small molecule inhibitors.
Yadav P, Chaudhary P, Chaudhary A … +2 more , Sargam S, Manna PP
Biochim Biophys Acta Rev Cancer · 2026 Jun · PMID 42288297 · Publisher ↗
Cancer immunotherapy has been a paradigm shift for treatment of advanced malignancies. Small-molecule inhibitors offer inherent advantages in terms of pharmacokinetics and drug ability, thereby providing an opportunity f...
Cancer immunotherapy has been a paradigm shift for treatment of advanced malignancies. Small-molecule inhibitors offer inherent advantages in terms of pharmacokinetics and drug ability, thereby providing an opportunity for cancer treatment and achieving better therapeutic effects. Immune checkpoint inhibitors (ICI) constitute a novel mechanism for the killing, and block evasion of the tumor cells leading to long lasting immune response, and offers promising advancement in clinical medicine. Programmed cell death protein 1 receptor and its ligand (PD-1/PD-L1) have demonstrated remarkable immune modulation. Antibodies against PD-1 or PD-L1 have shown significant promise although stability and immunogenicity issues pose critical disadvantages. In this review, we will discuss how PD-1/PD-L1 modulates the immune cells and tumor cells in the tumor microenvironment following immunotherapy. We will also discuss how the immunomodulatory potential of these inhibitors can be exploited via rational combinations with targeted therapy including immunotherapy and chemotherapy. Besides that, the current clinical and preclinical results of PD-1/PD-L1 will be highlighted in cancer including lymphoma in response to the host immune system. We will also summarize the pharmacokinetics and pharmacodynamics of this small molecule inhibitor including the significant role of nanoparticle (NP) controlled drug delivery system (DDS) using current data from clinical and pre-clinical trials on mono and combination immunotherapy to overcome therapeutic limitations of ICI. Combining the NP mediated DDS with ICI therapy could provide a profitable immunotherapeutic strategy for cancer treatment.
Lysine is more effective than arginine in two tryptophan-rich antimicrobial peptides.
Hackney A, Hartmann L, Parasnis R … +10 more , Leong A, Chen M, Knox L, Jaber J, Gao W, Dupuy F, Xiang W, Klousnitzer J, Deslouches B, Tristram-Nagle S
Biochim Biophys Acta Biomembr · 2026 Jun · PMID 42276501 · Publisher ↗
We compare biophysical and microbiological results to link structure and function in determining the mechanism of bacterial killing by two antimicrobial peptides (AMPs). Two 14-mer peptides were compared, each containing...
We compare biophysical and microbiological results to link structure and function in determining the mechanism of bacterial killing by two antimicrobial peptides (AMPs). Two 14-mer peptides were compared, each containing 6 tryptophans, in addition to 8 lysines (W6K8) or 8 arginines (W6R8). MIC values show W6K8 is more effective at killing bacteria, and less toxic to red blood cells than is W6R8. Small angle X-ray scattering (SAXS) shows W6K8 is more efficient at fusing unilamellar vesicles (ULVs) that mimic bacterial lipid model membranes (LMMs), and W6R8 is more efficient at fusing ULVs that mimic eukaryotic cells, suggesting that membrane destabilization is a requirement for both activities. Circular dichroism (CD) exhibits excitonic coupling suggesting that AMP aggregation is involved in the killing mechanism, while secondary structure is mostly random coil and beta-sheet. Differential interference contrast (DIC) microscopy confirms that W6K8 aggregates GUVs to a greater extent than does W6R8 in bacterial LMMs. X-ray diffuse scattering (XDS) indicates that W6K8 penetrates more deeply than W6R8 into bacterial LMMs compared to W6R8. XDS also reports that W6K8 condenses the lipid area more than W6R8 in bacterial LMMS, but that the opposite is true in eukaryotic LMMs. Fourier Transform Infrared Spectoscopy (FTIR) indicates that W6K8 destabilizes the gel phase of DPPG, while W6R8 does not. These five biophysical methods indicate differences that could be responsible for the different microbiological results.
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