The Type III Secretion System (T3SS) serves as a pivotal virulence apparatus for numerous Gram-negative bacterial pathogens, enabling them to infect both animal and plant hosts. Functioning as a molecular syringe, the T3SS directly translocates bacterial effector proteins from the bacterial cytoplasm into the interior of eukaryotic host cells. These effectors are central weapons that precisely manipulate a wide spectrum of host cellular physiological processes, ranging from cytoskeletal dynamics to immune signaling, to establish a favorable niche for bacterial survival and proliferation. Among the diverse arsenal of T3SS effectors, the YopJ family constitutes a critical group of virulence factors. Members of this family are characterized by a conserved catalytic triad structure—a hallmark of the CE clan of cysteine proteases that has been evolutionarily repurposed to confer acetyltransferase activity. A defining and intriguing feature of these enzymes is their stringent dependence on a host-derived eukaryotic cofactor, inositol hexakisphosphate (IP₆), for allosteric activation. This requirement acts as a sophisticated molecular safeguard, ensuring enzymatic activity only within the appropriate host environment, thereby preventing detrimental effects on the bacterium itself. While seminal studies on individual members such as Yersinia’s YopJ and Salmonella’s AvrA have provided deep mechanistic insights, a systematic and integrative understanding of the structure-function relationships across the entire family remains fragmented. Key questions persist regarding how a conserved catalytic core has diverged to recognize distinct host substrates in different kingdoms of life. To address this gap, this article provides a systematic review of the YopJ family, focusing on three interconnected aspects: their structural features, their catalytic mechanism, and their divergent immunosuppressive strategies in animal versus plant hosts. By conducting a comparative analysis of the sequences and resolved three-dimensional structures of three representative members (e.g., HopZ1a, PopP2, AvrA), we elucidate regions of significant variation embedded within the conserved core catalytic architecture. These variable regions, often involving surface loops and substrate-binding interfaces, are crucial determinants of target specificity and functional specialization. The functional divergence of this effector family is most apparent when comparing their modes of action in different hosts. In animal hosts, YopJ-family effectors primarily sabotage innate immune signaling pathways. They achieve this by acetylating key serine and threonine residues within the activation loops of critical kinases in the MAPK and NF‑κB pathways. This post-translational modification blocks the phosphorylation and subsequent activation of these kinases, leading to potent suppression of inflammatory cytokine production. Conversely, in plant hosts, the strategy broadens to dismantle the two-tiered plant immune system. YopJ homologs target a more diverse set of substrates, including immune-associated receptor-like cytoplasmic kinases (RLCKs), microtubule networks via tubulin acetylation (which disrupts cellular trafficking and signaling), and transcription factors central to defense gene regulation. This multi-target approach effectively suppresses both Pattern-Triggered Immunity (PTI) and Effector-Triggered Immunity (ETI). In conclusion, this synthesis aims to deepen the mechanistic understanding of YopJ family-mediated pathogenesis by integrating structural biology with cellular function across host kingdoms. Elucidating the precise molecular basis for substrate selection—how conserved platforms achieve target diversity—is a major frontier. Furthermore, this knowledge provides a vital theoretical foundation for developing novel anti-virulence strategies. Targeting the conserved IP₆-binding pocket or the catalytic acetyltransferase activity itself represents a promising avenue for designing broad-spectrum inhibitors that could disarm this critical family of bacterial effectors, potentially offering new therapeutic approaches against a range of pathogenic bacteria.

OBJECTIVE To investigate the mechanism by which Qiaobai cold compress solution （QBCS） improves acne vulgaris （AV） based on transcriptomics and animal experiments. METHODS Rats were randomly divided into a blank control group （ n ＝6） and a modeling group （ n ＝30）. AV models were established in the modeling group by topical application of oleic acid to the inner surface of both ears， combined with subcutaneous injection of Cutibacterium acnes suspension into the auricle. Successfully modeled rats were further divided into the model group， positive control group （Tretinoin cream， 0.045 g/kg）， and QBCS low-， medium-， high-dose groups [3.55， 7.11， 14.22 g/kg （calculated by the amount of crude drug） ] ， with 6 rats in each group. Rats in each d rug group were treated with the corresponding drugs once daily for 14 consecutive days. After the final administration， changes in the appearance of the ears and histopathological changes in the ear tissues were observed， and serum levels of inflammatory factors， including tumor necrosis factor-α （TNF-α）， interleukin-6 （IL-6） and IL-1β， were measured. Auricular tissues from the blank control group， model group and QBCS medium-dose group were collected for transcriptome sequencing. Differential expressed genes （DEGs） were screened and subjected to Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis， followed by validation using real-time quantitative polymerase chain reaction and Western blot assay. RESULTS Compared with the model group， rats in all QBCS groups showed alleviated auricular acne symptoms， with reduced epidermal thickening， sebaceous gland hyperplasia， and inflammatory cell infiltration. Serum levels of TNF-α （except for the QBCS low-dose group）， IL-6 （except for the QBCS low-dose group） and IL-1β were significantly decreased （ P ＜0.05）. A total of 590 DEGs were identified （blank control group vs. model group）， and 596 DEGs were identified （model group vs. QBCS medium-dose group）. Above DEGs （blank control group vs. model group） were mainly enriched in Toll-like receptor （TLR） and nuclear factor-kappa B （NF-κB） signaling pathways， etc. Validation experiments showed that， compared with model group， low-， medium- and high-dose of QBCS reduced， to varying degrees， the mRNA expression of TNF-α， TLR2， interferon-γ and CXC chemokine ligand 8 in the auricular tissues of AV rats， increased the mRNA expression of peroxisome-proliferator-activated receptor gamma and tumor protein 53， and inhibited the phosphorylation of NF-κB p65 protein as well as the expressions of TLR2 and myeloid differentiation primary response protein 88（MyD88） （ P ＜0.05）. CONCLUSIONS QBCS can alleviate auricular inflammation and skin lesions in AV rats. This effect may be related to inhibition of the TLR/MyD88/NF-κB signaling pathway， thereby suppressing the expression of downstream inflammatory factors such as TNF-α.

Objective: To investigate the relationship between 24 hour activity behaviors and fine motor development in preschool children, and to simulate the effects of reallocating time among different activity behaviors on fine motor development using isotemporal substitution analysis. Methods: From March to July 2022, a stratified cluster random sampling method was used to recruit 447 preschool children aged 3-6 years (254 boys and 193 girls) from Pingxiang City, Jiangxi Province. The 24 hour activity behaviors in preschool children were measured using ActiGraph wGT3-BT accelerometers and subjective sleep reports. Fine motor development was assessed using the Gesell Developmental Schedules. A component linear regression model was employed to analyze the impact of 24 hour activity behaviors on the development of fine motor activities, and the potential effects of adjusting activity behaviors were simulated through an isochoric substitution model. Results: The daily durations of sedentary behavior (SB) was ( 572.92 ±102.96) min (accounting for 39.79% of 24 h), the duration of light physical activity (LPA) was (131.21± 38.11 ) min ( 9.11% ), the duration of moderate to vigorous physical activity (MVPA) was (65.61±22.21) min (4.56%), and sleep duration was (670.65±57.58) min (46.82%). Sleep composition was positively associated with fine motor development ( β =2.74), while MVPA ( β =-0.84) and SB ( β =-1.93) compositions were negatively associated with fine motor development (all P <0.01). Isochoric substitution analysis showed that sleep had positive effects on the development of fine motor skills when replacing other activity behaviors (all P < 0.05), with the substitution effect for MVPA being the most significant and gradually increasing with the duration of substitution (60 min: β =28.66); sleep replacement of SB and LPA also showed positive effects (60 min: β =4.25, 2.00) (all P < 0.05). On the contrary, the substitution of sleep with MVPA showed negative effects (60 min: β =-7.86), and the substitution of LPA and SB with MVPA also showed negative effects (60 min: β =-5.65, -3.40) (all P <0.05). Conclusions The overall composition of 24 hour activity behaviors is associated with fine motor development in preschool children, with sleep playing a crucial role. Ensuring adequate sleep and optimizing the structure of activity behaviors may effectively promote the development of fine motor skills in preschool children.

To investigate the clinical characteristics and prognosis of extracranial malignant rhabdoid tumor (eMRT) in children, and to provide a reference for the clinical treatment of this disease.

Diabetic nephropathy（DN） is a common and severe microvascular complication of diabetes. In recent years， the classical herbal formula Shenqi dihuang decoction has demonstrated unique advantages in the clinical treatment of DN. This article conducts a systematic review of the mechanisms of action and clinical applications of Shenqi dihuang decoction in the treatment of DN. It reveals that the mechanism by which this formula improves DN involves multi-target synergistic regulation. For instance, Shenqi dihuang decoction exerts multiple pharmacological effects by regulating signaling pathways including phosphatidy linostiol 3-kinase/protein kinase B， AMP-activated protein kinase/silent information regulator 1/forkhead box O1， and nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathways.These effects include regulating glucose and lipid metabolism， inhibiting oxidative stress， reducing inflammation， improving insulin resistance， modulating cell death （apoptosis/autophagy/ferroptosis/pyroptosis）， and preventing renal fibrosis. Existing clinical studies indicate that Shenqi dihuang decoction and its modified formulas， alone or in combination with other therapeutic methods， can significantly improve glucose and lipid metabolism， reduce proteinuria， and delay renal function decline in patients with DN. These effects are superior to those of Western medicines such as irbesartan， valsartan， and empagliflozin， and the treatment demonstrates good safety. Future research should leverage systems biology and artificial intelligence technologies to further elucidate the integrated mechanisms in the treatment of DN by Shenqi dihuang decoction， thereby advancing the precision and standardization of its clinical application.

Mitochondria, the primary energy-producing organelles of the cell, also serve as signaling hubs and participate in diverse physiological and pathological processes, including apoptosis, inflammation, oxidative stress, neurodegeneration, and tumorigenesis. As semi-autonomous organelles, mitochondrial functionality relies on nuclear support, with mitochondrial biogenesis and homeostasis being stringently regulated by the nuclear genome. This interdependency forms a bidirectional signaling network that coordinates cellular energy metabolism, gene expression, and functional states. During mitochondrial damage or dysfunction, retrograde signals are transmitted to the nucleus, activating adaptive transcriptional programs that modulate nuclear transcription factors, reshape nuclear gene expression, and reprogram cellular metabolism. This mitochondrion-to-nucleus communication, termed “mitochondrial retrograde signaling”, fundamentally represents a mitochondrial “request” to the nucleus to maintain organellar health, rooted in the semi-autonomous nature of mitochondria. Despite possessing their own genome, the “fragmented” mitochondrial genome necessitates reliance on nuclear regulation. This genomic incompleteness enables mitochondria to sense and respond to cellular and environmental stressors, generating signals that modulate the functions of other organelles, including the nucleus. Evolutionary transfer of mitochondrial genes to the nuclear genome has established mitochondrial control over nuclear activities via retrograde communication. When mitochondrial dysfunction or environmental stress compromises cellular demands, mitochondria issue retrograde signals to solicit nuclear support. Studies demonstrate that mitochondrial retrograde signaling pathways operate in pathological contexts such as oxidative stress, electron transport chain (ETC) impairment, apoptosis, autophagy, vascular tension, and inflammatory responses. Mitochondria-related diseases exhibit marked heterogeneity but invariably result in energy deficits, preferentially affecting high-energy-demand tissues like muscles and the nervous system. Consequently, mitochondrial dysfunction underlies myopathies, neurodegenerative disorders, metabolic diseases, and malignancies. Dysregulated retrograde signaling triggers proliferative and metabolic reprogramming, driving pathological cascades. Mitochondrial retrograde signaling critically influences tumorigenesis and progression. Tumor cells with mitochondrial dysfunction exhibit compensatory upregulation of mitochondrial biogenesis, excessive superoxide production, and ETC overload, collectively promoting metastatic tumor development. Recent studies reveal that mitochondrial retrograde signaling—mediated by altered metabolite levels or stress signals—induces epigenetic modifications and is intricately linked to tumor initiation, malignant progression, and therapeutic resistance. For instance, mitochondrial dysfunction promotes oncogenesis through mechanisms such as epigenetic dysregulation, accumulation of mitochondrial metabolic intermediates, and mitochondrial DNA (mtDNA) release, which activates the cytosolic cGAS-STING signaling pathway. In normal cells, miR-663 mediates mitochondrion-to-nucleus retrograde signaling under reactive oxygen species (ROS) regulation. Mitochondria modulate miR-663 promoter methylation, which governs the expression and supercomplex stability of nuclear-encoded oxidative phosphorylation (OXPHOS) subunits and assembly factors. However, dysfunctional mitochondria induce oxidative stress, elevate methyltransferase activity, and cause miR-663 promoter hypermethylation, suppressing miR-663 expression. Mitochondrial dysfunction also triggers retrograde signaling in primary mitochondrial diseases and contributes to neurodegenerative disorders such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). Current therapeutic strategies targeting mitochondria in neurological diseases focus on 5 main approaches: alleviating oxidative stress, inhibiting mitochondrial fission, enhancing mitochondrial biogenesis, mitochondrial protection, and insulin sensitization. In AD patients, mitochondrial morphological abnormalities and enzymatic defects, such as reduced pyruvate dehydrogenase and α-ketoglutarate dehydrogenase activity, are observed. Platelets and brains of AD patients exhibit diminished cytochrome c oxidase (COX) activity, correlating with mitochondrial dysfunction. To model AD-associated mitochondrial pathology, researchers employ cybrid technology, transferring mtDNA from AD patients into enucleated cells. These cybrids recapitulate AD-related mitochondrial phenotypes, including reduced COX activity, elevated ROS production, oxidative stress markers, disrupted calcium homeostasis, activated stress signaling pathways, diminished mitochondrial membrane potential, apoptotic pathway activation, and increased Aβ42 levels. Furthermore, studies indicate that Aβ aggregates in AD and α‑synuclein aggregates in PD trigger mtDNA release from damaged microglial mitochondria, activating the cGAS-STING pathway. This induces a reactive microglial transcriptional state, exacerbating neurodegeneration and cognitive decline. Targeting the cGAS-STING pathway may yield novel therapeutics for neurodegenerative diseases like AD, though translation from bench to bedside remains challenging. Such research not only deepens our understanding of disease mechanisms but also informs future therapeutic strategies. Investigating the triggers, core molecular pathways, and regulatory networks of mitochondrial retrograde signaling advances our comprehension of intracellular communication and unveils novel pathogenic mechanisms underlying malignancies, neurodegenerative diseases, and type 2 diabetes mellitus. This review summarizes established mitochondrial-nuclear retrograde signaling axes, their roles in interorganellar crosstalk, and pathological consequences of dysregulated communication. Targeted modulation of key molecules and proteins within these signaling networks may provide innovative therapeutic avenues for these diseases.

Objective To investigate the effective components and therapeutic mechanism of Chaihu-Guizhi-Ganjiang decoction in treating chronic non-atrophic gastritis. Methods The primary and secondary ion fragments of chemical components of Chaihu-Guizhi-Ganjiang decoction were obtained by UHPLC-Q-TOF/MS. Comparing with reference standards and literature information, a comprehensive characterization of the chemical constituents of Chaihu-Guizhi-Ganjiang decoction was conducted. Then, the network pharmacology approach was applied to explore the therapeutic mechanism of Chaihu-Guizhi-Ganjiang decoction in treatment of chronic non-atrophic gastritis based on the components in plasma and verified by immunohistochemical results. Results A total of 24 absorbed components of Chaihu-Guizhi-Ganjiang decoction were characterized, including 11 flavonoid glycosides, 3 fatty acids, 3organic acids, 2 gingerols, 2 flavonoids and, 1 each of fatty aldehydes, triterpenoids and amino acids, which mainly acted on TNF-α, IL-6, STAT3, and PTGS2. It exerted therapeutic effects by modulating signaling pathways, including the IL-17 signaling pathway and the AGE-RAGE signaling pathway, etc. Conclusion This study provided the first exploration of the effective components and therapeutic mechanism of Chaihu-Guizhi-Ganjiang decoction in treatment of chronic non-atrophic gastritis by UHPLC-Q-TOF/MS, which could offer scientific references for its further research.

BACKGROUND: Chronic kidney disease (CKD) is associated with common pathophysiological processes, such as inflammation and fibrosis, in both the heart and the kidney. However, the underlying molecular mechanisms that drive these processes are not yet fully understood. Therefore, this study focused on the molecular mechanism of heart and kidney injury in CKD. METHODS: We generated an microRNA (miR)-26a knockout (KO) mouse model to investigate the role of miR-26a in angiotensin (Ang)-II-induced cardiac and renal injury. We performed Ang-II modeling in wild type (WT) mice and miR-26a KO mice, with six mice in each group. In addition, Ang-II-treated AC16 cells and HK2 cells were used as in vitro models of cardiac and renal injury in the context of CKD. Histological staining, immunohistochemistry, quantitative real-time polymerase chain reaction (PCR), and Western blotting were applied to study the regulation of miR-26a on Ang-II-induced cardiac and renal injury. Immunofluorescence reporter assays were used to detect downstream genes of miR-26a, and immunoprecipitation was employed to identify the interacting protein of LIM and senescent cell antigen-like domain 1 (LIMS1). We also used an adeno-associated virus (AAV) to supplement LIMS1 and explored the specific regulatory mechanism of miR-26a on Ang-II-induced cardiac and renal injury. Dunnett's multiple comparison and t -test were used to analyze the data. RESULTS: Compared with the control mice, miR-26a expression was significantly downregulated in both the kidney and the heart after Ang-II infusion. Our study identified LIMS1 as a novel target gene of miR-26a in both heart and kidney tissues. Downregulation of miR-26a activated the LIMS1/integrin-linked kinase (ILK) signaling pathway in the heart and kidney, which represents a common molecular mechanism underlying inflammation and fibrosis in heart and kidney tissues during CKD. Furthermore, knockout of miR-26a worsened inflammation and fibrosis in the heart and kidney by inhibiting the LIMS1/ILK signaling pathway; on the contrary, supplementation with exogenous miR-26a reversed all these changes. CONCLUSIONS Our findings suggest that miR-26a could be a promising therapeutic target for the treatment of cardiorenal injury in CKD. This is attributed to its ability to regulate the LIMS1/ILK signaling pathway, which represents a common molecular mechanism in both heart and kidney tissues.
Animals ; MicroRNAs/metabolism* ; Angiotensin II/toxicity* ; Mice ; Renal Insufficiency, Chronic/chemically induced* ; Mice, Knockout ; Disease Models, Animal ; Male ; Signal Transduction/genetics* ; LIM Domain Proteins/genetics* ; Mice, Inbred C57BL ; Cell Line ; Humans