Gastro-intestinal toxicity of chemotherapeutics in colorectal cancer:The role of inflammation

Chemotherapy-induced diarrhea(CID)is a common and often severe side effect experienced by colorectal cancer(CRC)patients during their treatment.As chemotherapy regimens evolve to include more efficacious agents,CID is increasingly becoming a major cause of dose limiting toxicity and merits further investigation.Inflammation is a key factor behind gastrointestinal(GI)toxicity of chemotherapy.Different chemotherapeutic agents activate a diverse range of pro-inflammatory pathways culminating in distinct histopathological changes in the small intestine and colonic mucosa.Here we review the current understanding of the mechanisms behind GI toxicity and the mucositis associated with systemic treatment of CRC.Insights into the inflammatory response activated during this process gained from various models of GI toxicity are discussed.The inflammatory processes contributing to the GI toxicity of chemotherapeutic agents are increasingly being recognised as having an important role in the development of anti-tumor immunity,thus conferring added benefit against tumor recurrence and improving patient survival.We review the basic mechanisms involved in the promotion of immunogenic cell death and its relevance in the treatment of colorectal cancer.Finally,the impact of CID on patient outcomes and therapeutic strategies to prevent or minimise the effect of GI toxicity and mucositis are discussed.     

Deflazacort alleviate pro-inflammatory cytokines expression,oxidative stress and histopathological alterations in collagen induced arthritis in Wistar rats

ObjectivesGlucocorticoids are important and frequently used class of anti-inflammatory drugs. Deflazacort (DFZ) is a glucocorticoid and an oxazolone derivative of prednisolone. As it has high anti-inflammatory and immunosuppressive potency, we studied inhibitory effect of DFZ on mediators regulating the pro-inflammatory response and oxidative stress induced in arthritis.MethodsFemale Wistar rats were immunized intradermally by collagen type II to induce collagen induced arthritis. Arthritic rats were treated with DFZ orally (6 mg kg⁻¹ body weight) until 28 days after the onset of clinical symptoms of disease. The effect of DFZ treatment in the rats was monitored by clinical scoring, biochemical parameters, immunohistochemistry and histopathological evaluation.ResultsDeflazacort significantly decreased the level of articular elastase, nitric oxide and lipid peroxidation whereas significantly increased the activity of catalase, superoxide dismutase and glutathione. Deflazacort down-regulated expression of pro-inflammatory molecules like TNF-α and COX-2. Histopathological evaluation revealed significant reduction of synovial hyperplasia and cellular infiltration in synovial membrane in DFZ treated group as compared to the diseased group.ConclusionsThis suggests that DFZ significantly down-regulates the expression of pro-inflammatory molecules such as TNF-α and COX-2 and alleviates the oxidative stress which make it a viable therapeutic option for treatment of arthritis.     

Intrathecal Gabapentin Increases Interleukin-10 Expression and Inhibits Pro-Inflammatory Cytokine in a Rat Model of Neuropathic Pain

We examined the possible anti-inflammatory mechanisms of gabapentin in the attenuation of neuropathic pain and the interaction between the anti-allodynic effects of gabapentin and interleukin-10 (IL-10) expression in a rat model of neuropathic pain. The anti-allodynic effect of intrathecal gabapentin was examined over a 7-day period. The anti-allodynic effects of IL-10 was measured, and the effects of anti-IL-10 antibody on the gabapentin were assessed. On day 7, the concentrations of pro-inflammatory cytokines and IL-10 were measured. Gabapentin produced an anti-allodynic effect over the 7-day period, reducing the expression of pro-inflammatory cytokines but increasing the expression of IL-10 (TNF-α, 316.0 ± 69.7 pg/mL vs 88.8 ± 24.4 pg/mL; IL-1β, 1,212.9 ± 104.5 vs 577.4 ± 97.1 pg/mL; IL-6, 254.0 ± 64.8 pg/mL vs 125.5 ± 44.1 pg/mL; IL-10, 532.1 ± 78.7 pg/mL vs 918.9 ± 63.1 pg/mL). The suppressive effect of gabapentin on pro-inflammatory cytokine expression was partially blocked by the anti-IL-10 antibody. Expression of pro-inflammatory cytokines was significantly attenuated by daily injections of IL-10. The anti-allodynic effects of gabapentin may be caused by upregulation of IL-10 expression in the spinal cord, which leads to inhibition of the expression of pro-inflammatory cytokines in the spinal cords.     

Role of ERK/MAPK signalling pathway in anti-inflammatory effects of Ecklonia cava in activated human mast cell line-1 cells

Objective:The anti-inflammatory effects of Ecklonia cava(EC)and its mechanism of action were examined in phorbol-12 myristate 13-acetate(30 nmol/L)and A23187(1μmol/L)(PMACI)stimulated human mast cell line-1 cells.Methods:Nitric oxide content,inducible nitric oxide synthase and cyclooxygenase-2 protein expression,pro-inflammatory cytokines including IL-1β,TNF-α,and IL-6 mRNA and protein expressions were determined.In addition,extracellular regulated protein kinases/mitogen-activated protein kinase(ERK/MAPK)activation was examined.Results:EC dose-dependently suppressed inducible nitric oxide synthase and cyclooxygenase-2 protein expression and subsequently it reduces nitric oxide content in PMACI stimulated human mast cell line-1 cells.EC dose-dependently inhibited the mRNA as well as protein expression of TNF-α,IL—1β,and TL-6 in the PMACI stimulated human mast cell line-1 cells without any cytotoxic effect.Furthermore,EC significantly inhibited PMACI induced phosphorylation of ERK1/2 in a dose-dependent manner without affecting the total protein levels.Conclusions:EC exert its anti-inflammatory actions via inhibition of ERK/MAPK signalling pathway,suggesting that EC is a potent and efficacious anti-inflammatory agent for mast cellmediated inflammatory diseases.     

COVID-19 adenovirus vector vaccine induces higher interferon and pro-inflammatory responses than mRNA vaccines in human PBMCs,macrophages and moDCs

BackgroundDuring the COVID-19 pandemic multiple vaccines were rapidly developed and widely used throughout the world. At present there is very little information on COVID-19 vaccine interactions with primary human immune cells such as peripheral blood mononuclear cells (PBMCs), monocyte-derived macrophages and dendritic cells (moDCs).MethodsHuman PBMCs, macrophages and moDCs were stimulated with different COVID-19 vaccines, and the expression of interferon (IFN-λ1, IFN-α1), pro-inflammatory (IL-1β, IL-6, IL-8, IL-18, CXCL-4, CXCL-10, TNF-α) and Th1-type cytokine mRNAs (IL-2, IFN-γ) were analyzed by qPCR. In addition, the expression of vaccine induced spike (S) protein and antiviral molecules were studied in primary immune cells and in A549 lung epithelial cells.ResultsAdenovirus vector (Ad-vector) vaccine AZD1222 induced high levels of IFN-λ1, IFN-α1, CXCL-10, IL-6, and TNF-α mRNAs in PBMCs at early time points of stimulation while the expression of IFN-γ and IL-2 mRNA took place at later times. AZD1222 also induced IFN-λ1, CXCL-10 and IL-6 mRNA expression in monocyte-derived macrophages and DCs in a dose-dependent fashion. AZD1222 also activated the phosphorylation of IRF3 and induced MxA expression. BNT162b2 and mRNA-1273 mRNA vaccines failed to induce or induced very weak cytokine gene expression in all cell models. None of the vaccines enhanced the expression of CXCL-4. AZD1222 and mRNA-1273 vaccines induced high expression of S protein in all studied cells.ConclusionsAd-vector vaccine induces higher IFN and pro-inflammatory responses than the mRNA vaccines in human immune cells. This data shows that AZD1222 readily activates IFN and pro-inflammatory cytokine gene expression in PBMCs, macrophages and DCs, but fails to further enhance CXCL-4 mRNA expression.     

Nod样受体蛋白3炎性体抑制剂格列苯脲对机械通气致小鼠急性肺损伤的保护作用

目的 探究Nod样受体蛋白3(Nod-like receptor protein-3,NLRP3)炎性体抑制剂格列苯脲对机械通气导致的小鼠急性肺损伤是否具有保护作用. 方法 28只7～9周的清洁级ICR雄性小鼠,按完全随机分组法分为4组:对照组(CON组,6只)、格列苯脲组(GLY组,6只)、机械通气组(VEN组,8只)和格列苯脲+机械通气组(GLY+VEN组,8只).VEN组和GLY+VEN组机械通气4h后与CON组及GLY组麻醉插管后4h测定肺泡灌洗液中蛋白含量及炎性细胞数量,测量肺组织湿/干重比(wet/dry,W/D),观察肺组织病理学改变,ELISA法检测肺组织IL-1β、IL-6、TNF-α的含量. 结果 VEN组肺泡灌洗液中蛋白浓度和细胞数量[(0.534±0.104) g/L和(3.4±0.7)×105/ml]比CON组[(0.167±0.021) g/L和(1.9±0.5) ×105/ml]升高(P＜0.01);GLY+VEN组肺泡灌洗液中蛋白浓度和细胞数量[(0.425±0.083) g/L和(2.4±0.6) ×105/ml]比VEN组下降(P＜0.05).VEN组肺组织W/D(5.1±0.5)与CON组(4.4±0.4)比较,差异有统计学意义(P＜0.01),GLY +VEN组肺组织W/D(4.7±0.4)与VEN组比较,差异有统计学意义(P＜0.05).VEN组和GLY+VEN组肺组织中IL-1β、IL-6和TNF-α蛋白表达与CON组比较,明显升高(P＜0.05),GLY+VEN组IL-1β和IL-6表达与VEN组比较,表达明显降低(P＜0.05).结论 机械通气前给予格列苯脲可有效减少小鼠肺组织炎症细胞聚集,减轻肺水肿,机制可能与其抑制炎性体的激活有关.     

Assessment of immunotoxicity induced by chemicals in human precision-cut lung slices (PCLS)

Occupational asthma can be induced by a number of chemicals at the workplace. Risk assessment of potential sensitizers is mostly performed in animal experiments. With increasing public demand for alternative methods, human precision-cut lung slices (PCLS) have been developed as an ex vivo model.Human PCLS were exposed to increasing concentrations of 20 industrial chemicals including 4 respiratory allergens, 11 contact allergens, and 5 non-sensitizing irritants. Local respiratory irritation was characterized and expressed as 75% (EC₂₅) and 50% (EC₅₀) cell viability with respect to controls. Dose–response curves of all chemicals except for phenol were generated. Local respiratory inflammation was quantified by measuring the production of cytokines and chemokines. TNF-α and IL-1α were increased significantly in human PCLS after exposure to the respiratory sensitizers trimellitic anhydride (TMA) and ammonium hexachloroplatinate (HClPt) at subtoxic concentrations, while contact sensitizers and non-sensitizing irritants failed to induce the release of these cytokines to the same extent. Interestingly, significant increases in T_H1/T_H2 cytokines could be detected only after exposure to HClPt at a subtoxic concentration.In conclusion, allergen-induced cytokines were observed but not considered as biomarkers for the differentiation between respiratory and contact sensitizers. Our preliminary results show an ex vivo model which might be used for prediction of chemical-induced toxicity, but is due to its complex three-dimensional structure not applicable for a simple screening of functional and behavior changes of certain cell populations such as dendritic cells and T-cells in response to allergens.     

Evidence in vitro of glial cell priming in the taiep rat

Cultured glial cells from the cerebellum of 15-day-old taiep rats produced NO, increased iNOS levels, up-regulated iNOS expression and promoted TNF release when stimulated with LPS and IFNgamma. These responses were much greater than in control cells. In taiep glial cells, NO production and iNOS levels and expression induced by the co-stimulatory signal were resistant to the inhibitory effect of TGFbeta1. The glial cell priming might have been generated by oligodendrocyte alteration in taiep rats.