Immunopharmacology and Immunotoxicology最新文献

Background: Our goal was to assess if febuxostat (FEB) could prevent ovarian damage caused by cyclophosphamide (CP).

Material and methods: Four sets were created: control group, FEB group: received FEB 10 mg/kg orally for 14 days, CPgroup: a single ip dose of CP (200 mg/kg) at 8^th day and CP+FEB group. Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-mullerian hormone (AMH), malondialdehyde (MDA), total antioxidant capacity (TAC), interluken-6 (IL-6), tumor necrosis factor alpha (TNF-α), Nod-like receptor protein 3 (NLRP3) were estimated. Apoptotic Bcl-2-associated protein x (Bax) and anti-apoptotic B-cell leukemia/lymphoma 2 protein (Bcl2) gene expression were measured. Histological alterations and immuno-expression of nuclear factor-kappa B (NF-κB) and toll like receptor4 (TLR4) were assessed.

Results: FSH, LH, MDA, IL-6, TNF-α, NLRP3 levels, Bax and Bax/Bcl-2 ratio gene expression, NF-κB and TLR4 immuno-expression were all significantly elevated in the CP group. AMH, TAC levels and Bcl-2 gene expression have significantly decreased. Every metric indicated a notable improvement with FEB.

Conclusion: By controlling the TLR4/NF-Κb/NLRP3 signaling pathway, FEB has strong mitigating effects against oxidative stress, inflammatory processes, and apoptosis that result from CP-induced ovarian toxicity.

Background: As a highly aggressive form of breast cancer, triple-negative breast cancer (TNBC) is characterized by significant metastatic potential, a lack of targeted therapies, and an unfavorable prognosis. Tussilagone (TUS), a bioactive sesquiterpene isolated from Tussilago farfara's medicinal herb, has shown anti-inflammatory and anticancer properties. However, its potential role in TNBC treatment and the underlying molecular mechanisms remain unexplored.

Methods: The antitumor effects of TUS on the proliferation, epithelial-mesenchymal transition (EMT), and metastasis of TNBC cell lines MDA-MB-231 and BT549 were assessed through cell viability, invasion, and colony formation assays. Western blot analysis was performed to detect Ki67, vimentin, E-cadherin, N-cadherin, PD-L1, LAG-3, TIM-3, and key TLR4/NF-κB regulators. Impact on the tumor immune microenvironment (TIME) was evaluated using CD8⁺ T cell co-culture, ELISA, and flow cytometry. The in vivo anti-tumor efficacy of TUS was investigated in a TNBC xenograft mouse model.

Results: TUS exhibited a dose-dependent inhibition of TNBC cell proliferation and invasion, reversed EMT by upregulating E-cadherin and downregulating N-cadherin and vimentin expression. It showed minimal cytotoxicity toward normal breast epithelial cells. TUS suppressed the TLR4/NF-κB pathway by downregulating TLR4, MyD88, and phosphorylated NF-κB, and decreased PD-L1 expression. Furthermore, TUS enhanced CD8⁺ T cell activation, increased cytokine secretion (IFN-γ, IL-2, TNF-α), reduced LAG-3 and TIM-3 expression, and attenuated CD8⁺ T cell apoptosis. Treatment of CD8⁺ T cells directly with TUS did not affect cytokine secretion or apoptosis, suggesting that its immunomodulatory effects are mediated through tumor cell modulation. In vivo studies demonstrated significant tumor growth inhibition by TUS without inducing toxicity.

Conclusion: This study demonstrated that TUS inhibited TNBC progression by suppressing the TLR4/NF-κB pathway, reversing EMT, and modulating TIME. These findings support the potential of TUS as a promising therapeutic candidate for TNBC and underscore the need for further clinical investigation.

Background: Edaravone dexborneol is an agent used to treat patients with acute ischemic stroke (AIS); however, the underlying mechanisms of this drug remain unclear.

Objective: To investigate whether Edaravone dexborneol protect against cerebral ischemia-reperfusion injury (CIRI), a common feature of AIS, by modulating neuroinflammation through the regulation of the CXC motif ligand 13 (CXCL13)/CXC chemokine receptor type 5 (CXCR5)/nuclear factor-κB (NF-κB) signaling pathway.

Materials and methods: Primary microglia were subjected to hypoxia-glucose deprivation and reoxygenation (OGD/R) treatment. A middle cerebral artery occlusion (MCAO) rat model was constructed. Various tests, such as cell counting kit-8 (CCK-8) assay, western blot, 2, 3, 5-triphenyl tetrazolium chloride staining, and neurobehavioral tests, were conducted.

Results: Our in vitro experiments showed Edaravone dexborneol alleviated OGD/R-induced microglia injury, modulated microglial M1/M2 polarization, and regulated the secretion of inflammatory cytokines. Subsequently, our in vivo experiments revealed Edaravone dexborneol exhibited superior efficacy compared to Edaravone in ameliorating the short-term and long-term neurological deficits, reducing brain infarction volume and brain water content, and decreasing the expression of CXCL13 and CXCR5 in MCAO rats. Furthermore, the expressions of CXCL13, CXCR5, p-NF-κB, IL-1β, and TNF-α were upregulated following MCAO but downregulated after treatment with Edaravone dexborneol, which was reversed by exogenous administration of rh-CXCL13.

Conclusion: Our results validate the protective efficacy of Edaravone dexborneol in OGD/R-induced microglia and MCAO rats. This effect may be attributed to its ability to mitigate neuroinflammation by modulating microglial M1/M2 polarization in vitro and inhibiting the CXCL13/CXCR5 axis and its associated NF-κB signaling pathway in vivo.

Background: This study aimed to investigate the impact of magnoflorine (Mag) on acute exercise-induced fatigue and its underlying mechanisms.

Methods: Seventy-two male Kunming mice were divided into six groups: a non-treatment control, a vehicle control (ddH₂O), a positive control (Gaoshan Hongjingtian Koufuye), and three Mag groups (10, 25, and 50 mg/kg). Antifatigue effects were assessed through organs and body weights, exercise endurance, and biochemical parameters, including superoxide dismutase (SOD), reactive oxygen species (ROS), malonydialdehyde (MDA), catalase (CAT), glutathione peroxidase (GPX), glutathione (GSH), total antioxidant capacity (T-AOC), glycogen, succinate dehydrogenase (SDH), malate dehydrogenase (MDH), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), nitric oxide (NO), and liver tissue histochemistry. Activation of the phosphoinositide-3-kinase/protein kinase B (PI3K/AKT) signaling pathway was evaluated using Western blot.

Results: No significant differences were observed in organs and body weights, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and liver cellular structures. Mag significantly prolonged exercise endurance in Rota-rod and forced swimming tests compared to controls. Mag increased hemoglobin (Hb), testosterone/corticosterone (T/C), and creatine kinase (CK) levels and decreased serum lactic acid (LD), lactate dehydrogenase (LDH), and blood urea nitrogen (BUN). Mag also enhanced glycogen storage, SDH, and MDH levels. Mechanistically, Mag exhibits antioxidant and anti-inflammatory properties in liver tissues and hepatocytes via activation of the PI3K/AKT signaling pathway.

Conclusion: Mag alleviated acute exercise-induced fatigue by modulating energy metabolism, antioxidation, and anti-inflammation through the PI3K/AKT signaling pathway. These findings suggest potential therapeutic implications for Mag in combating exercise-induced fatigue and related physiological stressors.

Background: The increasing use of silica nanoparticles (SiNPs) has raised concerns about their hazards to human health. However, immunotoxic effect remains insufficiently explored.

Objective: To assess: the immunotoxicity of orally administered SiNPs; role of inflammation, apoptosis, autophagy; and the protective role of vitamin C.

Methods: Eighty Sprague Dawley rats were randomly divided into four groups: control, SiNPs, vitamin C, and combined SiNPs + vitamin C. SiNPs and vitamin C were orally administered for 90 days. Immunotoxicity was assessed using flow cytometry for lymphocyte subsets (CD3+, CD4+, CD8+, CD19+, CD16+, CD56+), cytokine assays for IL-1β, IL-6, and IFN-γ, histopathological evaluation of bone marrow, and immunohistochemistry for Caspase-3 (apoptosis) and Beclin-1 (autophagy).

Results: SiNPs exposure caused significant elevations in CD3+, CD4+, CD8+, CD16+, and CD19+ cells and a reduction in CD56+ cells. Serum cytokine levels increased markedly in the SiNPs group than controls (107.7 ± 13.7 pg/mL, 22.9 ± 6.7 pg/mL, 13.5 ± 1.6 pg/mL vs. 53.5 ± 6.5 pg/mL, 9.38 ± 1.6 pg/mL, 6.7 ± 0.8 pg/mL respectively) showing a 2.01-fold rise in IL-1β and IFN-γ and a 2.44-fold rise in IL-6. Co-administration of vitamin C attenuated these increases, reducing IL-1β, IL-6, and IFN-γ by 0.63-, 0.56-, and 0.62-fold compared with SiNPs alone. Bone marrow showed decreased cellularity after SiNPs exposure, which vitamin C partially reversed. Caspase-3 expression was upregulated, while Beclin-1 was downregulated following SiNPs exposure, both ameliorated by vitamin C.

Conclusion: SiNPs induce immune dysfunction through inflammation, apoptosis, and autophagy inhibition. Vitamin C administration significantly counteracts these effects.

Purpose: Cancer cells often overexpressed specific receptors to support their proliferation and promote immunosuppressive tumor microenvironment. Tropomyosin receptor kinase C (TrkC) is known to be overexpressed in cancer, and implicated in promoting tumor progression and metastasis. This study investigates synergistic efficacy and immunomodulatory effect of a peptidomimetic TrkC-targeted ligand (IYIY) conjugated with dinitrophenol (DNP) hapten (IYIY-DNP), in combination with cyclophosphamide (CTX), an alkylating chemotherapeutic with immune-modulating properties.

Materials and methods: Female BALB/c mice were first immunized with DNP-KLH (Keyhole Limpet Hemocyanin) to elicit anti-DNP antibodies and subsequently implanted with TrkC-expressing murine 4T1 breast carcinoma cells. Tumor-bearing mice received 10 mg/kg IYIY-DNP, 25 mg/kg CTX, or their combination (IYIY-DNP+CTX), on alternating days for five cycles. Tumor growth was monitored for 21 days. On day 10, blood was collected for cytokine profiling, and tumor and lymphoid organs were collected postmortem for immune cells phenotyping.

Results: IYIY-DNP+CTX reduced tumor size by 71.11%, while IYIY-DNP and CTX monotherapy reduced it by 52.97% and 47.23%, respectively. Elevated levels of IL-2, IL-4, IL-6, IL-17A, IL-10, IFN- $\gamma$, and TNF-$\alpha$ while reducing TGF-β, were correlated with regulatory T cells (Tregs) inhibition as observed in IYIY-DNP+CTX. Immune cells phenotyping in tumor-draining lymph nodes (TDLNs), tumor tissues and spleen showed increased antitumor immune cells Th1, Th17 and cytotoxic T lymphocytes, correlating with the inhibition of tumor growth through IYIY-DNP+CTX administration.

Conclusion: IYIY-DNP+CTX significantly reduced TrkC⁺ tumor growth by suppressing immunosuppressive factors and enhancing immune-stimulating responses, helping the immune system fight cancer more effectively.

Background: Voclosporin was approved from the United States Food and Drug Administration (FDA) for treating adults with active lupus nephritis, in combination with a background immunosuppressive therapy regimen. Due to the limitations of clinical trials, real-world safety data on voclosporin in large samples are currently lacking. Therefore, this study aims to evaluate adverse events (AEs) associated with voclosporin.

Research design and methods: We retrospectively extracted reports on voclosporin-related AEs from the FDA's Adverse Event Reporting System (FAERS) database from January 2021 to December 2023. Various signal quantification techniques, including reporting odds ratios (ROR), proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma poisson shrinker, were employed for analysis.

Results: A total of 2,932 AEs of voclosporin were observed. 27 system organ classes and 87 preferred terms about voclosporin-induced AE signals were observed. The most frequent AEs associated with voclosporin were hypertension, headache, and therapy interrupted. Notably, we identified the absence of immediate treatment response exhibited the strongest signal intensity in the ROR algorithm.

Conclusion: These initial findings undeniably serve as a helpful point of reference for future study and safety oversight.

Objectives: The adherence to methotrexate (MTX) prolonged therapy in various cancers and autoimmune disorders is restricted due to its deleterious effects on several organs, like the liver, kidney, and intestine. Farnesol (FAR), a sesquiterpene alcohol found in various foods, essential oils, and herbs, exhibited promising antioxidant and anti-inflammatory impact in diverse experiments. The purpose of our study was to examine the possible mitigation of MTX-induced intestinal damage by FAR and the molecular pathways involved.

Methods: The rats were orally administered FAR (10 mg/kg) for 10 days and a single i.p. injection of MTX (20 mg/kg) on day 5. On day 11, samples of duodenal tissue were obtained for biochemical, histological, and molecular assessments.

Results: Our results demonstrated that FAR markedly ameliorated the degenerative changes induced by MTX in the duodenal mucosa along with preservation of mucosal goblet cells as manifested by PAS and Alcian blue staining. Besides, FAR enhanced the antioxidant and anti-inflammatory defenses via up-regulated expressions of sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor-gamma (PPAR-γ), and nuclear factor erythroid 2-related factor 2 (Nrf2) proteins. Moreover, the anti-inflammatory activity of FAR was emphasized by the substantial decrease in tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) duodenal contents in MTX-treated rats. Ultimately, FAR reduced duodenal apoptosis by down-regulating Bcl-2-associated X protein (Bax), cytochrome c, and cleaved caspase-3, while up-regulating B-cell lymphoma 2 (Bcl-2) expression demonstrated by the immunohistochemical investigation.Conclusion: FAR could protect against intestinal toxicity caused by MTX and thus increase the tolerability and adherence to prolonged MTX therapy.

Background: Moscatilin has been shown to effectively suppress inflammation in macrophages in mice treated with concanavalin A (ConA). However, further investigation is needed to fully elucidate the specific underlying mechanisms.

Methods: A murine model of autoimmune liver disease was induced by administering ConA. Inflammatory markers were quantified using enzyme-linked immunosorbent assay (ELISA), while M1 and M2 macrophage biomarkers were analyzed by western blotting. Apoptosis was assessed via TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, and immunohistochemical staining was used to identify macrophage surface biomarkers.

Results: Moscatilin significantly reduced ConA-induced liver injury, as evidenced by decreased levels of alanine aminotransferase (ALT) and aspartate transaminase (AST), leading to improved survival in mice. Subsequent experiments confirmed that moscatilin inhibited cell apoptosis by downregulating cleaved caspase-3 and Bax. Additionally, it exhibited anti-inflammatory effects by modulating levels of interleukin 1β (IL-1β) and tumor necrosis factor α (TNF-α), while promoting the expression of interleukin 10 (IL-10). Moreover, moscatilin influenced M1/M2 macrophage polarization by downregulating CD86 and inducible nitric oxide synthase (iNOS), and upregulating arginase 1 (Arg1) and CD206. Our findings suggest that moscatilin alleviates ConA-induced liver injury by inhibiting apoptosis and promoting M1/M2 macrophage polarization.

Conclusions: These results provide valuable insights into the potential therapeutic applications of moscatilin in autoimmune liver diseases.