Search Results (420)

Antibiotic resistance is a critical global health threat, already causing over 1.27 million deaths annually and projected to exceed 10 million by 2050. This crisis is compounded by stagnation in novel antibiotic discovery, highlighting the need for mechanism–based innovation. Here, we provide an integrative framework linking antibiotic mechanisms of action, bacterial resistance pathways, and emerging therapeutic strategies. Antibiotics are systematically categorized by their molecular targets, cell wall synthesis, membrane integrity, nucleic acid replication, protein synthesis, and metabolic pathways, while resistance mechanisms are outlined in parallel, including enzymatic degradation, target modification, efflux, and permeability barriers. We further highlight novel approaches such as structure–guided drug design, synergistic combinations, nanoparticle delivery, and artificial intelligence–driven discovery. Precision medicine and microbiome modulation are also emphasized as next–generation interventions. By bridging molecular mechanisms with translational strategies, this review outlines opportunities to guide antibiotic innovation and advance precision therapies against the escalating threat of antimicrobial resistance. Full article

The optimization of membrane permeability is a pivotal approach for mitigating late-stage failures in peptide drug development. By leveraging linker chemical diversity, stapled peptides utilize linker engineering to precisely modulate key physicochemical parameters—such as lipophilicity and conformational constraints—to overcome the desolvation energy penalty. This review systematically evaluates linker-based strategies for enhancing the permeability of stapled peptides, categorized into two primary dimensions: (1) high-throughput screening (HTS) compatibility, focusing on the integration of functionalized linkers into mRNA display, phage display, and DNA-encoded libraries (DELs) to identify lead scaffolds with inherent permeability potential during early discovery; and (2) post-screening structural refinement, covering rational design strategies including intramolecular hydrogen-bond (IMHB) shielding, “chameleonic” adaptations, and stimuli-responsive reversible stapling. Furthermore, we analyze the paradigm shift in assessment methodologies from qualitative imaging to quantitative cytosolic delivery assays, which have deepened our understanding of mechanisms such as the charge/lipophilicity threshold balance and metabolism-driven trapping. Overall, linker engineering provides a robust technical roadmap for developing the next generation of cell-permeable stapled peptide therapeutics. Full article

Membrane curvature is a fundamental biophysical property of cellular membranes that underlies essential processes such as vesicle formation, organelle shaping, intracellular trafficking, and membrane scission. While traditionally studied in the context of cell biology and membrane dynamics, membrane curvature is now emerging as a critical, albeit underrecognized, regulator of oncogenic transformation and tumor progression. Curvature not only governs the mechanical properties of the membrane but also influences the spatial localization and activation of key signaling proteins, including Ras family GTPases, whose oncogenic functions are closely dependent on membrane topology. Cancer is frequently associated with disruptions in the regulation of membrane curvature as a result of aberrant lipid metabolism, overexpression of curvature-modulating proteins, and cytoskeletal remodeling. These changes facilitate the hallmarks of malignancy such as uncontrolled proliferation, enhanced motility, immune evasion, metabolic rewiring, and therapy resistance. Notably, recent evidence reveals that curvature acts as a spatial cue for Ras activation, particularly during epithelial-to-mesenchymal transition (EMT), where curvature-driven Ras relocalization amplifies growth factor signaling and promotes metastasis. This review provides a comprehensive overview of the molecular determinants that generate and sense membrane curvature from lipid shape and membrane asymmetry, BAR domain proteins, and actin dynamics, and explores how these mechanisms are hijacked in cancer. We describe the feedback between membrane architecture and oncogenic pathways such as Ras/MAPK and PI3K/AKT, emphasizing the role of curvature in shaping signal transduction platforms. It should be noted that “curvature-driven signaling” is defined as signaling regulation that arises from membrane-geometry-dependent localization, clustering, or activation of signaling proteins, while “curvature-sensitive platforms” refer to membrane subdomains whose specific curvature selectively recruits and stabilizes signaling complexes. Furthermore, we examine how these biophysical alterations impact vesicular trafficking, organelle morphology, and secretion, all of which are co-opted to support tumor development. From a translational standpoint, we assess emerging therapeutic strategies designed to target curvature-regulating factors and leverage membrane topology for precision drug delivery. Innovations in nanomedicine, super-resolution imaging, and curvature-sensing biosensors are also discussed as tools for both diagnostics and therapeutic monitoring. By integrating advances in membrane biophysics, cancer signaling, and bioengineering, this review highlights membrane curvature as a central and actionable dimension of cancer biology. Full article

Phytocompounds undoubtedly are structurally diverse and play a crucial role in the development of novel therapeutic agents. 2-Hydroxy-4-methoxybenzaldehyde (HMB), from Hemidesmus indicus, is a potent antibacterial agent. Yet its pharmacophore has not been mechanistically defined. Here, we deconstructed HMB through a panel of structural derivatives to delineate the core structural determinants driving activity against foodborne pathogens. Structure–activity analysis revealed that the core benzaldehyde structure, rather than HMB itself, is the minimal active pharmacophore, with specific functional substitutions modulating antibacterial activity and membrane affinity. Integrating an experimental membrane assay with molecular dynamics simulations provided the first atomistic insight into how these derivatives interact with bacterial membrane lipids, demonstrating that substituent-driven modulation of hydrogen bonding dictates antibacterial potency. Specifically, electron-withdrawing groups enhanced membrane penetration and depolarization, particularly in Gram-positive pathogens. Time–kill kinetics and functional assays confirmed bactericidal action via membrane disruption rather than DNA interaction. Crucially, the active derivatives exhibited negligible cytotoxicity toward mammalian Vero cells, confirming their potential as selective and safe natural preservatives. This work provides a mechanistic blueprint for designing benzaldehyde-based antibacterials to combat antimicrobial resistance. Full article

Stimuli-responsive liposomal membranes have attracted growing interest as dynamic soft materials capable of regulating permeability, fusion, and cargo release in response to external or internal triggers. By incorporating functional molecular or nanostructured guests, such as photochromic compounds, plasmonic nanoparticles, or ionizable lipids, bilayers can be endowed with reversible and tunable properties. These modifications often rely on the precise control of lipid packing, phase behaviour, and the formation of transient membrane defects that facilitate molecular transport. This review aims to provide an overview of the molecular design strategies and underlying mechanisms used to engineer such responsive liposomal systems, with particular emphasis on light- and heat-triggered behaviours and on supramolecular approaches that modulate membrane structure and dynamics. Emerging trends, current limitations, and opportunities for future development in functional lipid-based materials and biointerfaces will also be discussed. Full article

This review critically examines how cyclodextrins modulate regulated cell death pathways and the implications for immunometabolism and therapeutic translation. Increasing evidence, however, indicates that cyclodextrins exert intrinsic biological activity by modulating cellular lipid homeostasis, membrane organization, and intracellular trafficking. In recent years, these properties have positioned cyclodextrins as unexpected regulators of regulated cell death (RCD) pathways, with broad implications for immunometabolism and therapeutic innovation. This review provides a comprehensive overview of the mechanisms by which native and chemically modified cyclodextrins influence major forms of regulated cell death, including apoptosis, autophagy-dependent cell death, pyroptosis, ferroptosis, and necroptosis. Particular attention is given to cholesterol sequestration, lipid raft disruption, lysosomal cholesterol mobilization, and transcriptional reprogramming via pathways such as TFEB (transcription factor EB) and AMPK (AMP-activated protein kinase), which collectively shape cell fate decisions. We further examine how cyclodextrin-mediated modulation of RCD intersects with immune metabolism, especially macrophage polarization and inflammasome activity, thereby influencing inflammatory responses and disease progression. Translational implications are discussed across diverse pathological contexts, including cancer, cardiovascular diseases, neurodegenerative disorders, inflammatory and autoimmune conditions, infectious diseases, and lysosomal storage disorders. Finally, emerging cyclodextrin-based delivery platforms, ranging from inclusion complexes to nanoparticles and polymeric systems, are evaluated with respect to their ability to achieve targeted modulation of cell death while minimizing off-target toxicity. Importantly, we critically discuss dose-dependent cytotoxicity, sterol depletion–related adverse effects, and formulation-dependent variability, which currently limit the clinical translation of cyclodextrin-mediated cell death modulation. By integrating mechanistic insights with pharmaceutical formulation strategies, this review delineates key challenges and opportunities for the rational design of cyclodextrin-based therapeutics. Overall, this review highlights cyclodextrins as bioactive modulators rather than inert carriers, underscoring their potential to inspire novel pharmacological strategies that integrate drug delivery, immunometabolism, and regulated cell death. Full article

This work introduces Hybrid Membrane–Neural P systems (HMN P systems), a computational model that integrates principles from membrane computing and spiking neural P systems. The resulting framework offers a versatile foundation for the development of bio-inspired arithmetic architectures. Within this setting, we propose a compact family of arithmetic kernels capable of executing signed addition, subtraction, multiplication, and division in both modular and non-modular arithmetic domains. By leveraging intrinsic spike aggregation, spike–anti-spike annihilation, and exhaustive rule application, the proposed designs achieve efficient and reliable arithmetic computation in a constant number of simulation steps under exhaustive semantics and assuming synchronized input, independent of operand values. Addition and subtraction are executed intrinsically upon spike arrival, requiring no internal computation steps, while multiplication and division are completed in a single simulation step by one neuron. Furthermore, we introduce a modular-reduction kernel that operates in two simulation steps with a single neuron, and leverage its modular structure to construct modular multiplication and division through composition with non-modular arithmetic modules. Comparative evaluations against representative SNP and SNQ arithmetic designs demonstrate that HMN kernels achieve operand-independent execution time while requiring fewer neurons. Distinct from most existing approaches, the HMN framework natively supports signed operands through a dual-spike representation, thereby eliminating the need for auxiliary sign-handling mechanisms. Asynchronous spike arrivals can be managed by an optional synchronization membrane; since this mechanism is decoupled from the arithmetic kernels, its overhead is excluded from kernel performance and reported separately. Collectively, these results establish HMN systems as an efficient and modular platform for constant-time arithmetic computation, offering reusable arithmetic kernels that serve as a foundation for higher-level constructions, including those arising in elliptic-curve and modular arithmetic. Full article

This study investigated the α-glucosidase inhibitory potential of enzymatic/alkaline treatments from Palmaria palmata using different proteases and pairwise combinations thereof. Treatments prepared with Alcalase^®, Flavourzyme^®, and Formea^® Prime, alone or in combination, were evaluated for dose-dependent inhibitory activity. Alcalase^®-derived treatments exhibited the highest α-glucosidase inhibition, achieving an IC₅₀ of 2.48 mg·mL⁻¹, outperforming other treatments and combinations. Membrane fractionation of the Alcalase^®-derived treatment into >5 kDa, 3–5 kDa, 1–3 kDa, and <1 kDa fractions revealed a size-dependent trend, with the <1 kDa fraction showing the strongest inhibition (IC₅₀ of 1.94 mg·mL⁻¹). Three peptides, RADIPFRRA, DGIAEAWLG, and FWSQIFGVAF, from the <1 kDa fraction were identified as potential α-glucosidase inhibitors using the BIOPEP-UWM database and were further selected based on a Peptide Ranker score above 0.6 for in silico docking analyses. Docking revealed distinct binding modes: RADIPFRRA and DGIAEAWLG occupied the catalytic cleft, interacting with key residues (Asp518, Asp616, Trp481, Trp613) consistent with competitive inhibition, whereas FWSQIFGVAF bound to a peripheral site, suggesting potential allosteric modulation. Physicochemical analysis further highlighted differences in charge and isoelectric point correlating with their binding behavior. Together, these findings demonstrate that low-molecular-weight peptides derived from P. palmata proteins, particularly those generated by Alcalase^®, possess significant α-glucosidase inhibitory activity, and provide structural insights for the rational design of peptide-based modulators of carbohydrate metabolism. Full article

Phytochemicals, including flavonoids, stilbenoids, alkaloids, terpenoids, and structurally related synthetic small molecules, exhibit a broad spectrum of beneficial pharmacological effects. These effects stem not only from interactions with specific protein targets but also from their capacity to modify the physical properties of biological membranes. A key membrane property influenced by these plant-derived compounds is the electrical potential drop at the membrane–water interface, which plays a crucial role in numerous cellular processes. Changes in membrane potential impact the function of embedded proteins and ion channels, thereby modulating cell signaling, transport, and pharmacological responses. This review compiles data on how diverse plant and synthetic small molecules alter membrane physical characteristics, particularly the dipole component of the boundary potential in lipid bilayers primarily composed of phosphatidylcholine, a predominant membrane lipid in mammals and fungi. In-depth analysis of structure–activity relationships in this context elucidates how various structural modifications affect the compounds’ ability to shift membrane electrical potential. Understanding these relationships can pinpoint molecular features that drive membrane interactions and facilitate the discovery and design of more potent dipole-modifying agents with therapeutic potential. Full article

Background: Mitochondrial dysfunction in microglia is an important pathogenic factor inducing the onset of Parkinson’s Disease (PD). To address this challenge, a novel hierarchical nano-delivery system was developed to deliver a PD therapeutic agent, wedelolactone (WED) to modulate mitochondrial dysfunction. Methods: The nano-delivery system (WED@RBCm-B6&RAP12-NPs) was coated with red blood membrane (RBCm) to avoid immune clearance and conjugated with the BBB-penetrating peptide CGHKAKGPRK (B6) and the microglia targeting peptide EAKIEKHNHYQK (RAP12). Results: The experimental results demonstrated that this novel nano-delivery system could increase its half-life in blood circulation effectively via evading immune recognition and clearance and enhanced its brain distribution by synergistic effect of B6 and RAP12. By specifically targeting microglia in PD mouse brain, the system increased pyruvate dehydrogenase (PDH) activity, leading to mitochondrial structural repair, reduced secretion of pro-inflammatory cytokines, and improved the inflammatory microenvironment. Conclusions: The result first designed and synthesis a dual targeting drug delivery system WED@RBCm-B6&RAP12-NPs which significantly alleviated mitochondrial dysfunction and warranted further study to develop therapeutic agent for PD treatment. Full article

Direct solar photovoltaic to electrolyser systems offer a promising pathway for producing low-carbon hydrogen, yet their performance and scalability remain limited by challenges that arise when variable solar generation is coupled to electrochemical conversion, with unresolved implications for electrolyser lifetime and hydrogen production cost. This review synthesises recent advances in photovoltaic technologies, electrolyser development and emerging deployment configurations to evaluate the technical, operational and environmental factors that shape system feasibility. The assessment draws on findings from experimental studies, modelling frameworks and techno-economic analyses to examine photovoltaic efficiency losses, thermal and material degradation, high-resolution intermittency effects, electrolyser dynamics, degradation mechanisms and storage interactions, and their combined influence on usage-dependent lifetime and cost behaviour. The results show that fluctuating solar input reduces conversion efficiency, increases transient overpotentials and accelerates degradation in both photovoltaic modules and electrolyser stacks. Technology-specific trade-offs persist, with alkaline water electrolysis constrained by limited flexibility, proton exchange membrane electrolysis by reliance on scarce catalyst materials, and anion exchange membrane and solid oxide electrolysis systems requiring further validation under real-world variability. Floating photovoltaic systems and agrivoltaics expand deployment opportunities but introduce additional constraints related to water quality, ecological impacts and power variability. Overall, the review finds that system-level integration, dynamic modelling, degradation-aware design and coordinated storage strategies are essential to unlocking reliable and scalable solar-to-hydrogen production. Full article

A hybrid membrane bioreactor (HMBR) enhances treatment performance by simultaneously utilizing organisms on both suspended and attached sludge, yet the microbial mechanisms underpinning their efficiency remain poorly understood. In this study, we investigate spatial variability within microbial communities in HMBRs and correlate this factor with pollutant removal capacity. High-throughput sequencing results revealed significant differences in community structure between suspended sludge, suspended media surfaces, and membrane module surfaces. Suspended sludge exhibited the highest species richness, whereas microbial communities on suspended media resembled those within the sludge, contrasting markedly with membrane surface communities. Key functional groups were enriched at specific locations: Pseudomonas and Comamonas dominate the surface of the suspension culture medium and participate in nitrification; phosphorus-accumulating organisms (PAOs), primarily from the Flavobacteriales and Planctomycetaceae phyla, were most abundant on suspended media surfaces. This spatial partitioning of functional microbes indicates cooperative division of labor. Media surfaces serve as primary sites for nitrification and phosphorus removal, whilst suspended sludge flocs and membrane module surfaces are the principal contributors to denitrification. The results of this study provide microbiological evidence for optimizing HMBR design and operation, confirming that spatial community structure is a key factor influencing performance. Full article

Luteolin (Ltn), a natural flavonoid, effectively inhibits microglial activation in Alzheimer’s disease (AD) with promising therapeutic potential, but its efficacy is severely limited by the blood–brain barrier (BBB). To overcome this obstacle, this study prepared poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs)—designated as TGN/RAP12-RBC-NPs@Ltn—which were coated with red blood cell membranes (RBCm) functionalized with two peptides, TGN (TGNYKALHPHN) and RAP12 (EAKIEKHNHYQK). The results demonstrated that TGN significantly enhanced BBB permeability, while RAP12 enabled effective targeting and delivery of TGN/RAP12-RBC-NPs@Ltn to microglial mitochondria in the brain. In addition, the presence of RBCm significantly inhibited the phagocytosis of NPs by macrophages, exerting a notable role in immune evasion. Meanwhile, the study confirmed that encapsulating Ltn within NPs significantly enhanced cognitive function in APP/PS1 mice, modulated the expression of key mitochondrial metabolic enzymes—pyruvate dehydrogenase (PDH) and its phosphorylated forms (pS232PDH, pS293PDH, pS300PDH)—in microglia, thereby ameliorating mitochondrial dysfunction and effectively regulating the neuroinflammatory environment in the mouse brain, and ultimately contributed to therapeutic efficacy. From this, it could be seen that TGN/RAP12-RBC-NPs@Ltn could significantly enhance the therapeutic effect of Ltn on AD, providing an effective treatment strategy for delaying the progression of AD. Full article

Acute and chronic kidney diseases remain significant challenges in regenerative medicine, with few therapies capable of reversing tissue injury or preventing progression. Bone marrow mesenchymal stem cell-derived exosomes (BM-MSC-Exos) are nanosized vesicles (30–150 nm) that have emerged as multifunctional nanotheranostic platforms, combining targeted therapeutic activity with imaging-enabled monitoring. In renal pathophysiology, BM-MSC-Exos exert anti-inflammatory, anti-fibrotic, angiogenic, and pro-regenerative effects. These actions are mediated by microRNAs, messenger RNAs, mitochondrial regulators, and bioactive proteins that modulate epithelial repair and immune responses. Recent bioengineering advances enable more precise BM-MSC-Exos design, including enrichment with synthetic RNAs or gene-editing components and membrane functionalization to enhance kidney tropism. In parallel, fluorescence, bioluminescence, and nanoparticle-based approaches support in vivo tracking. These tools allow real-time assessment of biodistribution and tubular uptake, strengthening evidence for target engagement. This review synthesizes current knowledge on BM-MSC-Exos in renal repair. We summarize contemporary strategies for cargo and surface engineering, outline imaging methodologies for in vivo tracking, and discuss how administration routes influence renal targeting. We also provide an updated overview of clinical trials evaluating exosomes as therapeutic agents or biomarkers in nephrology. Collectively, engineered BM-MSC-Exos represent a promising and increasingly sophisticated platform for precision-guided kidney therapy, supported by monitoring tools that facilitate preclinical evaluation of biodistribution and efficacy. Full article

RNA-based interventions are particularly promising for next-generation therapeutic strategies and hold significant potential when integrated with diagnostic modalities. Among noncoding RNAs, microRNAs (miRNAs) regulate gene expression post-transcriptionally and represent compelling targets for cancer therapy. However, their clinical translation remains hindered by instability, off-target effects, and limited delivery efficiency. Here, we report the microfluidic synthesis of hybrid lipid–polymer nanoparticles (LiPoNs) that co-deliver an AntimiR-21 and the magnetic resonance imaging contrast agent gadolinium diethylenetriamine penta-acetic acid (Gd-DTPA). The LiPoNs were obtained using coupled Hydrodynamic Flow Focusing (cHFF), enabling precise control over lipid–polymer self-assembly and surpassing the compositional limitations reported with conventional micromixers. The resulting AntimiR-21–Gd-DTPA–LiPoNs exhibited an average hydrodynamic diameter of 124 nm, narrow polydispersity (PDI < 0.2), and encapsulation efficiency up to 60%. In MDA-MB-231 breast cancer cells, treatment with AntimiR-21–LiPoNs induced suppression of miR-21 and a corresponding decrease in migratory capacity, demonstrating effective functional delivery and gene expression modulation. These findings establish a versatile microfluidic platform for engineering multifunctional lipid–polymer nanostructures whose hybrid architecture combines the biocompatibility and membrane fusion capability of lipids with the structural robustness and controlled release properties of polymers, thereby advancing RNA-based theranostic design for precision oncology and related applications. Full article