Immunopharmacology and Immunotoxicology最新文献

Background: One of the common findings in systemic sclerosis (SSc) patients has been long-term exposure to environmental toxins such as pesticides. However, the data available shows an equivocal association between pesticide exposure and autoimmunity in SSc.

Methods: We investigated the levels of organochlorine pesticides (OCPs) in blood of 20 SSc patients and 17 healthy controls, and also studied their effect in-vitro on T lymphocytes and their functional responses.

Results: We found higher levels of hexachlorocyclohexane (HCH- α-, β-, and γ) and o,p'-dichlorodiphenyltrichloroethane (DDT) metabolite (p,p΄-DDE) in blood of SSc patients. In vitro treatment of SSc patient PBMCs with either of HCH (100 mM) or DDT (50 µM) caused a significant increase merely in CD8⁺ memory (CD8⁺CD45RO⁺) T lymphocytes. We also observed reduced FoxP3 expression in CD4⁺CD25⁺ (regulatory T cells) of SSc patients. Neither HCH nor DDT exposure of SSc PBMCs altered significantly the secretion of IL-2, IL-10, or IFN-γ, but both of these pesticides elevated their IL-4 (a pro-fibrotic cytokine) secretion.

Conclusion: Taken together, our findings indicate that persistent exposure to these OCPs results in decreased lymphoproliferative activity which promotes disease activity by producing pro-fibrotic cytokine(s). Thus, SSc patients are less able to initiate or augment an immune response to foreign antigens, when there is substantial suppression of lymphocyte function, which increases their susceptibility to infection. Strategies to prevent and control pesticide exposure may play an important role in reducing the morbidity and mortality associated with this disease.

Objective: Triple-Negative Breast Cancer (TNBC), the most challenging subtype of Breast Cancer (BC), currently lacks targeted therapy, presenting a significant therapeutic gap in its management. Tumor Associated Macrophages (TAMs) play a significant role in TNBC progression and could be targeted by repolarizing them from M2 to M1 phenotype. Matairesinol (MAT), a plant lignan, has been shown to exhibit anticancer, anti-inflammatory and immunomodulatory activities. In this study, we explored how MAT-induced repolarization of THP-1-derived M2 macrophages towards the M1 phenotype, which could effectively target the TNBC cell line, MDA-MB-231.

Methods: The differential expression of genes in THP-1-derived macrophages at mRNA levels was evaluated by RNAseq assay. An inverted microscope equipped with a CMOS camera was utilized to capture the morphological variations in THP-1 cells and THP-1-derived macrophages. Relative mRNA expression of M1 and M2 specific marker genes was quantified by qRT-PCR. Cell viability and induction of apoptosis were evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide (JC-1 dye) assays, respectively.

Results: MAT reduced the viability of M2a and M2d macrophages and repolarized them to M1 phenotype. Conditioned medium (CM) from MAT-treated M2a and M2d macrophages significantly reduced the viability of TNBC cells by apoptosis.

Conclusion: Targeting M2 macrophages is an important strategy to regulate cancer progression. Our study provides evidence that MAT may be a promising drug candidate for developing novel anti-TNBC therapy. However, further studies are warranted to thoroughly elucidate the molecular mechanism of action of MAT and evaluate its therapeutic potential in TNBC in vitro and in vivo models.

Background: Ulcerative colitis (UC) is a frequent inflammatory bowel disease (IBD) that causes long-lasting inflammation in the innermost lining of the rectum and colon.

Objective: The aim of this study was to evaluate the therapeutic effect of Cannabis sativa (C. sativa) on the amelioration of acetic acid-induced colitis in rats.

Materials and methods: Group 1: normal control group was intrarectally administered saline solution (0.9%); group 2: acetic acid (AA) group was given AA intra-rectally (2 mL of 4% (v/v) in 0.9% NaCl) once.; group 3&4: This group represented the ulcerative colitis-induced rats that were injected with acetic acid intra-rectally, then s.c. injection with C. sativa (20 and 40 mg/kg daily for 8 days).

Results: Colonic architectural abnormality significantly improved after pretreatment with C. sativa. Additionally, it significantly reduced the MDA level and prevented the depletion of GSH content. Moreover, C. sativa administration showed suppressive activities on pro-inflammatory cytokines, including NF-κB, MAPK, ERK, PI3K, AKT, HIF-1α, and TLR4. Moreover, it significantly upregulated the level of SIRT and CB1 in the colon tissue.

Conclusion: This study provided a novel impact for CB1 receptor activation produced by C. sativa against AA-induced UC in rats through inhibiting the TLR-4 MAPK/ERK, PI3K, and NFκB signaling pathways.

Background: Rhino-Orbital-Cerebral Mucormycosis (ROCM) cases increased sharply in India during the second COVID-19 wave. Due to uncontrolled hyperglycemia, prolonged steroid use, and high ferritin levels, the immune system was dysregulated throughout this surge.

Methods: Our study examined post-COVID-19 ROCM patients' T regulatory cell (Treg), T helper 17 cell (Th17) and Myeloid derived suppressor cell (MDSC) levels before and after three months of treatment. T cell activation and MDSC profile were measured in peripheral blood from 20 post-COVID-19 mucormycosis patients and 20 age-matched controls.

Results: Compared to controls, cases had significantly greater Th17 cells (CD4⁺IL-23R⁺) before and after treatment (p < 0.05), with no significant change between pre- and post-treatment. In pretreatment cases, Treg cells (CD4⁺CD25⁺FoxP3⁺) were lower than controls, but dramatically increased (p < 0.05) following treatment. Further, these patients had significantly higher rates of monocytic (m) MDSCs (CD14⁺HLA-DR^low/-) compared to healthy persons (p < 0.05). Interestingly, after three months of treatment, mMDSC levels dropped to levels similar to healthy controls. Similarly, ROCM patients had higher levels of granulocytic (g) MDSCs (HLA-DR^low/-CD33⁺CD11b⁺CD66⁺) than healthy controls, although these levels normalized after three months. Patients had considerably greater expression levels of RORγt, TGF-β, and IL-10 mRNA before therapy compared to healthy controls. FoxP3 and Arg-1 mRNA expression was lower in pretreatment patients than in healthy people. After treatment, these individuals' IL-10, FoxP3, and Arg-1 mRNA expression increased.

Conclusion: MDSCs may play a role in mucormycosis immunological dysregulation, suggesting that restoring balance may improve patient outcomes.

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.