Search Results (37)

Background: Erythroblasts have recently been identified as host cells for malarial parasites, revealing a previously underappreciated host–parasite interaction. However, their extremely low abundance in peripheral blood has hindered progress, especially in elucidating the biological significance of parasitized erythroblasts (pEBs) in vivo. Methods: Here, we visualized pEBs in a murine model and established a method to increase their number in peripheral blood by immunizing mice with live Plasmodium yoelii 17XNL, followed by challenge with P. berghei ANKA. Results: Immunized mice were protected from cerebral malaria and survived longer, during which pEBs appeared in circulation and were detected using Giemsa-stained smears. All blood-stage parasite forms were identified within pEBs, including enucleating erythroblasts. Conclusions: This model enables in vivo/ex vivo analysis of pEB biology without bone marrow/spleen isolation, thus lowering technical/ethical barriers for the field. Full article

Background/Objectives: Senecio scandens Buch.-Ham. is a flavonoid-rich traditional medicinal plant with established immunomodulatory properties. However, the mechanisms underlying the immunoregulatory and intestinal protective effects of its flavonoid extract (Senecio scandens flavonoids—SSF) remain unclear. This study characterized SSF’s bioactive components and evaluated its efficacy against cyclophosphamide (CTX)-induced immunosuppression and intestinal injury. Methods: The constituents of SSF were identified using UHPLC/Q-Orbitrap/HRMS. Mice with CTX-induced immunosuppression were treated with SSF (80, 160, 320 mg/kg) for seven days. Immune parameters (organ indices, lymphocyte proliferation, cytokine, and immunoglobulin levels) and gut barrier integrity markers (ZO-1, Occludin, Claudin-1 protein expression; sIgA secretion; microbiota composition) were assessed. Network pharmacology combined with functional assays elucidated the underlying regulatory mechanisms. Results: Twenty flavonoids were identified in SSF, with six prototype compounds detectable in the blood. The SSF treatment significantly ameliorated CTX-induced weight loss and atrophy of the thymus and spleen. It enhanced splenic T- and B-lymphocyte proliferation by 43.6% and 29.7%, respectively; normalized the CD4⁺/CD8⁺ ratio (1.57-fold increase); and elevated levels of IL-2, IL-6, IL-10, TNF-α, IFN-γ, IgM, and IgG. Moreover, SSF reinforced the intestinal barrier by upregulating tight junction protein expression and sIgA levels while modulating the gut microbiota, enriching beneficial taxa (e.g., the Lachnospiraceae_NK4A136_group, Akkermansia) and suppressing pathogenic Alistipes. Mechanistically, SSF activated the TLR/MyD88/NF-κB pathway, with isoquercitrin identified as a pivotal bioactive constituent. Conclusions: SSF effectively mitigates CTX-induced immunosuppression and intestinal damage. These findings highlight SSF’s potential as a dual-functional natural agent for immunomodulation and intestinal protection. Subsequent research should validate isoquercitrin’s molecular targets and assess SSF’s clinical efficacy. Full article

Alzheimer’s disease (AD) and schizophrenia are traditionally considered distinct clinical entities, yet growing evidence highlights substantial overlap in their molecular and neuroinflammatory pathogenesis. This review explores current insights into the shared and divergent mechanisms underlying these disorders, with emphasis on neuroinflammation, autophagy dysfunction, blood–brain barrier (BBB) disruption, and cognitive impairment. We examine key signaling pathways, particularly spleen tyrosine kinase (SYK), the mechanistic (or mammalian) target of rapamycin (mTOR), and the S100 calcium-binding protein B (S100B)/receptor for advanced glycation end-products (RAGE) axis, that link glial activation, excitatory/inhibitory neurotransmitter imbalances, and impaired proteostasis across both disorders. Specific biomarkers such as S100B, matrix metalloproteinase 9 (MMP9), and soluble RAGE show promise for stratifying disease subtypes and predicting treatment response. Moreover, psychiatric symptoms frequently precede cognitive decline in both AD and schizophrenia, suggesting that mood and behavioral disturbances may serve as early diagnostic indicators. The roles of autophagic failure, cellular senescence, and impaired glymphatic clearance are also explored as contributors to chronic inflammation and neurodegeneration. Current treatments, including cholinesterase inhibitors and antipsychotics, primarily offer symptomatic relief, while emerging therapeutic approaches target upstream molecular drivers, such as mTOR inhibition and RAGE antagonism. Finally, we discuss the future potential of personalized medicine guided by genetic, neuroimaging, and biomarker profiles to optimize diagnosis and treatment strategies in both AD and schizophrenia. A greater understanding of the pathophysiological convergence between these disorders may pave the way for cross-diagnostic interventions and improved clinical outcomes. Full article

The spleen plays a critical role in the immune and hematopoietic systems of teleost fish, functioning as a major secondary lymphoid organ. This study provides a detailed morphological and ultrastructural assessment of the spleen in goldfish (Carassius auratus), focusing on its immunological organization and cellular diversity. Through light and transmission electron microscopy, we examined red and white pulps, identifying key features such as melanomacrophage centers (MMCs), ellipsoids, and various immune cell types. The red pulp was rich in sinusoidal capillaries and splenic cords, whereas the white pulp housed lymphocytes, dendritic cells, macrophages, and telocytes, all contributing to immune regulation. Notably, ellipsoids were surrounded by reticular and macrophage sheaths, forming a filtration barrier against pathogens. Ultrastructural analysis revealed diverse immune cells with active morphological traits, including macrophages with pseudopodia and pigment granules, dendritic cells with dendrite-like extensions, and epithelial reticular cells involved in forming the blood–spleen barrier. These findings highlight the complex immunological microarchitecture of the goldfish spleen and its functional relevance in teleost immune responses. Full article

Micro- and nano-plastics (MNPs) are small plastic particles that result from the breakdown of larger plastics. They are widely dispersed in the environment and pose a threat to wildlife and humans. MNPs are present in almost all everyday items, including food, drinks, and household products. Air inhalation can also lead to exposure to MNPs. Research in animals indicates that once MNPs are absorbed, they can spread to various organs, including the liver, spleen, heart, lungs, thymus, reproductive organs, kidneys, and even the brain by crossing the blood–brain barrier. Furthermore, MPs can transport persistent organic pollutants or heavy metals from invertebrates to higher levels in the food chain. When ingested, the additives and monomers that comprise MNPs can disrupt essential biological processes in the human body, thereby leading to disturbances in the endocrine and immune systems. During the 2019 coronavirus (COVID-19) pandemic, there was a significant increase in the global use of polypropylene-based face masks, leading to insufficient waste management and exacerbating plastic pollution. This review examines the existing research on the impact of MNP inhalation on human lung and kidney health based on in vitro and in vivo studies. Over the past decades, a wide range of studies suggest that MNPs can impact both lung and kidney tissues under both healthy and diseased conditions. Therefore, this review emphasizes the need for additional studies employing multi-approach analyses of various associated biomarkers and mechanisms to gain a comprehensive and precise understanding of the impact of MNPs on human health. Full article

Toxoplasma gondii is an obligate intracellular protozoan that infects humans and other mammals. The C57BL/6J mouse strain is regarded as an ideal model organism for studying T. gondii due to its susceptibility to T. gondii infection and its other advantages over other laboratory animals. However, systematic studies on the response dynamics of the susceptible C57BL/6J mice after oral infection with T. gondii cysts are lacking. To address this research gap, we investigated the spatiotemporal dynamics of infection, colonization, and antibody fluctuations in susceptible C57BL/6J mice orally infected with Type II T. gondii ME49 strain cysts. Mice were orally challenged with T. gondii cysts to examine the infection dynamics. Daily monitoring was conducted for 60 days post-infection (dpi) to assess animals’ clinical signs and survival rates. The parasite burden in various organs was quantified using qPCR targeting the T. gondii B1 gene. The serum antibody responses were evaluated using ELISA. The cyst burden in the mouse brain was assessed via histology and immunofluorescence. T. gondii infection induced clinical symptoms in the mice, including fever and weight loss. T. gondii rapidly invaded the mice’s small intestine, spleen, lungs, liver, and heart via the bloodstream within 1–5 dpi. T. gondii had breached the blood–brain barrier and colonized the brain by 7 dpi. The levels of Toxoplasma-specific IgG antibodies increased and stabilized for two months (until the experiment ended). Systemic parasite dissemination occurred rapidly, infiltrating most tissues and organs, leading to pronounced enteritis and multi-organ damage due to inflammation. The tachyzoites differentiated into bradyzoites when T. gondii infection progressed from the acute to the chronic phase in mice, forming tissue cysts in organs, including the muscles and brain. As a result, the predilection site of T. gondii in mice is the brain, which is where the cysts persisted for the host’s lifetime and continuously induced meningitis. These findings provide valuable insights into the spatiotemporal diffusion, colonization, predilection sites, temporal antibody dynamics, pathogen detection methodologies, and histopathological changes in C57BL/6J mice following oral infection with T. gondii cysts. These insights are important for elucidating T. gondii’s pathogenesis and host–T. gondii interaction. Full article

Background: Studies have demonstrated that resveratrol exerts several pharmacological effects. However, the pharmacokinetic parameters are not completely established. Objectives: This study describes the plasma pharmacokinetics and tissue distribution of resveratrol after administration by different routes and doses in rats. Methods: A reliable, simple, and sensitive HPLC method using UV detection for the quantification of resveratrol in rat plasma and tissues was developed and validated. In addition, a pharmacokinetic analysis using non-compartmental and population modeling was performed. Results: The pharmacokinetic parameters of resveratrol after the administration of 5 mg/kg via i.v. bolus calculated by non-compartmental analysis were a constant of elimination (ke) of 0.09 h⁻¹ ± 0.04, a half-life (t1/2) of 9.5 h ± 3.7, an apparent volume of distribution (Vd) of 5.8 L/kg ± 4.7, a clearance (Cl) of 0.39 L/h/Kg ± 0.26, and an area under the curve (AUC) of 6076 ng/h/mL ± 2959. The results obtained after the administration of 100 mg/kg p.o. were an elimination constant (ke) of 0.12 ± 0.07 h⁻¹, a half-life (t1/2) of 7.9 ± 4.2 h, the apparent volume distribution (Vd) of 13.3 ± 3.3 L/kg, a clearance (Cl) of 1.76 ± 0.49 L/h/Kg ± 0.26, and an area under the curve (AUC) of 6519 ± 1592 ng/h/mL. For the tissue distribution analysis, 10 mg/kg of resveratrol was intravenously administered to rats and the molecule was quantified in the liver, lung, kidney, heart, stomach, spleen, adipose tissue, and brain of the animals. Conclusions: The population pharmacokinetic modeling showed that resveratrol has a two-compartment model in both routes of administration and has a higher volume of distribution when it is given orally. In addition, resveratrol showed a high brain concentration after iv administration, which indicates that this molecule is capable of crossing the blood–brain barrier of animals, a crucial capacity for its neuroprotective activity. Full article

Plague is a zoonotic disease caused by Yersinia pestis, and it is endemic in Madagascar. The plague cycle involves wild and commensal rodents and their fleas; humans are an accidental host. Madagascar is the country where plague burden is the highest. Plague re-emerged in Mahajanga, the western coast of Madagascar, in the 1990s and infected populations in the popular and insalubrious zones. Sanitation is considered a primary barrier to infection by excluding pathogens from the environment and reservoirs. Poor housing and hygiene and proximity to rodents and fleas in everyday life are major and unchanged risk factors of plague. The aim of this study was to measure the impact of sanitation on Yersinia pestis bacteria in human and small mammal reservoirs and flea vectors. This study was conducted on 282 households within 14 neighborhoods. Two sessions of sampling were conducted in 2013 and 2016. Small mammals were trapped inside and around houses using live traps. Fleas, blood and spleen were sampled to detect Y. pestis infection and antibodies and determine the level of plague circulation before and after the installation of sanitation in order to assess the impact of sanitation improvement on inhabitant health. Two major types of housing can be described, i.e., formal and informal (traditional), scattered in all the suburbs. Among the small mammals captured, 48.5% were Suncus murinus, and 70% of houses were infested. After sanitation, only 30% of houses remained infested, and most of them were located around the market. Fleas were mostly Xenopsylla cheopis. Before and after intervention, the overall prevalence of fleas was the same (index 4.5) across the 14 suburbs. However, the number of houses with fleas drastically decreased, and the flea index increased significantly in rodent-infested houses. Rodent abundance also decreased from 17.4% to 6.1% before and after intervention, respectively. A serology study highlights that plague is still circulating in Mahajanga, suggesting that small mammals maintain enzootic plague transmission in the city. Full article

Obejectives: This study explored the immunomodulatory effects of a prebiotic formula consisting of 2′-fucosyllactose (2′-FL), galacto-oligosaccharides (GOSs), and fructo-oligosaccharides (FOSs) (hereinafter referred to as 2FGF) in cyclophosphamide (CTX)-induced immunosuppressed BALB/c mice and its underlying mechanisms. Methods: Sixty healthy female BALB/c mice were randomly divided into the following groups: normal control (NC) group; CTX treatment (CTX) group; 2FGF low-dose (2FGF-L) group; 2FGF medium-dose (2FGF-M) group; and 2FGF high-dose (2FGF-H) group. An immunosuppressed model was established in the 2FGF-H group by intraperitoneal injection of 80 mg/kg CTX. After 30 days of 2FGF intervention, peripheral blood, spleen tissue, thymus tissue, and intestinal tissue from the mice were collected and analyzed. The changes in weight and food intake of the mice were recorded weekly. Hematoxylin-eosin (HE) staining was used to observe the histological change of the spleen tissue. Enzyme-linked immunosorbent assay (ELISA) was employed to detect cytokine levels in peripheral blood. Flow cytometry was used to analyze T lymphocyte subgroup ratio of splenic lymphocytes. Western blot analysis was conducted on intestinal tissues to assess the expression of proteins involved in the tight junction, toll-like receptor 4 (TLR4), mitogen-activated protein kinase (MAPK), and nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) signaling pathways. Additionally, molecular techniques were used to analyze the intestinal microbiota. Results: The results showed that 2FGF restored CTX-induced splenic injury, increased the number of splenic T lymphocytes, and elevated serum cytokines such as interleukin-4 (IL-4) and IL-10. In the intestine, 2FGF upregulated the expression of intestinal epithelial tight junction proteins such as Claudin-1 and zonula occludens 1 (ZO-1), thereby enhancing intestinal barrier function and activating the MAPK and NF-κB pathways via TLR4. Furthermore, 2FGF elevated the α-diversity (Shannon and Simpson indices) of the gut microbiota in CTX-induced immunosuppressed mice, enriching bacteria species positively correlated with anti-inflammatory cytokines (e.g., IL-4) such as g_Streptomyces and g_Bacillus and negatively correlated with pro-inflammatory cytokines (e.g., IL-1β) such as g_Saccharomyces. The results suggest that 2FGF may enhance immunity via the gut–immune axis. Conclusions: The 2FGF prebiotic formula showed an immunomodulatory effect in CTX-induced immunosuppressed mice, and the mechanism of which might involve optimizing the gut flora, enhancing intestinal homeostasis, strengthening the intestinal barrier, and promoting the expression of immune factors by regulating the TLR-4/MAPK/NF-κB pathway. Full article

Spinal cord injury (SCI) leads to devastating sequelae, demanding effective treatments. Recent advancements have unveiled the role of neutrophil extracellular traps (NETs) produced by infiltrated neutrophils in exacerbating secondary inflammation after SCI, making it a potential target for treatment intervention. Previous research has established that intravenous administration of stem cell-derived exosomes can mitigate injuries. While stem cell-derived exosomes have demonstrated the ability to modulate microglial reactions and enhance blood–brain barrier integrity, their impact on neutrophil deactivation, especially in the context of NETs, remains poorly understood. This study aims to investigate the effects of intravenous administration of MSC-derived exosomes, with a specific focus on NET formation, and to elucidate the associated molecular mechanisms. Exosomes were isolated from the cell supernatants of amnion-derived mesenchymal stem cells using the ultracentrifugation method. Spinal cord injuries were induced in Sprague-Dawley rats (9 weeks old) using a clip injury model, and 100 μg of exosomes in 1 mL of PBS or PBS alone were intravenously administered 24 h post-injury. Motor function was assessed serially for up to 28 days following the injury. On Day 3 and Day 28, spinal cord specimens were analyzed to evaluate the extent of injury and the formation of NETs. Flow cytometry was employed to examine the formation of circulating neutrophil NETs. Exogenous miRNA was electroporated into neutrophil to evaluate the effect of inflammatory NET formation. Finally, the biodistribution of exosomes was assessed using ⁶⁴Cu-labeled exosomes in animal positron emission tomography (PET). Rats treated with exosomes exhibited a substantial improvement in motor function recovery and a reduction in injury size. Notably, there was a significant decrease in neutrophil infiltration and NET formation within the spinal cord, as well as a reduction in neutrophils forming NETs in the circulation. In vitro investigations indicated that exosomes accumulated in the vicinity of the nuclei of activated neutrophils, and neutrophils electroporated with the miR-125a-3p mimic exhibited a significantly diminished NET formation, while miR-125a-3p inhibitor reversed the effect. PET studies revealed that, although the majority of the transplanted exosomes were sequestered in the liver and spleen, a notably high quantity of exosomes was detected in the damaged spinal cord when compared to normal rats. MSC-derived exosomes play a pivotal role in alleviating spinal cord injury, in part through the deactivation of NET formation via miR-125a-3p. Full article

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by α-L-iduronidase deficiency. The standard treatment, enzyme replacement therapy with laronidase, has limited effectiveness in treating neurological symptoms due to poor blood–brain barrier penetration. An alternative is substrate reduction therapy using molecules, such as genistein, which crosses this barrier. This study evaluated the effectiveness of a combination of laronidase and genistein in a mouse model of MPS I. Over 12 weeks, MPS I and wild-type mice received laronidase, genistein, or both. Glycosaminoglycan (GAG) storage in visceral organs and the brain, its excretion in urine, and the serum level of the heparin cofactor II–thrombin (HCII-T) complex, along with behavior, were assessed. The combination therapy resulted in reduced GAG storage in the heart and liver, whereas genistein alone reduced the brain GAG storage. Laronidase and combination therapy decreased liver and spleen weights and significantly reduced GAG excretion in the urine. However, this therapy negated some laronidase benefits in the HCII-T levels. Importantly, the combination therapy improved the behavior of female mice with MPS I. These findings offer valuable insights for future research to optimize MPS I treatments. Full article

Animals experience stress when they are transported. In this experiment, sixty 4-month-old lambs were randomly divided into three groups: CG (basal diet), EG (basal diet + 375 mg/d/lamb electrolytic multivitamin) and NG (basal diet + 200 mg/d/lamb neomycin). The transportation day was recorded as the 0th day. Blood, liver, spleen, jejunum and colon were collected on the 0th, 7th and 14th day. The results were as follows: In EG and NG groups, the lamb weights (p < 0.01), IgA and IgG (p < 0.05) increased significantly. The concentrations of ACTH, E, COR, IL-1β, IL-6 and IFN-γ decreased significantly (p < 0.01). The content of colonic propionate increased significantly (p < 0.05). The villus height and V/C increased, and crypt depth decreased significantly (p < 0.01). The mRNA expressions of Occludin and MUC1, and the protein expression of Occludin in the jejunal mucosa, the mRNA expressions of ZO-1 and Occludin, and the protein expression in the colonic mucosa increased significantly (p < 0.01). The mRNA expression of TRAF6 and the protein expression of TLR4 in the jejunum decreased significantly (p < 0.05), as well as the mRNA expressions of TLR4, MyD88 and NF-kB, and the protein expression of NF-kB p65 and the mRNA expressions of TRAF6, TLR4 and NF-kB in the colon (p < 0.01). In conclusion, an electrolytic multivitamin could potentially improve the immunity and intestinal barrier function, and when it was added with 375 mg/d in the basal diet for each lamb from 2 d before transportation to 7 d after transportation, it had a better effect than neomycin. Full article

(1) Background: Inducing experimental stroke leads to biphasic immune responses, where the early activation of immune functions is followed by severe immunosuppression accompanied by spleen and thymus atrophy. Nicotinamide, a water-soluble B-group vitamin, is a known neuroprotectant against brain ischemia in animal models. We examined the effect of nicotinamide on the central and peripheral immune response in experimental stroke models. (2) Methods: Nicotinamide (500 mg/kg) or saline was intravenously administered to C57BL/6 mice during reperfusion after transiently occluding the middle cerebral artery or after LPS injection. On day 3, the animals were examined for behavioral performance and were then sacrificed to assess brain infarction, blood–brain barrier (BBB) integrity, and the composition of immune cells in the brain, thymus, spleen, and blood using flow cytometry. (3) Results: Nicotinamide reduced brain infarction and microglia/macrophage activation following MCAo (p < 0.05). Similarly, in LPS-injected mice, microglia/macrophage activation was decreased upon treatment with nicotinamide (p < 0.05), suggesting a direct inhibitory effect of nicotinamide on microglia/macrophage activation. Nicotinamide decreased the infiltration of neutrophils into the brain parenchyma and ameliorated Evans blue leakage (p < 0.05), suggesting that a decreased infiltration of neutrophils could, at least partially, be the result of a more integrated BBB structure following nicotinamide treatment. Our studies also revealed that administering nicotinamide led to retarded B-cell maturation in the spleen and subsequently decreased circulating B cells in the thymus and bloodstream (p < 0.05). (4) Conclusions: Cumulatively, nicotinamide decreased brain inflammation caused by ischemia–reperfusion injury, which was mediated by a direct anti-inflammatory effect of nicotinamide and an indirect protective effect on BBB integrity. Administering nicotinamide following brain ischemia resulted in a decrease in circulating B cells. This warrants attention with respect to future clinical applications. Full article

Background: ATP-binding cassette (ABC) transporters comprise a superfamily of genes encoding membrane proteins with nucleotide-binding domains (NBD). These transporters, including drug efflux across the blood–brain barrier (BBB), carry a variety of substrates through plasma membranes against substrate gradients, fueled by hydrolyzing ATP. The expression patterns/enrichment of ABC transporter genes in brain microvessels compared to peripheral vessels and tissues are largely uncharacterized. Methods: In this study, the expression patterns of ABC transporter genes in brain microvessels, peripheral tissues (lung, liver and spleen) and lung vessels were investigated using RNA-seq and Wes^TM analyses in three species: human, mouse and rat. Results: The study demonstrated that ABC drug efflux transporter genes (including ABCB1, ABCG2, ABCC4 and ABCC5) were highly expressed in isolated brain microvessels in all three species studied; the expression of ABCB1, ABCG2, ABCC1, ABCC4 and ABCC5 was generally higher in rodent brain microvessels compared to those of humans. In contrast, ABCC2 and ABCC3 expression was low in brain microvessels, but high in rodent liver and lung vessels. Overall, most ABC transporters (with the exception of drug efflux transporters) were enriched in peripheral tissues compared to brain microvessels in humans, while in rodent species, additional ABC transporters were found to be enriched in brain microvessels. Conclusions: This study furthers the understanding of species similarities and differences in the expression patterns of ABC transporter genes; this is important for translational studies in drug development. In particular, CNS drug delivery and toxicity may vary among species depending on their unique profiles of ABC transporter expression in brain microvessels and BBB. Full article

Microplastics are small plastic particles that come from the degradation of plastics, ubiquitous in nature and therefore affect both wildlife and humans. They have been detected in many marine species, but also in drinking water and in numerous foods, such as salt, honey and marine organisms. Exposure to microplastics can also occur through inhaled air. Data from animal studies have shown that once absorbed, plastic micro- and nanoparticles can distribute to the liver, spleen, heart, lungs, thymus, reproductive organs, kidneys and even the brain (crosses the blood–brain barrier). In addition, microplastics are transport operators of persistent organic pollutants or heavy metals from invertebrate organisms to other higher trophic levels. After ingestion, the additives and monomers in their composition can interfere with important biological processes in the human body and can cause disruption of the endocrine, immune system; can have a negative impact on mobility, reproduction and development; and can cause carcinogenesis. The pandemic caused by COVID-19 has affected not only human health and national economies but also the environment, due to the large volume of waste in the form of discarded personal protective equipment. The remarkable increase in global use of face masks, which mainly contain polypropylene, and poor waste management have led to worsening microplastic pollution, and the long-term consequences can be extremely devastating if urgent action is not taken. Full article