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Phytoconstituents from Neem with Multiple Activities
Published in Bhupinder Singh, Om Prakash Katare, Eliana B. Souto, NanoAgroceuticals & NanoPhytoChemicals, 2018
Suman Chaudhary, Rupinder Kaur Kanwar, Teenu Sharma, Bhupinder Singh, Jagat Rakesh Kanwar
NLGP is a nontoxic component of neem leaves, extracted and investigated for its potential role as an immunomodulator. Importantly, neem leaf protein contains an active ingredient, glycoprotein, which is known to exhibit immunotherapeutic, immunoprophylactic, and immunostimulatory activity (Chakraborty et al., 2008). This glycoprotein has the ability to replace the conventional therapies that, although reduce the tumor mass, also promote immunosuppressive milieu and cause inhibition of tumor effector cells. The potential of this functional ingredient in exerting antitumor activity was demonstrated by Chakraborty et al., in head and neck squamous cell carcinoma during which dysregulation between CXCL10 and CXCR3 inhibits the chemotaxis of cytotoxic cells at the tumor site. It was observed that treatment with NLGP enhanced the secretion of interferon γ (IFNγ), along with the upregulation of CXCR3A, the subsequent downregulation of CXCR3B, and an increase in the ratio of the chemokine (C-X-C motif) receptor (CXCR) 3A/CXCR3B, thus restoring the chemotaxis of peripheral blood mononuclear cells (PBMCs) towards head and neck squamous cells (Chakraborty et al., 2008). The immunomodulatory role of NLGP was also investigated in terms of observed upregulation of early activation markers, and a cluster of differentiation (CD69) and CD45RO. Also, there was an increased secretion of T-helper (Th) 1 cytokine interferon-γ observed. Thus, the study effectively indicated the potential role of NLGP in upregulating a type 1 response and maintaining normal immune homeostasis in immunosuppressed hosts (Bose et al., 2009). A recent study has shown that NLGP impedes B16-melanoma in mice, thus enhancing their survival. Subcutaneous treatment of NLGP weekly for four weeks was able to restrict melanoma growth and maintain 35% tumor-free mice on day 60 post-treatment. It suggested a direct association of the anticarcinogenic effect of NLGP with the dominance of type 1 chemokines/cytokines, enhancement in the activity of CD8+ T cells and downregulation of suppressive cellular functions (Barik et al., 2015). In conclusion, NLGP could efficiently diminish tumor growth through the activation of subdued T-cell function in the tumor microenvironment along with maintaining optimum type-1/regulatory balance. Another study evaluated this immunomodulatory role of nontoxic NLGP by pretreating a solid tumor with NLGP in mice. Results demonstrated vascular normalization in carcinoma and melanoma, along with reduction of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR2), and CD31. The treatment caused CD8+ T cells to infiltrate within the tumor, which lead to regulation of VEGF-VEGFR2 signalling, thus preventing aberrant neovascularization (Banerjee et al., 2014).
Toxicity and occupational exposure assessment for hydroprocessed esters and fatty acids (HEFA) alternative jet fuels
Published in Journal of Toxicology and Environmental Health, Part A, 2020
Teresa R. Sterner, Brian A. Wong, Karen L. Mumy, R. Arden James, James Reboulet, Darol E. Dodd, Richard C. Striebich, David R. Mattie
There were only minimal changes in gene expression at 200 mg/m3. The predominant changes in gene expression occurred at 2000 mg/m3 and predominantly involved chemokine genes. Overall, male and female rats displayed similar concentration response effects, both in magnitude and direction of changes in gene expression. More specifically, a single gene (IL1F6 = Interleukin 1 family member 6) was significantly upregulated at ≥200 mg/m3; fold changes were less than 2 across exposures. At 700 mg/m3 there were 32 genes with significant differential expression and 53 at 2000 mg/m3, with 29 of those common to both concentrations. The magnitude of changes in gene expression at the 200 and 700 mg/m3 was low, however, with only a single gene (SPP1, Secreted Phosphoprotein 1) demonstrating a fold change greater than 2 (2.8 at 700 mg/m3) with an elevation to 16.2 at 2000 mg/m3. There were 13 genes at 2000 mg/m3 that exhibited a fold change of greater than 2. The 13 included SPP1, integrin alpha M (ITGAM), interleukin 1 receptor type II (IL1R2), and C-C motif chemokine receptor 8 (CCR8); 9 were chemokine ligands (CCL2, CCL12 CCL22, CCL7, CCL17, CCL9, CXCL10, CXCL11 and CXCL6).
Animal models and mechanisms of tobacco smoke-induced chronic obstructive pulmonary disease (COPD)
Published in Journal of Toxicology and Environmental Health, Part B, 2023
Priya Upadhyay, Ching-Wen Wu, Alexa Pham, Amir A. Zeki, Christopher M. Royer, Urmila P. Kodavanti, Minoru Takeuchi, Hasan Bayram, Kent E. Pinkerton
Long-term TS exposure and systemic inflammation that results from chronic airway inflammation also play significant roles in lung tissue damage, adverse remodeling, and vascular dysfunction when mediators are released by inflammatory cells, epithelial cells, and fibroblasts (Figure 1). Inhaled TS in the lungs stimulates activation of macrophages and airway epithelial cells to release chemotactic factors, including interferon-γ-induced protein 10 (IP10; CXCL10), monokine induced by interferon-γ (MIG; CXCL9), interferon-induced T cell α-chemoattractant (I-TAC; CXCL11), interleukin (IL)-6, IL-8, and leukotriene B4, which results in accumulation of neutrophils and CD8+ T cells within the airways (Barnes et al. 2015; Mabley, Gordon, and Pacher 2011; Tanner and Single 2020). The protease, Granzyme B, excreted by CD8+ T cells, was implicated in degradation of extracellular matrix (ECM) leading to tissue remodeling associated with emphysema (Tanner and Single 2020). Proteases released by neutrophils and alveolar macrophages break down connective tissue and elastin in the alveoli contributing to localized (centrilobular) and generalized (panlobular) emphysema (Barnes et al. 2015; Tanner and Single 2020). TS-induced protease/antiprotease imbalance and oxidative stress are key inflammatory processes that promote COPD pathogenesis (Barnes et al. 2015; Fischer, Voynow, and Ghio 2015; Fricker, Deane, and Hansbro 2014). Neutrophil elastase, matrix metalloproteinases (MMPs), and MMP inhibitors play critical roles in development and progression of emphysema and COPD (Gharib, Manicone, and Parks 2018; Ghosh et al. 2019; Vlaykova and Dimov 2014; Zhou et al. 2020). Accumulation and hyperactivation of neutrophils produces mucous (goblet) cell metaplasia and mucus hypersecretion (Shaykhiev 2019). Macrophages and epithelial cells also secrete transforming growth factor (TGF)-β to stimulate proliferation of the epithelium, smooth muscle, and fibroblasts, resulting in fibrosis, airway remodeling, and chronic bronchitis (Barnes et al. 2015; Herfs et al. 2012; Tanner and Single 2020).
Docosahexaenoic acid impacts macrophage phenotype subsets and phagolysosomal membrane permeability with particle exposure
Published in Journal of Toxicology and Environmental Health, Part A, 2021
Paige Fletcher, Raymond F. Hamilton, Joseph F. Rhoderick, James J. Pestka, Andrij Holian
Macrophage phenotype was assessed within lung and spleen tissues. Sections of the tissues were snap-frozen on the day of harvest and RNA was isolated (TRIzol®, Thermo Fisher Scientific) according to manufacturer’s instructions. All RNA was converted to cDNA (iScript RT Supermix, Bio-Rad; Hercules, CA, USA) and qPCR analysis performed (SsoAdvanced Univ. SYBR Green Supermix, Bio-Rad) according to manufacturer’s instructions to determine macrophage phenotype: M1 [CXCL10, IL-1β, TNFα, iNos (Dong and Ma 2018; Genin et al. 2015; Hesketh et al. 2017; Jiang and Zhu 2016; Labonte, Tosello-Trampont, and Hahn 2014; Mantovani et al. 2004; Ohama et al. 2015; Tomioka 2016)], M2a [FN1, CD206, Fizz1, YM1 (Dong and Ma 2018; Genin et al. 2015; Hesketh et al. 2017; Jiang and Zhu 2016; Labonte, Tosello-Trampont, and Hahn 2014; Tomioka 2016)], M2b [CCL1, LIGHT, CXCL3, SPHK1 (Edwards et al. 2006; He et al. 2013; Hesketh et al. 2017; Jiang and Zhu 2016; Labonte, Tosello-Trampont, and Hahn 2014; Mantovani et al. 2004; Ohama et al. 2015; Tomioka 2016)], and M2c [CD163, CXCL13, TIMP1, TLR8 (Hesketh et al. 2017; Jiang and Zhu 2016; Koscsó et al. 2013; Labonte, Tosello-Trampont, and Hahn 2014; Mantovani et al. 2004; Ohama et al. 2015; Tomioka 2016)]. All qPCR primers with associated positive controls and reference genes used were validated PrimePCR SYBR Green assays from Bio-Rad. All signals were collected via 384-well CFX Maestro (Bio-Rad, supplied by Dr. Patel at FYR Diagnostics, Missoula, MT, USA and Dr. Kreitinger at Dermaxon, Missoula, MT, USA) and levels were normalized to reference gene β-2 microglobulin (B2m; ΔCq). Relative gene expressions of MWCNT and SiO2 of control-fed mice were normalized to DM-only of control-fed mice (ΔΔCq) to assess particle effect. The relative gene expressions of DM-only, MWCNT, and SiO2 of the 1% DHA-fed mice were normalized to DM-only, MWCNT, and SiO2 of the control-fed mice, respectively (ΔΔCq) to assess diet effect. The ΔΔCq values were analyzed within a heat-map. A dominant phenotype shift was indicated by an upregulation of gene expression of at least 3 of 4 genes within each phenotype or a trending increase indicated by upregulation of two of the four genes.