Search Results (4,569)

Fasciolosis, caused by the liver fluke Fasciola gigantica, remains a major parasitic disease affecting livestock in tropical regions and results in substantial economic losses. Although anthelmintic drugs are widely used for disease control, increasing reports of drug resistance highlight the need for alternative strategies such as vaccination. In this study, a recombinant digestive protein-based chimeric antigen (rFgCHI-DP) composed of three F. gigantica antigens—cathepsin L1 (FgCL1), cathepsin B1 (FgCB1), and saposin-like protein 2 (FgSAP2)—was designed and expressed in Escherichia coli. The mature regions of these proteins were sequentially linked to form a single chimeric construct. The recombinant protein was successfully expressed and purified under denaturing conditions, producing a protein of approximately 62 kDa. To evaluate its immunogenicity, BALB/c mice were immunized with rFgCHI-DP formulated with Quil A adjuvant. Indirect ELISA revealed that immunization induced antigen-specific IgG responses. Antibody responses showed strong reactivity toward FgCL1 and FgCB1, whereas the response against FgSAP2 was comparatively lower. Western blot analysis further demonstrated that antibodies generated against rFgCHI-DP recognized native parasite antigens. Immunolocalization also revealed that the anti-rFgCHI-DP antibodies could detect targeted antigens in the cecal epithelium of the parasite. These findings indicate that the adult-stage chimeric protein rFgCHI-DP is immunogenic in mice and capable of inducing specific antibody responses against F. gigantica. The results support the potential of rFgCHI-DP as a candidate antigen for future fasciolosis vaccine development. Full article

The potential health hazards caused by microwave exposure have attracted increasing attention. Microwave radiation has been reported to induce oxidative stress in neural tissues, which is considered one of the primary mechanisms underlying its adverse effects on central nervous system function. The hippocampus is sensitive to microwave radiation, whereas underlying cellular and molecular mechanisms remain incompletely understood. In this study, microwave-exposed mice exhibited significantly impaired performance in the Go/No-go, Y-maze, and novel object recognition tests at 6 h and 7 days post-exposure, indicating deficits in hippocampus-dependent working memory. Single-cell RNA sequencing of hippocampal tissues from control and microwave-exposed mice yielded 94,088 high-quality cells across eight major cell types. Astrocyte sub-clustering identified five transcriptionally distinct subpopulations, with Astrocyte_S100a6 and Astrocyte_Son proportions increased and Astrocyte_Serpinf1 decreased in the radiation group. Analysis of astrocyte transcriptional state transitions showed microwave-exposed astrocytes were preferentially distributed toward terminal reactive states with depletion at early homeostatic nodes. Cell–cell communication analysis revealed increased total interactions and interaction strength following radiation. Astrocyte outgoing signaling was increased for pathways associated with vascular remodeling, phagocytic regulation, and neuroinflammation, while pathways related to trophic support were decreased. Incoming signaling showed increased activity in pathways linked to phagocytic recruitment and inflammatory mediation. Taken together, these findings indicate that microwave exposure is associated with hippocampus-dependent working memory deficits accompanied by transcriptional remodeling of astrocyte subpopulation composition, directional astrocyte state transitions toward reactive phenotypes, and broad alterations in astrocyte-centered intercellular communication, providing a cellular and molecular framework for understanding astrocyte involvement in microwave radiation-associated hippocampal dysfunction. Full article

Growth hormone-releasing hormone (GHRH) antagonists have displayed anti-neoplastic activity against a multitude of cancers in vitro, as well as in vivo, via xenografted tumors in nude mice. Following a successful demonstration of GHRH antagonists treating non-Hodgkin’s lymphoma and the discovery of GHRH mRNA and peptide products in immune cells, GHRH antagonism was explored in acute myeloid leukemia (AML), a disease characterized by a malignant expansion of immature myeloid progenitors, and poor 5-year survival. Targeted therapies have yielded breakthroughs in treatment response and overall survival, such as all-trans retinoic acid/arsenic trioxide (ATRA/ATO) for acute promyelocytic leukemia (APL), or FLT3 inhibitors, IDH inhibitors, and menin inhibitors for AML harboring actionable genetic lesions. However, therapeutic resistance remains a major barrier to durable remission. GHRH receptor (GHRH-R) has been reported in several experimental models of AML, including drug-resistant sublines. Significant time- and dose-dependent reduction in leukemic growth was observed in vitro and in vivo following MIA-602 treatment. FLT3 inhibitor resistance has been associated with activation of PI3K/AKT, ERK/MAPK, inflammatory, stromal, and apoptotic escape pathways. The documented effects of GHRH-R antagonism raise the possibility that it could influence signaling networks relevant to therapeutic resistance in AML. This hypothesis remains speculative; to date no studies have stratified AML by FLT3 status in the context of GHRH-R expression or GHRH antagonism, and there is currently no evidence that MIA-602 directly alters FLT3 receptor signaling or inhibitor sensitivity. Full article

A fraction of the insulin-stimulated uptake of long-chain fatty acids (FAs) is mediated by the FA translocase cluster of differentiation 36 (CD36) in white adipocytes. Intracellular vesicle-localized CD36 is redistributed to the plasma membrane following insulin stimulation, enhancing the uptake of long-chain FAs across the plasma membrane. We previously developed an epitope-tagged CD36 reporter, which enabled the visualization and quantification of the plasma membrane translocation of CD36. Herein, we demonstrate that the insulin-stimulated CD36 translocation is regulated by the phosphoinositide 3-kinase (PI3K)/Akt2/Rac1/RalA axis in adipocytes of subcutaneous white adipose tissue (WAT) in living mice. The uptake of long-chain FAs by insulin was completely abrogated in white adipocytes isolated from adipocyte-specific rac1-knockout (adipo-rac1-KO) mice. Correspondingly, the translocation of CD36 to the plasma membrane by insulin was also totally inhibited in Rac1-deficient white adipocytes. PI3K and Akt2 acted upstream of Rac1, and the guanin nucleotide exchange factor FLJ00068 served as a regulator for Rac1. Furthermore, the involvement of another small GTPase RalA was suggested by inhibitory effects of a dominant-negative mutant. Taken together, these results support the notion that insulin regulates the plasma membrane translocation of CD36 by mechanisms similar to those for the translocation of the glucose transporter GLUT4 in white adipocytes. Full article

The current use of artificial light during the natural dark phase has acquired contaminant dimensions, known as “light pollution”. It is well known that exposure to dim light at night (dLAN) during the postnatal period severely impairs the immune system and related organs, but few reports have demonstrated the effects of dLAN during the fetal period. This study, therefore, examines whether exposure to dim light at night during two critical developmental windows (i.e., prenatal and postnatal periods) leads to long-lasting dysregulation of circadian, behavioral, and immune organization, as well as spleen immune responses, in early adulthood. To address this question, these outcomes were assessed using two defined sampling time points. To answer this question, we exposed two groups of C57BL/6J male mice to dim night light during the gestational and postnatal periods and compared them with control groups that were exposed to light–dark conditions (12 h each, LD). Parametric and non-parametric activity/rest values were analyzed with circular statistics. Compared to their controls, we found differences in alpha, onset, offset, M10, and L5 start time in dLAN groups. We also assessed the transcript levels of clock genes and inflammatory mediators in spleen tissue and found a dampening of daily variation in mRNA expression in both experimental groups. Finally, we used an ovalbumin (OVA) allergy challenge to test the B-cell response in the spleen and found a significantly higher cell recruitment to the spleen and more anti-OVA IgE. Together, these results clearly show that dLAN, at two ZT sampling points, affects peripheral molecular clocks and responses in the spleen, and that these effects are independent of the life stage at which exposure to dim light at night occurs. Full article

Insulin resistance (IR) is a significant risk factor for various diseases, particularly during pregnancy. Dietary patterns have been reported to influence IR susceptibility. High-protein (HP) diet has gained popularity for its role in weight management. However, whether trimethylamine N-oxide (TMAO), which is produced in the liver from gut microbiota-derived metabolites of dietary protein, influences IR remains uncertain. In this study, we established a pregnant mouse model to examine the effect of an HP diet on IR, assess its impact on liver function, and investigate associated signaling pathways. The role of gut microbiota was also evaluated. We found that the HP diet induced liver injury in pregnant mice following significantly decreased body weight. The HP diet also elevated plasma TMAO levels and upregulated hepatic FMO₃ expression. Transcriptomic analysis revealed enrichment of insulin-related signaling pathways in the HP group, with notable downregulation of the Insrr gene. IR was induced through the IRS-1/PI3K/Akt signal pathway. Gut microbiota composition was disrupted in HP group, characterized by an increased Firmicutes/Bacteroidetes ratio and a higher abundance of the TMA-producing genus Coprococcus, indicating an elevated potential for TMA generation. Furthermore, several amino acid metabolism pathways closely linked to IR were also enriched in the HP group. In conclusion, our study demonstrates that HP diet induces liver injury and increases IR risk during pregnancy. Gut microbiota contributes to this process, in part through an enhanced capacity for TMA production. These findings highlight the need for greater attention to dietary patterns in pregnancy to mitigate metabolic risks. Full article

Background/Objectives: Renal ischemia–reperfusion injury (IRI) is a major cause of acute kidney injury and delayed graft function after kidney transplantation. Oxidative stress, mitochondrial dysfunction, and tubular epithelial cell apoptosis are central events in renal IRI. Sophocarpine (SOP), a quinolizidine alkaloid derived from Sophora species, has reported antioxidant and anti-apoptotic activities, but its effects in renal IRI remain unclear. This study investigated the role and function of SOP in renal IRI. Methods: A bilateral renal IRI mouse model and a hypoxia/reoxygenation (H/R) model in HK-2 human proximal tubular epithelial cells were used. Renal function, histological injury, apoptosis, reactive oxygen species, malondialdehyde, superoxide dismutase activity, glutathione, mitochondrial morphology, mitochondrial membrane potential, and mitochondrial dynamics-related proteins were evaluated. SIRT1 dependency was examined using Sirt1 small interfering RNA in HK-2 cells and EX527-mediated SIRT1 inhibition in mice. Results: SOP pretreatment reduced serum creatinine and blood urea nitrogen levels, attenuated tubular injury and apoptosis, decreased oxidative stress, and preserved mitochondrial morphology and function after renal IRI. Similar protective effects were observed in HK-2 cells exposed to H/R. SOP increased SIRT1 and PGC-1α expression, whereas Sirt1 knockdown or pharmacological SIRT1 inhibition weakened the antioxidant and mitochondrial protective effects of SOP. Conclusions: SOP attenuates renal IRI-associated oxidative stress and mitochondrial dysfunction, at least in part through the SIRT1/PGC-1α axis. These findings support further investigation of SOP as a candidate renoprotective compound for ischemic kidney injury. Full article

Local immune cell activation and vascular remodelling are characteristic pathogenic features of pulmonary arterial hypertension (PAH). HIV and schistosome infections have been individually associated with PAH. However, whether co-infection with these pathogens has a distinct impact on the development of pulmonary vascular disease remains poorly understood, partly due to the lack of experimental animal models. In a novel non-infectious model of HIV and Schistosoma pulmonary co-exposure based on lung embolisation of S. mansoni eggs in HIV-transgenic (HIV) mice, we previously reported exacerbated endothelial remodelling and dysfunction, along with increased pulmonary arterial pressure; which were associated with a unique profile of pro-inflammatory cytokines in the lung. In the present study, we used flow cytometric analysis of isolated lung leukocytes and immunofluorescence staining to characterise the pulmonary immune cell landscape associated with individual or combined exposure to HIV and schistosome. Compared with mice exposed to HIV (untreated HIV mice) or schistosome (egg-treated wild-type mice), co-exposed (egg-treated HIV mice) animals showed significantly increased numbers of interstitial and alveolar macrophages, patrolling-type monocytes, NKT and γδ T cells, and reduced CD8⁺ αβ T cells. Other lung immune cells, including inflammatory-type monocytes, eosinophils/neutrophils, dendritic cells, CD4⁺ αβ T cells, NK cells and B cells were not significantly affected in the co-exposure condition. Taken together, these results show for the first time that combined pulmonary exposure to HIV and Schistosoma, as it may occur in co-infected individuals, alters the local immune cell landscape in a manner distinct from that of individual exposure. Furthermore, these findings may contribute to a better understanding of the complex inflammatory processes involved in the pathogenesis of PAH, thereby supporting the development of therapies targeting pathogenic immune cells in pulmonary vascular disease associated with HIV and Schistosoma co-morbidity. Full article

Background and Objectives: Breast cancer remains one of the most common malignancies worldwide, and early detection plays a crucial role in improving treatment outcomes and reducing mortality. Several experimental studies using animal models of breast cancer have explored the potential of terahertz-based technologies in this field. However, their preclinical evidence base in breast cancer remains heterogeneous and has not been systematically synthesized with a focus on experimental models, imaging protocols, and barriers to translation. Methods: We conducted a descriptive systematic review, according to PRISMA guidelines, of 10 articles selected from a total of 372 identified across four databases—PubMed, Embase, Web of Science, and Cochrane—regarding the diagnostic performance of terahertz (THz) imaging in breast cancer animal models. We included studies that used rodent models diagnosed with breast cancer, subsequently confirmed through histological examination, and extracted relevant data. Results: The results were synthesized using a narrative approach. Most studies used C57BL/6J mice with E0771 cell line-induced breast tumors, with histopathology as the reference standard. In the reflection mode, at frequencies between 0.1 and 4 THz, the identification of tumoral, fibrous, fat, and muscle tissues was possible. Conclusions: Overall, the available preclinical evidence supports THz imaging as a promising proof-of-concept approach for breast tissue characterization, but not yet as a standardized or clinically translatable diagnostic platform. Future studies should use harmonized animal models, standardized acquisition and specimen-handling protocols, transparent reporting of classification workflows, and consistent outcome metrics to enable comparison across studies and to clarify the biological and biophysical determinants of THz contrast in breast cancer. Full article

Allomyrinasin is an antimicrobial peptide derived from the larvae of the edible insect Allomyrina dichotoma and has been reported to exert anti-inflammatory activity, although its role in metabolic regulation remains unclear. This study aimed to investigate the metabolic and hepatoprotective effects of allomyrinasin in a high-fat diet (HFD)–induced obese mouse model. Male C57BL/6J mice were fed an HFD for 6 weeks to induce body weight gain and hyperglycemia, followed by 10 weeks of oral administration of allomyrinasin (0.1 mg/kg/day) under continued HFD conditions, with metformin used as a positive control. Metabolic parameters related to glucose homeostasis, insulin sensitivity, lipid metabolism, hepatic injury, oxidative stress, inflammation, and fibrotic responses were evaluated. Allomyrinasin significantly attenuated HFD-associated body weight gain and improved glucose tolerance and insulin sensitivity. These effects were accompanied by favorable modulation of serum lipid profiles and suppression of hepatic lipogenic signaling, including reduced expression of key regulators of de novo lipogenesis. In parallel, allomyrinasin mitigated hepatic inflammatory, fibrotic, and oxidative stress-related alterations, as reflected by improvements in biochemical markers and molecular analyses. Collectively, these findings indicate that allomyrinasin contributes to the improvement of metabolic regulation and hepatic homeostasis in HFD-fed mice. Our results support allomyrinasin as a promising food-applicable bioactive peptide and potential functional ingredient for the prevention or management of obesity-related metabolic disorders. Full article

Background: Glioblastoma (GBM) is among the malignant tumors with the lowest five-year survival rate. Current treatments offer limited efficacy and first-line options are scarce, highlighting the urgent need for novel drugs. Cariprazine can cross the blood–brain barrier and has been reported to inhibit certain tumors; however, its effect on GBM remains unknown. This study aims to elucidate its anti-GBM effects and mechanisms. Methods: Cell proliferation and apoptosis were assessed by wound healing, Transwell, colony formation assays, flow cytometry and JC−10 staining. Co-immunoprecipitation (Co-IP) examined the effect of cariprazine on D2/D3–ARRB2 interaction. Direct binding of cariprazine to ARRB2 was determined by molecular docking and CETSA. Western blotting and immunofluorescence detected changes in proliferation and apoptosis-related proteins. In vivo anti-GBM activity was evaluated in subcutaneous mouse models. Results: Cariprazine inhibited GBM cell proliferation and migration, promoted apoptosis, and showed low astrocyte toxicity. In mice, it suppressed GBM allograft growth without overt systemic toxicity. These effects were mediated through D2/D3 receptors, as cariprazine disrupted the D2/D3–ARRB2 interaction and thereby inhibited ERK signaling. It also upregulated ARRB2, further inhibiting the growth of GBM. Molecular docking and CETSA confirmed the direct binding of cariprazine to ARRB2 at LEU-245 and PHE-246. Conclusions: This study is the first to repurpose cariprazine for GBM, elucidating a unique ARRB2-centered dual mechanism, thus offering a new therapeutic strategy. Full article

Oligodendrocytes (OLs) are essential for myelin formation in the central nervous system, and their loss or dysfunction is a hallmark of various demyelinating and neurodegenerative disorders. Although oligodendrocyte precursor cells (OPCs) represent a promising cell source for remyelination therapies, existing protocols for generating OPCs from human-induced pluripotent stem cells (iPSCs) are often limited by prolonged culture duration, low efficiency, and cellular heterogeneity. Here, we report an efficient and reproducible platform for generating OPCs from iPSC-derived neural progenitor cells (iNPCs) through stage-specific modulation of developmental signaling pathways. Directed differentiation of iNPCs recapitulated key developmental transitions, progressing through OLIG2⁺/NKX2.2⁺ progenitors to CD140a⁺/O4⁺ OPCs within a significantly shortened timeframe compared to conventional approaches. Notably, iNPC-derived spheres functioned as a progenitor-like niche, enabling sustained OPC production through serial replating. Purified OPCs could differentiate into MBP⁺ oligodendrocytes and demonstrated myelination capacity both in vitro, via nanofiber ensheathment and in vivo following transplantation into shiverer (shi/shi) mice, where they formed myelin sheaths around host axons. Despite these advances, OPC differentiation and maturation efficiencies remained suboptimal, highlighting the need for further optimization. Collectively, our findings establish a scalable and time-efficient strategy for iPSC-derived OPC generation and underscore their potential for disease modeling and cell-based remyelination therapies. Full article

Background: Obesity is closely associated with gut microbiota dysbiosis. Nervonic acid (NA; (15Z)-15-tetracosenoic acid) is a bioactive fatty acid with reported metabolic effects. This study aimed to investigate the associations between NA administration, gut microbiota composition changes, and host metabolic phenotypes in high-fat diet (HFD)-fed mice. Methods: C57BL/6J mice were fed an HFD for 12 weeks and concurrently administered NA at doses of 20, 40, and 60 mg/(kg·d) by gavage. Metabolic parameters, histopathological changes, and fecal microbiota composition (via 16S rRNA gene sequencing) were evaluated. Results: NA administration was associated with significantly attenuated HFD-induced increases in body weight and adipose tissue mass, as well as marked reductions in serum total cholesterol, triglycerides, and low-density lipoprotein cholesterol (all p < 0.05). Hepatic steatosis and adipose tissue inflammation were also attenuated. 16S rRNA gene sequencing revealed that NA was associated with the counteraction of HFD-induced gut microbiota dysbiosis, including alterations in α-diversity and community structure. NA was associated with higher relative abundances of taxa such as Blautia, Oscillibacter, Faecalibaculum, Parabacteroides, Dubosiella, and Odoribacter and lower relative abundances of Lachnoclostridium, Mucispirillum, and Alistipes. Within-group correlation analyses showed that genera with higher relative abundances were inversely associated with lipid parameters and adiposity, whereas genera with lower relative abundances correlated positively with these metabolic indicators. Conclusions: NA administration was associated with bidirectional changes in gut microbiota composition—the enrichment of certain taxa and the suppression of others—concomitant with the amelioration of HFD-induced metabolic dysfunction. These findings indicate correlations between NA, gut microbiota alterations, and improved metabolic phenotypes; however, causality remains to be established. Full article

Objectives: The rhizome of Iris tectorum Maxim. (Chuan She Gan), commonly used as a substitute for She Gan in Sichuan and other regions, is traditionally applied for inflammation-related disorders. This study aimed to evaluate the anti-inflammatory activity of Chuan She Gan ethanolic extract (CSG) and elucidate its molecular mechanism. Methods: CSG was prepared by 85% ethanol extraction and analyzed by HPLC to identify representative constituents. In LPS-stimulated RAW264.7 macrophages, nitrite accumulation and iNOS activity, cytokine production and inflammatory gene expression were evaluated using Griess assays, ELISA, and qRT-PCR, respectively. NF-κB and AP-1/MAPK signaling were determined using luciferase reporter assays and Wwestern blotting. Serum inflammatory cytokine levels of endotoxemic mice were measured by ELISA. Results: Four characteristic isoflavones/glycosides in CSG were identified, including tectoridin, iridin, tectorigenin, and irigenin. In LPS-activated RAW264.7 macrophages, CSG not only dose-dependently suppressed supernatant NO by inhibiting iNOS activity and downregulating iNOS expression, but also reduced IL-6, MCP-1, and intracellular pro-IL-1β at the protein and mRNA levels. Mechanistic analyses indicated that CSG attenuated NF-κB activation by reducing IκBα phosphorylation and limiting p65 nuclear accumulation, while AP-1/MAPK signaling remained largely unchanged. In endotoxemic mice, a single oral gavage of CSG (50–200 mg/kg) significantly lowered serum IL-6, MCP-1, and TNF-α levels. Conclusions: CSG showed anti-inflammatory activity in LPS-stimulated macrophages and endotoxemic mice. In LPS-stimulated macrophages, CSG suppressed inflammatory mediator production primarily through the inhibition of NF-κB signaling. In endotoxemic mice, CSG reduced the serum levels of pro-inflammatory cytokines. These findings provide pharmacological basis for the traditional use of Chuan She Gan. Full article

Diospyros comorensis Hiern is a medicinal plant traditionally utilized in the management of cardiovascular disorders. Despite its common use, the pharmacological properties and phytochemical composition remain unexplored. This study aimed to evaluate the vasorelaxant, diuretic, and antioxidant activities, as well as toxicity and phytochemical profiling, of a methanol–water extract of D. comorensis leaves (MDCR) and a decoction of D. comorensis leaf (DDCR) extract. The main phytochemicals were quantified using High-Performance Liquid Chromatography (HPLC). Antioxidant capacity was assessed using DPPH and FRAP assays. The vasorelaxant effect was evaluated in vitro on phenylephrine-precontracted aortic rings. Diuretic activity was determined by measuring Wistar rats’ urine output and electrolyte levels (Na⁺, Cl⁻, and K⁺). Toxicity was assessed using Swiss mice. The extracts showed a total phenolic content (TPC) of 29,693.02 ± 3493.75 mg GAE/100 g DW (Folin–Ciocalteu method), which was markedly higher than the total phenolics quantified by HPLC (3743.12 ± 457.32 mg/100 g DW, representing 76.38% of the total bioactive fraction). Among the quantified constituents, ellagic acid (56.36%) was the main compound. Both extracts exhibited marked antioxidant capacity along with significant vasorelaxant effects on phenylephrine-precontracted rat aorta rings, with EC50 values of 3.83 ± 0.81 µg/mL for MDCR and 4.87 ± 0.79 µg/mL for DDCR. Acute toxicity was not observed with either extract. The identified compounds may be involved in the observed antioxidant and pharmacological effects. These results show experimental evidence useful to support the traditional use of D. comorensis leaves in managing high blood pressure and highlight the antihypertensive potential of this Comorian endemic species. Further studies are necessary to characterize the biological mechanisms involved and relative bioactive substances. Reporting the pharmacological activities of D. comorensis may contribute to the sustainable use of natural resources in the Comoros Islands and Madagascar. Full article