Organs Of Mice Research Articles

Pathophysiology and preclinical relevance of experimental graft-versus-host disease in humanized mice.

Graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantations (allo-HCT) used for the treatment of hematological malignancies and other blood-related disorders. Until recently, the discovery of actionable molecular targets to treat GVHD and their preclinical testing was almost exclusively based on modeling allo-HCT in mice by transplanting bone marrow and splenocytes from donor mice into MHC-mismatched recipient animals. However, due to fundamental differences between human and mouse immunology, the translation of these molecular targets into the clinic can be limited. Therefore, humanized mouse models of GVHD were developed to circumvent this limitation. In these models, following the transplantation of human peripheral blood mononuclear cells (PBMCs) into immunodeficient mice, T cells recognize and attack mouse organs, inducing GVHD. Thereby, humanized mice provide a platform for the evaluation of the effects of candidate therapies on GVHD mediated by human immune cells in vivo. Understanding the pathophysiology of this xenogeneic GVHD is therefore crucial for the design and interpretation of experiments performed with this model. In this article, we comprehensively review the cellular and molecular mechanisms governing GVHD in the most commonly used model of xenogeneic GVHD: PBMC-engrafted NOD/LtSz-PrkdcscidIL2rγtm1Wjl (NSG) mice. By re-analyzing public sequencing data, we also show that the clonal expansion and the transcriptional program of T cells in humanized mice closely reflect those in humans. Finally, we highlight the strengths and limitations of this model, as well as arguments in favor of its biological relevance for studying T-cell reactions against healthy tissues or cancer cells.

Green Synthesis of Silver Nanoparticles Using Doxycycline: Evaluation of Antimicrobial Potential and Organ-specific Toxicity

Silver nanoparticles (Ag-NPs) have wide applicability as antimicrobial, biomedical, and anti-cancer drug delivery systems. This study aimed to synthesize Ag-NPs using green methodology to assess their antimicrobial properties and toxicity. Ag-NPs were prepared using doxycycline, an antibiotic serving as a reducing and capping agent. The synthesized Ag-NPs were characterized by ultraviolet-visible spectrophotometry, X-ray diffraction, scanning electron microscopy, and Fourier-transform infrared spectrometry. The antimicrobial efficacy of doxycycline-mediated Ag-NPs was assessed on Candida species in vitro and for toxicity in male albino mice in vivo. The Ag-NPs showed a surface plasmon resonance at 411 nm, indicating a 90 nm average size and spherical shape. Toxicity was tested on mouse organs (liver, kidney, spleen, heart and stomach) using three Ag-NP doses (50, 100, 200 mg/kg) over 14 days. The synthesized Ag-NPs produced large inhibition zones against two well-known fungal species, C. albicans and C. tropicalis, demonstrating their antimicrobial potential. The Ag-NPs showed varying degrees of toxicity in different mouse organs, depending on the administered dose, with more pronounced adverse effects observed at higher concentrations. Periodic administration of Ag-NPs at low-dose volumes holds promise as a safe approach to their use as antimicrobial agents. Low-dose Ag-NPs are minimally toxic and show strong antimicrobial efficacy.

Abstract 4119213: A Novel Animal Model for Pulmonary Hypertension: Lung Endothelial Specific Deletion of Egln1 in Mice

Background: Pulmonary arterial hypertension (PAH) is a disastrous disease that is characterized by high blood pressure in the pulmonary arteries which has the potential to lead to heart failure over time. Previously, our lab found that endothelial-specific knockout of Egln1 , encoding prolyl 4-hydroxylase-2 (PHD2), induced spontaneous pulmonary hypertension (PH). Recently, we elucidated that Tmem100 is a lung-specific endothelial gene using Tmem100 CreERT2 mice. We reason that lung endothelial-specific deletion of Egln1 could lead to the development of PH without affecting other organs’ Egln1 gene expression and defect. Methods: Tm em100-CreERT2 mice were crossed with Egln1 flox/flox mice to generate Egln1 f/f ; Tmem100 CreERT2 (LiCKO) mice. Western blot and immunofluorescent staining were performed to verify the knockout efficacy of Egln1 in multiple organs of LiCKO mice. PH phenotypes including hemodynamics, right heart size and function, and pulmonary vascular remodeling were evaluated by right heart catheterization and echocardiography measurement. Results: Tamoxifen treatment induced Egln1 deletion in the lung ECs but no other organs in adult LiCKO mice. LiCKO mice exhibited an increase in right ventricular systolic pressure (RVSP, ~35 mmHg) and right heart hypertrophy. Echocardiography measurement showed right heart hypertrophy and cardiac and pulmonary arterial dysfunction. Pulmonary vascular remodeling including pulmonary wall thickness and muscularization of distal pulmonary arterials was enhanced in LiCKO mice compared to wild-type mice. Conclusions: Tmem100 promoter-mediated lung endothelial knockout of Egln1 in mice develops spontaneous PH. LiCKO mice could be a novel mouse model for PH to study lung and other organ crosstalk.

Synthesis and evaluation of fluorinated piperazine-hydroxyethylamine analogues as potential antiplasmodial candidates.

In this manuscript, twenty-one novel fluorinated piperazine-hydroxyethylamine analogues were synthesized and tested against Plasmodium falciparum (Pf). Among tested compounds, two 13g and 14g exhibited promising inhibitory activity on Pf3D7 withIC50 values of 0.28 and 0.09 µM, respectively. Neither of the hits exhibited cytotoxicity on HepG2 cells up to 150 µM and Vero cells up to 20 µM. Compounds 13g and 14g were also evaluated against chloroquine-resistant PfDd2 and displayed IC50 values of 0.11 and 0.10 µM, respectively. Next, 13g and 14g were administered to the Plasmodium berghei mice model at 30mg/kg intraperitoneally for four consecutive doses, which showed 25% and 50% reduction in the parasitemia load, respectively. The efficacy of hits 13g and 14g was improved along with mean survival time when administered in combination with artesunate. On liver-stage parasites, compounds 13g and 14g showed >90% inhibition at 1µM. Compound 14g was also tested for toxicity in mice at 100 mg/kg dose, which revealed no abnormality in mice organs. Preliminary pharmacokinetic studies of compound 14g exhibited absorption and maintained a presence in the body for more than six hours.

Evaluation of safety and biomedical potential of water-soluble oat lignin Avena sativa L.

The study of the value of lignin for biomedical use is generating growing interest. For the first time, the safety and biological efficacy of lignin from the stems of the oat Avena sativa L. were studied, necessary for a preliminary assessment of its biomedical potential, have been studied. In vitro experiments, a sample of oat lignin exhibited cytotoxicity to the HeLa, A549, and HT-29 cancer cell lines, depending on the concentration. At maximum concentrations 125 and 150 μg/ml, it reduced their survival and increased the level of reactive oxygen species. In vivo experiments, a sample of oat lignin, with acute (from 5 to 250 mg/kg body weight) and chronic (300, 1200 and 2000 mg/kg body weight) administration, did not have a toxic or genotoxic effect on the organs of mice. The biological efficacy of the oat lignin was manifested in activation of repair processes in bone marrow and thyroid gland, a decrease in the level of abnormal spermatozoa in males, stimulation of reproductive performance of females and in increase in research activity and a decrease in the level of anxiety in animals. The results indicate the prospects for further study of the medical and biological potential lignin of the oat.

Copper functionalized, pro-angiogenic, and skin regenerative scaffolds based on novel chitosan/APDEMS modified sepiolite-based formulation.

Biomaterials-based scaffolds are extensively explored for their proangiogenic and tissue regenerative abilities. The present study aimed to develop wound healing scaffolds based on chitosan/aminopropyldiethoxymethylsilane (APDEMS) modified sepiolite, loaded with copper (0-0.25 g), characterized by FTIR, SEM, mechanical, TGA and analyzed biomedically. The FTIR and SEM confirmed the silane-induced cross-linking and incorporation of copper leading to better dispersion of individual components in the scaffolds. Based on other physicochemical observations, the best scaffold was CS/MS/Cu0.1 (99.5 % increased Young's modulus compared to chitosan, maximum swelling = 900 %, equilibrium time = 70 min); So, CS/MS/Cu0.1 and 0.25 were chosen for further analysis. The CAM assay showed significantly increased angiogenesis in CS/MS/Cu0.1 and 0.25 groups, lacking any developmental anomalies in chick embryos, at lower copper concentrations. The scaffolds' wound healing potential and in-vivo toxicity were assessed by wound excision and histopathology of various organs in mice, respectively. The rate of wound contraction in the CS/MS/Cu0.1 group was significantly (P < 0.05) greater than the control. The abovementioned results corroborated the histological and biochemical findings regarding more collagen deposition in regenerated skin sections and insignificant deviations in biochemical parameters of treated mice, respectively. The formulated biomaterials have proven promising materials for promoting angiogenesis in chick models and accelerating regeneration in mice skin.

STEMIN and YAP5SA, the future of heart repair?

This review outlines some of the many approaches taken over a decade or more to repair damaged hearts. We showcase the recent breakthroughs in organ regeneration elicited by reprogramming factors OCT3/4, SOX2, KLF4, and C-MYC (OKSM). Transient OKSM transgene expression rejuvenated senescent organs in mice. OKSM transgenes also caused murine heart cell regeneration. A triplet alanine mutation of the N-terminus of Serum Response Factor's MADS box SRF153(A3), termed STEMIN, and the YAP mutant, YAP5SA synergized and activated OKSM and NANOG in adult rat cardiac myocytes; thus, causing rapid nuclear proliferation and blocked myocyte differentiation. In addition, ATAC seq showed induced expression of growth factor genes FGFs, BMPs, Notchs, IGFs, JAK, STATs and non-canonical Wnts. Injected STEMIN and YAP5SA synthetic modifying mRNA (mmRNA) into infarcted adult mouse hearts, brought damaged hearts back to near normal contractility without severe fibrosis. Thus, STEMIN and YAP5SA mmRNA may exert additional regenerative potential than OKSM alone for treating heart diseases.

Mapping of β3-Adrenergic Receptor in Living Cells with a Ligand-Guided Fluorescent Probe.

Tracking the dynamic distribution of native proteins in living cells or tissues in real time is essential for understanding the functional mechanisms involved in their physiological or pathological processes. The β3-adrenergic receptor (β3-AR) has important biological functions. It is expected to be a diagnostic indicator for aging, yet current probes for β-ARs are unable to dynamically monitor β3-AR in real time, which impedes the progress of β3-AR research. Here, we developed a ligand-directed anchoring probe, β3-ARP, that precisely covalently anchors with native β3-AR in living cells, for the diagnosis of senescence. The ligand-directed anchoring probe selectively recognizes and traces β3-AR and can achieve dynamic observation and monitoring of β3-AR in living cells, including the interaction between lipid droplets and mitochondria. Moreover, we were able to directly probe the distribution of β3-AR in various organs of aging mice in situ and track the location of native β3-AR in different types of primary neuronal cells using β3-ARP and two-photon imaging, which revealed the aberrant accumulation of lipid droplets and the distribution of β3-AR in neurological diseases. This research has resulted in a new covalently anchoring fluorescent probe, β3-ARP, which could serve as a powerful tool to explore the link between β3-AR and age-related diseases.

5′-tRNAGly(GCC) halves generated by IRE1α are linked to the ER stress response

Transfer RNA halves (tRHs) have various biological functions. However, the biogenesis of specific 5′-tRHs under certain conditions remains unknown. Here, we report that inositol-requiring enzyme 1α (IRE1α) cleaves the anticodon stem-loop region of tRNAGly(GCC) to produce 5′-tRHs (5′-tRH-GlyGCC) with highly selective target discrimination upon endoplasmic reticulum (ER) stress. Levels of 5′-tRH-GlyGCC positively affect cancer cell proliferation and modulate mRNA isoform biogenesis both in vitro and in vivo; these effects require co-expression of two nuclear ribonucleoproteins, HNRNPM and HNRNPH2, which we identify as binding proteins of 5′-tRH-GlyGCC. In addition, under ER stress in vivo, we observe simultaneous induction of IRE1α and 5′-tRH-GlyGCC expression in mouse organs and a distantly related organism, Cryptococcus neoformans. Thus, collectively, our findings indicate an evolutionarily conserved function for IRE1α-generated 5′-tRH-GlyGCC in cellular adaptation upon ER stress.

Intra-specific variations in Schistosoma mansoni and their possible contribution to inconsistent virulence and diverse clinical outcomes.

Schistosoma mansoni was introduced from Africa to the Americas during the transatlantic slave trade and remains a major public health problem in parts of South America and the Caribbean. This study presents a comprehensive comparative analysis of three S. mansoni strains with different geographical origins-from Liberia, Belo Horizonte and Puerto Rico. We demonstrated significant variation in virulence and host-parasite interactions. We investigated the phenotypic characteristics of the parasite and its eggs, as well as the immunopathologic effects on laboratory mouse organ systems. Our results show significant differences in worm morphology, worm burden, egg size, and pathologic organ changes between these strains. The Puerto Rican strain showed the highest virulence, as evidenced by marked liver and spleen changes and advanced liver fibrosis indicated by increased collagen content. In contrast, the strains from Liberia and Belo Horizonte had a less pathogenic profile with less liver fibrosis. We found further variations in granuloma formation, cytokine expression and T-cell dynamics, indicating different immune responses. Our study emphasizes the importance of considering intra-specific variations of S. mansoni for the development of targeted therapies and public health strategies. The different virulence patterns, host immune responses and organ pathologies observed in these strains provide important insights for future research and could inform region-specific interventions for schistosomiasis control.

Genetic framework sequencing analysis of Candida tropicalis in dairy cow mastitis and study of pathogenicity and drug resistance

Candida tropicalis (C. tropicalis) is a zoonotic pathogen that is widespread in the environment and in recent years an increasing number of dairy cows have been infected with the fungus causing mastitis in cows.In this study, 37 milk samples from the udders of cows with clinical mastitis were collected from a dairy farm in Guangxi Province, China, from which C. tropicalis was isolated and identified, and then the isolated fungi were subjected to genome frame map sequencing, genome functional analysis as well as comparative genome analysis of the sequencing results, and combined with the virulence test of the fungi and drug sensitivity test of the fungi determined in infected mice, the resistance genes and pathogenicity of the fungi were Analysis of resistance genes and pathogenicity.Our study results revealed the isolation and characterisation of C. tropicalis from diseased cows, with a genome length of approximately 14.27 Mb. Functional annotation of the genome identified 4068 genes associated with C. tropicalis. The strain exhibited a chemoresistance mutation in the gene cyp51,a virulence-enhancing mutation in the gene VTC4, and mutations in genes linked to drug resistance. Pathogenicity tests demonstrated that C. tropicalis could induce damage to the internal organs of mice, leading to different levels of cyanosis in the abdominal cavity, white necrotic foci on the surface of internal organs, lung hemorrhage, and enlargement of the spleen and thymus.Histological sections also revealed varying degrees of hemorrhage and degenerative changes in the cells of different organs in the mice. Drug sensitivity tests showed that the fungus was highly sensitive to nystatin and ketoconazole, moderately sensitive to amphotericin B, and insensitive to antibiotics such as itraconazole, gentamicin, and penicillin. In conclusion, C. tropicalis isolated from dairy cows in the Guangxi region in this study was pathogenic and resistant to azoles such as itraconazole and fluconazole, and this study provides a theoretical basis for the further screening of novel resistance genes in C. tropicalis, as well as providing a certain reference for the drugs used for the treatment of fungal cow mastitis in this region.

Structural Engineering of Cationic Block Copolymer Architectures for Selective Breaching of Prokaryotic and Eukaryotic Biological Species.

Positively charged antimicrobial polymers are known to cause severe damage to biological systems, and thus synthetic strategies are urgently required to design next-generation nontoxic cationic macromolecular architectures for healthcare applications. Here, we report a structural-engineering strategy to build cationic linear and star-block copolymer nanoarchitectures having identical chemical composition, molar mass, nanoparticle size, and positive surface charge, yet they differ distinctly in their biological action in breaching prokaryotic species such as E. coli (Gram-negative bacteria) without affecting eukaryotic species like red-blood and mammalian cells. For this purpose, linear and star-block structures are built on a polycaprolactone biodegradable platform having an imidazolium positive handle. Under physiological conditions, the linear architecture exhibits toxicity indiscriminately to all biological species, whereas its star counterpart is remarkably selective in membrane breaching action toward bacteria while maintaining inertness toward eukaryotic species. Confocal microscopy analysis of HPTS fluorescent dye-loaded star-polymer nanoparticles substantiated their antimicrobial action in E. coli. Tissue-penetrable near-infrared fluorescent dye (IR-780) loaded NP aided the in vivo biodistribution analysis and ex vivo quantification of cationic species' accumulations in vital organs in mice. Azithromycin, a clinical water-insoluble macrolide, is delivered from the star platform to accomplish synergistic antimicrobial activity by the combination of bactericidal-bacteriostatic action of the polymer carrier and drug together in a single system.

Manifestation of polystyrene microplastic accumulation in brain with emphasis on morphometric and histopathological changes in limbic areas of Swiss albino mice

The widespread problem of microplastic (MP) contamination is becoming a major threat to the globe. Although most of the research to date has concentrated on the physiological impacts of MPs exposure, a relatively new field of study is beginning to examine its effects on the behaviour and limbic regions of the brain. In this study, exposure to polystyrene MPs (PS-MPs) for acute and sub-chronic durations negatively affected cognition and induced anxiety-like behaviour in mice. PS-MPs were detected in vital organs of mice, including the brain, which induced neurobehavioural and pathological changes in the limbic system. Furthermore, morphometric analysis revealed a significant decrease in the total cell count in the Dentate Gyrus (DG) and Cornu Ammonis (CA) regions of the hippocampus. Signs of neuronal injury and dystrophic changes were observed in the cortex, amygdala, and hypothalamus, potentially affecting anxiety and fear responses. Our study thus provides insight into the effect of PS-MPs on the neurobiology of the brain’s limbic system and related behavioural alterations.

Hypothalamic representation of the imminence of predator threat detected by the vomeronasal organ in mice.

Animals have the innate ability to select optimal defensive behaviors with appropriate intensity within specific contexts. The vomeronasal organ (VNO) serves as a primary sensory channel for detecting predator cues by relaying signals to the medial hypothalamic nuclei, particularly the ventromedial hypothalamus (VMH), which directly controls defensive behavioral outputs. Here, we demonstrate that cat saliva contains predator cues that signal the imminence of predator threat and modulate the intensity of freezing behavior through the VNO in mice. Cat saliva activates VNO neurons expressing the V2R-A4 subfamily of sensory receptors, and the number of VNO neurons activated in response to saliva correlates with both the freshness of saliva and the intensity of freezing behavior. Moreover, the number of VMH neurons activated by fresh, but not old, saliva positively correlates with the intensity of freezing behavior. Detailed analyses of the spatial distribution of activated neurons, as well as their overlap within the same individual mice, revealed that fresh and old saliva predominantly activate distinct neuronal populations within the VMH. Collectively, this study suggests that there is an accessory olfactory circuit in mice that is specifically tuned to time-sensitive components of cat saliva, which optimizes their defensive behavior to maximize their chance of survival according to the imminence of threat.

Hypothalamic representation of the imminence of predator threat detected by the vomeronasal organ in mice

Animals have the innate ability to select optimal defensive behaviors with appropriate intensity within specific contexts. The vomeronasal organ (VNO) serves as a primary sensory channel for detecting predator cues by relaying signals to the medial hypothalamic nuclei, particularly the ventromedial hypothalamus (VMH), which directly controls defensive behavioral outputs. Here, we demonstrate that cat saliva contains predator cues that signal the imminence of predator threat and modulate the intensity of freezing behavior through the VNO in mice. Cat saliva activates VNO neurons expressing the V2R-A4 subfamily of sensory receptors, and the number of VNO neurons activated in response to saliva correlates with both the freshness of saliva and the intensity of freezing behavior. Moreover, the number of VMH neurons activated by fresh, but not old, saliva positively correlates with the intensity of freezing behavior. Detailed analyses of the spatial distribution of activated neurons, as well as their overlap within the same individual mice, revealed that fresh and old saliva predominantly activate distinct neuronal populations within the VMH. Collectively, this study suggests that there is an accessory olfactory circuit in mice that is specifically tuned to time-sensitive components of cat saliva, which optimizes their defensive behavior to maximize their chance of survival according to the imminence of threat.

Sex and organ specific proteomic responses to vitamin C deficiency in the brain, heart, liver, and spleen of Gulo-/- mice.

Recent advances in mass spectrometry have indicated that the water-soluble antioxidant vitamin C differentially modulates the abundance of various proteins in the hepatic tissue of female and male mice. In this study, we performed LC-MS/MS to identify and quantify proteins that correlate with serum vitamin C concentrations in the whole brain, heart, liver, and spleen tissues in mice deficient for the enzyme L-Gulonolactone oxidase required for vitamin C synthesis in mammals. This work shows for the first time that various biological processes affected by a vitamin C deficiency are not only sex specific dependent but also tissue specific dependent even though many proteins have been identified and quantified in more than three organs. For example, the abundance of several complex III subunits of the mitochondrial electron transport chain correlated positively with the levels of serum vitamin C only in the liver and not in the other tissues examined in this study even though such proteins were identified in all the organs analyzed. Western blot analyses on the Uqcrc1 and Uqcrfs1 complex III subunits validated the mass spectrometry results. Interestingly, the ferritin subunits represented the few quantified protein complexes that correlated positively with serum vitamin C in all the organs examined. Concomitantly, serum ferritin light chain 1 was inversely correlated with vitamin C levels in the serum. Thus, our study provides an initial comprehensive atlas of proteins significantly correlating with vitamin C in four organs in mice that will be a useful resource to the scientific community.

Pathogenicity of psychrotolerant strains of Antarctic Pseudogmynoascus fungi reveals potential opportunistic profiles

Recent studies have demonstrated the presence of fungal taxa in the extreme ecosystems of Antarctica that are known to opportunistically infect humans and animals. Among these are members of the genus Pseudogymnoascus, including some that are genetically similar to P. destructans, known to be pathogenic to bats. We evaluated the in vitro and in vivo pathogenic potential of 11 Pseudogymnoascus spp. strains recovered from Antarctica. All strains were able to grow at temperatures up to 28 °C and displayed in vitro pathogenicity through hemolytic activity, growth at different pH levels, production of hydrolytic enzymes, spore diameters, tolerance to oxidative stress, hypoxia, and halotolerance. Among them, Pseudogymnoascus sp. UFMG 8532 exhibited strong in vitro pathogenicity and in preliminary in vivo assay killed 100 % of Tenebrio molitor larvae within one day. The pathogenicity of the same strain was also tested using immunosuppressed BALB/c mouse models. Survival of BALB/c mice was affected, with oscillations between weight gain and loss, and impacts on sensory function, reflexes and autonomic function. Histopathological data from the organs of infected mice showed evidence of inflammatory processes, with numerous neutrophils, a small number of macrophages, fluid accumulation inside the lungs and intense hyperemia. Our results indicate that Antarctic Pseudogymnoascus spp. strains obtained from various substrates/habitats in maritime Antarctica may possess intrinsic virulence factors and pathogenic potential for immunosuppressed animals and humans in the region. Given that the Antarctic environment is an important reservoir for Pseudogymnoascus species, which display growth performance across a range of temperatures, it is possible that increasing temperatures in the maritime Antarctic could activate dormant genes or biochemical pathways, select virulent species and/or strains, and facilitate their spread within and beyond the region. The ability of Pseudogymnoascus species to grow slowly even at 28°C, coupled with their potential in vitro and in vivo virulence factors, suggests that these fungi might be undergoing an opportunistic transition due to the effects of climate change on the Antarctic Peninsula.

Effect of primary copper metabolism disturbance on elemental, protein, and lipid composition of the organs in Jackson toxic milk mouse.

Toxic milk (txJ) is an autosomal recessive mutation in the Atp7b gene in the C3H/HeJ strain, observed at The Jackson Laboratory in Maine, USA. TxJ mice exhibit symptoms similar to those of human Wilson's disease (WD). The study aimed to verify organ involvement in a mouse model of WD. TxJ mice and control animals were sacrificed at 2, 4, 8, and 14months of age. Total X-ray Fluorescence Spectroscopy (TXRF) was used to determine the elemental concentration in organs. Tissue chemical composition was measured by Fourier Transform Infrared Spectroscopy (FTIR). Additionally, hybrid mapping of FTIR and microXRF was performed. Elevated concentrations of Cu were observed in the liver, striatum, eye, heart, and duodenum of txJ mice across age groups. In the striatum of the oldest txJ mice, there was lower lipid content and a higher fraction of saturated fats. The secondary structure of striatum proteins was disturbed in txJ mice. In the livers of txJ mice, higher concentrations of saturated fats and disturbances in the secondary structure of proteins were observed. The concentration of neurofilaments was significantly higher in txJ serum. The distribution of Cu deposits in brains was uniform with no prevalence in any anatomic structure in either group, but significant protein structure changes were observed exclusively in the striatum of txJ. In this txJ animal model of WD, pathologic copper accumulation occurs in the duodenum, heart, and eye tissues. Increased copper concentration in the liver and brain results in increased saturated fat content and disturbances in secondary protein structure, leading to hepatic injury and neurodegeneration.

Cadmium-induced lung injury disrupts immune cell homeostasis in the secondary lymphoid organs in mice

Cadmium is a well-known toxic heavy metal that poses significant health risks, particularly through inhalation, smoking, and the consumption of contaminated food. Exposure to cadmium is linked to the development and exacerbation of chronic lung diseases such as pulmonary fibrosis and chronic obstructive pulmonary disease (COPD). This study investigated the systemic effects of intratracheal cadmium chloride (0.5mg/kg) instillation in C57BL/6 mice. All parameters, including inflammation assessment, lung function evaluation (using Flexi-vent), and immunophenotyping of T-cells in secondary lymphoid organs (spleen and mediastinal lymph nodes), were analyzed 14 days after Cd exposure. The results demonstrated that cadmium exposure led to significant immune cell infiltration in bronchoalveolar lavage (BAL) fluid, altered pro-inflammatory cytokine levels, and was associated with impaired lung function, characterized by increased lung resistance and Newtonian resistance. Analysis of T-cell populations revealed no significant changes in total T-cells in mediastinal lymph nodes and spleen, but a decrease in CD4+ T-cells and an increase in CD8+ T-cells were observed. These findings suggest that cadmium disrupts T-cell homeostasis in secondary lymphoid organs. Further research is crucial to elucidate the mechanisms underlying cadmium-induced lung injury and immune dysregulation, essential for developing effective therapeutic interventions against chronic lung diseases caused by cadmium exposure.

Synergistic chemo-photothermal anticancer effect of pH-responsive curcumin loaded mesoporous silica decorated reduced graphene

Synergistic chemo-photothermal therapy is employed to treat cancer. In this work, the curcumin loaded mesoporous silica on reduced graphene oxide (Cur-mSiO2@rGO) is synthesized. The mSiO2@rGO nanocarrier combines rGO to absorb NIR radiations with mSiO2 to load the drug. The mSiO2@rGO thus functions as bimodal photothermal agent and pH-responsive drug nanocarrier. Curcumin loaded onto the nanocarrier possesses antiproliferative, antioxidant, anti-inflammatory, pro-apoptotic, and antiangiogenic characteristics. It has anticancer potential against malignancies of stomach, liver, breast, lungs, and prostate. Breast cancer (BCa) is a major health concern worldwide. Curcumin inhibits BCa by mechanisms including apoptosis, cell cycle arrest, and modulation of signaling pathways. Moreover, curcumin blocks transcription factor (NF-κB), PI3K/AKT signaling, and STAT3 protein to inhibit liver cancer cell growth and survival. Cur-mSiO2@rGO targets cancer cells with enhanced loading capacity of 92 ± 1.02 % curcumin which is specifically released in the acidic tumor environment. NIR lamp irradiation at 808 nm ablates cancer cells to demonstrate the high photothermal conversion efficiency of rGO. In vitro experiments prove that synergistic chemo-photothermal therapy effectively kills cancer cells (HepG2 and MCF-7) compared to the single chemotherapeutic treatment. The toxicity of Cur-mSiO2@rGO is analyzed in vivo by the serum biochemical analysis, and biosafety by histopathological examination of vital body organs. A 1000 mg/kg specific dose of Cur-mSiO2@rGO shows no toxic effect on mice organs. Additionally, the in vivo studies confirm that Cur-mSiO2@rGO with NIR reduces tumor growth. Therefore, the multifunctional Cur-mSiO2@rGO can be a safe chemopreventive nanocarrier in tumor management and cancer photothermal therapy.