Immunopharmacology and Immunotoxicology最新文献

Background: Arsenic-trioxide (ATO) is an effective therapy for acute promyelocytic leukemia. Unfortunately, its utility is hindered by the risk of myocardial injury. Both bisoprolol (BIS) and trimetazidine (TMZ) have various pharmacological features, including anti-oxidant, anti-inflammatory, and anti-apoptotic properties.

Aim: The cardioprotective effects of BIS and TMZ were studied, and their mechanistic role in ameliorating ATO-induced myocardial injury.

Materials and methods: Forty male Wistar rats were randomly allotted into five groups as follows: normal control group (received normal saline, orally), ATO group (7.5 mg/kg, orally), BIS (8 mg/kg, orally), TMZ (60 mg/kg, orally), and finally combination group (BIS+TMZ+ATO). Following 21 days, samples of serum and cardiac tissues were obtained to perform biochemical, molecular, and histopathological investigations.

Results: The present study showed that ATO caused myocardial injury evidenced by changes in serum biomarkers (Aspatate aminotransferase, alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, creatine kinase-MB, and cardiac troponin-1), electrolyte imbalance, and lipid profiles alongside histopathologic changes. In addition, ATO administration significantly elevated malondialdehyde, nicotinamide adenine dinucleotide phosphate hydrogen oxidase, myloperoxidase, total nitrite, inducible nitric oxide synthase, tumor necrosis factor-alpha, interleukin-1β, interleukin-6, 8-Hydroxy-2'-deoxyguanosine, nuclear factor NF-kappa-B p65 subunit, glycogen synthase kinase-3 beta, and caspase-3 expression contemporaneously with down-regulation of reduced glutathione, glutathione peroxidase, superoxide dismutase, catalase, heme oxygenase 1, nuclear factor erythroid 2-related factor 2, phosphatidylinositol-3 kinase, p-PI3K, and Bcl-2 expression. Interestingly, pretreatment with BIS and TMZ significantly reversed the detrimental effects of ATO-induced myocardial injury at both cellular and molecular levels. Otherwise, combining the two drugs displayed more enhancement than each drug alone.

Conclusion: The present research depicted that BIS and TMZ have the potential to protect the heart and provide therapeutic benefits by preventing acute heart injury induced by ATO. This is achieved by reversing the redox-sensitive pathway, reducing inflammation, and inhibiting apoptosis.

Objective: Autoimmune hepatitis (AIH) is a chronic progressive autoimmune disease with unclear etiology. As a bioactive metabolite of Vitamin D, 1,25(OH)₂D₃ can stimulate the production of tolerogenic dendritic cells (DCs) that overexpress programmed cell death ligand 1 (PD-L1). Although these cells have been shown to play a part in autoimmune diseases, their role in AIH remains unclear.

Methods: This study aimed to investigate the potential effect of 1,25(OH)₂D₃-modulated DCs (PD-L1^high VD3-DCs) in a murine model of experimental autoimmune hepatitis (EAH).

Results: Our results showed that intravenous injection of PD-L1^high VD3-DCs significantly attenuated liver injury and EAH severity in mice. In addition, PD-L1^high VD3-DC infusion improved the imbalance between splenic regulatory T cells (TFR) and follicular helper T (TFH) cells in EAH mice by increasing the number of TFR cells and restoring TFR/TFH ratio. Also, PD-L1^high VD3-DC infusion selectively promoted TFR expansion and inhibited TFH differentiation. Furthermore, PD-L1^high VD3-DC infusion increased TGF-β and IL-10 production, inhibited IL-21 secretion, upregulated key TFH transcriptional factors, and reduced the levels of serum immunoglobulins in EAH mice.

Conclusions: To sum up, PD-L1^high VD3-DC infusion could control EAH progression in mice by regulating TFR/TFH imbalance, indicating PD-L1^high VD3-DC infusion might be a promising therapeutic approach for AIH treatment.

Background: Acute lung injury is a crucial pathological state, particularly in some severe infectious respiratory illnesses, distinguished by acute inflammation, pulmonary edema, hypoxia, and neutrophil recruitment. Cytokine-induced neutrophil chemoattractant (CINC) and macrophage inflammatory protein-2 (MIP-2) play a vital role in neutrophil recruitment.

Objective: Here, we validated the potential repressing effect of atorvastatin on acute lung injury induced by lipopolysaccharide (LPS) in mice.

Materials and methods: Mice were injected with LPS (250 μg/kg; i.p.) daily for 7 days, and atorvastatin (25 and 50 mg/kg; orally) daily along with LPS.

Results: Atorvastatin ameliorated oxidative stress as evidenced by increased reduced glutathione (GSH) and nuclear factor-erythroid 2 related factor 2 (Nrf2) levels and decreased malondialdehyde (MDA) levels. Additionally, it lessened inflammatory biomarkers including tumor necrosis factor-alpha (TNF-α), mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), CINC, and MIP-2, as well as hypoxia biomarker hypoxia-inducible factor-1α (HIF-1α). Moreover, atorvastatin slowed the progression of lung tissue histological lesions.

Conclusion: Collectively, the present study suggests that, atorvastatin effectively protects against LPS-induced acute lung injury through inhibition of oxidative stress, inflammation, hypoxia, and neutrophil recruitment.

Objective: Ocular chemical burns are a leading cause of blindness. The cornea is injured by alkali-induced oxidative disturbances and an inflammatory response. The aim of this study was to evaluate the protective effects of aloin, an antioxidant, and anti-inflammatory compound, on corneal alkali burn.

Materials and methods: Mice eyes were injured by NaOH and subsequently treated with aloin eye drop and intraperitoneal injection. Pathological characteristics of the eyes were examined, and corneal samples were collected for further analysis.

Results: Aloin diminished neutrophil infiltration and the production of proinflammatory cytokines. Aloin also attenuated apoptosis in human corneal epithelial cells (HCEs) by reducing oxidative stress through the activation of the Nrf2 pathway. Additionally, aloin suppressed the formation of neutrophil extracellular traps (NETs) and inhibited their deposition on the cornea. Moreover, aloin mitigated alkali-induced apoptosis in HCEs caused by NETs.

Conclusions: These findings suggest that aloin has potential as an antioxidant and anti-inflammatory compound for treating corneal alkali burn by inhibiting NETs formation and promoting Nrf2.

Objective: This study aimed to demonstrate the protective effect of beta-carotene against STZ-induced DN in rats and explore the possible underlying mechanisms that may have mediated such condition.

Material and methods: Wistar rats were allocated into four groups. Normal group received distilled water for 3 weeks. The other three groups were rendered diabetic by an intraperitoneal dose of STZ (50 mg/kg), 48 h later, group 2: received the vehicle and served as control, groups (3 &4) received orally beta-carotene in doses of 10 and 20 mg/kg, respectively for 3 weeks. Then serum and renal tissue were collected for biochemical, molecular, immunohistopathological, and histopathological examination.

Results: Beta-carotene ameliorated the reduction in body weight, reduced blood glucose, elevated serum insulin, reduced blood urea nitrogen, and serum creatinine levels. Beta-carotene elevated phosphorylated 5' adenosine monophosphate-activated protein kinase (p-AMPK)/AMPK, alleviated phosphorylated mammalian target of rapamycin (p-mTOR)/mTOR, reduced interleukin 1 beta (IL-1β), increased Beclin 1, LC3II/LC3I, and reduced p62 renal contents. Moreover, it elevated renal SIRT1 gene expression and reduced renal tumor necrosis factor-alpha (TNF-α) and caspase-3 protein expressions.

Conclusion: Beta-carotene exerted renoprotective effect against STZ-induced DN and histopathological alterations through alleviating hyperglycemia, attenuating inflammation, activating AMPK/SIRT1/autophagy pathway, and combating apoptosis.

Objective: Aging is one of the main risk factors for breast cancer. However, the impact of environmental risk factors, such as pesticide exposure, on the clinical outcomes of patients with breast cancer, depending on disease onset, remains unclear.

Material and methods: This study analyzed clinicopathological data from 188 women with breast cancer, who were either occupationally or domestically exposed to pesticides, or not exposed, according to their age at disease onset (early onset ≤50 years and late onset >50 years). Additionally, interleukin 4 (IL-4), interleukin 17A (IL-17A), and interleukin 12 (IL-12) levels were measured in plasma samples, and clinicopathological data were assessed.

Results: In the late-onset group, a greater frequency of low-grade tumors was detected in the exposed patients compared to the unexposed group (23.14 vs. 45.45%, p = 0.0181). A higher frequency of high-risk stratification for recurrence and death was found in early-onset patients when comparing exposed and unexposed groups (10.0 vs. 30.0%, p = 0.0488). Regarding the molecular subtypes of breast cancer, patients in the late-onset group showed a higher frequency of triple-negative tumors than unexposed women with the same disease onset (20.0 vs. 40.63%, p < 0.0001). IL-12 levels were significantly lower in exposed patients in the early-onset group compared to unexposed patients in the same group. Early-onset patients showed a principal component that positively correlated with pesticide exposure, IL-1β, IL-17A, and IL-4, while late-onset patients showed negative correlations between pesticide exposure and IL-12, IL-4, and IL-17A.

Discussion and conclusions: These findings suggest that pesticide exposure induces an inflammaging-like state in younger women, contributing to an increased risk of developing more severe disease.

Objectives: 5-Fluorouracil (5-FU) is a chemotherapy drug commonly prescribed in cancer management. Unfortunately, intestinal mucositis restricts 5-FU clinical use. Vinpocetine (VNP) is a synthetic alkaloid that is derived from vincamine. Our study was conducted to elucidate the intestinal protective effects of VNP on 5-FU intestinal injury in rats and explore the underlying mechanisms.

Materials and methods: 5-FU was injected i.p. for five days, while VNP was given P.O (5 and 10 mg/kg).

Results: VNP effectively mitigates oxidative stress by a significant increase in GSH and SOD and decreasing MDA content mediated by Nrf2, HO-1 upregulation, and significant Keap1 downregulation. VNP mitigated inflammatory perturbations by decreasing MPO, TNF-α, IL-1β, and IL-6 facilitated by downregulating NF-κB and TLR4 and upregulating SOCS3 levels. In addition, the RIPK1, RIPK3, MLKL, and caspase-8 expression levels were significantly decreased, evidenced improvement of intestinal necroptosis by VNP.

Conclusion: Hence, VNP potently prevents intestinal injury induced by 5-FU by modulating Keap1/Nrf2/HO-1, NF-κB/TLR4/SOCS3, and RIPK1/RIPK3/MLKL signals.

Background: The significance of local radiotherapy (RT) in advanced non-small-cell lung cancer (NSCLC) is well documented. However, the advent of immunotherapy has raised questions regarding the synergistic survival benefits or potential adverse effects.

Objective: This study aimed to explore whether a combination of RT and systematic immune checkpoint inhibitors (ICIs) can improve the survival outcomes for NSCLC patients.

Methods: Based on collected data patients who received RT were defined as the RT group, and those who had not for any site were defined as the non-RT group. Propensity score matching (PSM) was employed to mitigate bias. The primary endpoint was progression-free survival (PFS), with secondary endpoints including overall survival (OS) and treatment-related adverse events (AEs).

Results: Out of 709 patients (235 in RT group and 474 in non-RT group) were included, with 213 patients per group. The median PFS of the RT group was better than that of the non-RT group (13.8 months versus 9.5 months; p < 0.0001), although no superiority in median overall survival (OS) of the RT group was observed (p = 0.715). However, among the cohort of patients with ≤3 metastases, the median OS of the RT group improved significantly (HR = 0.60, [95% CI 0.44-0.83]; p = 0.004). Treatment-related AEs occurred in 94.5% of RT group patients and in 94.9% of non-RT group patients (p = 0.792), which indicated no observable increase in AEs from RT.

Conclusions: These results demonstrate the tolerability of RT when administered along with immunotherapy, suggesting its potential to positively impact the survival outcomes of NSCLC patients.

Background: In Egypt, aluminum phosphide (ALP) is one of the most serious health problems that threaten the health system, with a very high mortality rate that ranges from 30%-100% of cases, according to medical facilities. ALP records suicidal deaths related to the toxin ingestion in Egypt, which accounts for 70% of the deaths. Patients usually deteriorate early; death is expected in the first 48 h. The aim of this study is to investigate the early recorded neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in anticipation of the ALP-intoxicated patients' outcome.

Patients and methods: Thirty-three subjects diagnosed with ALP poisoning were divided into two groups according to their need for mechanical ventilation and whether they could survive or not. A complete blood count (CBC) was done immediately after admission, and NLR and PLR were calculated. Patients' conditions were evaluated by arterial blood gases (ABG), random blood sugar (RBS), sodium (Na⁺), potassium (K⁺), and an electrocardiogram (ECG).

Results: There were significant differences in the need for ICU and mechanical ventilation between the different NLR groups. There was also a highly significant difference in the patient's fate. Increased NLR was associated with a high incidence of mechanical ventilation and death in ALP-poisoned patients.

Conclusion: The early assessment of NLR can be valuable in predicting death and the need for ICU admission. NLR ≥ 3.35 can predict death in ALP-poisoned patients. Early CBC and calculation of NLR are promising tools that are easy and more accurate than the presence of leukocytosis or leucopenia.

Background: The aberrant H-type vessel formation was found to be intimately linked to subchondral bone remodeling during osteoarthritis (OA) development. Herein, we investigated the role and mechanism of osteoblast-secreted slit guidance ligand 3 (Slit3) in H-type vessel formation during OA progression.

Methods: Slit3 protein levels in subchondral bone samples of OA patients were detected. The isolated osteoblasts were transfected with Slit3 overexpression or knockdown plasmids, and their conditioned medium was cultured with endothelial progenitor cells (EPCs). The migration, tube formation, VEGF, and H-type vessel marker protein CD31 and endomucin (EMCN) levels in EPCs were accessed. The interactions between Slit3 and roundabout (Robo) family members were validated by Co-IP assay. Besides, whether the Slit3/Robo signaling affects the transforming growth factor β1 (TGF-β1)/SMADs pathway was determined. Additionally, sh-Slit3 was injected into OA mice, followed by the detection of articular cartilage degradation, subchondral bone remodeling, and H-type vessel formation.

Results: Slit3 was upregulated in subchondral bone tissues of OA patients. Slit3 overexpression in osteoblasts intensified the migration and H-type vessel formation of EPCs, while Slit3 knockdown showed the opposite results. Slit3 overexpression enhanced Robo1 protein level. Robo1 knockdown abrogated Slit3-mediated migration and H-type vessel formation in EPCs. Slit3 activated the TGF-β1/SMADs pathway in EPCs, which might be associated with H-type vessel formation in EPCs. Additionally, Slit3 silencing restrained articular cartilage degradation, aberrant subchondral bone formation, and H-type vessel formation in OA mice.

Conclusion: Inhibition of Slit3/Robo1 signaling alleviates osteoarthritis in mice by reducing abnormal H-type vessel formation in the subchondral bone.