Reduced Neutrophil Infiltration Research Articles

Knockout of Zeb2 ameliorates progression of renal tubulointerstitial fibrosis in a mouse model of renal ischemia-reperfusion injury.

Zeb2, a zinc finger E-box-binding homeobox transcription factor, regulates transforming growth factor (TGF)-β signaling pathway. However, its role in the pathogenesis of acute kidney injury (AKI) and AKI-to-chronic kidney disease (CKD) transition is unclear. We evaluated Zeb2 function in a bilateral renal ischemia-reperfusion injury (IRI)-induced AKI model using proximal tubule-specific Zeb2 conditional knockout (Zeb2-cKO) and wild-type (WT) mice, and in renal biopsy samples. In Zeb2-cKO mice, the levels of plasma creatinine and blood urea nitrogen post-IRI were significantly lower than that in WT mice. Immunohistological analysis revealed mild tubular injury, reduced neutrophil infiltration, fewer fibrotic changes and reduced expression of fibrotic proteins [collagen type IV, α-smooth muscle actin (α-SMA), fibronectin and connective tissue growth factor (CTGF)], at 3-14 days post-IRI. Zeb2 expression was upregulated in proximal tubular cells post-IRI in WT mice. Zeb2 siRNA transfection reduced TGF-β-stimulated mRNA and protein expression of collagen type IV, α-SMA, fibronectin and CTGF in cultured renal tubular cells. Patients with AKI-to-CKD transition exhibited high Zeb2 expression in renal tubules, as revealed by renal biopsy. Hypoxia and CoCl2-treatment upregulated Zeb2 promoter activity and mRNA and protein expression in cultured renal tubular epithelial cells, suggesting a regulatory role for hypoxia. Zeb2 was upregulated in renal tissues in both mice and humans with AKI. Zeb2 regulates fibrotic pathways in the pathogenesis of AKI and AKI-to-CKD transition. Therefore, inhibition of Zeb2 could be a potential therapeutic strategy for AKI.

The Prevention Effect of Bacillus subtilis on Escherichia coli-Induced Mastitis in Mice by Suppressing the NF-κB and MAPK Signaling Pathways.

Mastitis, common inflammation of the mammary gland, caused by various factors, is a challenge for the dairy industry. Escherichia coli (E. coli), a Gram-negative opportunistic pathogen, is one of the major pathogens causing clinical mastitis which is characterized by reduced milk production and recognizable clinical symptoms. Bacillus subtilis (B. subtilis) has been reported to have the ability to limit the colonization of pathogens and has immune-stimulatory effects on epithelial cells. The purpose of this study was to explore the preventive role of B. subtilis H28 on E. coli-induced mastitis in mice. The mastitis model was established by nipple duct injection of E. coli into mice, while B. subtilis H28 was utilized 2h before E. coli injection. Furthermore, pathological changes in the mammary gland were evaluated by hematoxylin-eosin (H&E) staining. Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of proinflammatory cytokines (TNF-α, IL-1β, and IL-6). We also observed changes in Toll-like receptor 4 (TLR4), nuclear transcription factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) expression by using western blotting. The results revealed that B. subtilis H28 pretreatment reduced neutrophil infiltration in the mammary gland tissues, significantly decreased the secretion of TNF-α, IL-1β, and IL-6, and downregulated the activation of TLR4 and the phosphorylation of p65 NF-κB, IκB, p38, and ERK. In conclusion, our results indicated that B. subtilis H28 can ameliorate E. coli-induced mastitis and suggest a new method for the prevention of mastitis.

FJU-C28 inhibits the endotoxin-induced pro-inflammatory cytokines expression via suppressing JNK, p38 MAPK and NF-κB signaling pathways.

Despite marked improvements in supportive care, the mortality rate of acute respiratory distress syndrome due to the excessive inflammatory response caused by direct or indirect lung injury induced by viral or bacterial infection is still high. In this study, we explored the anti‐inflammatory effect of FJU‐C28, a new 2‐pyridone‐based synthetic compound, on lipopolysaccharide (LPS)‐induced inflammation in vitro and in vivo models. FJU‐C28 suppressed the LPS‐induced mRNA and protein expression of iNOS, COX2 and proinflammatory cytokines. The cytokine protein array results showed that LPS stimulation enhanced the secretion of IL‐10, IL‐6, GCSF, Eotaxin, TNFα, IL‐17, IL‐1β, Leptin, sTNF RII, and RANTES. Conversely, the LPS‐induced secretion of RANTES, TIMP1, IL‐6, and IL‐10 was dramatically suppressed by FJU‐C28. FJU‐C28 suppressed the LPS‐induced expression of RANTES, but its parental compound FJU‐C4 was unable to diminish RANTES in cell culture media or cell lysates. FJU‐C28 blocked the secretion of IL‐6 and RANTES in LPS‐activated macrophages by regulating the activation of JNK, p38 mitogen‐activated protein kinase (MAPK) and nuclear factor‐κB (NF‐κB). FJU‐C28 prevented the LPS‐induced decreases in lung function including vital capacity (VC), lung compliance (C chord), forced expiratory volume at 100 ms (FEV100), and forced vital capacity (FVC) in mice with LPS‐induced systemic inflammatory responses. FJU‐C28 also reduced neutrophil infiltration in the interstitium, lung damage and circulating levels of IL‐6 and RANTES in mice with systemic inflammation. In conclusion, these findings suggest that FJU‐C28 possesses anti‐inflammatory activities to prevent endotoxin‐induced lung function decrease and lung damages by down‐regulating proinflammatory cytokines including IL‐6 and RANTES via suppressing the JNK, p38 MAPK and NF‐κB signaling pathways.

Inhibition of vascular adhesion protein 1 protects dopamine neurons from the effects of acute inflammation and restores habit learning in the striatum

BackgroundChanges in dopaminergic neural function can be induced by an acute inflammatory state that, by altering the integrity of the neurovasculature, induces neuronal stress, cell death and causes functional deficits. Effectively blocking these effects of inflammation could, therefore, reduce both neuronal and functional decline. To test this hypothesis, we inhibited vascular adhesion protein 1 (VAP-1), a membrane-bound protein expressed on the endothelial cell surface, that mediates leukocyte extravasation and induces oxidative stress.MethodWe induced dopaminergic neuronal loss by infusing lipopolysaccharide (LPS) directly into the substantia nigra (SN) in rats and administered the VAP-1 inhibitor, PXS-4681A, daily.ResultsLPS produced: an acute inflammatory response, the loss of dopaminergic neurons in the SN, reduced the dopaminergic projection to SN target regions, particularly the dorsolateral striatum (DLS), and a deficit in habit learning, a key function of the DLS. In an attempt to protect SN neurons from this inflammatory response we found that VAP-1 inhibition not only reduced neutrophil infiltration in the SN and striatum, but also reduced the associated striatal microglia and astrocyte response. We found VAP-1 inhibition protected dopamine neurons in the SN, their projections to the striatum and promoted the functional recovery of habit learning. Thus, we reversed the loss of habitual actions, a function usually dependent on dopamine release in DLS and sensitive to striatal dysfunction.ConclusionsWe establish, therefore, that VAP-1 inhibition has an anti-inflammatory profile that may be beneficial in the treatment of dopamine neuron dysfunction caused by an acute inflammatory state in the brain.

Ibrutinib reduces neutrophil infiltration, preserves neural tissue and enhances locomotor recovery in mouse contusion model of spinal cord injury.

Following acute spinal cord injury (SCI), excessive recruitment of neutrophils can result in inflammation, neural tissue loss and exacerbation of neurological outcomes. Ibrutinib is a bruton’s tyrosine kinase inhibitor in innate immune cells such as the neutrophils that diminishes their activation and influx to the site of injury. The present study evaluated the efficacy of ibrutinib administration in the acute phase of SCI on neural tissue preservation and locomotor recovery. Ibrutinib was delivered intravenously at 3.125 mg/kg either immediately, 12 hours after, or both immediately and 12 hours after SCI induction in adult male C57BL/6 mice. Neutrophil influx into the lesion area was evaluated 24 hours following SCI using light microscopy and immunohistochemistry methods. Animals’ body weight changes were recorded, and their functional motor recovery was assessed based on the Basso mouse scale during 28 days after treatment. Finally, spinal cord lesion volume was estimated by an unbiased stereological method. While animals’ weight in the control group started to increase one week after injury, it stayed unchanged in treatment groups. However, the double injection of ibrutinib led to a significantly lower body weight compared to the control group at 4 weeks post-injury. Mean neutrophil counts per visual field and the lesion volume were significantly decreased in all ibrutinib-treated groups. In addition, ibrutinib significantly improved locomotor functional recovery in all treated groups, especially in immediate and double-injection groups. Neural tissue protection and locomotor functional recovery suggest ibrutinib treatment as a potent immunotherapeutic intervention for traumatic SCI that warrants clinical testing.

Inhibition of Granuloma Triglyceride Synthesis Imparts Control of Mycobacterium tuberculosis Through Curtailed Inflammatory Responses.

Lipid metabolism plays a complex and dynamic role in host-pathogen interaction during Mycobacterium tuberculosis infection. While bacterial lipid metabolism is key to the success of the pathogen, the host also offers a lipid rich environment in the form of necrotic caseous granulomas, making this association beneficial for the pathogen. Accumulation of the neutral lipid triglyceride, as lipid droplets within the cellular cuff of necrotic granulomas, is a peculiar feature of pulmonary tuberculosis. The role of triglyceride synthesis in the TB granuloma and its impact on the disease outcome has not been studied in detail. Here, we identified diacylglycerol O-acyltransferase 1 (DGAT1) to be essential for accumulation of triglyceride in necrotic TB granulomas using the C3HeB/FeJ murine model of infection. Treatment of infected mice with a pharmacological inhibitor of DGAT1 (T863) led to reduction in granuloma triglyceride levels and bacterial burden. A decrease in bacterial burden was associated with reduced neutrophil infiltration and degranulation, and a reduction in several pro-inflammatory cytokines including IL1β, TNFα, IL6, and IFNβ. Triglyceride lowering impacted eicosanoid production through both metabolic re-routing and via transcriptional control. Our data suggests that manipulation of lipid droplet homeostasis may offer a means for host directed therapy in Tuberculosis.

Hepatic Ischemia/Reperfusion Injury involves functional tryptase/PAR-2 signaling in liver sinusoidal endothelial cell population

Mast cells (MCs) are tissue-resident effector cells that could be the earliest responder to release a unique, stimulus-specific set of mediators in hepatic ischemia–reperfusion (IR) injury However, how MCs function in the hepatic IR has remained a formidable challenge due to the substantial redundancy and functional diverse of these mediators. Tryptase is the main protease for degranulation of MCs and its receptor-protease-activated receptor 2 (PAR-2) is widely expressed in endothelial cells. It is unclear whether and how tryptase/PAR-2 axis participates in hepatic IR. We employed an experimental warm 70% liver IR model in mice and found that tryptase was accumulated in the circulation during hepatic IR and positively correlated with liver injury. Tryptase inhibition by protamine can significantly down-regulate the expression of adhesion molecules and reduce neutrophil infiltration within the liver. The level of inflammatory factors and chemokines were also consistent with the pathological change of the liver. In addition, the treatment with exogeneous tryptase in MC-deficient mice can induce the damage observed in wild type mice in the context of liver IR. In vitro, neutrophil infiltration and inflammatory factor secretion were regulated by Tryptase/PAR-2, involving the adhesion molecule expression to regulate neutrophil adhesion dependent on NF-κB pathway. Conclusion: tryptase/PAR-2 participates in liver injury through the activation of LSECs in the early phase of liver IR.

The Protective Effects of Indole-3-carbinol on Stomach Injury in Rats

The objective of this research was to analyze the protective effect of indole-3-carbinol against the stomach injury induced by acetylsalicylic acid. Male rats were randomly divided into eight groups of six animals in each group. Control group, OMP group, I3C group, OMP+I3C group, AA group, AA+OMP group, AA+I3C group, and AA+OMP+I3C group. The control rats were received distilled water and the experimental rats were received AA at a dose of 500 mg/kg body weight, OMP at a dose of 20 mg/kg body weight, and I3C at a dose of 50 mg/kg body weight either alone or in combination with each other, orally for seven consecutive days. Results of the present study showed ulcer protection in indole-3-cabinol treated rats was confirmed by histoarchitecture, which was comprised of the reduced size of ulcer crater and restoration of mucosal epithelium. Thus, reduced neutrophil infiltration, antiapoptotic and antioxidant action have a pivotal role in the gastroprotective effect of indole-3-carbinol. Keywords: Histopathological; Stomach; Acetylsalicylic acid; Indole-3-carbinol; Rats

Gingival-Derived Mesenchymal Stem Cells Protect Against Sepsis and Its Complications.

ObjectiveIn the present study, we separated and characterized mouse gingival-derived mesenchymal stem cells (GMSCs) and investigated whether GMSCs can improve lipopolysaccharide (LPS)-induced sepsis and its complications.MethodsNinety-six ICR mice were randomly divided into the following groups: the control (Sham), LPS, and LPS + MSC groups. Mice received 5 mg/kg LPS intraperitoneally to induce sepsis. Histopathological micrographs illustrated organ injury. We detected systemic inflammation, blood glucose levels, and serum levels of high-mobility group box 1 (HMGB1) and lactate. In addition, pulmonary inflammation, lung permeability, and oxidative stress-related indicators in lung tissue were measured.ResultsWe successfully separated a novel population of MSCs from mouse gingiva. These cells had MSC-associated properties, such as a typical fibroblast-like morphology, multiple differentiation potential, and certain phenotypes. Cell-based therapy using GMSCs significantly improved the survival rate, systemic inflammation, hypoglycemia, multiple organ dysfunction syndrome (MODS), and aortic injury during sepsis. GMSCs administration reduced pulmonary inflammation, lung permeability, and oxidative stress injury. GMSCs administration reduced neutrophil infiltration partly because GMSCs inhibited neutrophil chemoattractants tumor necrosis factor (TNF-α), C-X-C motif chemokine ligand (CXCL-1), and Interleukin (IL-8). GMSCs impaired LPS-induced HMGB1 and lactate release during sepsis.ConclusionGMSCs administration is a novel therapeutic strategy targeting aerobic glycolysis for the treatment of sepsis because GMSCs impair LPS-induced HMGB1 and lactate release. GMSCs alleviate lung injury partly because GMSCs exert immune effects, inhibit neutrophilic inflammation, and reduce oxidative stress injury.

Addressing the liver progenitor cell response and hepatic oxidative stress in experimental non-alcoholic fatty liver disease/non-alcoholic steatohepatitis using amniotic epithelial cells

BackgroundNon-alcoholic fatty liver disease is the most common liver disease globally and in its inflammatory form, non-alcoholic steatohepatitis (NASH), can progress to cirrhosis and hepatocellular carcinoma (HCC). Currently, patient education and lifestyle changes are the major tools to prevent the continued progression of NASH. Emerging therapies in NASH target known pathological processes involved in the progression of the disease including inflammation, fibrosis, oxidative stress and hepatocyte apoptosis. Human amniotic epithelial cells (hAECs) were previously shown to be beneficial in experimental models of chronic liver injury, reducing hepatic inflammation and fibrosis. Previous studies have shown that liver progenitor cells (LPCs) response plays a significant role in the development of fibrosis and HCC in mouse models of fatty liver disease. In this study, we examined the effect hAECs have on the LPC response and hepatic oxidative stress in an experimental model of NASH.MethodsExperimental NASH was induced in C57BL/6 J male mice using a high-fat, high fructose diet for 42 weeks. Mice received either a single intraperitoneal injection of 2 × 106 hAECs at week 34 or an additional hAEC dose at week 38. Changes to the LPC response and oxidative stress regulators were measured.ResultshAEC administration significantly reduced the expansion of LPCs and their mitogens, IL-6, IFNγ and TWEAK. hAEC administration also reduced neutrophil infiltration and myeloperoxidase production with a concurrent increase in heme oxygenase-1 production. These observations were accompanied by a significant increase in total levels of anti-fibrotic IFNβ in mice treated with a single dose of hAECs, which appeared to be independent of c-GAS-STING activation.ConclusionsExpansion of liver progenitor cells, hepatic inflammation and oxidative stress associated with experimental NASH were attenuated by hAEC administration. Given that repeated doses did not significantly increase efficacy, future studies assessing the impact of dose escalation and/or timing of dose may provide insights into clinical translation.

Role of Extracellular Vimentin in Cancer-Cell Functionality and Its Influence on Cell Monolayer Permeability Changes Induced by SARS-CoV-2 Receptor Binding Domain.

The cytoskeletal protein vimentin is secreted under various physiological conditions. Extracellular vimentin exists primarily in two forms: attached to the outer cell surface and secreted into the extracellular space. While surface vimentin is involved in processes such as viral infections and cancer progression, secreted vimentin modulates inflammation through reduction of neutrophil infiltration, promotes bacterial elimination in activated macrophages, and supports axonal growth in astrocytes through activation of the IGF-1 receptor. This receptor is overexpressed in cancer cells, and its activation pathway has significant roles in general cellular functions. In this study, we investigated the functional role of extracellular vimentin in non-tumorigenic (MCF-10a) and cancer (MCF-7) cells through the evaluation of its effects on cell migration, proliferation, adhesion, and monolayer permeability. Upon treatment with extracellular recombinant vimentin, MCF-7 cells showed increased migration, proliferation, and adhesion, compared to MCF-10a cells. Further, MCF-7 monolayers showed reduced permeability, compared to MCF-10a monolayers. It has been shown that the receptor binding domain of SARS-CoV-2 spike protein can alter blood–brain barrier integrity. Surface vimentin also acts as a co-receptor between the SARS-CoV-2 spike protein and the cell-surface angiotensin-converting enzyme 2 receptor. Therefore, we also investigated the permeability of MCF-10a and MCF-7 monolayers upon treatment with extracellular recombinant vimentin, and its modulation of the SARS-CoV-2 receptor binding domain. These findings show that binding of extracellular recombinant vimentin to the cell surface enhances the permeability of both MCF-10a and MCF-7 monolayers. However, with SARS-CoV-2 receptor binding domain addition, this effect is lost with MCF-7 monolayers, as the extracellular vimentin binds directly to the viral domain. This defines an influence of extracellular vimentin in SARS-CoV-2 infections.

Neutrophil Decoys with Anti‐Inflammatory and Anti‐Oxidative Properties Reduce Secondary Spinal Cord Injury and Improve Neurological Functional Recovery

AbstractFollowing spinal cord injury (SCI), immune cell infiltration creates an inflammatory and oxidative microenvironment (known as the secondary injury), which causes neuron death and spinal cord damage, and dramatically hinders neurological functional recovery. Strategies that inhibit the infiltration and/or function of neutrophils offer promises for SCI treatment because they can reduce the secondary injury; however, such strategies remain largely unexplored. Herein, a strategy using neutrophil membrane‐coated nanoparticles (NPs) as decoys (neutrophil decoy, ND) is presented to reduce local neutrophil infiltration and relieve oxidative stress in the injured spinal cord after SCI. Coated with membranes of activated neutrophils, the NDs inherit multiple receptors from the “parent” neutrophils, which can adsorb and neutralize the elevated neutrophil‐related cytokines. In addition, polydopamine NPs with multi‐antioxidative properties (selected as the core for ND) scavenge excessive reactive oxygen and nitrogen species. In a contusion model of SCI, ND treatment significantly reduces neutrophil infiltration and reprograms the inflammatory and oxidative microenvironment in injured spinal cords. Importantly, ND treatment significantly improves neural regeneration and functional recovery in rats. Such a nano‐decoy platform opens up new approaches for efficiently treating SCI.

Parabacteroides produces acetate to alleviate heparanase-exacerbated acute pancreatitis through reducing neutrophil infiltration

BackgroundThe endoglycosidase heparanase which degrades heparan sulfate proteoglycans, exerts a pro-inflammatory mediator in various inflammatory disorders. However, the function and underlying mechanism of heparanase in acute pancreatitis remain poorly understood. Here, we investigated the interplay between heparanase and the gut microbiota in the development of acute pancreatitis.MethodsAcute pancreatitis was induced in wild-type and heparanase-transgenic mice by administration of caerulein. The differences in gut microbiota were analyzed by 16S ribosomal RNA sequencing. Antibiotic cocktail experiment, fecal microbiota transplantation, and cohousing experiments were used to assess the role of gut microbiota.ResultsAs compared with wild-type mice, acute pancreatitis was exacerbated in heparanase-transgenic mice. Moreover, the gut microbiota differed between heparanase-transgenic and wild-type mice. Heparanase exacerbated acute pancreatitis in a gut microbiota-dependent manner. Specially, the commensal Parabacteroides contributed most to distinguish the differences between wild-type and heparanase-transgenic mice. Administration of Parabacteroides alleviated acute pancreatitis in wild-type and heparanase-transgenic mice. In addition, Parabacteroides produced acetate to alleviate heparanase-exacerbated acute pancreatitis through reducing neutrophil infiltration.ConclusionsThe gut–pancreas axis played an important role in the development of acute pancreatitis and the acetate produced by Parabacteroides may be beneficial for acute pancreatitis treatment.AXqtS6bvN-oakcGDurjdFQVideo abstract

Air Pollution Relates to Airway Pathology in Children with Wheezing.

Rationale: Outdoor air pollution contributes to asthma development and exacerbations, yet its effects on airway pathology have not been defined in children.Objectives: To explore the possible link between air pollution and airway pathology, we retrospectively examined the relationship between environmental pollutants and pathological changes in bronchial biopsy specimens from children undergoing a clinically indicated bronchoscopy.Methods: Structural and inflammatory changes (basement membrane [BM] thickness, epithelial loss, eosinophils, neutrophils, macrophages, mast cells, and lymphocytes) were quantified in biopsy specimens by using immunohistochemistry. The association between exposure to particulate matter less than 10 μm in aerodynamic diameter (PM10), SO2 and NO2 and biopsy findings was evaluated by using a generalized additive model with Gamma family to allow for overdispersion, adjusted for atmospheric pressure, temperature, humidity, and wheezing.Results: Overall, 98 children were included (age 5.3 ± 2.9 yr; 53 with wheezing/45 without wheezing). BM thickness increased with prolonged exposure to PM10 (rate ratio [RR], 1.29; 95% confidence interval [CI], 1.09–1.52), particularly in children with wheezing. Prolonged exposure to PM10 was also associated with eosinophilic inflammation in children with wheezing (RR, 3.16; 95% CI, 1.35–7.39). Conversely, in children without wheezing, increased PM10 exposure was associated with a reduction of eosinophilic inflammation (RR, 0.12; 95% CI, 0.02–0.6) and neutrophilic inflammation (RR, 0.36; 95% CI, 0.14–0.89). Moreover, NO2 exposure was also linked to reductions in neutrophil infiltration (RR, 0.57; 95% CI, 0.34–0.93) and eosinophil infiltration (RR, 0.33; 95% CI, 0.14–0.77).Conclusions: Different patterns of association were observed in children with wheezing and in children without wheezing. In children without wheezing, exposure to PM10 and NO2 was linked to reduced eosinophilic and neutrophilic inflammation. Conversely, in children with wheezing, prolonged exposure to PM10 was associated with increased BM thickness and eosinophilic inflammation, suggesting that it might contribute to asthma development by promoting airway remodeling and inflammation.

Role of Brahma-related gene 1 (Brg1) in heart disease

Role of Brahma-related gene 1 (Brg1) in heart disease

Evaluation of Neutrophil Dynamics Change by Protective Effect of Tadalafil After Renal Ischemia/Reperfusion Using In Vivo Real-time Imaging.

Neutrophils play a major role in ischemia/reperfusion injury (IRI) in renal transplantation and acute kidney injury. However, it has been difficult to observe changes in neutrophil dynamics over time in living mice kidney. We investigate neutrophil dynamics in IRI in living mice using novel in vivo multiphoton microscope imaging techniques and characterize the renoprotective effects of a selective phosphodiesterase 5 inhibitor, tadalafil. Wild-type and endothelial nitric oxide synthase knockout mice, a model of endothelial dysfunction, were used to establish in vivo real-time imaging in living mouse kidneys. Neutrophils were labeled green with Ly-6G monoclonal antibody, and plasma flow was labeled red with BSA. Tadalafil was administered orally 1 h before surgery. Both kidney pedicles were reperfused after 37°C warm ischemia for 45 min. Our novel approach revealed that neutrophils were trapped in glomerulus within a few minutes after reperfusion. They gradually increased over time and infiltrated neutrophils were observed in the tubular lumen and peritubular capillary. The neutrophils were clearly visualized rolling on peritubular capillary plexus at 3 μm/min. The administration of tadalafil significantly reduced neutrophil influx into the glomerulus in both wild-type and endothelial nitric oxide synthase knockout mice. Reduced neutrophil infiltration in tadalafil groups, which was confirmed by flow cytometry, resulted in histopathologically decreased tubular injury. The expression of vascular cell adhesion molecule 1 and kidney injury molecule 1 was partially prevented by tadalafil. Use of a novel technique contributed to elucidation of neutrophil dynamics after reperfusion. Tadalafil has a potential for inhibiting neutrophil infiltration in renal IRI.

Protective Effect of a Formulation Containing Pistacia atlantica Oleo-Gum-Resin and Honey on Experimental Model of Acetic Acid-Induced Colitis in Rats

Background and objectives: Inflammatory bowel disease (IBD) is a recurrent chronic inflammatory disease of the gastrointestinal tract. In Iranian traditional medicine, the oleo-gum-resin of the genus Pistacia is recommended for treatment of various diseases including gastrointestinal disorders. The present study investigated the therapeutic action of a combination of Pistacia atlantica subspecies kurdica oleo-gum-resin and honey in acetic acid-induced colitis in rats. Methods: Pistacia atlantica oleo-gum-resin was mixed with honey. The mixture was suspended in distilled water. Following induction of colitis with 4% acetic acid in all animals, except in sham group,themixture was orally administered for two consecutive days at the concentrations of 100, 200, 400 mg/kg. Other groups included the control, sham and a standard group (dexamethasone). Microscopic and histopathologic examinations were conducted in inflamed colonic tissue. The inflammatory biomarkers of colitis including interleukin 6 (IL-6), tumor necrosis factor (TNF-α), and myeloperoxidase (MPO) and the gene expression level of toll like receptor-4 (TLR-4) were assessed. Results: Pistacia atlantica oleo-gum-resin+ honey induced significant progress in macroscopic and microscopic scores. Colonic levels of MPO, IL-6, and TNF-α significantly declined in rats treated with the mixture; while significant decrease in mucosal gene expression of TLR-4 and significant improvement of colitis were observed. Pistacia atlantica oleo-gum-resin (400 mg/kg) + honey (400 mg/kg)reduced inflammation of the bowel and colonic ulcer severity shown by downregulation of inflammation cytokines, reduction of neutrophil infiltration, and suppression of TLR-4 expression. Conclusion: The combination might be a promising supplement for treatment of inflammatory disorders.

OMO-1 reduces progression and enhances cisplatin efficacy in a 4T1-based non-c-MET addicted intraductal mouse model for triple-negative breast cancer

c-MET is considered a driver of cancer progression, impacting tumor growth and tumor-supporting stroma. Here, we investigated the therapeutic efficacy of OMO-1, a potent and selective c-MET inhibitor, in an immunocompetent intraductal mouse model for triple-negative breast cancer (TNBC). OMO-1 reduced non-c-MET addicted 4T1 tumor progression dose dependently as monotherapeutic and provided additional disease reduction in combination with cisplatin. At the stromal level, OMO-1 significantly reduced neutrophil infiltration in 4T1 tumors, promoted immune activation, and enhanced cisplatin-mediated reduction of tumor-associated macrophages. OMO-1 treatment also reduced 4T1 tumor hypoxia and increased expression of pericyte markers, indicative for vascular maturation. Corroborating this finding, cisplatin delivery to the 4T1 primary tumor was enhanced upon OMO-1 treatment, increasing cisplatin DNA-adduct levels and tumor cell death. Although verification in additional cell lines is warranted, our findings provide initial evidence that TNBC patients may benefit from OMO-1 treatment, even in cases of non-c-MET addicted tumors.

Lansoprazole a Proton Pump Inhibitor Prevents IBD by Reduction of Oxidative Stress and NO Levels in the Rat

The inflammatory disease's increased prevalence leads to a major concern around the world. Still, there is a lack of effective and successful therapy in the reversal of Inflammatory Bowel Disease (IBD) symptoms. Whereas, reactive oxygen species (ROS) production and muddled defense capacity of antioxidants in IBD subjects reported several times. Many proton pump inhibitors have been reported previously for their anti-inflammatory effect. The present study is aimed to assess the ameliorative effect of lansoprazole in experimentally induced IBD in rats. Thirty-six female Sprague Dawley rats were divided equally into six groups based on their body weight. Lansoprazole (1, 5, and 10 mg/kg, p.o.) and 5-aminosalicylate (5-ASA, 100 mg/kg, p.o.) served as standard control respectively, given for 18 days once a day. On the 11th day of the study, colitis was induced by intrarectal instillation of 2, 4-Dinitrobenzene sulfonic acid (DNBS), and treatment was continued for the next 7 days. Administration of lansoprazole (at 5 and 10 mg/kg) significantly reduced DAI (Disease Activation Index) and CMDI (Colon Macroscopic Damage Index); which further justifies a reduction in colon inflammation grades, as well as histopathological changes, and reflected by the stalling of body weight. The anti-inflammatory effects were indicated by lowered MPO (myeloperoxidase) and SOD (superoxide dismutase) in colon tissue as well as restores colonic NO (nitric oxide) level. The study shows lansoprazole improved DAI and CMDI scores, reduction of neutrophil infiltration, and an improved antioxidant status indicating an anti-ulcerative effect in DNBS-induced experimental colitis that is comparable with 5-ASA treatment.

Engineered Lactobacillus paracasei Producing Palmitoylethanolamide (PEA) Prevents Colitis in Mice.

Palmitoylethanolamide (PEA) is an N-acylethanolamide produced on-demand by the enzyme N-acylphosphatidylethanolamine-preferring phospholipase D (NAPE-PLD). Being a key member of the larger family of bioactive autacoid local injury antagonist amides (ALIAmides), PEA significantly improves the clinical and histopathological stigmata in models of ulcerative colitis (UC). Despite its safety profile, high PEA doses are required in vivo to exert its therapeutic activity; therefore, PEA has been tested only in animals or human biopsy samples, to date. To overcome these limitations, we developed an NAPE-PLD-expressing Lactobacillus paracasei F19 (pNAPE-LP), able to produce PEA under the boost of ultra-low palmitate supply, and investigated its therapeutic potential in a murine model of UC. The coadministration of pNAPE-LP and palmitate led to a time-dependent release of PEA, resulting in a significant amelioration of the clinical and histological damage score, with a significantly reduced neutrophil infiltration, lower expression and release of pro-inflammatory cytokines and oxidative stress markers, and a markedly improved epithelial barrier integrity. We concluded that pNAPE-LP with ultra-low palmitate supply stands as a new method to increase the in situ intestinal delivery of PEA and as a new therapeutic able of controlling intestinal inflammation in inflammatory bowel disease.