Patients with chronic pain commonly exhibit elevated inflammatory markers in the blood that correlate with reported pain and pain-related disability. Although inflammation is traditionally seen as a driver of chronic pain, recent transcriptomic data challenge this view, highlighting the beneficial role of acute inflammation in pain resolution. Here, we present evidence pointing to the overall dynamics of the inflammatory response being critical for pain resolution with the initial acute inflammatory response necessary to trigger pain resolution processes. We posit that chronic pain reflects an inability to resolve inflammation rather than its mere presence. Pharmacological or nonpharmacological reactivation of acute inflammatory pathways may thus provide novel therapeutic strategies targeting pain resolution instead of merely mitigating pain perception. This novel hypothesis regarding the effect of inflammation on pain is an example of what can be learned using unbiased approaches such as human transcriptomics. We believe that the near future will feature more examples of hypothesis generation using human genetics followed up by mechanistic experimentation in animal models.

Calcium/calmodulin-dependent protein kinase II (CAMKII) is a critical regulator of cardiac electrophysiology. However, the role of the four bases deletion polymorphism in Camk2d which codes delta subunit of CAMKII, particularly those involving intron sequences, remains poorly understood. This study aimed to investigate the impact of Camk2d c.1044+125_128delGTTT missing polymorphism on cardiac morphology and arrhythmogenesis in normal adult Sprague-Dawley (SD) rats. A total of 85 SD rats were genotyped by Sanger sequencing, revealing a distribution of 25.9% wild-type (WT), 48.2% heterozygous, and 25.9% homozygous variants. Echocardiography, Hematoxylin-Eosin staining, Masson's trichrome staining and transmission electron microscopy indicated no significant differences in cardiac structure or baseline function among the three groups. In freely moving rats, premature atrial arrhythmias were detected in 2 of 9 WT rats, 1 of 9 heterozygous rats, and 1 of 9 homozygous rats. Premature ventricular contractions (PVCs) were observed in none of 9 WT or homozygous rats, 3 of 9 heterozygous rats, with one heterozygous rat exhibiting frequent PVCs. Electrical programmed stimulation revealed a higher incidence of inducible atrial fibrillation in homozygous rats compared to WT rats and a higher incidence of inducible ventricular tachycardia in heterozygous rats compared to WT rats. These findings suggest that deletion polymorphism in the intron sequences of Camk2d are unexpectedly common in normal SD rat populations and that such polymorphism predispose to ventricular arrhythmias without overt structural heart disease. Our study highlights the potential arrhythmogenic risk associated with non-coding DNA sequence alterations in Camk2d and underscores the importance of genetic screening in experimental animal models.

Fei Wei formula attenuates pulmonary fibrosis by inhibiting lactate-driven endothelial mesenchymal transition via its target of HSP90ab1.

Abstract Description Scrub typhus is an understudied mite-borne disease, caused by intracellular bacteria Orientia tsutsugamushi (Ot). Humoral immunity in scrub typhus patients is short-lived, but the underlying mechanism remains unknown. There is also a knowledge gap regarding adaptive immune responses to clinically prevalent Ot strains, in humans or experimental animal models. This study used C57BL/6 mice with severe (Karp) and self-limiting Ot infection (Gilliam) with an objective of defining strain-associated differences in B cell and germinal center (GC) responses. Compared to the Karp counterparts, Gilliam-infected mice had lower splenic bacterial burdens, but showed 1) higher IgM, IgG, and IgG2c responses, 2) strong follicular and marginal zone B cell responses and expansion of regulatory T cell subsets, and 3) evidence of organized GCs that were maintained throughout infection. To verify whether GC loss during Karp infection was due to poorly regulated, excessive inflammatory responses, we compared spleen RNAseq profiles. Karp-infected mice had significant upregulation of pathways involved in inflammation (TNF, IFNg, IL-1) and recruitment of innate immune cells (neutrophils, eosinophils, macrophages, mononuclear cells) on days 4 and 8. In contrast, Gilliam-infected mice upregulated genes involved with B and T cell responses at day 12. Collectively, these Ot strain-related patterns help fill the knowledge gap of adaptive immune responses and explain transient immunity to scrub typhus. Funding Sources NIAID R01 AI132674 NIAID R21 AI156536 NIH T32-AI060549 Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)

Development of PLX-R18, a promising and novel countermeasure for radiation-associated injuries.

Mendelian Randomization Reveals Causalities Between DNA Methylation and Schizophrenia.

LINC00673 promotes osteosarcoma progression through the miR-92b-3p/DUSP1 axis.

Dihydroartemisinin inhibits galectin-1-induced ferroptosis resistance and peritoneal metastasis of gastric cancer via the Nrf2-HO-1 pathway.

Pulmonary arterial hypertension (PAH) is a progressive vascular disease characterized by pulmonary endothelial dysfunction, vascular remodeling, and right ventricular failure. Despite recent advances, the underlying molecular mechanisms remain incompletely understood, and curative treatments are still lacking. Loss of BMPR2 signaling is a hallmark of PAH pathogenesis, yet the mechanisms leading to BMPR2 destabilization are not fully defined. Smad ubiquitination regulatory factor 1 (Smurf1), an E3 ubiquitin ligase, has been implicated in the degradation of BMPR2 and downstream signaling proteins; however, the regulation of Smurf1 and its therapeutic potential remain largely unexplored. We assessed Smurf1 expression in lung tissues from PAH patients, experimental animal models, and pulmonary artery endothelial cells (PAECs). Epigenetic regulation of Smurf1 was examined using ChIP-qPCR, EP300 gain- and loss-of-function studies, and pharmacological inhibition with the selective EP300 inhibitor A485. Functional consequences of Smurf1 inhibition were evaluated in vitro using transcriptomic profiling, proliferation assays, and BMPR2-Smad signaling analyses. In vivo therapeutic efficacy was tested in monocrotaline (MCT)-induced PAH rats treated with the selective Smurf1 inhibitor Smurf1-IN-A01. Smurf1 expression was elevated in PAH patient lungs, experimental models, and PAECs. Increased histone H3K27 acetylation and EP300 occupancy at the Smurf1 promoter implicated epigenetic activation. EP300 inhibition reduced H3K27ac enrichment, suppressed Smurf1 expression, and restored BMPR2 signaling. Smurf1 blockade with Smurf1-IN-A01 reprogrammed the transcriptomic landscape of PAH-PAECs, downregulating inflammatory, fibrotic, and angiogenic gene networks. Functionally, Smurf1 inhibition decreased pathological endothelial proliferation and enhanced BMPR2-mediated Smad1/5/9 activation. In vivo, Smurf1- IN-A01 improved pulmonary hemodynamics, reduced vascular remodeling and fibrosis, and restored BMPR2 signaling in MCT-PAH rats. Our study identifies Smurf1 as an epigenetically regulated driver of endothelial dysfunction and vascular remodeling in PAH. Targeting Smurf1 restores BMPR2 signaling, reprograms pathogenic processes, and offers a novel therapeutic strategy for PAH.

Background: Periodontal disease, the most prevalent chronic inflammatory condition in dentistry, not only causes periodontal attachment loss, tooth mobility, and tooth loss, impacting mastication, aesthetics, and phonation, but also serves as a significant risk factor for various systemic diseases, posing a serious threat to overall human health. Consequently, investigating the pathogenesis of periodontal disease and developing effective preventive and therapeutic strategies are critical tasks in clinical dental research. Objective: To establish and evaluate experimental animal models applicable for periodontal disease research, and to systematically compare the advantages and disadvantages of different modeling methods, thereby providing a reference for related mechanistic studies and the development of therapeutic interventions. Methods: Through a literature review, we systematically summarized current common methods for constructing animal models of periodontal disease. This included the selection of small and large animal species, and various modeling techniques such as molar ligation, local gingival injection of lipopolysaccharide (LPS), local inoculation with periodontal pathogens, high-sugar diet induction, and chemical induction. Results: Different modeling methods possess distinct characteristics suitable for varying research objectives. Molar ligation is straightforward and reproducible but may cause mechanical damage; bacterial inoculation models more closely mimic the human disease process but require controlled infection conditions; dietary and chemical methods can simulate specific pathological conditions but often involve longer experimental periods. A comprehensive comparison provides a basis for model selection. Conclusion: Animal models are indispensable tools for studying the pathogenesis of periodontal disease and evaluating new therapies. The appropriate selection of a modeling method based on specific research needs enhances experimental reliability and applicability, thereby advancing research in the prevention and treatment of periodontal disease.

Depression is a debilitating mental disorder closely linked to neuroinflammation and dysregulated microglial activity. This study investigates a novel nanotherapeutic strategy utilizing geniposide (GEN)-loaded biomimetic nanoparticles (CSPG@CM) to target microglia and modulate heme oxygenase-1 (HMOX1), a key regulator of oxidative stress and neuroinflammation. Through the synergistic application of systems pharmacology frameworks, computational biological analysis, and both cell-based and animal experimental models, this study demonstrated that GEN-loaded nanoparticles significantly enhance drug bioavailability and specificity, facilitating precise microglial targeting. Treatment with CSPG@CM nanoparticles upregulates HMOX1 expression, suppresses pro-inflammatory cytokine release, and promotes neuronal survival. In a chronic unpredictable mild stress (CUMS) mouse model, CSPG@CM nanoparticles alleviate depressive behaviors, reduce neuroinflammation, and restore neuronal homeostasis. Compared to free GEN, the nanoparticle formulation exhibits superior therapeutic efficacy by overcoming limitations in traditional antidepressant treatments. These findings highlight the potential of nanoparticle-based drug delivery systems for precise modulation of neuroinflammatory pathways, offering a promising avenue for developing innovative antidepressant therapies.

BackgroundImmunogenic cell death (ICD) is a type of regulated cell death (RCD) that activates adaptive immune responses and shapes the immune microenvironment. Its role in idiopathic pulmonary fibrosis (IPF), a progressive and fatal lung disease, remains unclear. This study aims to identify ICD-related gene signatures and evaluate their prognostic value in IPF through bioinformatic analysis and experimental validation.MethodsGene expression profiles and clinical data from 176 IPF patients and 20 healthy controls were obtained from the GSE70866 dataset. A set of 34 ICD-related genes was curated from literature. Differential expression analysis, univariate Cox regression, and least absolute shrinkage and selection operator (LASSO)-penalized Cox regression were used to identify prognostic genes and construct a risk model. The model was validated internally and using an independent cohort (GSE70867). Immune cell infiltration was assessed via CIBERSORT. Expression of identified genes was further validated in a bleomycin-induced pulmonary fibrosis mouse model using quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) and Western blot.ResultsTen ICD-related genes were differentially expressed in IPF patients and associated with prognosis. A three-gene prognostic signature (IL10, CASP1, NLRP3) was established. Patients were stratified into high- and low-risk groups with significantly different overall survival (P<0.05). The risk score proved to be an independent prognostic factor for IPF. Time-dependent receiver operating characteristic (ROC) analysis showed strong predictive performance for 1-, 2-, and 3-year survival. Immune profiling revealed significant differences in mast cells, natural killer cells, and dendritic cells between risk groups. In the mouse model, mRNA and protein expression of IL10, CASP1, and NLRP3 were significantly upregulated in fibrotic lungs.ConclusionsWe developed and validated a novel ICD-related gene signature capable of predicting prognosis in IPF patients. The three-gene risk model may serve as a promising tool for risk stratification and personalized treatment planning in IPF.

BackgroundMedial arterial calcification (MAC) increases vascular stiffness and reduces arterial compliance, often leading to serious systemic vascular diseases. However, research progress in this field has been limited by the lack of effective animal models. To address this gap and facilitate MAC research, this study established a novel experimental animal model of MAC in wild-type C57BL/6J mice and developed corresponding pathological grading standards.MethodsTo establish an optimal MAC modeling protocol, we systematically compared key parameters, including wire diameter, modeling duration, and combination with a vitamin D3 (VD3) diet. The resulting model was then subjected to interventional treatments with various calcification inhibitors. For pathological assessment, a four-tier histopathological grading system was established to categorize calcification severity based on its extent and distribution. Tissue sections were analyzed by hematoxylin and eosin and Von Kossa staining. The expression of inflammatory factors and bone-related proteins was analyzed by immunohistochemistry (IHC), while macrophage markers (CD68, CD86) were further characterized by immunofluorescence (IF).ResultsThe most effective method was identified as endothelial injury of the common carotid artery (CCA) using a 0.45 mm rough guide wire combined with a VD3 diet for 3 months, achieving a 100% MAC incidence. Compared with those in the sham group, the CCAs of the mice in the experimental group were infiltrated with activated macrophages and inflammatory factors such as interleukin-1beta (IL-1β) and interleukin-6 (IL-6). Calcifcation inhibitors etidronate and SNF472 significantly prevented MAC occurrence, showing inhibition rates of 45.45% (P=0.006) and 50% (P=0.002), respectively, conpared to the VD3 group (Fisher’s exact test).ConclusionsThis study not only establishes a MAC animal model by inducing injury to the CCA combined with a VD3 diet but also introduces a corresponding pathological scoring system. Together, this model, coupled with this associated grading method, provides a valuable toolset for future basic medical research, drug screening, and investigations into the genetic mechanisms of MAC.

IntroductionEquine abortus salmonellosis, caused by Salmonella abortus equi (S. abortus equi), is a contagious disease primarily characterized by abortion in pregnant equine animals. Due to its high pathogenicity and increasing incidence, this disease has attracted significant scientific attention. While the causes of abortion in mares are multifactorial and may involve numerous pathogenic factors, the specific impact of S. abortus equi on the vaginal microecological environment and its pivotal role as the primary causative agent of abortion remain poorly understood.ResultsFurther analysis led to the successful isolation and identification of S. abortus equi from vaginal samples of aborted mares. A highly pathogenic isolate, designated as XJ2032, was selected for further analysis. To gain a more profound understanding of the functional genomic composition and genetic traits of this strain, whole-genome sequencing was conducted, and sophisticated bioinformatics techniques were employed to predict and annotate its gene sequences. Furthermore, animal model experiments, and PCR-based molecular biological detection methods were utilized to assess the virulence and drug resistance genes of the isolated strain XJ2032, further confirming its pathogenic potential.ConclusionWhole-genome sequencing analysis confirmed that strain XJ2032 is indeed S. abortus equi. Although its genome structure is largely conserved, some rearrangements and inversions were identified. The strain harbors multiple virulence genes and drug resistance genes, including horizontally transferable genes and mobile genetic elements. These findings suggest that genomic islands and bacteriophages play a vital role in the pathogenicity and genetic diversity of S. abortus equi.

Abstract Background and Aims Peritoneal dialysis (PD) fluids are designed to remove excess water and uremic toxins along an osmotic gradient created by high glucose concentrations (1,360–3,860 mg/dL). Multiple PD fluid exchanges per day add up to a glucose exposure of 50% of the recommended daily energy intake for a healthy diet by intraperitoneal administration alone. Albeit this glucose exposure has been associated with adverse metabolic outcomes in end-stage kidney disease (ESKD) patients on PD, mechanistic studies remain elusive. The aim of this study was to explore the systemic effects of PD induced glucose exposure and the underlying mechanisms leading to adverse clinical outcomes. Method In a murine animal experiment, PD was conducted for 7 weeks via an implanted PD catheter in healthy mice and mice with chronic kidney disease (CKD, via 5/6 nephrectomy). PD and CKD+PD groups were compared to healthy control (HC) and CKD mice otherwise housed and treated with identical conditions. Glucose absorption after intraperitoneal administration of PD fluid was assessed using dynamic small animal positron emission tomography (µPET) scans with subsequent computed tomography (CT) imaging and a glucose analog radiotracer (10 MBq 2-[18F]fluoro-2-deoxy-D-glucose, [18F]FDG). Systemic effects of PD induced glucose exposure were investigated with a combination of multiplexed single-cell imaging mass cytometry, untargeted tissue proteomics, spatial transcriptomics, and enzyme histochemistry of hepatic tissue, routine serum chemistry and targeted serum metabolomics, gut microbiome analysis with 16S rRNA sequencing, and immunofluorescence staining of the gut and gut-vascular barrier. Findings of the experimental animal models were then translated to a previously published cohort of patients on automated PD. In this clinical cohort relationships between peritoneal glucose loads and systemic effects were assessed using linear mixed-effects models. Results During PD treatment, intraperitoneally administered glucose was rapidly taken up by the liver, evident in dynamic µPET scans. Chronic PD treatment (independent of CKD effects) induced hepatic metabolic inflammation, with activation of acute phase response signaling (FDR P &amp;lt; 0.05), the liver X receptor/retinoid X receptor pathway (FDR P &amp;lt; 0.05), significant reduction of hepatic tissue resident macrophages (F4/80+CD11b-, P = 0.016), and glucose-to-cholesterol shunting with activation of fatty acid metabolism resulting in significantly elevated serum cholesterol levels (P = 0.00001) despite an absence of hepatic steatosis or glycogen storage. Hepatic tissue resident macrophage depletion was further associated with increased oxidative stress with pentose phosphate pathway cycling and lipopolysaccharide deposition in (peri) portal areas, without increased gut permeability or gut dysbiosis, but elevated serum bilirubin (P = 0.001). In a clinical cohort of n = 61 automated PD patients intraperitoneal glucose loads were significantly associated with serum gamma-glutamyl transferase levels as marker of hepatic oxidative stress (P = 0.007) and systemic inflammation (P = 0.000007). Conclusion This is the first study to report hepatic oxidative stress and metabolic inflammation induced by PD. The systemic effects of this hepatic glucotoxicity become further evident in stimulation of systemic inflammation in patients on PD. This suggests translatability of the identified pathomechanisms that may contribute to increased cardiometabolic risk in clinical PD. These findings reframe the current understanding of PD and its associated comorbidity burden and may allow to identify novel therapeutic approaches to improve clinical outcomes of ESKD patients on PD.

The rapid global spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) since 2019 emphasizes the need to understand its transmission routes, which mainly comprise airborne and contact transmission. Contact transmission, where the virus spreads through direct or indirect contact, is key to the disease epidemiology. Therefore, investigating contact transmission in animal models is crucial for understanding SARS-CoV-2 behavior and developing effective preventive measures. Although ferrets, cats, and hamsters have been established as models for studying contact transmission, the susceptibility of mice (the most commonly used experimental animal model) to SARS-CoV-2 contact infection remains uncertain. In this study, we investigated whether SARS-CoV-2 can spread via contact transmission in adult K18-hACE2 mice with different genetic backgrounds, including those with mitomycin C-induced immunodeficiency. We conducted contact-transmission experiments by co-housing K18-hACE2 mice intranasally infected with SARS-CoV-2 S type (isolated in Korea) alongside uninfected adult K18-hACE2 mice. Mice with genetically different backgrounds subjected to contact infection exhibited no changes in clinical signs or histopathological changes in the respiratory tract and extrapulmonary organs. Additionally, neither SARS-CoV-2 nor neutralizing antibodies were detected in any of the tested samples. Their immune responses remained unchanged, and contact transmission was not observed, even in immunodeficient mice. Collectively, these findings suggest that adult K18-hACE2 mice are not susceptible to contact infection with SARS-CoV-2, highlighting the role of immune mechanisms in viral spread and the limitations of this model for studying human transmission pathways. Our results underscore the importance of utilizing appropriate animal models to accurately elucidate transmission dynamics.IMPORTANCEUnderstanding the mechanisms of severe acute respiratory syndrome coronavirus-2 infection and transmission is essential for preventing and treating coronavirus disease 2019. Varying opinions exist regarding the occurrence of contact infection in mice. Here, we aimed to induce contact infection under various conditions in K18-hACE2 mice. By measuring clinical symptoms, viral loads, and neutralizing-antibody titers and conducting pathological analyses, we demonstrated that contact infection did not occur in K18-hACE2 mice. These findings underscore the importance of selecting appropriate experimental animal models to guide future studies on viral infections.

Silica dust is known as the most important risk factor of chronic obstructive pulmonary disease (COPD), and COPD is a leading cause of the third mortality worldwide. Workers exposed to silica dust are at increased risk of COPD as a result of being exposed to silica particles for extended periods of time. While clear links have been established between silica exposure and the development of COPD, the mechanisms are still poorly understood. However, both cigarette and silica combination exposure can be easy to result in COPD. Here we review the current understanding of silica-induced COPD, including incubation period, and the use of experimental animal models for better understanding these mechanisms of pathogenesis. The review summarizes important new knowledge and presents new research directions that are likely to provide new insights, diagnosis and treatments of silica-induced COPD.

Genetic and epigenetic processes are intertwined in a complex manner in order to enhance the development of breast cancer by regulating the fundamental cellular processes including DNA repair, proliferation, differentiation and metastasis. This review provides an overview of the findings of animal model experiments to explain the causes of the significant changes in genetic aspect including RAD51C mutations and dys-regulation of the BAF chromatin remodeling complex and epigenetic alterations, such as DNA methylation, histone modification, and microRNA dys-regulation. The animal models are where the researcher can study the mechanism by which these changes of the molecules cause tumorigenesis, stimulate tumor growth and metastatic potential. The data received in the course of such studies denotes the dynamism and reversibility of the epigenetic processes which may be utilized in treating diseases by selectively regulating the expression of the said molecules with an aim of modifying DNA methylation, histone-modifying enzymes, and miRNAs. Integration of genetic and epigenetic understanding will not only enhance our understanding of breast cancer biology, but also design the precision therapies, and also expose potential biomarkers that can be utilized to identify and diagnose the disease at the earliest phase. In total, the significance of the animal-based research in the context of finding mechanistic information and design interventions to limit the occurrence of breast cancer is highlighted in this review as a foundation of the subsequent use of the translation research and clinical interventions.

Background. While the efficacy of statins, which are cholesterol-lowering agents, in preventing subarachnoid hemorrhage (SAH) has been examined in experimental animal models and some clinical studies, findings remain inconclusive. This study aimed to investigate the association between statin use and the risk of SAH. Methods. We conducted a large population-based case-control study using data from the Japanese Health Insurance Claims Database from January 2005 to August 2021. This nationwide database includes the data of individuals aged 0 to 74 years. Cases were defined as patients hospitalized with a first diagnosis of SAH (International Classification of Diseases, Tenth Revision code I60) during this period. 4 controls per case were randomly selected and matched by age, sex, and follow-up period using incidence density sampling. Statin exposure (use, recency, and duration) was evaluated before the incidence of SAH. Conditional logistic regression, adjusted for patient characteristics, was used to assess the association between statin use and SAH risk. We also investigated whether this association varies with a history of hypertension, diabetes, cerebrovascular disease, unruptured intracranial aneurysms, and the use of antihypertensive medications.

Breast cancer remains the most prevalent malignancy among women, necessitating the development of novel therapeutic strategies. Experimental animal models that closely mimic human breast cancer are crucial for advancing these therapies. This study utilized the criteria of the tumour, node, metastasis (TNM) staging system and variations in metabolic rates to develop models representing stages II and IV of human breast cancer, using the MBL-6 mouse breast cancer cell line. We assessed tumor growth curves in vivo and investigated distant metastasis to organs such as the liver, lungs, lymph nodes, and spleen. Carcinoma-associated fibroblasts (CAFs) were isolated, and their proliferation rates, inflammatory enzyme expression, and matrix metalloproteinase levels were compared between stages II and IV. By analyzing tumor kinetics and metabolic differences, we were able to predict tumor size and progression at each stage. Our results revealed that CAFs isolated from both stages exhibited similar phenotypic characteristics. However, CAFs from stage II tumors showed higher expression of indoleamine 2,3-dioxygenase 1 (IDO1), while those from stage IV tumors had higher levels of inducible nitric oxide synthase (iNOS). These distinct expression patterns suggest unique microenvironmental features at different stages of tumor progression. Further investigation of the cancer microenvironment may provide valuable insights for selecting targeted therapies and improving disease management.