Immunopharmacology and Immunotoxicology最新文献

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.

Background: Acute lung injury (ALI) represents a diverse clinical condition characterized by significant complications and death rates. Naftidrofuryl (NAF) is a vasodilator drug with reported anti-inflammatory properties.

Objective: This study aimed to explore the effects of NAF administration on lipopolysaccharide (LPS)-induced ALI through in vitro experiments using the human leukemia monocytic cell line (THP-1) and in vivo ALI-rat model, while investigating the potential underlying mechanisms.

Methodology: Inflammatory biomarkers for macrophage phenotypes were evaluated in vitro. Additionally, rats were classified into the following groups: Group I, Control, receiving daily intraperitoneal (ip) saline. Group II: NAF-treated rats (45 mg/kg/day, ip), Group III: LPS-treated rats (3 mg/kg, ip at day one), then continued with saline, Group IV: NAF+LPS-treated rats. This study lasted 28 days, after which the rats were sacrificed. Biochemical and histopathological analyses were conducted on pulmonary tissue.

Results: The in vitro results highlighted the activation of macrophages from both phenotypes following LPS administration, indicating a disrupted macrophage environment characterized by altered levels of CD11b, CD38, CD206, IL-10, and LY6G/LY6C, as assessed by western blotting. NAF incorporation into LPS-treated samples significantly regulated all measured markers. The in vivo findings indicated an activated pro-inflammatory status, evidenced by elevated levels of TNF-α, IL-1β, IL-6, and iNOS in the LPS-treated group. The NLRP3/TLR4 pathway was activated, resulting in further disruption of redox and inflammatory homeostasis. Rats in Group-IV exhibited improved regulation of assessed parameters, characterized by decreased inflammation and modulation of the NLRP3/TLR4 pathway.

Conclusion: NAF may serve as a potential pulmonary protective agent against ALI by restoring inflammatory homeostasis and modulating various inflammatory pathways.

Objective: Sepsis-induced cardiotoxicity (SIC) is a critical complication characterized by inflammation, oxidative stress, and apoptosis, leading to myocardial dysfunction. The short-acting opioid analgesic remifentanil (REMI) possesses antioxidant and anti-inflammatory properties. This study aimed to evaluate the cardioprotective effects of REMI on lipopolysaccharide (LPS)-induced SIC by examining inflammation, oxidative stress, apoptosis, and mitochondrial function.

Materials and methods: Thirty-two female Wistar albino rats were divided into four groups: control, lipopolysaccharide (LPS), LPS+REMI, and REMI. Myocardial and aortic tissues were analyzed for histopathology, immunoexpression of Caspase-3 (Cas-3), nuclear factor kappa beta (NF-κB), and tumor necrosis factor alpha (TNF-α). Oxidative stress markers, including total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI), were measured. Mitochondrial apoptosis-related gene expression of AMP-activated protein kinase (AMPK), BCL2 Associated X (BAX), B-cell lymphoma 2 (BCL-2), Sirtuin 1 (SIRT1), and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) was assessed.

Results: LPS administration induced severe histopathological damage, increased oxidative stress (elevated TOS and OSI), and upregulated apoptotic (Cas-3, BAX/BCL-2 imbalance) and inflammatory (NF-κB, TNF-α) markers. REMI treatment significantly alleviated myocardial and aortic injury, reducing the histopathological score. It markedly decreased Cas-3, NF-κB, and TNF-α expression, lowered TOS and OSI levels, and modulated the BAX/BCL-2. Furthermore, REMI restored the expression of AMPK, SIRT1, and PGC-1α genes, indicating a protective effect on mitochondrial biogenesis and energy metabolism.

Conclusions: REMI exhibits significant cardioprotective effects in LPS-induced SIC by attenuating inflammation, oxidative stress, and apoptosis while preserving mitochondrial homeostasis.

Objectives: Cannabidiol (CBD), the primary component of Cannabis sativa, has a neuroprotective and anti-inflammatory properties. Due to its modulation of multiple molecular targets within the central nervous system, CBD holds therapeutic promise for various neurological and psychiatric disorders.

Methods: This study aimed to evaluate the potential protective effects of CBD and/or low-dose ionizing radiation (LDR) in a rat model of hepatic encephalopathy (HE) induced by thioacetamide (TAA). Male Wistar rats received two (i.p.) injections of thioacetamide (TAA) at a dose of 200 mg/kg b.w. with a one-day interval between doses. Cannabidiol was administered i.p. at a dose of 20 mg/kg b.w. for seven consecutive days. Two LDR doses were applied (0.2 Gy each) with a one-day interval between exposures. The experimental design included assessment of oxidative stress and inflammatory markers, as well as neurobehavioral and histopathological evaluations.

Results: Treatment with CBD and/or LDR significantly reduced oxidative stress and inflammation, as evidenced by modulation of nuclear factor kappa B (NF-κB), apoptosis signal-regulating kinase 1 (ASK1), and c-Jun N-terminal kinase (JNK). Additionally, notable improvements were observed in levels of nicotinamide adenine dinucleotide (NAD), serotonin (5-hydroxytryptamine, 5-HT), and liver function enzymes. Behavioral performance, assessed using the Morris water maze, revealed cognitive enhancement, which was further confirmed by histological examination of brain and liver tissues.

Conclusion: Both CBD and LDR exhibited promising protective effects against TAA-induced hepatic encephalopathy, mitigating brain and liver damage through anti-inflammatory and antioxidant mechanisms. Thus, this supporting their potential as adjunct therapies in managing HE and related neuroinflammation.