Search Results (780)

Kidney toxicity remains a major dose-limiting complication of radiation therapy and platinum-based chemotherapy, yet the molecular determinants of renal susceptibility and resilience to these genotoxic treatments are incompletely understood. Podocytes are particularly vulnerable to such insults, and emerging evidence implicates lipid dysregulation in podocyte injury. This study investigated the role of sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B), a podocyte-enriched lipid-modulating enzyme, in radiation- and cisplatin-induced nephrotoxicity. Using a doxycycline-inducible, podocyte-specific SMPDL3B transgenic mouse model, renal injury was assessed following focal kidney irradiation, cisplatin administration, or their combination through functional assays, histopathology, ultrastructural analysis, immunofluorescence, and targeted lipidomics. Combined radiation and cisplatin exposure markedly reduced podocyte SMPDL3B expression, accompanied by podocyte depletion, glomerular basement membrane remodeling, proteinuria, and impaired renal function. These structural and functional abnormalities were associated with the selective accumulation of long-chain ceramide-1-phosphate species. In contrast, podocyte-specific induction of SMPDL3B preserved glomerular architecture, maintained renal function, and prevented pathological ceramide-1-phosphate elevation. Collectively, these findings identify SMPDL3B as a key regulator of podocyte stability and lipid homeostasis during chemoradiation stress. Enhancing SMPDL3B activity may represent a mechanistically grounded strategy to mitigate treatment-induced kidney injury while preserving anticancer efficacy. Full article

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality. It usually arises in cirrhotic liver, where chronic inflammation and fibrosis create a tumor-permissive microenvironment. Dysregulation of microRNAs (miRNAs), particularly upregulation of the oncomiR miR-221 and loss of the tumor suppressor miR-199a-3p represent key drivers of liver carcinogenesis. The TG221 transgenic mouse, designed to overexpress miR-221 in hepatocytes, provides a relevant in vivo platform for mechanistic studies and for testing preventive and therapeutic approaches. The TG221 model recapitulates miR-221-driven tumorigenesis, including suppression of p27, p57 and Bmf. It is characterized by steatohepatitic injury and accelerated tumor formation after genotoxic challenge. In the cirrhotic CCl₄-induced background, TG221 mice develop fibrosis and cirrhosis followed by dysplastic and malignant lesions, mirroring the natural history of human HCC. Metformin administered during early fibrosis prevented macroscopic tumor formation and suppressed PI3K/AKT/mTOR signaling. Anti-miR-221 and miR-199a-3p mimics reduced tumor burden, restored tumor-suppressive pathways and improved liver integrity, thus indicating feasible chemopreventive strategies. From a therapeutic point of view, miR-199a-3p replacement synergized with palbociclib and overcame sorafenib resistance. A miR-199a-3p-responsive oncolytic adenovirus achieved tumor-selective replication with minimal toxicity. This review highlights the importance of the TG221 transgenic mouse as a powerful model for studying miRNA-driven hepatocarcinogenesis and enables preclinical evaluation of RNA-based chemopreventive and therapeutic approaches. Metformin, miRNA inhibition, miRNA replacement and miRNA-guided viral therapies emerge as promising approaches for advancing precision prevention and treatment strategies in HCC. Full article

Late-onset sporadic Alzheimer’s disease (LOAD) is the most common form of dementia. The disease is characterized by progressive loss of memory and behavioral changes followed by neurodegeneration of all cortical areas. While the contribution of genetic and environmental factors is important, advanced aging remains the most important disease risk factor. Because LOAD does not naturally occur in most animal species, except humans, studies have traditionally relied on the use of transgenic mouse models recapitulating early-onset familial Alzheimer’s disease (EOAD). Hence, the development of more representative LOAD models through reprograming of patient-derived cells into neuronal, glial, and immune cells became a necessity to better understand the disease’s origin and pathophysiology. Herein, and focusing on neurons, we review current work in the field and compare results obtained with two different reprograming methods to generate LOAD patient’s neuronal cells: the induced pluripotent stem cell and induced neuron technologies. We also evaluate if these models can faithfully mimic cellular and molecular pathologies observed in LOAD patients’ brains. Full article

Alzheimer’s disease (AD) is increasingly recognized as a disorder that extends beyond amyloid-β (Aβ) and tau pathology. To this end, growing evidence suggests that aberrant neuronal cell cycle re-entry (CCR) may contribute to neurodegeneration. To investigate this mechanism, we profiled the expression of 84 cell cycle-related genes in the brains of aged APP/PS1 mice, a widely used transgenic model of AD, and compared them with age-matched non-transgenic littermates. Our analysis revealed 32 differentially expressed genes (DEGs), 8 of which exhibited significant changes (fold change > 2, p < 0.05). Several of these DEGs, including CDC7 and CCNC, displayed consistent dysregulation in human AD brains as assessed using the AMP-AD knowledge portal, supporting their translational relevance. Furthermore, integration with miRNA prediction analyses identified candidate post-transcriptional regulators of these DEGs, highlighting novel layers of regulation. Collectively, our results provide the first systematic overview of cell cycle gene dysregulation in aged APP/PS1 mice, establish cross-species concordance with human AD, and propose miRNA–gene interactions as potential contributors to neuronal vulnerability. These findings underscore the importance of cell cycle pathways in AD pathogenesis and point to new avenues for therapeutic exploration. Full article

Background/Objectives: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the global COVID-19 pandemic, which led to hundreds of millions of human infections and more than seven million deaths worldwide. Major variants of concern, particularly the Omicron variant and its associated subvariants, can escape the vaccines developed so far to target previous strains/subvariants. Therefore, effective vaccines that broadly neutralize different Omicron subvariants and show good protective efficacy are needed to prevent further spread of Omicron. The spike (S) protein, including its receptor-binding domain (RBD), is a key vaccine target. Methods: Here, we designed a unique mRNA vaccine encoding Omicron-KP.3 RBD based on RBD-truncated S protein backbone of an earlier Omicron subvariant EG.5 (KP3 mRNA), and evaluated its stability, immunogenicity, neutralizing activity, and protective efficacy in a mouse model. Results: Our data showed that the nucleoside-modified, lipid nanoparticle-encapsulated mRNA vaccine was stable at various temperatures during the period of detection. In addition, the vaccine elicited potent antibody responses with broadly neutralizing activity against multiple Omicron subvariants, including KP.2, KP.3, XEC, and NB.1.8.1. This mRNA vaccine protected immunized transgenic mice from challenge with SARS-CoV-2 Omicron-KP.3. Immune serum also protected against subsequent virus challenge, with the level of protection associating positively with the serum neutralizing antibody titer. Conclusions: Taken together, the data presented herein suggest that this newly designed mRNA vaccine has potential against current and future Omicron subvariants. Full article

Over a quarter of human pregnancies are associated with complications, including fetal growth restriction, pre-eclampsia and gestational diabetes. These are major causes of maternal and fetal morbidity and mortality, and also lead to a 3–5-fold increased risk of subsequent development of cardio-metabolic diseases. Although the mechanistic details remain elusive, a dysfunctional placenta is central to the pathophysiology of these conditions. The placenta ensures sufficient nutrient supply to the fetus without compromising maternal wellbeing. This balance is achieved by the secretion of large quantities of placental-derived peptide hormones into the maternal circulation. Consequently, the placenta is susceptible to endoplasmic reticulum (ER) stress, and we were the first to demonstrate the presence of ER stress in placentas from complicated pregnancies. The mouse placenta provides an ideal model for studying the impact of ER stress as it is composed of two distinct regions, an endocrine zone and a transport zone. Therefore, perturbation of placental endocrine function by ER stress can be generated without directly affecting its capacity for nutrient exchange. In this review, we summarise the current literature on how transgenic mouse models enhance our understanding of ER stress-mediated perturbation of placental endocrine function, and its contribution to the pathophysiology of pregnancy complications and life-long health. Full article

Polyphenols like dihydroquercetin, rutin, and rifampicin show promise for Alzheimer’s disease (AD) therapy due to their ability to inhibit amyloid-β (Aβ) aggregation and reduce reactive oxygen species (ROS), garnering significant recent interest. However, their efficacy is substantially diminished because excess metal ions present in amyloid plaques can chelate these compounds. Therefore, reshaping the metal microenvironment in the patient’s brain is particularly important for the therapeutic effect of AD. To address the above issues, we have constructed a composite system formed by NH₂-MIL-101(Fe) (MOF), dihydroquercetin (DHQ), and D-penicillamine (D-pen). Due to the lack of π-π interaction and the low adsorption energy between D-pen/MOF, the release order and speed of D-pen was much faster than DHQ, thus achieving metal microenvironment regulation and ensuring the therapeutic effect of DHQ. In a 5 × FAD transgenic mouse model, DD@MOF treated and improved spatial learning and memory deficits. Therefore, the DD@MOF based on polyphenolic compounds provides a potential research direction for intervention in Alzheimer’s disease through chelating copper ions and antioxidant properties. Full article

Macrophages accumulate in visceral adipose tissue (VAT) during hypertension and may contribute to hypertension-associated inflammation. Exercise has shown beneficial effects on hypertension; however, the exact mechanisms by which the activated immune cells lead to the protective effects remain unclear. Our study aimed to determine how exercise influences VAT inflammation by modulating the macrophage polarization in hypertensive mice. Renin transgenic (R+) mice were used as a hypertensive mouse model and subjected to exercise (8 weeks). The body weight and blood pressure were monitored, VAT morphology was assessed by H&E and Masson Trichrome staining, macrophage polarization was determined by immunostaining and flow cytometry, and macrophage phenotype-related proteins were analyzed within the VAT via Western Blots. Results showed that exercise reduced the adipocyte size and collagen content of VAT and increased cell infiltration in R+ mice. Immunostaining and flow cytometry data showed that the ratio of pro-inflammatory macrophages (M1) to anti-inflammatory macrophages (M2) was increased in the VAT of R+ mice, while exercise corrected the macrophage polarization, which was consistent with protein level changes in VAT. Together, our data suggest that exercise improves vascular remodeling and VAT function (reduced adipocyte size, loss of collagen) by modulating VAT inflammation (polarization of macrophages) in hypertensive mice. Full article

Alzheimer’s disease (AD) is considered one of the leading causes of death in the United States, and there is no effective cure for it. Understanding the neuropathological mechanisms underlying AD is essential for identifying early, reliable biomarkers and developing effective therapies. In this paper, we report on a comprehensive multimodal study of AD pathology using the 5xFAD mouse model. We employed light-scattering techniques, Partial Wave Spectroscopy (PWS) and Inverse Participation Ratio (IPR), to detect nanoscale structural alterations in brain tissues, nuclear components, and mitochondria. To support the light-scattering experiments, behavior, and histopathological studies were conducted. These analyses revealed significant increases in structural heterogeneity and mass density fluctuations in the brains of 5xFAD mice compared with Non-transgenic controls. Behavioral assessment performed using the Novel Object Recognition test demonstrated memory impairment in 5xFAD mice, reflected by a reduced recognition index. Histopathological analysis further revealed increased amyloid beta plaques and microglia activation in the hippocampus and cortex of 5xFAD mice compared with Non-transgenic controls. An increase in structural disorder within brain tissues can be attributed to higher mass density fluctuations, likely arising from macromolecular rearrangement driven by amyloid beta aggregation and neuroinflammatory responses as the disease progresses. Our findings suggest that PWS and IPR-derived metrics provide sensitive biophysical indicators of early cellular and subcellular disruption, offering potential as quantitative biomarkers for the detection of AD. Full article

Background/Objectives: Radiolabeled fibroblast activation protein inhibitors (FAPIs) are emerging as promising imaging agents assessing fibrotic diseases. This study evaluates [⁶⁸Ga]Ga-DATA^5m.SA.FAPi for imaging pulmonary fibrosis in two mouse models, bleomycin-induced (BLM) and a transgenic (fra-2^tg) model, both displaying characteristics of human pulmonary fibrotic diseases. Methods: In the BLM model, C57BL/6 mice were treated with bleomycin or isotonic sodium chloride (controls) for 4, 5, and 6 weeks, followed by [⁶⁸Ga]Ga-DATA^5m.SA.FAPi PET/CT scans. Fra-2^tg mice and wildtype (WT) littermates underwent at 7, 11, and 18/19 weeks of age a PET/CT scan. The selected timepoints correspond to early, middle, and late disease stages for each model. Imaging was complemented by ex vivo quantification, histological, and immunohistochemical (IHC) analyses. Results: In BLM mice, pulmonary [⁶⁸Ga]Ga-DATA^5m.SA.FAPi uptake showed a trend toward increase as early as 5 weeks of treatment compared with the controls, which was confirmed by ex vivo analysis (BLM: 3.31 ± 0.29%ID/g, n = 5; control: 1.61 ± 0.29%ID/g, n = 4; p = 0.0035). In fra-2^tg mice, no significant differences could be detected. IHC revealed elevated pulmonary FAP expression specifically at early (BLM) and mild (fra-2^tg) disease stages, whereas for BLM, tracer uptake was more pronounced at later stages. Conclusions: Our findings complement and extend observations from previous studies and support the potential of FAPI tracers as molecular imaging agents for pulmonary fibrosis. Full article

Evidence increasingly indicates that synaptic vesicle dysfunction emerges early in Parkinson’s disease (PD), preceding overt dopaminergic neuron loss rather than arising solely as a downstream consequence of neurodegeneration. α-Synuclein (αSyn), a presynaptic protein that regulates vesicle clustering, trafficking, and neurotransmitter release under physiological conditions, exhibits dose-, conformation-, and context-dependent actions that distinguish its normal regulatory roles from pathological effects observed in disease models. This narrative review synthesizes findings from a structured search of PubMed and Scopus, with emphasis on α-syn-knockout (αSynKO) and BAC transgenic (αSynBAC) mouse models, which do not recapitulate the full human PD trajectory but provide complementary insights into αSyn physiological function and dosage-sensitive vulnerability. Priority was given to studies integrating ultrastructural approaches—such as cryo-electron tomography, high-pressure freezing/freeze-substitution TEM, and super-resolution microscopy—with proteomic and lipidomic analyses. Across these methodologies, several convergent presynaptic alterations are consistently observed. In vivo and ex vivo studies associate αSyn perturbation with impaired vesicle acidification, consistent with altered expression or composition of vacuolar-type H⁺-ATPase subunits. Lipidomic analyses reveal age- and genotype-dependent remodeling of vesicle membrane lipids, particularly curvature- and charge-sensitive phospholipids, which may destabilize αSyn–membrane interactions. Complementary biochemical and cell-based studies support disruption of SNARE complex assembly and nanoscale release-site organization, while ultrastructural analyses demonstrate reduced vesicle docking, altered active zone geometry, and vesicle pool disorganization, collectively indicating compromised presynaptic efficiency. These findings support a synapse-centered framework in which presynaptic dysfunction represents an early and mechanistically relevant feature of PD. Rather than advocating αSyn elimination, emerging therapeutic concepts emphasize preservation of physiological vesicle function—through modulation of vesicle acidification, SNARE interactions, or membrane lipid homeostasis. Although such strategies remain exploratory, they identify the presynaptic terminal as a potential window for early intervention aimed at maintaining synaptic resilience and delaying functional decline in PD. Full article

Mouse models of human autoimmune diseases and inflammation are a challenging field because of the relatively low homology between the human and mouse immune systems. At the same time, inflammation plays a significant role in the pathogenesis of many diseases, strongly impacting quality of life and mortality. Cyclophilin A (CypA) is a pro-inflammatory factor, the ligand of immunosuppressive cyclosporin A, which mediates inflammation through multiple signaling pathways. Here, we describe a novel transgenic mouse model with Cre-dependent expression of the hPPIA gene in vascular endothelium and secretion of CypA into the bloodstream, which shows elevated blood levels of CypA upon activation. Being mostly asymptomatic under standard conditions, these mice exhibited more severe inflammation when provided with 3% dextran sulfate sodium solution instead of drinking water for 7 days. Inflammation symptoms precisely resembled those of ulcerative colitis and included deterioration of the colon crypts alongside the relatively normal duodenum. These results show that the elevated blood level of CypA enhances induced inflammation but does not cause inflammation by itself, suggesting its role in pro-inflammatory positive feedback loops and making CypA a suitable anti-inflammatory target. Moreover, our mouse strain is an applicable colitis model and can be used further in emerging inflammation research and testing anti-CypA targeted therapy. Full article

Zingeria biebersteiniana, a grass species with the lowest known chromosome number among angiosperms (2n = 2x = 4), offers a distinctive platform for cytogenetic and grass research. Despite its unique karyotype and potential for molecular and educational applications, no transformation system has previously been reported for this species. Here, we establish a reproducible Agrobacterium tumefaciens-mediated transformation protocol for Z. biebersteiniana, optimized through comparative evaluation of three tissue culture media. A modified Khromov medium with Plant Preservative Mixture supported robust callus induction and plant regeneration, enabling the successful introduction of a GFP–mouse talin1 fusion construct driven by the rice Actin-1 promoter. Transgenic lines were validated via PCR amplification of the hygromycin resistance gene, and GFP signals were observed in transformed individuals. However, the expression pattern was less specific than previously reported in rice, potentially due to species-specific differences in mouse Talin1 protein localization. Although actin filament visualization in mature pollen remained unspecific, the protocol provides a foundational tool for future molecular and functional genomics and genetics studies. This work represents the first documented genetic transformation of Z. biebersteiniana, expanding its utility as a model system in plant biology and genomics. Full article

Age-related changes are associated with mitochondrial dysfunction, which is often caused by the accumulation of mutations in mitochondrial DNA (mtDNA). One common model of aging and age-related diseases involves mice with a mutant DNA polymerase γ (PolG^mut) whose proofreading function is impaired, which leads to the accumulation of mutations in mtDNA. The main limitation of such a model is that introducing a mutation into the mouse’s own gene leads to the accumulation of mutations in mtDNA over several generations, making it impossible to rule out whether mtDNA mutations or compensatory effects are the cause of functional impairments such as accelerated aging. This paper describes two lines of transgenic animals with inducible expression of PolG^mut. This inducible system prevents mutation accumulation in the germline, promoting stable reproduction and reproducibility of mice, increasing experimental flexibility for various studies of mitochondrial diseases. PolG^mut activation at different stages of life and different tissues allows us to study the progression of pathological changes during mitochondrial aging over time and detect the onset of mutation accumulation. The simplicity, reproducibility, and temporal control of this system represent a significant methodological improvement for studying mitochondrial mutagenesis and the pathophysiology of aging. Using this model, we demonstrated that the most pronounced pathology in these animals is accelerated thymus involution and the accumulation of cytotoxic effector CD8+ T cells in the peripheral immune organs, while no significant abnormalities were observed in other organs and systems. These data probably indicate that mtDNA mutations primarily impair T-cell immune function. Full article