A new capacity of gut microbiota: Fermentation of engineered inorganic carbon nanomaterials into endogenous organic metabolites.

Carbon-based nanomaterials (CNMs) have recently been found in humans raising a great concern over their adverse roles in the hosts. However, our knowledge of the in vivo behavior and fate of CNMs, especially their biological processes elicited by the gut microbiota, remains poor. Here, we uncovered the integration of CNMs (single-walled carbon nanotubes and graphene oxide) into the endogenous carbon flow through degradation and fermentation, mediated by the gut microbiota of mice using isotope tracing and gene sequencing. As a newly available carbon source for the gut microbiota, microbial fermentation leads to the incorporation of inorganic carbon from the CNMs into organic butyrate through the pyruvate pathway. Furthermore, the butyrate-producing bacteria are identified to show a preference for the CNMs as their favorable source, and excessive butyrate derived from microbial CNMs fermentation further impacts on the function (proliferation and differentiation) of intestinal stem cells in mouse and intestinal organoid models. Collectively, our results unlock the unknown fermentation processes of CNMs in the gut of hosts and underscore an urgent need for assessing the transformation of CNMs and their health risk via the gut-centric physiological and anatomical pathways.

Dynamic intracellular exchange of nanomaterials' protein corona perturbs proteostasis and remodels cell metabolism.

The nanomaterial­protein "corona" is a dynamic entity providing a synthetic­natural interface mediating cellular uptake and subcellular distribution of nanomaterials in biological systems. As nanomaterials are central to the safe-by-design of future nanomedicines and the practice of nanosafety, understanding and delineating the biological and toxicological signatures of the ubiquitous nanomaterial­protein corona are precursors to the continued development of nano­bio science and engineering. However, despite well over a decade of extensive research, the dynamics of intracellular release or exchange of the blood protein corona from nanomaterials following their cellular internalization remains unclear, and the biological footprints of the nanoparticle­protein corona traversing cellular compartments are even less well understood. To address this crucial bottleneck, the current work screened evolution of the intracellular protein corona along the endocytotic pathway from blood via lysosomes to cytoplasm in cancer cells. Intercellular proteins, including pyruvate kinase M2 (PKM2), and chaperones, displaced some of the initially adsorbed blood proteins from the nanoparticle surface, which perturbed proteostasis and subsequently incited chaperone-mediated autophagy (CMA) to disrupt the key cellular metabolism pathway, including glycolysis and lipid metabolism. Since proteostasis is key to the sustainability of cell function, its collapse and the resulting CMA overdrive spell subsequent cell death and aging. Our findings shed light on the consequences of the transport of extracellular proteins by nanoparticles on cell metabolism.

Nanoplastic Stimulates the Amyloidogenesis of Parkinson's Alpha-Synuclein NACore.

Environmental plastic wastes are potential health hazards due to their prevalence as well as their versatility in initiating physical, chemical, and biological interactions and transformations. Indeed, recent research has implicated the adverse effects of micro- and nano-plastics, including their neurotoxicity, yet how plastic particulates may impact the aggregation pathway and toxicity of amyloid proteins pertinent to the pathologies of neurological diseases remains unknown. Here, electrospray ionization time-of-flight mass spectrometry (ESI-TOF-MS) is employed to reveal the polymorphic oligomerization of NACore, a surrogate of alpha-synuclein that is associated with the pathogenesis of Parkinson's disease. These data indicate that the production rate and population of the NACore oligomers are modulated by their exposure to a polystyrene nanoplastic, and these cellular assays further reveal an elevated NACore toxicity in microglial cells elicited by the nanoplastic. These simulations confirm that the nanoplastic-NACore association is promoted by their hydrophobic interactions. These findings are corroborated by an impairment in zebrafish hatching, survival, and development in vivo upon their embryonic exposure to the nanoplastic. Together, this study has uncovered the dynamics and mechanism of amyloidogenesis elevated by a nanoplastic trigger, shedding a new light on the neurological burden of plastic pollution.

Uncovering Intermolecular Interactions Driving the Liquid-Liquid Phase Separation of the TDP-43 Low-Complexity Domain via Atomistic Dimerization Simulations.

Liquid-liquid phase separation (LLPS) of transactive response DNA-binding protein of 43 kDa (TDP-43), which exerts multiple functions in the splicing, trafficking, and stabilization of RNA, mediates the formation of membraneless condensates with crucial physiological roles, while its aberrant LLPS is linked to multiple neurodegenerative diseases. However, due to the heterogeneous and dynamic nature of LLPS, major gaps remain in understanding the precise intermolecular interactions driving LLPS and how specific mutations alter LLPS dynamics. Here, we investigated the molecular mechanisms underlying the LLPS of the TDP-43 low-complexity domain (LCD) by simulating the dimerization process using all-atom discrete molecular dynamics with microsecond-long simulations. Our results showed that the TDP-43 LCD was intrinsically disordered, with helical structures consistent with prior nuclear magnetic resonance studies. Phase separation propensity was assessed by simulating the dimerization of the TDP-43 LCD and four mutants, showing that A321G, W334G, and M337V inhibited self-association, while G335D promoted it, fully consistent with experimental reports. During the dimerization process, two peptides experienced both elastic and nonelastic collisions, and the self-associated dimer featured both high- and low-contact states. These results suggested that the dimerization process of the TDP-43 LCD was accordingly dynamic and heterogeneous. Additionally, we identified crucial regions containing hydrophobic clusters and aromatic residues in the N-terminus, central region, and C-terminus that were essential for the self-association of the TDP-43 LCD. These residues with high binding affinities can act as stickers to form peptide networks in LLPS. Together, our simulation provides a comprehensive picture of the intermolecular interactions driving the phase separation of the TDP-43 LCD, offering insights into both physiological functions and pathological mechanisms.

Serum apolipoprotein A-I depletion is causative to silica nanoparticles-induced cardiovascular damage.

The rapid development of nanotechnology has greatly benefited modern science and engineering and also led to an increased environmental exposure to nanoparticles (NPs). While recent research has established a correlation between the exposure of NPs and cardiovascular diseases, the intrinsic mechanisms of such a connection remain unclear. Inhaled NPs can penetrate the air-blood barrier from the lung to systemic circulation, thereby intruding the cardiovascular system and generating cardiotoxic effects. In this study, on-site cardiovascular damage was observed in mice upon respiratory exposure of silica nanoparticles (SiNPs), and the corresponding mechanism was investigated by focusing on the interaction of SiNPs and their encountered biomacromolecules en route. SiNPs were found to collect a significant amount of apolipoprotein A-I (Apo A-I) from the blood, in particular when the SiNPs were preadsorbed with pulmonary surfactants. While the adsorbed Apo A-I ameliorated the cytotoxic and proinflammatory effects of SiNPs, the protein was eliminated from the blood upon clearance of the NPs. However, supplementation of Apo A-I mimic peptide mitigated the atherosclerotic lesion induced by SiNPs. In addition, we found a further declined plasma Apo A-I level in clinical silicosis patients than coronary heart disease patients, suggesting clearance of SiNPs sequestered Apo A-I to compromise the coronal protein's regular biological functions. Together, this study has provided evidence that the protein corona of SiNPs acquired in the blood depletes Apo A-I, a biomarker for prediction of cardiovascular diseases, which gives rise to unexpected toxic effects of the nanoparticles.

Exploring Peptido-Nanocomposites in the Context of Amyloid Diseases.

Therapeutic peptides are a major class of pharmaceutical drugs owing to their target-binding specificity as well as their versatility in inhibiting aberrant protein-protein interactions associated with human pathologies. Within the realm of amyloid diseases, the use of peptides and peptidomimetics tailor-designed to overcome amyloidogenesis has been an active research endeavor since the late 90s. In more recent years, incorporating nanoparticles for enhancing the biocirculation and delivery of peptide drugs has emerged as a frontier in nanomedicine, and nanoparticles have further demonstrated a potency against amyloid aggregation and cellular inflammation to rival strategies employing small molecules, peptides, and antibodies. Despite these efforts, however, a fundamental understanding of the chemistry, characteristics and function of peptido-nanocomposites is lacking, and a systematic analysis of such strategy for combating a range of amyloid pathogeneses is missing. Here we review the history, principles and evolving chemistry of constructing peptido-nanocomposites from bottom up and discuss their future application against amyloid diseases that debilitate a significant portion of the global population.

Direct Observation of Seeded Conformational Conversion of hIAPP In Silico Reveals the Mechanisms for Morphological Dependence and Asymmetry of Fibril Growth.

Rapid growth of amyloid fibrils via a seeded conformational conversion of monomers is a critical step of fibrillization and important for disease transmission and progression. Amyloid fibrils often display diverse morphologies with distinct populations, and yet the molecular mechanisms of fibril elongation and their corresponding morphological dependence remain poorly understood. Here, we computationally investigated the single-molecular growth of two experimentally resolved human islet amyloid polypeptide fibrils of different morphologies. In both cases, the incorporation of monomers into preformed fibrils was observed. The conformational conversion dynamics was characterized by a small number of fibril growth intermediates. Fibril morphology affected monomer binding at fibril elongation and lateral surfaces as well as the seeded conformational conversion dynamics at the fibril ends, resulting in different fibril elongation rates and populations. We also observed an asymmetric fibril growth as in our prior experiments, attributing to differences of two fibril ends in terms of their local surface curvatures and exposed hydrogen-bond donors and acceptors. Together, our mechanistic findings afforded a theoretical basis for delineating different amyloid strains-entailed divergent disease progression.

New Monoterpenoid Indole Alkaloids from Tabernaemontana crassa Inhibit ß-Amyloid42 Production and Phospho-Tau (Thr217).

Eleven monoterpenoid indole alkaloids, including three new ones, tabercrassines A-C (1-3), were isolated from the seeds of Tabernaemontana crassa. Tabercrassine A (1) is an ibogan-ibogan-type bisindole alkaloid which is formed by the polymerization of two classic ibogan-type monomers through a C3 unit aliphatic chain. Their structures were established by extensive analysis of HRESIMS, NMR, and ECD spectra. Cellular assays showed that alkaloids 1-3 all reduce Aß42 production and inhibit phospho-tau (Thr217), a new biomarker of Alzheimer's disease [AD] associated with BACE1-, NCSTN-, GSK3ß-, and CDK5-mediated pathways, suggesting these alkaloids' potential against AD.

Chemical and Biophysical Signatures of the Protein Corona in Nanomedicine.

An inconvenient hurdle in the practice of nanomedicine is the protein corona, a spontaneous collection of biomolecular species by nanoparticles in living systems. The protein corona is dynamic in composition and may entail improved water suspendability and compromised delivery and targeting to the nanoparticles. How much of this nonspecific protein ensemble is determined by the chemistry of the nanoparticle core and its surface functionalization, and how much of this entity is dictated by the biological environments that vary spatiotemporally in vivo? How do we "live with" and exploit the protein corona without significantly sacrificing the efficacy of nanomedicines in diagnosing and curing human diseases? This article discusses the chemical and biophysical signatures of the protein corona and ponders challenges ahead for the field of nanomedicine.

Modulating Nanodroplet Formation En Route to Fibrillization of Amyloid Peptides with Designed Flanking Sequences.

Soluble oligomers populating early amyloid aggregation can be regarded as nanodroplets of liquid-liquid phase separation (LLPS). Amyloid peptides typically contain hydrophobic aggregation-prone regions connected by hydrophilic linkers and flanking sequences, and such a sequence hydropathy pattern drives the formation of supramolecular structures in the nanodroplets and modulates subsequent fibrillization. Here, we studied LLPS and fibrillization of coarse-grained amyloid peptides with increasing flanking sequences. Nanodroplets assumed lamellar, cylindrical micellar, and spherical micellar structures with increasing peptide hydrophilic/hydrophobic ratios, and such morphologies governed subsequent fibrillization processes. Adding glycine-serine repeats as flanking sequences to Aß16-22, the amyloidogenic core of amyloid-ß, our computational predictions of morphological transitions were corroborated experimentally. The uncovered inter-relationships between the peptide sequence pattern, oligomer/nanodroplet morphology, and fibrillization pathway, kinetics, and structure may contribute to our understanding of pathogenic amyloidosis in aging, facilitate future efforts ameliorating amyloidosis through peptide engineering, and aid in the design of novel amyloid-based functional nanobiomaterials and nanocomposites.