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Tripterygium glycosides tablets (TGT) are effective against autoimmune diseases but cause significant drug-induced liver injury (DILI) that limits clinical use. While TGT disrupts hepatic iron-lipid homeostasis and co-administration with Total Glucosides of Peony (TGP) mitigates its toxicity, the multi-cellular mechanisms remain unclear. In the current study, using integrative single-cell RNA sequencing and pathological validation in controlled mouse models (TGT vs.Con and TGT + TGP vs. TGT.) we elucidated a pathogenic iron-lipid axis driving hepatotoxicity via cellular cascades. TGT initiated Kupffer cell M1 polarization, releasing pro-inflammatory cytokines (TNF-α and IL-1β) that recruited neutrophils and induced NETosis-mediated oxidative stress. Concurrently, hepatic endothelial cells developed iron overload with increased Hamp and decreased Slc40a1, alongside inflammatory damage, while hepatocytes exhibited fatty acid metabolic dysfunction and lipid peroxidation, collectively propagating adipocyte hyperplasia and perilipin-2-driven lipid accumulation. Critically, TGP rescued toxicity by reversing Kupffer cell M1-to-M2 polarization with decreased iNOS and increased CD206, suppressing NET formation with decreased Ly6G and CitH3, alleviating iron deposition with reduced Prussian blue staining, and normalizing lipid metabolism with decreased oil red O staining and perilipin-2. This study identifies the iron-lipid axis as the central driver of TGT-induced liver injury, which is mediated by a sequential multi-cellular cascade involving Kupffer cells, neutrophils, endothelial cells, hepatocytes, and adipocytes. These findings position TGP as a multi-target detoxification agent that mechanistically disrupts this axis and establishes a cellular hierarchy blueprint for metabolic toxicity intervention, supporting its potential as a rescue strategy for precision medicine and detoxification screening. Graphical abstract

Due to changes in the dietary structure of individuals, the incidence of digestive tract tumors has increased significantly in recent years, causing a serious threat to the life and health of patients. This has in turn led to an increase in cancer prevention research. Many studies have shown that epigallocatechin-3-gallate (EGCG), an active ingredient in green tea, is in direct contact with the digestive tract upon ingestion, which allows it to elicit a significant antagonizing effect on digestive tract tumors. The main results of EGCG treatment include the prevention of tumor development in the digestive tract and the induction of cell cycle arrest and apoptosis. EGCG can be orally administered, is safe, and combats other resistances. The synergistic use of cancer drugs can promote the efficacy and reduce the anti-allergic properties of drugs, and is thus, favored in medical research. EGCG, however, currently possesses several shortcomings such as poor stability and low bioavailability, and its clinical application prospects need further development. In this paper, we have systematically summarized the research progress on the ability of EGCG to antagonize the activity and mechanism of action of digestive tract tumors, to achieve prevention, alleviation, delay, and even treat human gastrointestinal tract tumors via exogenous dietary EGCG supplementation or the development of new drugs containing EGCG.

Traumatic spinal cord injury (SCI) is a devastating neurological condition that results in a loss of motor and sensory function. Although extensive research to develop treatments for SCI has been performed, to date, none of these treatments have produced a meaningful amount of functional recovery after injury. The primary injury is caused by the initial trauma to the spinal cord and results in ischemia, oxidative damage, edema, and glutamate excitotoxicity. This process initiates a secondary injury cascade, which starts just a few hours post-injury and may continue for more than 6 months, leading to additional cell death and spinal cord damage. Inflammation after SCI is complex and driven by a diverse set of cells and signaling molecules. In this review, we utilize an extensive literature survey to develop the timeline of local immune cell and cytokine behavior after SCI in rodent models. We discuss the precise functional roles of several key cytokines and their effects on a variety of cell types involved in the secondary injury cascade. Furthermore, variations in the inflammatory response between rats and mice are highlighted. Since current SCI treatment options do not successfully initiate functional recovery or axonal regeneration, identifying the specific mechanisms attributed to secondary injury is critical. With a more thorough understanding of the complex SCI pathophysiology, effective therapeutic targets with realistic timelines for intervention may be established to successfully attenuate secondary damage.

The management of diabetic ulcer (DU) to rescue stalled wound healing remains a paramount clinical challenge due to the spatially and temporally coupled pathological wound microenvironment that features hyperglycemia, biofilm infection, hypoxia and excessive oxidative stress. Here we present a pH-switchable nanozyme cascade catalysis (PNCC) strategy for spatial–temporal modulation of pathological wound microenvironment to rescue stalled healing in DU. The PNCC is demonstrated by employing the nanozyme of clinically approved iron oxide nanoparticles coated with a shell of glucose oxidase (Fe 3 O 4 -GOx). The Fe 3 O 4 -GOx possesses intrinsic glucose oxidase (GOx), catalase (CAT) and peroxidase (POD)-like activities, and can catalyze pH-switchable glucose-initiated GOx/POD and GOx/CAT cascade reaction in acidic and neutral environment, respectively. Specifically, the GOx/POD cascade reaction generating consecutive fluxes of toxic hydroxyl radical spatially targets the acidic biofilm (pH ~ 5.5), and eradicates biofilm to shorten the inflammatory phase and initiate normal wound healing processes. Furthermore, the GOx/CAT cascade reaction producing consecutive fluxes of oxygen spatially targets the neutral wound tissue, and accelerates the proliferation and remodeling phases of wound healing by addressing the issues of hyperglycemia, hypoxia, and excessive oxidative stress. The shortened inflammatory phase temporally coupled with accelerated proliferation and remodeling phases significantly speed up the normal orchestrated wound-healing cascades. Remarkably, this Fe 3 O 4 -GOx-instructed spatial–temporal remodeling of DU microenvironment enables complete re-epithelialization of biofilm-infected wound in diabetic mice within 15 days while minimizing toxicity to normal tissues, exerting great transformation potential in clinical DU management. The proposed PNCC concept offers a new perspective for complex pathological microenvironment remodeling, and may provide a powerful modality for the treatment of microenvironment-associated diseases. Graphical Abstract

Reactive oxygen species (ROS)-induced apoptosis is a promising treatment strategy for malignant neoplasms. However, current systems are highly dependent on oxygen status and/or external stimuli to generate ROS, which greatly limit their therapeutic efficacy particularly in hypoxic tumors. Herein, we develop a biomimetic nanoflower based on self-assembly of nanozymes that can catalyze a cascade of intracellular biochemical reactions to produce ROS in both normoxic and hypoxic conditions without any external stimuli. In our formulation, PtCo nanoparticles are firstly synthesized and used to direct the growth of MnO 2 . By adjusting the ratio of reactants, highly-ordered MnO 2 @PtCo nanoflowers with excellent catalytic efficiency are obtained, where PtCo behaves as oxidase mimic and MnO 2 functions as catalase mimic. In this way, the well-defined MnO 2 @PtCo nanoflowers not only can relieve hypoxic condition but also induce cell apoptosis significantly through ROS-mediated mechanism, thereby resulting in remarkable and specific inhibition of tumor growth. Hypoxic tumors are resistant to dynamic therapy, limiting potential treatment options. Here, the authors describe a nanoflower where oxidase mimicking PtCo nanoparticles are decorated with catalase mimicking MnO 2 to reverse tumor hypoxia and generate reactive oxygen species for dynamic therapy.

Bioinspired multi-compartment architectures are desired in synthetic biology and metabolic engineering, as credited by their cell-like structures and intrinsic ability of assembling catalytic species for spatiotemporal control over cascade reactions like in living systems. Herein, we describe a general Pickering double emulsion-directed interfacial synthesis method for the fabrication of multicompartmental MOF microreactors. This approach employs multiple liquid–liquid interfaces as a controllable platform for the self-completing growth of dense MOF layers, enabling the microreactor with tailor-made inner architectures and selective permeability. Importantly, simultaneous encapsulation of incompatible functionalities, including hydrophilic enzyme and hydrophobic molecular catalyst, can be realized in a single MOF microreactor for operating chemo-enzymatic cascade reactions. As exemplified by the Grubb’ catalyst/CALB lipase driven olefin metathesis/ transesterification cascade reaction and glucose oxidase (GOx)/Fe-porphyrin catalyzed oxidation reaction, the multicompartmental microreactor exhibits 2.24–5.81 folds enhancement in cascade reaction efficiency in comparison to the homogeneous counterparts or physical mixture of individual analogues, due to the restrained mutual inactivation and substrate channelling effects. Our study prompts further design of multicompartment systems and the development of artificial cells capable of complex cellular transformations. The cell-like structures and the ability of assembling catalytic species are interesting features of bioinspired multicompartment architectures but it remains a challenge to build them. Here, the authors describe a Pickering double emulsion-directed interfacial synthesis to fabricate multi-compartmented metal-organic framework microreactors. The cell-like structures and the ability of assembling catalytic species are interesting features of bioinspired multicompartment architectures but it remains a challenge to build them. Here, the authors describe a Pickering double emulsion-directed interfacial synthesis to fabricate multi-compartmented metal-organic framework microreactors.

Cells may die from accidental cell death (ACD) or regulated cell death (RCD). ACD is a biologically uncontrolled process, whereas RCD involves tightly structured signaling cascades and molecularly defined effector mechanisms. A growing number of novel non-apoptotic forms of RCD have been identified and are increasingly being implicated in various human pathologies. Here, we critically review the current state of the art regarding non-apoptotic types of RCD, including necroptosis, pyroptosis, ferroptosis, entotic cell death, netotic cell death, parthanatos, lysosome-dependent cell death, autophagy-dependent cell death, alkaliptosis and oxeiptosis. The in-depth comprehension of each of these lethal subroutines and their intercellular consequences may uncover novel therapeutic targets for the avoidance of pathogenic cell loss.

A DNA nanostructure can be used to create a multi-enzyme complex in which an artificial swinging arm facilitates hydride transfer between two coupled dehydrogenases. Swinging arms are a key functional component of multistep catalytic transformations in many naturally occurring multi-enzyme complexes 1 . This arm is typically a prosthetic chemical group that is covalently attached to the enzyme complex via a flexible linker, allowing the direct transfer of substrate molecules between multiple active sites within the complex 2 , 3 , 4 . Mimicking this method of substrate channelling outside the cellular environment requires precise control over the spatial parameters of the individual components within the assembled complex. DNA nanostructures can be used to organize functional molecules with nanoscale precision 5 , 6 , 7 and can also provide nanomechanical control 8 , 9 , 10 , 11 . Until now, protein–DNA assemblies 12 have been used to organize cascades of enzymatic reactions by controlling the relative distance and orientation of enzymatic components 13 , 14 , 15 , 16 or by facilitating the interface between enzymes/cofactors and electrode surfaces 17 , 18 . Here, we show that a DNA nanostructure can be used to create a multi-enzyme complex in which an artificial swinging arm facilitates hydride transfer between two coupled dehydrogenases. By exploiting the programmability of DNA nanostructures, key parameters including position, stoichiometry and inter-enzyme distance can be manipulated for optimal activity.

An important goal of synthetic biology is to create biochemical control systems with the desired characteristics from scratch. Srinivas et al. describe the creation of a biochemical oscillator that requires no enzymes or evolved components, but rather is implemented through DNA molecules designed to function in strand displacement cascades. Furthermore, they created a compiler that could translate a formal chemical reaction network into the necessary DNA sequences that could function together to provide a specified dynamic behavior. Science , this issue p. eaal2052 A compiler specifies dynamic response behaviors in DNA strand displacement reactions. Chemistries exhibiting complex dynamics—from inorganic oscillators to gene regulatory networks—have been long known but either cannot be reprogrammed at will or rely on the sophisticated enzyme chemistry underlying the central dogma. Can simpler molecular mechanisms, designed from scratch, exhibit the same range of behaviors? Abstract chemical reaction networks have been proposed as a programming language for complex dynamics, along with their systematic implementation using short synthetic DNA molecules. We developed this technology for dynamical systems by identifying critical design principles and codifying them into a compiler automating the design process. Using this approach, we built an oscillator containing only DNA components, establishing that Watson-Crick base-pairing interactions alone suffice for complex chemical dynamics and that autonomous molecular systems can be designed via molecular programming languages.

This review summarized heat stress-mediated morphological and physiological changes in maize and elucidated the molecular mechanisms responsible for maize response to heat stress. Furthermore, plausible approaches to dissecting the regulatory network associated with heat stress response and improving maize adaptation to global warming have been discussed. This figure was made using BioRender . An increase in temperature and extreme heat stress is responsible for the global reduction in maize yield. Heat stress affects the integrity of the plasma membrane functioning of mitochondria and chloroplast, which further results in the over-accumulation of reactive oxygen species. The activation of a signal cascade subsequently induces the transcription of heat shock proteins. The denaturation and accumulation of misfolded or unfolded proteins generate cell toxicity, leading to death. Therefore, developing maize cultivars with significant heat tolerance is urgently required. Despite the explored molecular mechanism underlying heat stress response in some plant species, the precise genetic engineering of maize is required to develop high heat-tolerant varieties. Several agronomic management practices, such as soil and nutrient management, plantation rate, timing, crop rotation, and irrigation, are beneficial along with the advanced molecular strategies to counter the elevated heat stress experienced by maize. This review summarizes heat stress sensing, induction of signaling cascade, symptoms, heat stress-related genes, the molecular feature of maize response, and approaches used in developing heat-tolerant maize varieties.