Showing papers on "Intraperitoneal injection published in 2020"

Protective effects of vitamin E on cadmium-induced apoptosis in rat testes.

Abstract: Cadmium (Cd) is a toxic metal that is involved in apoptosis. The present study was conducted to investigate the mechanism of Cd-induced apoptosis and the protective effects of vitamin E on rat testes. Thirty-two adult Wistar rats were divided into four groups. The control group was injected with saline and three other groups received Cd, Cd+vitamin E, and vitamin E. Intraperitoneal injection was performed for 28 days. On the 29th day, the rats were slaughtered, their peritoneum was opened, and their left testis removed and weighed. The mRNA expression of apoptosis and mitochondrial dynamics genes were assessed using real-time PCR, and caspase-3/7 activation using the caspase-3/7 Assay. The groups were not significantly different in terms of testicular weight. Compared with the control group, the mRNA expression levels of Bax and caspase-9 genes increased in the rats’ testes receiving Cd, the mRNA expression levels of mitofusin 1 (Mfn1) and mitofusin2 (Mfn2) genes decreased, and those of Bcl-2 remained unchanged. Vitamin E was found to significantly decrease the mRNA expression of Bax and caspase-9 genes and increase the mRNA Mfn1, Mfn2, and Bcl-2 in the rats’ testes receiving Cd. The ratio of Bax/Bcl-2 and caspase-3/7 activity increased in the Cd-exposed rats compared with the control. Vitamin E remarkably attenuated the Cd-induced effects. According to the obtained results, Cd exerts its apoptotic effects through the mitochondrial pathway by increasing the ratio of Bax/Bcl-2 and activating caspases in the rats’ testes, and vitamin E plays a protective role against Cd-induced apoptosis.

Reconstituted High-density Lipoprotein Therapy Improves Survival in Mouse Models of Sepsis.

Abstract: BACKGROUND High-density lipoproteins exert pleiotropic effects including antiinflammatory, antiapoptotic, and lipopolysaccharide-neutralizing properties. The authors assessed the effects of reconstituted high-density lipoproteins (CSL-111) intravenous injection in different models of sepsis. METHODS Ten-week-old C57BL/6 mice were subjected to sepsis by cecal ligation and puncture or intraperitoneal injection of Escherichia coli or Pseudomonas aeruginosa pneumonia. CSL-111 or saline solution was administrated 2 h after the sepsis. Primary outcome was survival. Secondary outcomes were plasma cell-free DNA and cytokine concentrations, histology, bacterial count, and biodistribution. RESULTS Compared with saline, CSL-111 improved survival in cecal ligation and puncture and intraperitoneal models (13 of 16 [81%] survival rate vs. 6 of 16 [38%] in the cecal ligation and puncture model; P = 0.011; 4 of 10 [40%] vs. 0 of 10 [0%] in the intraperitoneal model; P = 0.011). Cell-free DNA concentration was lower in CSL-111 relative to saline groups (68 [24 to 123] pg/ml vs. 351 [333 to 683] pg/ml; P < 0.001). Mice injected with CSL-111 presented a decreased bacterial count at 24 h after the cecal ligation and puncture model both in plasma (200 [28 to 2,302] vs. 2,500 [953 to 3,636] colony-forming unit/ml; P = 0.021) and in the liver (1,359 [360 to 1,648] vs. 1,808 [1,464 to 2,720] colony-forming unit/ml; P = 0.031). In the pneumonia model, fewer bacteria accumulated in liver and lung of the CSL-111 group. CSL-111-injected mice had also less lung inflammation versus saline mice (CD68+ to total cells ratio: saline, 0.24 [0.22 to 0.27]; CSL-111, 0.07 [0.01 to 0.09]; P < 0.01). In all models, no difference was found for cytokine concentration. Indium bacterial labeling underlined a potential hepatic bacterial clearance possibly promoted by high-density lipoprotein uptake. CONCLUSIONS CSL-111 infusion improved survival in different experimental mouse models of sepsis. It reduced inflammation in both plasma and organs and decreased bacterial count. These results emphasized the key role for high-density lipoproteins in endothelial and organ protection, but also in lipopolysaccharide/bacteria clearance. This suggests an opportunity to explore the therapeutic potential of high-density lipoproteins in septic conditions.

Disulfiram and Its Copper Chelate Attenuate Cisplatin-Induced Acute Nephrotoxicity in Rats Via Reduction of Oxidative Stress and Inflammation

Abstract: The use of cisplatin (CP) in chemotherapy of resistant cancers is limited due to its dose-dependent nephrotoxicity. Disulfiram (DSF), the aversion therapy for alcoholism, has recently emerged as an anticancer and chemopreventive agent. Its anticancer activity is potentiated in the presence of copper. However, such use of copper leads to several adverse effects. In the present study, the protective effect of DSF and its copper chelate (Cu-DEDC) against CP-induced nephrotoxicity in rats was evaluated. Nephrotoxicity was induced by a single intraperitoneal injection of CP (5 mg/kg). The treatment groups included control (vehicle treated), CP (CP-treated), CP + DSF (CP followed by DSF), CP + DSF + Cu (CP followed by DSF and CuCl2), CP + Cu-DEDC (CP followed by Cu-DEDC), and CP + AMF (amifostine pre-treated and CP-treated). The DSF, Cu-DEDC, and CuCl2 were administered orally at 50 mM/kg/day dose for 5 days post CP injection. AMF served as a standard chemo protectant, administered intravenously 30 min prior to CP. The markers of oxidative stress, inflammation, and kidney function estimated on the 6th day revealed that both DSF and Cu-DEDC significantly attenuated the CP-induced rise in the serum/urine creatinine and blood urea nitrogen (BUN). The CP-induced rise in serum alkaline phosphatase (ALPase) was reversed by these drugs. Both drugs reduced the levels of malondialdehyde and nitric oxide (NO) in kidney tissues. These drugs reversed CP-induced depletion of SOD, catalase, and GSH in the kidneys. There was a significant reduction in the CP-induced TNF-α and IL-1β production along with prevention of histological alterations. Above observations indicate that DSF and Cu-DEDC may have significance as adjuvants to protect against CP-induced nephrotoxicity.

Inhibition of Lipopolysaccharide-Induced Inflammation of Chicken Liver Tissue by Selenomethionine via TLR4-NF-κB-NLRP3 Signaling Pathway

Abstract: Selenium (Se) is important in many physiological processes, such as antioxidant processes and inflammation. The aim of our experiments was to investigate the molecular mechanism that selenomethionine could reduce the lipopolysaccharide (LPS)-induced inflammation by inhibiting the TLR4-NF-κB-NLRP3 signaling pathway. Eighty broilers were randomly and evenly divided into two groups, giving normal Se content diets (Con group, 0.2 mg Se/kg diet) and Se-rich basal diets (Se group, 0.5 mg selenomethionine/kg diet) for 90 days. Se-rich basal diets were based on 0.2 mg/kg sodium selenite contained. Five hours before euthanized, 20 broilers were randomly selected from each group and given lipopolysaccharide (200 μg/kg BW) by intraperitoneal injection, Con+LPS group and Se+LPS group, respectively. The Con group and Se group were given equal saline by intraperitoneal injection. We observed the microscopic pathological changes of liver tissue detected oxidative stress by kit and detected the expression of inflammatory factors, heat shock protein (HSP), and nod-like receptor protein 3 (NLRP3)-related genes by qRT-PCR and Western blot. With the microscope, we found the Con+LPS group had obvious inflammatory lesions such as sinusoidal congestion, but the damage was significantly alleviated in the Se+LPS group. In the Con+LPS group, the activity of GSH-Px and the content of GSH were significantly decreased compared with those in the Con group; however, they are increased in the Se group and in the Se + LPS group. Inflammatory factors (MyD88, NF-κB, TNF-α, IL-1β, IL-6, IL-12, IL-18, iNOS, and COX-2), heat shock proteins (HSP27, HSP60, HSP70, and HSP90), and the expression of NLRP3 and caspase-1 increased in the Con+LPS group compared with those in the Con group, while they were lower in the Se+LPS group than in the Con+LPS group. We concluded that selenomethionine inhibits the LPS-induced inflammation of liver tissue via suppressing the TLR4-NF-κB-NLRP3 signaling pathway.

Lactobacillus rhamnosus GG Attenuates Lipopolysaccharide-Induced Inflammation and Barrier Dysfunction by Regulating MAPK/NF-κB Signaling and Modulating Metabolome in the Piglet Intestine

Abstract: BACKGROUND Probiotic Lactobacillius rhamnosus GG (LGG) shows beneficial immunomodulation on cultured cell lines in vitro and in mouse models. OBJECTIVE The aim was to investigate the effects of LGG on intestinal injury and the underlying mechanisms by elucidating inflammatory signaling pathways and metabolomic response to LPS stimulation in the piglet intestine. METHODS Piglets (Duroc × Landrace × Large White, including males and female; 8.6 ± 1.1 kg) aged 28 d were assigned to 3 groups (n = 6/group): oral inoculation with PBS for 2 wk before intraperitoneal injection of physiological saline [control (CON)] or LPS (25 μg/kg body weight; LPS) or oral inoculation with LGG for 2 wk before intraperitoneal injection of LPS (LGG+LPS). Piglets were killed 4 h after LPS injection. Systemic inflammation, intestinal integrity, inflammation signals, and metabolomic characteristics in the intestine were determined. RESULTS Compared with CON, LPS stimulation significantly decreased ileal zonula occludens 1 (ZO-1; 44%), claudin-3 (44%), and occludin (41%) expression; increased serum diamineoxidase (73%), D-xylose (19%), TNF-α (43%), and IL-6 (55%) concentrations; induced p38 mitogen-activated protein kinase (p38 MAPK; 85%), extracellular signal-regulated kinase (ERK; 96%), and NF-κB p65 phosphorylation (37%) (P < 0.05). Compared with LPS stimulation alone, LGG pretreatment significantly enhanced the intestinal barrier by upregulating expressions of tight junction proteins (ZO-1, 73%; claudin-3, 55%; occludin, 67%), thereby decreasing serum diamineoxidase (26%) and D-xylose (28%) concentrations, and also reduced serum TNF-α expression (16%) and ileal p38 MAPK (79%), ERK (43%) and NF-κB p65 (37%) phosphorylation levels (P < 0.05). Metabolomic analysis showed clear separation between each group. The concentrations of caprylic acid [fold-change (FC) = 2.39], 1-mono-olein (FC = 2.68), erythritol (FC = 4.62), and ethanolamine (FC = 4.47) significantly increased in the intestine of LGG + LPS piglets compared with the LPS group (P < 0.05). CONCLUSIONS These data suggest that LGG alleviates gut inflammation, improves intestinal barrier function, and modulates the metabolite profile of piglets challenged with LPS. This trial was registered at the Zhejiang University (http://www.lac.zju.edu.cn) as ZJU20170529.

Minocycline reduces inflammatory response and cell death in a S100B retina degeneration model

Abstract: Previous studies noted that intravitreal injection of S100B triggered a glaucoma-like degeneration of retina and optic nerve as well as microglia activation after 14 days. The precise role of microglia in our intravitreal S100B model is still unclear. Hence, microglia were inhibited through minocycline. The aim is to investigate whether microglia have a significant influence on the degeneration process or whether they are only a side effect in the model studied here. Minocycline was applied daily in rats by intraperitoneal injection using two different concentrations (13.5 mg/kg body weight, 25 mg/kg body weight). One day after treatment start, S100B or PBS was intravitreally injected in one eye per rat. The naive groups received no injections. This resulted in a total of five groups (naive n = 14, PBS n = 14, S100B n = 13, 13.5 mg/kg mino n = 15, 25 mg/kg mino n = 15). At day 14, electroretinogram measurements were performed, followed by immunofluorescence and label-free quantitative proteomics analysis. The focus of these investigations was on the survival of RGCs as well as their axons, the response of the microglia, and the identification of further pathological modes of action of S100B. The best signal transmission was detected via ERG in the 13.5 mg/kg mino group. The inhibition of the microglia protected optic nerve neurofilaments and decreased the negative impact of S100B on RGCs. However, the minocycline treatment could not trigger complete protection of RGCs. Furthermore, in retina and optic nerve, the minocycline treatment reduced the number and activity of S100B-triggered microglia in a concentration-dependent manner. Proteomics analysis showed that S100B application led to numerous metabolic functions and cellular stress, mainly an increased inflammatory response, glycolysis, and mitochondrial dysfunction, which caused oxidative stress in the retina. Importantly, the protective capability of lower dose of minocycline was unraveled by suppressing the apoptotic, inflammatory, and the altered metabolic processes caused by S100B insult in the retina. Intravitreally injected S100B not only led to a pro-inflammatory microglial reaction, but also a mitochondrial and metabolic dysfunction. Also, these results suggest that an excessive microglial response may be a significant degenerative factor, but not the only trigger for increased cell death.

Intravenously Transplanted Human Multilineage-Differentiating Stress-Enduring Cells Afford Brain Repair in a Mouse Lacunar Stroke Model

Abstract: Background and Purpose- Multilineage-differentiating stress-enduring cells are endogenous nontumorigenic reparative pluripotent-like stem cells found in bone marrow, peripheral blood, and connective tissues. Topically administered human multilineage-differentiating stress-enduring cells into rat/mouse stroke models differentiated into neural cells and promoted clinically relevant functional recovery. However, critical questions on the appropriate timing and dose, and safety of the less invasive intravenous administration of clinical-grade multilineage-differentiating stress-enduring cell-based product CL2020 remain unanswered. Methods- Using an immunodeficient mouse lacunar model, CL2020 was administered via the cervical vein in different doses (high dose=5×104 cells/body; medium dose=1×104 cells/body; low dose=5×103 cells/body) at subacute phase (≈9 days after onset) and chronic phase (≈30 days). Cylinder test, depletion of human cells by diphtheria toxin administration, immunohistochemistry, and human specific-genome detection were performed. Results- Tumorigenesis and adverse effects were not detected for up to 22 weeks. The high-dose group displayed significant functional recovery compared with the vehicle group in cylinder test in subacute-phase-treated and chronic-phase-treated animals after 6 weeks and 8 weeks post-injection, respectively. In the high-dose group of subacute-phase-treated animals, robust and stable recovery in cylinder test persisted up to 22 weeks compared with the vehicle group. In both groups, intraperitoneal injection of diphtheria toxin abrogated the functional recovery. Anti-human mitochondria revealed CL2020 distributed mainly in the peri-infarct area at 1, 10, and 22 weeks and expressed NeuN (neuronal nuclei)- and MAP-2 (microtubule-associated protein-2)-immunoreactivity. Conclusions- Intravenously administered CL2020 was safe, migrated to the peri-infarct area, and afforded functional recovery in experimental stroke.

Investigating the route of administration and efficacy of adipose tissue-derived mesenchymal stem cells and conditioned medium in type 1 diabetic mice

Abstract: Type 1 diabetes (T1D) is a chronic autoimmune disease destroying the insulin-producing beta cells. Recently, stem cell therapy has been tested to treat T1D. In the present study, we aim to investigate the effects of intraperitoneal and intravenous infusion of multipotent mesenchymal stem/stromal cells (MSCs) and MSC-conditioned medium (MSC-CM) in an experimental model of diabetes, induced by multiple injections of Streptozotocin (STZ). The adipose tissue-derived MSC and MSC-CM were isolated from C57Bl/6 male mice and characterized. Later, MSC and MSC-CM were injected intraperitoneally or intravenously into mice. The blood glucose, urinary glucose, and body weight were measured, and the percentages of CD4+ CD25+ FOXP3+ T cells as well as the levels of IFN-γ, TGF-β, IL-4, IL-17, and IL-10 were evaluated. Our results showed that both intraperitoneal and intravenous infusions of MSC and MSC-CM could decrease the blood glucose, recover pancreatic islets, and increase the levels of insulin-producing cells. Furthermore, the percentage of CD4+ CD25+ FOXP3+ T cells was increased after intraperitoneal injection of MSC or MSC-CM and intravenous injection of MSCs. After intraperitoneal injection of the MSC and MSC-CM, the levels of inflammatory cytokines reduced, while the levels of anti-inflammatory cytokines increased. Together current data showed that although both intraperitoneal and intravenous administration had beneficial effects on T1D animal model, but intraperitoneal injection of AD-MSC and AD-MSC-CM was more effective than systemic administration.

Effects of phenanthrene on oxidative stress and inflammation in lung and liver of female rats

Abstract: Phenanthrene (Phe) female rat model was established to explore the effects of Phe on oxidative stress and inflammation. The rats were randomly divided into three groups including control (C), low (L), and high (H) group. Phe was supplied to L and H groups at the dosage of 180 mg/kg and 900 mg/kg orally at first day, and with the dose 90 mg/kg and 450 mg/kg by intraperitoneal injection at the last 2 days. The C group was enriched with the same volume of corn oil. The blood, lung, and liver tissues were collected. The superoxide dismutase (SOD), malonaldehyde (MDA), and 8-hydroxy-2-deoxyguanosine (8-OHdG) were detected to evaluate oxidative stress. The protein and mRNA expressions of interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), and interleukin 10 (IL-10) were detected to evaluate inflammation. Further, the forkhead box transcription factor 3 (Foxp3) was analyzed to hint the injury mechanism of inflammation. The results showed SOD and MDA in lung and liver, and serum 8-OHdG elevated significantly in H groups (P < .05). Meanwhile, there were significant increases in the protein and mRNA expression of TNF-α and IL-6 in lung and liver of H groups (P < .05). In addition, the protein and mRNA expressions of TGF-β and Foxp3 were all decreased significantly in both lung and liver of H groups (P < .05). Results demonstrated that an obvious change of Phe exposure could induce oxidative stress and inflammation in female rats. This is a first pilot study to explore the association between Phe exposure and oxidative stress and inflammation using a female rat model.

Protective Effect of Low Molecular Weight Peptides from Solenocera crassicornis Head against Cyclophosphamide-Induced Nephrotoxicity in Mice via the Keap1/Nrf2 Pathway.

Abstract: The major component of the Solenocera crassicornis head protein hydrolysates-fraction 1 (SCHPs-F1) are low molecular weight peptides (MW < 1 kDa). In this study, we investigated the potential renoprotective effects of SCHPs-F1 in a cyclophosphamide (CTX) toxicity mouse model. In brief, 40 male mice were randomly divided into 5 groups and received either saline or 80 mg/kg body weight (BW) CTX by intraperitoneal injection for 5 days, followed by either saline or SCHPs-F1 (100, 200, and 400 mg/kg BW) by intragastric administration for 15 days. SCHPs-F1 treatment significantly reversed the CTX-induced decreases in the levels of blood urea nitrogen (BUN), creatinine (CRE), and cytochrome P450 (CYP450), as well as the renal histological lesions. Furthermore, the results indicated that SCHPs-F1 potentially alleviated CTX-induced nephrotoxicity through mitigating inflammatory responses, oxidative stress, and apoptosis status of the kidneys, as evidenced by decreased levels of malondialdehyde (MDA), interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ and increased levels of total antioxidant capacity (T-AOC), catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Moreover, overexpression of pro-apoptotic proteins pair B-cell lymphoma-2 (Bcl-2)-associated X (Bax)/Bcl-2, cysteinyl aspartate specific proteinase (caspase)-3 and caspase-9 in renal tissues were suppressed by treatment with SCHPs-F1. In addition, the protein levels of the antioxidant factor nuclear factor erythroid-2 related factor 2 (Nrf2) and the expression levels of its downstream target genes heme-oxygenase (HO-1), glutamate-cysteine ligase modifier subunit (GCLM) and NAD(P)H dehydrogenase (quinone) 1 (NQO-1) were stimulated by treatment with SCHPs-F1 in the CTX-induced renal injury model. Taken together, our data suggested that SCHPs-F1 could provide a novel potential strategy in mitigating the nephrotoxicity caused by CTX.

Synthesis, characterization, and intraperitoneal biochemical studies of zinc oxide nanoparticles in Rattus norvegicus

Abstract: In the present work, zinc oxide nanoparticles (ZnO-NPs) were synthesized in the presence of poly(ethylene glycol) which is a biocompatible agent in living systems. The sub-chronic effects of ZnO-NPs were investigated based on biochemical parameters and histological changes applied to Rattus norvegicus. The structural, morphology, and size characterization of nanoparticles were studied by applying techniques as XRD, SEM, FTIR, and TEM. 8-week intraperitoneal injection of ZnO-NPs at a dose of 100 mg/kg leads to significant changes in liver enzymes, malondialdehyde (MDA) content, and tissue histopathological changes. The animal group which was treated with 50 mg/kg of ZnO-NPs presented elevated blood urea nitrogen and creatinine levels, but the liver enzymes and liver histopathology were found to be in normal level. The rats exposed to increasing dose of ZnO-NPs (100 mg/kg) showed necrosis of germinal epithelium and sertoli cells in the seminiferous tubules. The current study clearly demonstrated the dose-dependent toxicity of zinc oxide nanoparticles.

Establishing a nonlethal and efficient mouse model of male gonadotoxicity by intraperitoneal busulfan injection.

Abstract: An ideal animal model of azoospermia would be a powerful tool for the evaluation of spermatogonial stem cell (SSC) transplantation. Busulfan has been commonly used to develop such a model, but 30%-87% of mice die when administered an intraperitoneal injection of 40 mg kg-1. In the present study, hematoxylin and eosin staining, Western blot, immunofluorescence, and quantitative real-time polymerase chain reaction were used to test the effects of busulfan exposure in a mouse model that received two intraperitoneal injections of busulfan at a 3-h interval at different doses (20, 30, and 40 mg kg-1) on day 36 or a dose of 40 mg kg-1 at different time points (0, 9, 18, 27, 36, and 63 days). The survival rate of the mice was 100%. When the mice were treated with 40 mg kg-1 busulfan, dramatic SSC depletion occurred 18 days later and all of the germ cells were cleared by day 36. In addition, the gene expressions of glial cell line-derived neurotrophic factor (GDNF), fibroblast growth factor 2 (FGF2), chemokine (C-X-C Motif) ligand 12 (CXCL12), and colony-stimulating factor 1 (CSF1) were moderately increased by day 36. A 63-day, long-term observation showed the rare restoration of endogenous germ cells in the testes, suggesting that the potential period for SSC transplantation was between day 36 and day 63. Our results demonstrate that the administration of two intraperitoneal injections of busulfan (40 mg kg-1 in total) at a 3-h interval to mice provided a nonlethal and efficient method for recipient preparation in SSC transplantation and could improve treatments for infertility and the understanding of chemotherapy-induced gonadotoxicity.

Potential Therapeutic Effects of Endothelial Cells Trans-Differentiated From Wharton's Jelly-derived Mesenchymal Stem Cells on Altered Vascular Functions in Aged Diabetic Rat Model

Abstract: Diabetes mellitus in elderly represents an exceptional subset in the population vulnerable to cardiovascular events. As aging, diabetes mellitus and hypertension share common pathways, an ideal treatment should possess the ability to counter more than one of, if not all, the underlying mechanisms. Stem cells emerged as a potential approach for complicated medical problems. We tested here the possible role of trans-differentiated endothelial cells (ECs) in the treatment of diabetes mellitus in old rats. Mesenchymal stem cells where isolated from umbilical cord Wharton’s Jelly and induced to differentiate into endothelial like-cells using vascular endothelial growth factor-enriched media. Thirty aged male Wistar albino rats were used in the present study. Rats were divided (10/group) into: control group (18–20 months old, weighing 350–400 g, received single intraperitoneal injection as well as single intravenous injection via tail vein of the vehicles), aged diabetic group (18–20 months old, weighing 350–400 g, received single intraperitoneal injection of 50 mg/kg streptozotocin, and also received single intravenous injection of saline via tail vein), and aged diabetic + ECs group (18–20 months old, weighing 350–400 g, received single intraperitoneal injection of 50 mg/kg streptozotocin, and also received single intravenous injection of 2*106 MSC-derived ECs in 0.5 ml saline via tail vein) groups. Assessment of SBP, aortic PWV, and renal artery resistance was performed. Serum levels of ET1, ANG II, IL-6, TNF-α, MDA, ROS, and VEGF were evaluated, as well as the aortic NO tissue level and eNOS gene expression. Histopathological and immunostaining assessments of small and large vessels were also performed. Induction of diabetes in old rats resulted in significant increase in SBP, aortic PWV, renal artery resistance, and serum levels of ET1, ANG II, IL-6, TNF-α, MDA, ROS, and VEGF. While there was significant decrease in aortic NO tissue level and eNOS gene expression in the aged diabetic group when compared to aged control group. ECs treatment resulted in significant improvement of endothelial dysfunction, inflammation and oxidative stress. We report here the potential therapeutic role of trans-differentiated ECs in aged diabetics. ECs demonstrated anti-inflammatory, antioxidant, gene modifying properties, significantly countered endothelial dysfunction, and improved vascular insult.

Treatment with the Ketone Body D-β-hydroxybutyrate Attenuates Autophagy Activated by NMDA and Reduces Excitotoxic Neuronal Damage in the Rat Striatum In Vivo.

Abstract: BACKGROUND The ketone bodies (KB), β-hydroxybutyrate (BHB) and acetoacetate, have been proposed for the treatment of acute and chronic neurological disorders, however, the molecular mechanisms involved in KB protection are not well understood. KB can substitute for glucose and support mitochondrial metabolism increasing cell survival. We have reported that the D-isomer of BHB (D-BHB) stimulates autophagic degradation during glucose deprivation in cultured neurons increasing cell viability. Autophagy is a lysosomal degradation process of damaged proteins and organelles activated during nutrient deprivation to obtain building blocks and energy. However, impaired or excessive autophagy can contribute to neuronal death. OBJECTIVE The aim of the present study was to test whether D-BHB can preserve autophagic function in an in vivo model of excitotoxic damage induced by the administration of the glutamate receptor agonist, N-methyl-Daspartate (NMDA), in the rat striatum. METHODS D-BHB was administered through an intravenous injection followed by either an intraperitoneal injection (i.v+i.p) or a continuous epidural infusion (i.v+pump), or through a continuous infusion of D-BHB alone. Changes in the autophagy proteins ATG7, ATG5, BECLIN 1 (BECN1), LC3, Sequestrosome1/p62 (SQSTM1/ p62) and the lysosomal membrane protein LAMP2, were evaluated by immunoblot. The lesion volume was measured in cresyl violet-stained brain sections. RESULTS Autophagy is activated early after NMDA injection but autophagic degradation is impaired due to the cleavage of LAMP2. Twenty-four h after NMDA intrastriatal injection, the autophagic flux is re-established, but LAMP2 cleavage is still observed. The administration of D-BHB through the i.v+pump protocol reduced the content of autophagic proteins and the cleavage of LAMP2, suggesting decreased autophagosome formation and lysosomal membrane preservation, improving autophagic degradation. D-BHB also reduced brain injury. The i.v+i.p administration protocol and the infusion of D-BHB alone showed no effect on autophagy activation or degradation.

Cyanidin-3-O-Glucoside-Rich Haskap Berry Administration Suppresses Carcinogen-Induced Lung Tumorigenesis in A/JCr Mice.

Abstract: In our previous study, we demonstrated that cyanidin-3-O-glucoside (C3G)-rich haskap (Lonicera caerulea L.) berry extracts can attenuate the carcinogen-induced DNA damage in normal lung epithelial cells in vitro. Here, the efficacy of lyophilized powder of whole haskap berry (C3G-HB) in lowering tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, (NNK)-induced lung tumorigenesis in A/JCr mice was investigated. Three weeks after daily oral administration of C3G-HB (6 mg of C3G in 0.2 g of C3G-HB/mouse/day), lung tumors were initiated by a single intraperitoneal injection of NNK. Dietary C3G-HB supplementation was continued, and 22 weeks later, mice were euthanized. Lung tumors were visualized through positron emission tomography (PET) and magnetic resonance imaging (MRI) 19 weeks after NNK injection. Dietary supplementation of C3G-HB significantly reduced the NNK-induced lung tumor multiplicity and tumor area but did not affect tumor incidence. Immunohistochemical analysis showed reduced expression of proliferative cell nuclear antigen (PCNA) and Ki-67 in lung tissues. Therefore, C3G-HB has the potential to reduce the lung tumorigenesis, and to be used as a source for developing dietary supplements or nutraceuticals for reducing the risk of lung cancer among high-risk populations.

Alpha-Mangostin Improves Cardiac Hypertrophy and Fibrosis and Associated Biochemical Parameters in High-Fat/High-Glucose Diet and Low-Dose Streptozotocin Injection-Induced Type 2 Diabetic Rats.

Abstract: Purpose The aim of present study was to analyze the effect of alpha-mangostin on cardiac hypertrophy and fibrosis and biochemical parameters in high-fat/high-glucose diet and low-dose streptozotocin injection (HF/HG/STZ)-induced type 2 diabetic rats. Methods Diabetes was induced in male Wistar rats by giving a combination of high-fat/high-glucose (HF/HG) diet for 3 weeks and followed by low-dose streptozotocin intraperitoneal injection (STZ; 35 mg/kg) at Week-3 and the HF/HG diet was continued until 8 weeks. The diabetic rats were then divided into four groups (each, n=6): untreated diabetic group (HF/HG/STZ); diabetic group treated with metformin 200 mg/kg/day (HF/HG/STZ+Metformin); diabetic group treated with alpha-mangostin 100 mg/kg/day (HF/HG/STZ+AM100); and diabetic group treated with alpha-mangostin 200 mg/kg/day (HF/HG/STZ+AM200) and all were given by oral gavage for 8 weeks. We also included a control group (C) treated with AM200 (C+AM200). The role of alpha-mangostin was assessed through its effect on blood glucose levels, HOMA-IR, blood pressure, body weight, pro-inflammatory cytokines in cardiac tissue, serum aminotransferases (ALT and AST), lipid profiles (cholesterol and triglyceride), blood urea nitrogen (BUN), uric acid, cardiac hypertrophy and fibrosis. Results Diabetic rats treated with alpha-mangostin in both doses for 8 weeks showed decrease in blood glucose levels, HOMA-IR, and blood pressure. Alpha-mangostin treatment also prevented HF/HG/STZ-induced changes in the activities of ALT, AST, BUN, uric acid, lipid profiles, and pro-inflammatory cytokines, which were comparable with the standard drug metformin, while alpha-mangostin did not show any significant effects on control rats (p>0.05). The cardiac hypertrophy and fibrosis were also attenuated in diabetic rats treated with alpha-mangostin in both doses. Conclusion These data suggest that administration of alpha-mangostin can effectively attenuate diabetes-induced alteration in cardiac hypertrophy and fibrosis as well as biochemical parameters in HF/HG/STZ rats.

Effect of Hypoxia Preconditioned Adipose-Derived Mesenchymal Stem Cell Conditioned Medium on Cerulein-Induced Acute Pancreatitis in Mice

Abstract: Purpose: Acute pancreatitis (AP) is an inflammatory disorder distinguished by tissue injury and inflammation of the pancreas. Using paracrine potential of mesenchymal stem cells (MSCs) provides a useful clinical approach in treating inflammatory diseases. We investigated the therapeutic effects of adipose-derived MSC conditioned medium (CM) and hypoxia preconditioned adipose-derived MSC conditioned medium (HCM) in cerulein-induced AP in mice. Methods: AP was induced in C57BL/6 mice by intraperitoneal injection of cerulein (75 μg/ kg/h × 7 times). One hour following the last injection of cerulein, mice were treated with intraperitoneal injection of CM and HCM (500 µL/mice/30 min × 3 times). Twelve hours following the treatment, serum levels of amylase and lipase were measured. In addition, pancreas pathological changes, immunohistochemical examinations for evaluation of IL-6 expression and pancreatic myeloperoxidase (MPO) enzyme activity were analyzed. Results: The in vitro results of the morphological, differentiation and immunophenotyping analyses confirmed that hypoxia preconditioned MSCs (HP-MSCs) conserve MSCs characteristics after preconditioning. However, HP-MSCs significantly expressed high mRNA level of hypoxia inducible factor 1-α and higher level of total protein. The in vivo findings of the current study showed that CM and HCM significantly reduced the amylase & lipase activity, the severity of pancreas tissue injury and the expression of IL-6 and MPO enzyme activity compared with the AP group. However, no significant difference between CM and HCM groups was demonstrated. Conclusion: Use of CM and HCM can attenuate cerulein-induced AP and decrease inflammation in the pancreas tissue in AP mice.

Streptozotocin (STZ)-Induced Diabetes Affects Tissue Trace Element Content in Rats in a Dose-Dependent Manner.

Abstract: The objective of the present study was investigation of tissue trace element distribution in a streptozotocin model of DM1 in rats. DM1 was modeled in 2-month-old male Wistar rats (n = 30) using intraperitoneal injection of 45 mg/kg b.w. (STZ1) and 55 mg/kg b.w. streptozotocin (STZ2), whereas control animals were injected with physiological saline. The rats were subjected to oral glucose tolerance test (OGTT) and HbA1c level assessment at day 14. At day 30, blood serum, liver, kidney, and heart samples were collected for tissue trace element assessment using inductively coupled plasma mass spectrometry (ICP-MS). STZ-treated rats were characterized by lack of significant weight gain and elevated HbA1c and blood glucose levels. ICP-MS analysis demonstrated a dose-dependent accumulation of Cu, Mn, Mo, and Se levels in the liver. Correspondingly, the dose-dependent increase in renal Cu, Mn, V, and Zn levels was significant, whereas the observed trend for kidney V and Mo accumulation was nearly significant. The patterns of trace element content in the myocardium of STZ-exposed rats were quite different from those observed for liver and kidney. Only cardiac Zn content was characterized by a significant decrease. Serum Co, Cr, Cu, Se, V, and Mo levels were characterized by a significant decrease in response to STZ-induced diabetes. Generally, the obtained data demonstrate that diabetes is associated with altered copper, manganese, molybdenum, chromium, and vanadium handling. In turn, only altered Zn status may provide a link to diabetic cardiotoxicity. However, the particular mechanisms of both impaired metal handling in STZ diabetes and their potential anti-diabetic activity require further investigation.

Pre-treatment with the viral Toll-like receptor 3 agonist poly(I:C) modulates innate immunity and protects neutropenic mice infected intracerebrally with Escherichia coli

Abstract: Individuals with impaired immunity are more susceptible to infections than immunocompetent subjects. No vaccines are currently available to induce protection against E. coli meningoencephalitis. This study evaluated the potential of poly(I:C) pre-treatment to induce trained immunity. Poly(I:C) was administered as a non-specific stimulus of innate immune responses to protect immunocompetent and neutropenic wild-type mice from a subsequent challenge by the intracranial injection of E. coli K1. Three days prior to infection, mice received an intraperitoneal injection of poly(I:C) or vehicle. Kaplan-Meier survival curves were analyzed. In short-term experiments, bacterial titers and the inflammatory response were characterized in the blood, cerebellum, and spleen homogenates. NK cell subpopulations in the brain and spleen were analyzed by flow cytometry. Numbers of microglia and activation scores were evaluated by histopathology. Pre-treatment with 200 μg poly(I:C) increased survival time, reduced mortality, and enhanced bacterial clearance in the blood, cerebellum, and spleen at early infection in neutropenic mice. Poly(I:C)-mediated protection correlated with an augmented number of NK cells (CD45+NK1.1+CD3−) and Iba-1+ microglial cells and a higher production of IFN-γ in the brain. In the spleen, levels of CCL5/RANTES and IFN-γ were increased and sustained in surviving poly(I:C)-treated animals for 14 days after infection. In immunocompetent animals, survival time was not significantly prolonged in poly(I:C)-treated animals although poly(I:C) priming reduced brain bacterial concentrations compared with vehicle-injected animals at early infection. Pre-treatment with the viral TLR3 agonist poly(I:C) modulated innate immune responses and strengthened the resistance of neutropenic mice against E. coli K1 meningoencephalitis.

Liraglutide combined with human umbilical cord mesenchymal stem cell transplantation inhibits beta-cell apoptosis via mediating the ASK1/JNK/BAX pathway in rats with type 2 diabetes.

Abstract: Objective Accumulating evidence suggests an association between beta-cell apoptosis and the ASK1/JNK/BAX pathway. The aim of this study was to investigate the effects of a combined therapy of liraglutide and human umbilical cord mesenchymal stem cells (hUC-MSCs) on the glucose metabolism and islet beta-cell apoptosis, and further explore its relationship to the ASK1/JNK/BAX pathway. Method Type 2 diabetes mellitus (T2DM) rat model was induced by a high-sugar and high-fat diet and intraperitoneal injection of low-dose streptozotocin (STZ) (30 mg/kg). Three days after STZ injection, diabetic rats were randomly treated with subcutaneous injection of liraglutide (200 μg/kg/12 h) for 8 weeks and or hUC-MSCs (1 × 106 /rat) at the first and fifth weeks. Diabetes-related physical and biochemical parameters, pancreatic histopathological changes, immunohistochemical staining, quantitative real-time polymerase chain reaction, and western blot were used to measure the expression of apoptosis signal-regulating kinase 1 (ASK1), Jun N-terminal kinase (JNK), Bcl-2 associated X protein (BAX), and B-cell lymphoma-2 (Bcl-2). Results Eight weeks after liraglutide or human umbilical cord mesenchymal stem cell administration, FPG, HbA1c , glucagon, body weight, and pancreatic ASK1, JNK, and BAX mRNA and proteins were significantly decreased, and the levels of serum C-p, INS and GLP-1, ratio of insulin positive area, and Bcl-2 expression were significantly increased in three treatment groups compared with T2DM group (P Conclusion Liraglutide combined with hUC-MSCs improve glucose metabolism and inhibit islet beta-cell apoptosis in a ASK1/JNK/BAX pathway-dependent manner.

Assessment of the effect of sodium hydrogen sulfide (hydrogen sulfide donor) on cisplatin-induced testicular toxicity in rats

Abstract: Cisplatin (CIS) is an antineoplastic drug able to produce free radicals that are capable to induce various side effects in different tissues. Hydrogen sulfide (H2S) has notable antioxidant, anti-apoptotic, and anti-inflammatory effects in different systems but its role in male reproductive system is not fully understood. In the present research, the effect of sodium hydrosulfide (NaHS) on cisplatin-induced testicular toxicity in male rats was studied. Thirty-two Sprague–Dawley rats were equally divided into 4 groups. The control group was treated with normal saline by intraperitoneal injection. The NaHS group received NaHS (200 μg/kg/day) intraperitoneally for 15 days. The CIS group received single dose of cisplatin (5 mg/kg) intraperitoneally, while the combination of CIS and NaHS was given to the CIS+ NaHS group. At the end of the study, body and testicular weights, plasma testosterone level, histological and morphometrical alterations, inflammation via IL-1β protein, lipid peroxidation, and activity of antioxidant enzymes (including glutathione peroxidase, superoxide dismutase, and catalase) of testicular tissue were evaluated. CIS injection revealed a significant decrease (p < 0.01) in body and testis weights, plasma testosterone concentration, diameter of seminiferous tubules, germinal epithelium thickness, the number of Sertoli cells, spermatogonia and spermatocyte, Johnsen’s testicular score, and testicular antioxidant enzymes, whereas it caused a significant increase (p < 0.01) in lumen diameter of the seminiferous tubules, level of lipid peroxidation, and IL-1β protein expression when compared with the control group. NaHS administration to CIS-treated rats provided marked improvement (p < 0.05) in all biochemical, histological, and morphometrical changes induced by CIS. The beneficial effects of NaHS were mediated, at least partly, by its antioxidant and anti-inflammatory properties.

Protective Effect of Polydeoxyribonucleotide Against CCl4-Induced Acute Liver Injury in Mice.

Abstract: Purpose Polydeoxyribonucleotide (PDRN) is a substance known to suppress inflammation and accelerate wound healing. In this experiment, the effect of PDRN treatment on carbon tetrachloride (CCl4)-evoked acute liver injury (ALI) was investigated using mice. Methods We analyzed the levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and conducted hematoxylin and eosin staining in accompany with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling staining. Western blot analysis was also conducted to assess the expressions of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, adenosine A2A receptor, Bcl-2-associated X protein (Bax), and B-cell lymphoma 2 (Bcl-2). The mice were received intraperitoneal injection of 10-mL/kg CCl4, 4 times, once every 2 days. The mice in the PDRN treatment groups received intraperitoneal injection of 200-μL distilled water comprising each concentration of PDRN for 7 days starting 1 day after first CCl4 injection. Results ALT and AST concentrations in the serum were reduced and TNF-α, IL-1β, and IL-6 expressions were decreased by PDRN injection in CCl4-evoked ALI mice. PDRN injection suppressed Bax versus Bcl-2 ratio and reduced the percentage of TUNE-positive cells in CCl4-evoked ALI mice. PDRN injection overexpressed adenosine A2A receptor in CCl4-evoked ALI mice. Conclusion The therapeutic efficacy of PDRN also can be expected for CCl4-evoked acute urogenital injury in addition to ALI. The current research suggests that PDRN may be used for the therapeutic agent of CCl4-evoked ALI.

A Treg-Selective IL-2 Mutein Prevents the Formation of Factor VIII Inhibitors in Hemophilia Mice Treated With Factor VIII Gene Therapy.

Abstract: Hemophilia A is a genetic disorder that results in the deficiency of functional factor VIII protein, which plays a key role in blood coagulation. Currently, the majority of hemophilia A patients are treated with repeated infusions of factor VIII protein. Approximately 30% of severe hemophilia A patients develop neutralizing antibodies to factor VIII (known as factor VIII inhibitors) due to treatment, rendering factor VIII protein infusions ineffective. Previously, mice receiving murine IL-2 complexed with α-murine IL-2 mAbs (JES6-1A12) showed a lack of factor VIII inhibitor formation after factor VIII treatment, which was associated with the proliferation and the activation of factor VIII-specific regulatory T cells (Tregs). In this paper, we evaluated if an Fc-fused mutated protein analog of mouse IL-2, named Fc.Mut24, engineered to selectively promote the expansion of Tregs in vivo can modulate factor VIII-specific immune responses. The mice received one intraperitoneal injection of Fc.Mut24. When the regulatory T cell population reached its highest frequency and peak activation, the mice received a hydrodynamic injection of factor VIII plasmid (day 4) followed by a second Fc.Mut24 dose (day 7). Peripheral blood was collected weekly. Flow cytometry was used to characterize the peripheral blood cell populations, while ELISA and Bethesda assays were used to assess the inhibitor concentrations and the functional titers in plasma. The activated partial thromboplastin time assay was used to assess the functional activities of factor VIII in blood. The mice receiving Fc.Mut24 showed a dramatic and transient increase in the population of activated Tregs after Fc.Mut24 injection. Factor VIII gene therapy via hydrodynamic injection resulted in high anti-factor VIII inhibitor concentrations in control PBS-injected mice, whereas the mice treated with Fc.Mut24 produced no inhibitors. Most significantly, there were no inhibitors generated after a second hydrodynamic injection of factor VIII plasmid administered at 19 weeks after the first injection in Fc.Mut24-treated mice. The mice receiving Fc.Mut24 maintained high levels of factor VIII activity throughout the experiment, while the control mice had the factor VIII activity dropped to undetectable levels a few weeks after the first factor VIII plasmid injection. Our data show that human therapies analogous to Fc.Mut24 could potentially provide a method to prevent inhibitor formation and induce long-term immune tolerance to factor VIII in hemophilia patients.

Vinpocetine reduces cisplatin-induced acute kidney injury through inhibition of NF-κB pathway and activation of Nrf2/ARE pathway in rats

Abstract: Acute kidney injury is a complex clinical disease that is associated with a high incidence of morbidity and mortality. Drug-induced acute kidney injury occurs in approximately 19–33% of hospitalized patients. Cisplatin, one of the most commonly used and effective chemotherapeutic drugs not only exerts anti-tumor effects but also causes renal toxicity damage, affecting its clinical application. Vinpocetine is an anti-inflammatory and antioxidant drug that predominately acts in the nervous system. In this study, we investigated the effects and mechanisms of vinpocetine in an animal model of cisplatin-induced acute renal injury. Rats were randomly divided into three experimental groups. During a 10-day trial, rats in the control group were administered a physiological saline solution; rats in the model group received a 5 mg/kg intraperitoneal injection of cisplatin; and rats in the cisplatin + vinpocetine group received a 5 mg/kg intraperitoneal injection of cisplatin as well as a 5 mg/kg dose of vinpocetine via gavage. We observed that following cisplatin administration, the rats exhibited an increase in blood urea and creatinine levels as well as an increase in their inflammation and oxidative stress levels. In renal tissue, cisplatin caused the morphological changes typical of acute tubular injury. Vinpocetine reduced the cisplatin-induced acute renal function damage and tubular injury. In both in vivo and in vitro experiments, we found that vinpocetine can confer protection of rat renal cells by inhibiting the NF–κB signaling pathway and activating the Nrf2/ARE signaling pathway. Therefore, vinpocetine is a promising therapeutic drug for the treatment of cisplatin-induced acute kidney injury.

Therapeutic Effects of Hyaluronic Acid in Peritonitis-Induced Sepsis in Mice.

Abstract: Intra-abdominal infection is the second most common cause of sepsis, and the mortality rate from abdominal sepsis remains high. High molecular weight (HMW) hyaluronic acid (HA) has been studied in sterile injury models as an anti-inflammatory and anti-permeability agent. This study evaluated the therapeutic effects of intraperitoneal HMW HA administration in mice with peritonitis-induced sepsis. Sepsis was induced in C57BL/6 mice by cecal ligation and puncture (CLP), followed 4 h later by an intraperitoneal injection of HMW HA (20 mg/kg) solution or phosphate buffered saline (PBS). Survival, physiological data, organ injury, bacterial burden, and inflammatory cytokine levels were assessed in the CLP mice. To assess the effect of HA on macrophage phagocytosis activity, RAW264.7 cells, primed with lipopolysaccharide, were exposed with either PBS or HMW HA (500 μg/mL) prior to exposure to 10 CFU of E coli bacteria. HMW HA instillation significantly improved blood oxygenation, lung histology, and survival in CLP mice. Inflammatory cytokine levels in the plasma and bacterial burdens in the lung and spleen were significantly decreased by HA administration at 24 h after CLP. At 6 h after CLP, HA significantly decreased bacterial burden in the peritoneal lavage fluid. HMW HA administration significantly increased E coli bacterial phagocytosis by RAW264.7 cells in part through increased phosphorylation of ezrin/radixin/moesin, a known downstream target of CD44 (a HA receptor); ezrin inhibition abolished the enhanced phagocytosis by RAW264.7 cells induced by HA. Intraperitoneal administration of HMW HA had therapeutic effects against CLP-induced sepsis in terms of suppressing inflammation and increasing antimicrobial activity.

Mono-PEGylation of a Thermostable Arginine-Depleting Enzyme for the Treatment of Lung Cancer.

Abstract: L-arginine (L-Arg) depletion induced by randomly PEGylated arginine deiminase (ADI-PEG20) can treat arginosuccinate synthase (ASS)-negative cancers, and ADI-PEG20 is undergoing phase III clinical trials. Unfortunately, ASS-positive cancers are resistant to ADI-PEG20. Moreover, the yield of ADI production is low because of the formation of inclusion bodies. Here, we report a thermostable arginine-depleting enzyme, Bacillus caldovelox arginase mutant (BCA-M: Ser161->Cys161). An abundant amount of BCA-M was easily obtained via high cell-density fermentation and heat treatment purification. Subsequently, we prepared BCA-M-PEG20, by conjugating a single 20 kDa PEG monomer onto the Cys161 residue via thio-chemistry. Unlike ADI-PEG20, BCA-M-PEG20 significantly inhibited ASS-positive lung cancer cell growth. Pharmacodynamic studies showed that a single intraperitoneal injection (i.p). administration of 250 U/mouse of BCA-M-PEG20 induced low L-Arg level over 168 h. The mono-PEGylation of BCA-M prolonged its elimination half-life from 6.4 to 91.4 h (a 14-fold increase). In an A549 lung cancer xenograft model, a weekly administration of 250 U/mouse of BCA-M-PEG20 suppressed tumor growth significantly. We also observed that BCA-M-PEG20 did not cause any significant safety issue in mouse models. Overall, BCA-M-PEG20 showed excellent results in drug production, potency, and stability. Thereby, it has great potential to become a promising candidate for lung cancer therapy.

Intraperitoneal oil application causes local inflammation with depletion of resident peritoneal macrophages

Abstract: Oil is frequently used as a solvent to inject lipophilic substances into the peritoneum of laboratory animals. Although mineral oil causes chronic peritoneal inflammation, little is known whether other oils are better suited. Here we show that olive, peanut, corn or mineral oil causes xanthogranulomatous inflammation with depletion of resident peritoneal macrophages. However, there were striking differences in the severity of the inflammatory response. Peanut and mineral oil caused severe chronic inflammation with persistent neutrophil and monocyte recruitment, expansion of the vasculature and fibrosis. Corn and olive oil provoked no or only mild signs of chronic inflammation. Mechanistically, the vegetal oils were taken up by macrophages leading to foam cell formation and induction of cell death. Olive oil triggered caspase-3 cleavage and apoptosis, which facilitates the resolution of inflammation. Peanut oil and, to a lesser degree, corn oil triggered caspase-1 activation and macrophage pyroptosis, which impairs the resolution of inflammation. As such, intraperitoneal oil administration can interfere with the outcome of subsequent experiments. As a proof-of-principle, intraperitoneal peanut oil injection was compared to its oral delivery in a thioglycolate-induced peritonitis model. The chronic peritoneal inflammation due to peanut oil injection impeded the proper recruitment of macrophages and the resolution of inflammation in this peritonitis model. In summary, the data indicate that it is advisable to deliver lipophilic substances like tamoxifen by oral gavage instead of intraperitoneal injection.