Induction Of Inflammation Research Articles

Reduced oxycodone brain delivery in rats due to lipopolysaccharide-induced inflammation: microdialysis insights into brain disposition and sex-specific pharmacokinetics

BackgroundOxycodone, a widely used opioid analgesic, has an unbound brain-to-plasma concentration ratio (Kp,uu) greater than unity, indicating active uptake across brain barriers associated with the putative proton-coupled organic cation (H+/OC) antiporter system. With this study, we aimed to elucidate oxycodone's CNS disposition during lipopolysaccharide (LPS)-induced systemic inflammation in Sprague–Dawley rats.MethodsUsing brain microdialysis, we dynamically and simultaneously monitored unbound oxycodone concentrations in blood, striatum, lateral ventricle, and cisterna magna following intravenous administration of oxycodone post-LPS challenge.ResultsOur results indicated a reduced, sex-independent brain net uptake of oxycodone across the blood–brain barrier (BBB) measured in the striatum. Notably, the LPS challenge has significantly altered the systemic pharmacokinetics (PK) of oxycodone, in a sex-specific manner, leading to lower clearance and higher blood concentrations in females compared to LPS-treated males and healthy rats of both sexes. Proteomic analysis using Olink Target 96 Mouse Exploratory assay confirmed the induction of systemic inflammation and neuroinflammation. The inflammation led to an increased paracellular transport, measured using 4 kDa dextran, while preserving net active uptake of oxycodone across both BBB and the blood-cerebrospinal fluid barrier (BCSFB), with Kp,uu values of 2.7 and 2.5, respectively. The extent of uptake was 1.6-fold lower (p < 0.0001) at the BBB and unchanged at the BCSFB after the LPS challenge compared to that in healthy rats. However, the mean exposure of unbound oxycodone in the brain following LPS was similar to that in healthy rats, primarily due to the LPS-induced changes in systemic exposure.ConclusionsThese findings highlight the dissimilar responses at blood–brain interfaces during LPS-induced inflammation. Advancing the knowledge of neuropharmacokinetic mechanisms, specifically those involving the H+/OC antiporter system, will enable the development of more effective therapeutic strategies during inflammation conditions.Graphical

Cxcl10 is protective during mouse-adapted SARS-CoV-2 infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of the coronavirus disease 2019 (COVID-19) pandemic, remains endemic worldwide. Circulating levels of the chemokine CXCL10 are strongly positively associated with poor outcome; however, its precise role in SARS-CoV-2 pathogenesis and its suitability as a therapeutic target have remained undefined. Here, we challenged mice genetically deficient in Cxcl10 with a mouse-adapted strain of SARS-CoV-2. Infected male, but not female, Cxcl10-/- mice displayed increased mortality compared to wild type controls. Histopathological damage, inflammatory gene induction and virus load in the lungs of male mice were not broadly influenced by Cxcl10 deficiency. However, accumulation of B and T lymphocytes in the lung parenchyma of infected mice was reduced in the absence of Cxcl10. Thus, during acute SARS-CoV-2 infection, Cxcl10 regulates lymphocyte infiltration in lung and confers protection against mortality. Our preclinical model results do not support targeting CXCL10 therapeutically in severe COVID-19.

Molecular and cellular markers in chickens exposed to stressors and the ability of feed supplements to overcome negative effects – a review

Abstract Performance of chickens is negatively impacted by stressors such as heat stress, infection with Campylobacter jejuni, the mycotoxins – aflatoxin B1 and deoxynivalenol, the glucocorticoid dexethasone, insecticides and Eimeria tenella. Effects of stressors include reduced gastrointestinal function and induction of inflammation. Stressors influence the following molecular and cellular structures and functions: gastro-intestinal integrity, villus height, crypt depth, mast cell number, expression of pro-inflammatory cytokines, concentrations of leukocytes, and antioxidant status. In multiple studies, adverse effects of multiple stressors were overcome partly by supplementation. The utility of these parameters is discussed of these are considered and recommendations/guidelines for future research made.

Childhood-onset lupus nephritis is characterized by complex interactions between kidney stroma and infiltrating immune cells.

Children with systemic lupus erythematosus (SLE) are at increased risk of developing kidney disease, termed childhood-onset lupus nephritis (cLN). Single-cell transcriptomics of dissociated kidney tissue has advanced our understanding of LN pathogenesis, but loss of spatial resolution prevents interrogation of in situ cellular interactions. Using a technical advance in spatial transcriptomics, we generated a spatially resolved, single-cell resolution atlas of kidney tissue from eight patients with cLN and four control individuals. Annotated cells were assigned to 30 reference cell types, including major kidney subsets and infiltrating immune cells. Analysis of spatial distribution demonstrated that individual immune lineages localized to specific regions in cLN kidneys, including myeloid cells that trafficked to inflamed glomeruli and B cells that clustered within tubulointerstitial immune hotspots. Gene expression varied as a function of tissue location, demonstrating how incorporation of spatial data can provide new insights into the immunopathogenesis of SLE. Alterations in immune phenotypes were accompanied by parallel changes in gene expression by resident kidney stromal cells. However, there was little correlation between histologic scoring of cLN disease activity and glomerular cell transcriptional signatures at the level of individual glomeruli. Last, we identified modules of spatially correlated gene expression with predicted roles in induction of inflammation and the development of tubulointerstitial fibrosis. Single-cell spatial transcriptomics allowed insights into the molecular heterogeneity of cLN, paving the way toward more targeted and personalized treatment approaches.

Fungal Influences on Cancer Initiation, Progression, and Response to Treatment.

Fungal dysbiosis is increasingly recognized as a key factor in cancer, influencing tumor initiation, progression, and treatment outcomes. This review explores the role of fungi in carcinogenesis, with a focus on mechanisms such as immunomodulation, inflammation induction, tumor microenvironment remodeling, and interkingdom interactions. Fungal metabolites are involved in oncogenesis, and antifungals can interact with anticancer drug, including eliciting potential adverse effects and influencing immune responses. Furthermore, mycobiota profiles have potential as diagnostic and prognostic biomarkers, emphasizing their clinical relevance. The interplay between fungi and cancer therapies can impact drug resistance, therapeutic efficacy, and risk of invasive fungal infections associated with targeted therapies. Finally, emerging strategies for modulating mycobiota in cancer care are promising approaches to improve patient outcomes.

Complement component 3 promotes regeneration of olfactory receptor neurons

Olfactory receptor neurons (ORNs) in the olfactory epithelium are characterized by high regenerative capacity even after birth, but the molecular mechanisms involved in ORN regeneration remain unclear. Complement component 3 (C3) has been shown to promote tissue regeneration, so we hypothesized that C3 activates innate immunity and also promotes regeneration of ORNs. Here, we investigate the role of C3 in ORN regeneration. We used C3 knockout (KO) and wild-type C57BL/6J mice in this study to examine the olfactory regeneration process for 42 days after methimazole-induced olfactory disorder. To compare the regenerative process after ORN damage between C3 KO and wild-type mice, we conducted olfactory behavioral tests and immunohistological analysis and examined growth factors and inflammatory cell induction. C3 KO mice showed delayed olfactory recovery with lower olfactory epithelial thickness. In C3 KO mice, ORN maturation was delayed in association with increased accumulation of immature ORNs. In the normal ORN regeneration process, undesirable immature ORNs are produced and eliminated by apoptosis. C3 deficiency reduced neutrophils induced during ORN regeneration, suggesting the involvement of C3 in ORN regeneration through neutrophil-dependent elimination of undesired ORNs. C3 is therefore suggested to have promoted ORN regeneration by preventing the accumulation of immature ORNs. In addition, C3 may assist ORN maturation by participating in ORN axon selection like synaptic pruning. Our results indicate that C3, which is activated during pathogen infection, also promotes recovery from ORN damage. These findings may lead to new therapeutic strategies for olfactory disorder.

Anti- Inflammatory Activities Of The Methanol Leaf Extract And Fractions Of Elaesis Guineensis In In-Vivo Animals

Abstract Objective Objective of this paper is to investigate the preliminary anti-inflammatory property of the leaves and its fractions of Elaesis guineensis using egg induced albumin and formaldehyde induced arthritis models in rats. Method Egg albumin induced inflammation was induced by sub-plantar injection of 0.1 ml of fresh undiluted egg albumin. The volume of distilled water displaced by the treated paw was measured at 0.5,1, 2, 3, 4, 5, and 6 hours after induction of inflammation. Formaldehyde-induced arthritis was induced after 30 min by sub-plantar injection of 0.1 ml of 2.5% formaldehyde solution and was repeated on day 3. Arthritis was assessed by measuring the volume of distilled water displaced by the paw before induction of arthritis and once every day for ten days, starting from day one, after induction of arthritis. Results The acute toxicity test revealed that the plant extract was safe even at 5000 mg/kg dose level. The methanol extract (ME) showed a dose-dependent inhibition of egg albumin-induced acute inflammation that peaked at the dose of 200 mg/kg, while the fractions of the extract showed that the hexane and ethyl acetate fractions had the highest activity during the experiment. Similarly, the crude extract of the formaldehyde induced arthritis showed a dose-dependent inhibition making the 200 mg/kg the most active dose level. Additionally, it was observed that among the fractions of the extract the hexane fraction (HF) showed the most significant inhibitory activity when compared to other fractions Conclusion this study establishes that the methanol leaf extract and fractions ofElaesis guineensis possess significant anti-inflammatory activity

Phenolic Metabolites Protocatechuic Acid and Vanillic Acid Improve Nitric Oxide Bioavailability via the Akt-eNOS Pathway in Response to TNF-α Induced Oxidative Stress and Inflammation in Endothelial Cells.

Background/Objectives: Reduced nitric oxide (NO) bioavailability secondary to excess-superoxide-driven oxidative stress is central to endothelial dysfunction. Previous studies suggest that phenolic metabolites may improve NO bioavailability, yet limited research is available in response to an inflammatory mediator. Therefore, we assessed the effects of cyanidin-3-glucoside (C3G) and its phenolic metabolites protocatechuic acid (PCA) and vanillic acid (VA) on NO bioavailability in a TNF-α induced inflammatory environment. Methods: Primary human umbilical vein endothelial cells (HUVECs) were supplemented with either C3G, PCA, or VA at 1 μM for 24 h before being stimulated with TNF-α 20 ng/mL for an additional 24 h. Measurements included cell viability, apoptosis, reactive oxygen species (ROS), nitrite concentrations, and endothelial nitric oxide synthase (eNOS) and Akt at the mRNA and protein level. Results: Phenolic metabolites did not increase the eNOS expression or nitrite levels in the unstimulated environment; rather, the metabolites mediated NO bioavailability in response to TNF-α induced oxidative stress, with increased viability, eNOS mRNA, phosphorylation, and nitrite levels. Conclusions: Phenolic metabolites, in the presence of TNF-α, can improve NO bioavailability at physiologically relevant concentrations via the Akt-eNOS pathway. This demonstrates that the induction of inflammation is a prerequisite for phenolic metabolites to promote protective properties in endothelial cells by activating the Akt-eNOS pathway.

Inflammation-Triggering Engineered Macrophages (MacTriggers) Enhance Reactivity of Immune Checkpoint Inhibitor Only in Tumor Tissues.

Background: We have previously reported engineered macrophages (MacTriggers) that can accelerate the release of tumor necrosis factor-α in response to M2 polarization. MacTriggers are characterized by two original characteristics of macrophages: (1) migration to tumors; and (2) polarization to the M2 phenotype in tumors. Intravenously administered MacTriggers efficiently accumulated in the tumors and induced tumor-specific inflammation. This study reports a novel methodology for enhancing the anti-tumor effects of immune checkpoint inhibitors (ICIs). Results: In this study, we newly found that the intravenously administered MacTriggers in BALB/c mouse models upregulated the expression levels of immune checkpoint proteins, such as programmed cell death (PD)-1 in CD8+ T cells and PD-ligand 1 (PD-L1) in cancer cells and macrophages. Consequently, in two ICI-resistant tumor-inoculated mouse models, the combined administration of MacTrigger and anti-PD-1 antibody (aPD-1) synergistically inhibited tumor growth, whereas monotherapy with aPD-1 did not exhibit anti-tumor effects. This synergistic effect was mainly from aPD-1 enhancing the tumor-attacking ability of CD8+ T cells, which could infiltrate into the tumors following MacTrigger treatment. Importantly, no side effects were observed in normal tissues, particularly in the liver and spleen, indicating that the MacTriggers did not enhance the aPD-1 reactivity in normal tissues. This specificity was from the MacTriggers not polarizing to the M2 phenotype in normal tissues, thereby avoiding inflammation and increased PD-1/PD-L1 expression. MacTriggers could enhance aPD-1 reactivity only in tumors following tumor-specific inflammation induction. Conclusions: Our findings suggest that the MacTrigger and aPD-1 combination therapy is a novel approach for potentially overcoming the current low ICI response rates while avoiding side effects.

Utilizing follicular fluid on endometrial stromal cells enhances decidualization by induced inflammation.

Polycystic ovary syndrome (PCOS) is a disease associated with inflammation and the follicular fluid of this patient contains proinflammatory cytokines. Abdominal obesity (AO) is also linked to increased levels of proinflammatory cytokines. This study investigated the induction of inflammation and decidualization of in vitro cultured endometrial stromal cells (ESCs) obtained from women with a normal uterus using the follicular fluid of PCOS and non-PCOS patients with or without abdominal obesity. Forty patients under 35 years old, referred to the Royan Institute, were divided into four groups: PCOS with AO, PCOS without AO, non-PCOS with AO, and non-PCOS without AO. Follicular fluid samples were added to the culture medium of ESCs for each group. The rate of decidualization was measured by examining decidual markers. The study also investigated morphological changes in uterine endometrial cells, cell migration rates, and gene expression across all groups. We found that the non-PCOS group without AO had the highest decidualization potential and the highest expression of decidualization markers (P ≤ 0.05). Groups with an inflammatory phenotype of PCOS or abdominal obesity showed the highest expression of decidual pathway markers. The expression levels of inflammatory and proliferative markers in the PCOS group with AO were significantly higher than in the other groups (P ≤ 0.05). The inflammatory profile present in the follicular fluid may trigger the decidualization process. Consequently, in the future, follicular fluid could be utilized as a natural supplement with human cells to promote decidualization and enhance endometrial receptivity in assisted reproductive technology.

The human milk oligosaccharide 3'sialyllactose reduces low-grade inflammation and atherosclerosis development in mice.

Macrophages contribute to the induction and resolution of inflammation and play a central role in chronic low-grade inflammation in cardiovascular diseases caused by atherosclerosis. Human milk oligosaccharides (HMOs) are complex unconjugated glycans unique to human milk that benefit infant health and act as innate immune modulators. Here, we identify the HMO 3'sialyllactose (3'SL) as a natural inhibitor of TLR4-induced low-grade inflammation in macrophages and endothelium. Transcriptome analysis in macrophages revealed that 3'SL attenuates mRNA levels of a selected set of inflammatory genes and promotes the activity of liver X receptor (LXR) and sterol regulatory element binding protein-1 (SREBP1). These acute antiinflammatory effects of 3'SL were associated with reduced histone H3K27 acetylation at a subset of LPS-inducible enhancers distinguished by preferential enrichment for CCCTC-binding factor (CTCF), IFN regulatory factor 2 (IRF2), B cell lymphoma 6 (BCL6), and other transcription factor recognition motifs. In a murine atherosclerosis model, both s.c. and oral administration of 3'SL significantly reduced atherosclerosis development and the associated inflammation. This study provides evidence that 3'SL attenuates inflammation by a transcriptional mechanism to reduce atherosclerosis development in the context of cardiovascular disease.

Antiviral Effect of Melatonin on Caco-2 Cell Organoid Culture: Trick or Treat?

Melatonin is a hormone naturally produced by the body that has recently been found to have antiviral properties. However, its antiviral mechanisms are not entirely understood. Using Caco-2 cells, we developed a gastrointestinal organoid model to investigate the impact of melatonin on cellular organoid culture response to Poly I:C-induced viral inflammation in the gastrointestinal tract. Melatonin was found to have different effect when applied as a pretreatment before the induction of viral inflammation or as a treatment after it. Melatonin pretreatment after Poly I:C stimulation did not protect organoids from size reduction but enhanced cell proliferation, especially when lower (1 and 10 µM) melatonin concentrations were used. On the other hand, treatment with melatonin after the induction of viral inflammation helped to maintain the size of the organoids while reducing cell proliferation. In pretreated cells, reduced IFNLR1 expression was found, while melatonin treatment increased IFNLR1 expression and reduced the production of viral cytokines, such as IFNλ1 and STAT1-3, but did not prevent from apoptosis. The findings of this study emphasize the importance of type III IFNs in antiviral defense in epithelial gastrointestinal cells and shed more light on the antiviral properties of melatonin as a potential therapeutic substance.

Hepatoprotective effects of the xanthine oxidase inhibitor Febuxostat against thioacetamide-induced liver injury in rats: The role of the Nrf2/ HO-1 and TLR4/ NF-κB pathways

Experimental models of liver injury have been established utilizing thioacetamide (TAA), a classic liver toxic chemical that causes organ damage via oxidative stress and inflammatory induction. This study examined the impact of Febuxostat (a xanthine oxidase inhibitor; Febu, 10–15 mg/kg, orally) against TAA (500 mg/kg, i.p.) -induced liver injury in rats.Febu significantly attenuated TAA-induced alterations in liver function parameters, in addition to promoting hepatic antioxidant effects through a significant elevation of Heme-oxygenase-1(HO-1), nuclear factor erythroid 2-related factor2 (Nrf2), reduced glutathione (GSH) and superoxide dismutase (SOD) levels and reduction in hepatic malondialdehyde (MDA) content. Moreover, Febu improved the hepatic anti-inflammatory status by increasing the anti-inflammatory cytokine Interleukin (IL-10) level and reducing the levels of the pro-inflammatory cytokines (Nuclear factor kappa B (NF-κB), IL-1β, high-mobility group box1 (HMGB1), receptor for advanced glycation end products (RAGE), and toll-like receptor4 (TLR4) levels, in addition to suppressing the increased protein and mRNA expression levels of tumor necrosis factor alpha (TNF-α) and IL-6, hepatic expression of TNF-α and activated mitogen-activated protein kinases (p-JNK/p-p38 MAPK). Histopathologically, Febu markedly normalized TAA-induced alteration in liver sections. In conclusion, Febu, in a dose-dependent fashion, refines TAA-induced hepatotoxicity by enhancing antioxidant capabilities and decreasing inflammatory signals.

Liposome encapsulating pine bark extract in Nile tilapia: Targeting interrelated immune and antioxidant defense to combat coinfection with Aeromonas hydrophila and Enterococcus faecalis

Application of smart delivery systems for encapsulation of natural ingredients provides novel avenues and is being frequently developed. Thus, we aimed to highlight the effects of cyclosome liposomal pine bark extract (CL-PBE) on Nile tilapia growth, immunomodulation, antioxidant capacity and resistance against coinfection with Aeromonas hydrophila and Enterococcus faecalis and their associated virulence genes. The experiment was conducted on four fish groups receiving a control diet (control) along with three baseline meals supplemented with 200, 400 and 600 mg/kg diet of CL-PBE (CL-PBE 200, 400 and 600, respectively). At the end of the 12-weeks feeding trial, the tilapias were intraperitoneally challenged with virulent A. hydrophila strain and five days later, E. faecalis challenge was carried out. The results revealed that tilapias fed diets fortified with CL-PBE displayed significantly enhanced growth rate and feed conversion ratio in a dose-dependent manner. Moreover, we demonstrated that CL-PBE had potent antioxidant property presented by modulation of several markers of oxidative stress; substantial reductions in reactive oxygen species, hydrogen peroxide and malondialdehyde levels, an elevation in total antioxidant capacity and boosting glutathione peroxidase (GSH-Px), catalase (CAT) and superoxide dismutase (SOD) activities in fish serum and muscle tissues. This was also correlated with augmenting the expression of CAT, SOD, GSH-Px, Nrf2 and caspase-1 genes alongside reducing those of COX-2, HSP70 and iNOS genes in response to CL-PBE. Our data demonstrated that CL-PBE fortification counteracted the overly pronounced inflammatory response-mediated induction of IL-1β, TNF-α, MHCII and TLR2 genes at the transcriptional levels post coinfection together with promotion in MUC2 and IL-10 genes expression. Notably, our findings displayed optimal well-functioning fish immune system post dietary supplementation of CL-PBE for the protection against coinfection with A. hydrophila and E. faecalis. This was evident from the decline of their counts and hence encompassing the capacity to reduce cumulative mortality percentage in conjunction with interference with their virulence via the significant downregulatory effects of CL-PBE on E. faecalis esp and gelE and A. hydrophila act and fla virulence genes. Taken together, our study strongly suggested dietary inclusion of CL-PBE for Nile tilapias with superior growth performance and significant economic benefits coupled with potent stimulatory effects on antioxidant capacity and immune response expediting our detailed understanding of how coinfection with A. hydrophila and E. faecalis was controlled.

The pathogenic responses elicited during exposure of human intestinal cell line with Giardia duodenalis excretory-secretory products and the potential attributed endocytosis mechanism.

Giardia duodenalis, an important zoonotic protozoan parasite, adheres to host intestinal epithelial cells (IECs) via the ventral disc and causes giardiasis characterized mainly by diarrhea. To date, it remains elusive how excretory-secretory products (ESPs) of Giardia enter IECs and how the cells respond to the entry. Herein, we initially demonstrated that ESPs evoked IEC endocytosis in vitro. We indicated that ESPs contributed vitally in triggering intrinsic apoptosis, pro-inflammatory responses, tight junction (TJ) protein expressional changes, and autophagy in IECs. Endocytosis was further proven to be implicated in those ESPs-triggered IEC responses. Ten predicted virulent excretory-secretory proteins of G. duodenalis were investigated for their capability to activate clathrin/caveolin-mediated endocytosis (CME/CavME) in IECs. Pyridoxamine 5'-phosphate oxidase (PNPO) was confirmed to be an important contributor. PNPO was subsequently verified as a vital promoter in the induction of giardiasis-related IEC apoptosis, inflammation, and TJ protein downregulation. Most importantly, this process seemed to be involved majorly in PNPO-evoked CME pathway, rather than CavME. Collectively, this study identified Giardia ESPs, notably PNPO, as potentially important pathogenic factors during noninvasive infection. It was also noteworthy that ESPs-evoked endocytosis might play a role in triggering giardiasis-inducing cellular regulation. These findings would deepen our understanding about the role of ESPs, notably PNPO, in the pathogenesis of giardiasis and the potential attributed endocytosis mechanism.

From colon wall to tumor niche: Unraveling the microbiome's role in colorectal cancer progression.

Colorectal cancer (CRC) is influenced by perturbations in the colonic microbiota, characterized by an imbalance favoring pathogenic bacteria over beneficial ones. This dysbiosis contributes to CRC initiation and progression through mechanisms such as carcinogenic metabolite production, inflammation induction, DNA damage, and oncogenic signaling activation. Understanding the role of external factors in shaping the colonic microbiota is crucial for mitigating CRC progression. This study aims to elucidate the gut microbiome's role in CRC progression by analyzing paired tumor and mucosal tissue samples obtained from the colon walls of 17 patients. Through sequencing of the V3-V4 region of the 16S rRNA gene, we characterized the tumor microbiome and assessed its association with clinical variables. Our findings revealed a significant reduction in alpha diversity within tumor samples compared to paired colon biopsy samples, indicating a less diverse microbial environment within the tumor microenvironment. While both tissues exhibited dominance of similar bacterial phyla, their relative abundances varied, suggesting potential colon-specific effects. Fusobacteriota enrichment, notably in the right colon, may be linked to MLH1 deficiency. Taxonomy analysis identified diverse bacterial genera, with some primarily associated with the colon wall and others unique to this region. Conversely, several genera were exclusively expressed in tumor tissue. Functional biomarker analysis identified three key genes with differential abundance between tumor microenvironment and colon tissue, indicating distinct metabolic activities. Functional biomarker analysis revealed three key genes with differential abundance: K11076 (putrescine transport system) and K10535 (nitrification) were enriched in the tumor microenvironment, while K11329 (SasA-RpaAB circadian timing mediator) dominated colon tissue. Metabolic pathway analysis linked seven metabolic pathways to the microbiome. Collectively, these findings highlight significant gut microbiome alterations in CRC and strongly suggest that long-term dysbiosis profoundly impacts CRC progression.

Alginate-modified graphene oxide anchored with lactoperoxidase as a novel bioactive nanocombination for colorectal cancer therapy

It is imperative to explore new biocompatible drugs with low toxicity for use in medicinal fields such as fighting tumors. Bovine lactoperoxidase (BLPO) stems from the most important enzymes in the bovine whey that provide a proper pattern for nano-formulation with nanomaterials. LPO is a suitable protein to be coated or adsorbed to alginate modified graphene oxide (GO-SA), which forms the modified GO-SA-LPO hybrid structure. This novel combination provides LPO stability with strong anticancer effects and boosts immunity response. The characterization results obtained from different techniques confirmed a successful LPO adsorption on the GO-SA composite surface. Moreover, nano-formulation of LPO with GO-SA composite exhibited a reduction in its size and overall charge. In addition, the experimental results showed greater LPO activity stability in the modified GO-SA-LPO nanocombination than free LPO after storage for 10 weeks at 4 °C. The in vitro study, a crucial step in the validation of our approach, demonstrated that the modified GO-SA-LPO nanocombination showed a potent anticancer selectivity toward colon cancer cell lines more than GO-SA composite or free form of LPO, which enhanced in a dose-dependent manner with high safety manner against normal cells. The apoptotic effect of this novel nanocombination was confirmed by the greatest variations in the expression of both well-known apoptosis genes (p53 and Bcl-2), severe changes in the cellular morphology, DNA fragmentation, and nuclear staining with fluorescence yellow and orange of the target cancer cells. Also, this superior efficacy of the modified GO-SA-LPO nanocombination was induced by suppressing some pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin (IL-6), and necrosis factor-kappa B (NF-ĸB). Our observations presented that the modified nanocombination of LPO may offer a novel remedy for treating colon tumors via induced apoptosis pathway, inflammation reduction, and immune response improvement.

G-CSFR-induced leukocyte transendothelial migration during the inflammatory response is regulated by the ICAM1-PKCa axis: based on multiomics integration analysis

As an indispensable inflammatory mediator during sepsis, granulocyte colony-stimulating factor (G-CSF) facilitates neutrophil production by activating G-CSFR. However, little is known about the role of intracellular downstream signalling pathways in the induction of inflammation. To explore the functions of molecules in regulating G-CSFR signalling, RNA sequencing and integrated proteomic and phosphoproteomic analyses were conducted to predict the differentially expressed molecules in modulating the inflammatory response after G-CSFR expression was either up- or downregulated, in addition to the confirmation of their biological function by diverse experimental methods. In the integrated bioinformatic analysis, 3190 differentially expressed genes (DEGs) and 1559 differentially expressed proteins (DEPs) were identified in multiple-group comparisons (p < 0.05, FC > ± 1.5) using enrichment analyses, as well as those classic pathways such as the TNF, NFkappaB, IL-17, and TLR signalling pathways. Among them, 201 proteins, especillay intercellular cell adhesion molecule-1 (ICAM1) and PKCa, were identified as potential molecules involved in inflammation according to the protein–protein interaction (PPI) analysis, and the leukocyte transendothelial migration (TEM) pathway was attributed to the intervention of G-CSFR. Compared with the control and TNF-a treatment, the G-CSFR (G-CSFROE)-overexpressing led to an obvious increase in the number of leukocytes with the TEM phenotype. Mechanically, the expression of ICAM1 and PKCa was significantly up- and downregulated by G-CSFROE, which directly led to increased TEM; moreover, PKCa expression was negatively regulated by ICAM1 expression, leading to aberrant leukocyte TEM. Altogether, the ICAM1‒PKCa axis was found a meaningful target in the leukocyte TEM induced by G-CSFR upregulation.

Preventive and therapeutic effects of molecular iodine in a model of diabetes mellitus induced by streptozotocin

Diabetes mellitus (DM) is a multifactorial condition that involves oxidative alterations and dysbiosis of the gut microbiota associated with an imbalance in glucose metabolism. Therefore, the need to develop integrative therapies that are both effective and have fewer side effects has become evident in recent years. Molecular iodine (I2) has antioxidant effects in preclinical hyperglycemic models. The present work analyzes the preventive and therapeutic effects of oral I2 supplementation in a DM model induced by low doses of streptozotocin (STZ). Male CD1 mice (12 weeks old) were divided into the following groups: control, STZ (20 mg/kg/day, i.p., for 5 days), I2 (0.2 mg/Kg in drinking water), preventive (STZ + I2), and therapeutic (I2 supplementation from day 35 to day 90; STZ + I2(Ther)). The supplementation with I2 prevented and normalized hyperglycemia, hypercholesterolemia, and hypertriglyceridemia associated with STZ, preserving pancreatic, liver, muscle, and adipose tissue morphology and normalizing inflammatory gene induction (TLR2, TLR4, NFkβ, TNFα) in several tissues. Furthermore, compared to the STZ group, the presence of I2 favored a more significant abundance of beneficial bacteria that support the integrity of the intestinal epithelial barrier and higher α-diversity. In conclusion, the I2 supplement has preventive and therapeutic effects, reducing oxidative damage and reestablishing microbiota diversity following STZ exposure.

Investigating the protective effects of epigallocatechin-gallate against polystyrene microplastics-induced biochemical and hematological alterations in rats

BackgroundPolystyrene microplastics (PS-MPs) are widely used and found in drinking water and food, concerns have been raised about their potential health effects, especially in causing oxidative stress and inflammation in living organisms. ObjectivesThe aim of this study was to investigate the protective effects of epigallocatechin-gallate (EGCG), a natural antioxidant and anti-inflammatory compound, against PS-MPs-induced biochemical and hematological alterations in rats. MethodsMale Wistar rats were divided into four groups: control, EGCG-treated (80 mg∙ kg-1/d), PS-MPs-exposed (0.01 mg∙kg-1/d), and PS-MPs+EGCG-treated groups. PS-MPs were orally administered for 56 days, while EGCG was given concomitantly by gavage. At the end of the treatment period, blood samples were collected for hematological and biochemical analyses. Oxido-nitrergic stress markers, including malondialdehyde (MDA), nitric oxide (NO), reactive nitrogen species (RONS) and reduced glutathione (GSH), Superoxide dismutase (SOD), catalase (CAT), as well as inflammatory markers, such as tumor necrosis factor alpha (TNF-α), interferon gamma (IFY-γ) and interleukin-10 (IL-10), were also measured in serum. ResultsTreatment with PS-MPs caused a significant increase in MDA, RONS, NO levels and a decrease in SOD, CAT and GSH levels, indicating the induction of oxido-nitrergic stress. PS-MPs also caused an increase in the levels of TNF-α, IFY-γ, MPO and decreased IL-10, indicating the induction of inflammation. Additionally, PS-MPs caused alterations in hematological and serum transaminase parameters, including a decrease in red blood cell count, hemoglobin, and hematocrit levels, neutrophil and eaosinophil and an increase in white blood cell count, lymphocyte count, AST, ALT, ALP, LDH and GGT. PS-MPs also caused disturbances in electrolyte balance and renal function markers. However, treatment with EGCG significantly attenuated these alterations induced by PS-MPs, indicating its protective effects. ConclusionThe results of this study demonstrate that EGCG can protect against PS-MPs-induced biochemical and hematological alterations in rats, possibly through its antioxidant and anti-inflammatory properties.