Inhibition Of IL-6 Expression Research Articles

NR1D1 activation alleviates inflammatory response through inhibition of IL-6 expression in bovine endometrial epithelial cells

NR1D1 activation alleviates inflammatory response through inhibition of IL-6 expression in bovine endometrial epithelial cells

Specialized pro-resolving mediator 7S MaR1 inhibits IL-6 expression via modulating ROS/p38/ERK/NF-κB pathways in PM10-exposed keratinocytes

Specialized pro-resolving mediator 7S MaR1 inhibits IL-6 expression via modulating ROS/p38/ERK/NF-κB pathways in PM₁₀-exposed keratinocytes

Simultaneously blocking ANGPTL3 and IL-1β for the treatment of atherosclerosis through lipid-lowering and anti-inflammation.

Blood lipid levels play a critical role in the progression of atherosclerosis. However, even with adequate lipid reduction, significant residual cardiovascular risk remains. Therefore, it is necessary to seek novel therapeutic strategies for atherosclerosis that can not only lower lipid levels but also inhibit inflammation simultaneously. The fusion protein FD03-IL-1Ra was designed by linking the Angiopoietin-like 3 (ANGPTL3) nanobody and human interleukin-1 receptor antagonist (IL-1Ra) sequences to a mutated human immunoglobulin gamma 1 (IgG1) Fc. This construct was transfected into HEK293 cells for expression. The purity and thermal stability of the fusion protein were assessed using SDS-PAGE, SEC-HPLC, and differential scanning calorimetry. Binding affinities of the fusion protein to ANGPTL3 and IL-1 receptor were measured using Biacore T200. The biological activity of the fusion protein was validated through in vitro experiments. The therapeutic efficacy of the fusion protein was evaluated in an ApoE-/- mouse model of atherosclerosis, including serum lipid level determination, histological analysis of aorta and aortic sinus sections, and detection of inflammatory and oxidative stress markers. ImageJ software was utilized for quantitative image analysis. Statistical analysis was performed using one-way ANOVA followed by Bonferroni post hoc test. The FD03-IL-1Ra fusion protein was successfully expressed, with no polymer formation detected, and it demonstrated good thermal and conformational stability. High affinity for both murine and human ANGPTL3 was exhibited by FD03-IL-1Ra, and it was able to antagonize hANGPTL3's inhibition of LPL activity. FD03-IL-1Ra also showed high affinity for both murine and human IL-1R, inhibiting IL-6 expression in A549 cells induced by IL-1β stimulation, as well as suppressing IL-1β-induced activity inhibition in A375.S2 cells. Our study revealed that the fusion protein effectively lowered serum lipid levels and alleviated inflammatory responses in mice. Furthermore, the fusion protein enhanced plaque stability by increasing collagen content within atherosclerotic plaques. These findings highlighted the potential of bifunctional interleukin-1 receptor antagonist and ANGPTL3 antibody fusion proteins for ameliorating the progression of atherosclerosis, presenting a promising novel therapeutic approach targeting both inflammation and lipid levels.

Mizoribine Promotes Molecular Chaperone HSP60/HSP10 Complex Formation.

It has been reported that Mizoribine is an immunosuppressant used to suppress rejection in renal transplantation, nephrotic syndrome, lupus nephritis, and rheumatoid arthritis. The molecular chaperone HSP60 alone induces inflammatory cytokine IL-6 and the co-chaperone HSP10 alone inhibits IL-6 induction. HSP60 and HSP10 form a complex in the presence of ATP. We analyzed the effects of Mizoribine, which is structurally similar to ATP, on the structure and physiological functions of HSP60-HSP10 using Native/PAGE and transmission electron microscopy. At low concentrations of Mizoribine, no complex formation of HSP60-HSP10 was observed, nor was the expression of IL-6 affected. On the other hand, high concentrations of Mizoribine promoted HSP60-HSP10 complex formation and consequently suppressed IL-6 expression. Here, we propose a novel mechanism of immunosuppressive action of Mizoribine.

NF-kB Regulation and the Chaperone System Mediate Restorative Effects of the Probiotic Lactobacillus fermentum LF31 in the Small Intestine and Cerebellum of Mice with Ethanol-Induced Damage.

Probiotics are live microorganisms that yield health benefits when consumed, generally by improving or restoring the intestinal flora (microbiota) as part of the muco-microbiotic layer of the bowel. In this work, mice were fed with ethanol alone or in combination with the probiotic Lactobacillus fermentum (L. fermentum) for 12 weeks. The modulation of the NF-κB signaling pathway with the induction of Hsp60, Hsp90, and IkB-α by the probiotic occurred in the jejunum. L. fermentum inhibited IL-6 expression and downregulated TNF-α transcription. NF-κB inactivation concurred with the restoration of the intestinal barrier, which had been damaged by ethanol, via the production of tight junction proteins, ameliorating the ethanol-induced intestinal permeability. The beneficial effect of the probiotic on the intestine was repeated for the cerebellum, in which downregulation of glial inflammation-related markers was observed in the probiotic-fed mice. The data show that L. fermentum exerted anti-inflammatory and cytoprotective effects in both the small intestine and the cerebellum, by suppressing ethanol-induced increased intestinal permeability and curbing neuroinflammation. The results also suggest that L. fermentum could be advantageous, along with the other available means, for treating intestinal diseases caused by stressors associated with inflammation and dysbiosis.

Deficiency of HtrA4 in BeWo cells downregulates angiogenesis through IL-6/JAK/STAT3 signaling

In a previous study, we investigated the effects of high-temperature requirement factor A4 (HtrA4) deficiency on trophoblasts using the BeWo KO cell line. However, the effects of this deficiency on angiogenesis remain unclear. To explore the role of HtrA4 in angiogenesis, HUVECs were co-cultured with wild-type BeWo cells (BeWo WT), BeWo KO, and HtrA4-rescued BeWo KO (BeWo KO-HtrA4 rescue) cells. Dil staining and dextran analysis revealed that HUVECs co-cultured with BeWo KO formed tubes, but they were often disjointed compared to those co-cultured with BeWo WT, BeWo KO-HtrA4 rescue, and HUVECs controls. RT-PCR, ELISA, and western blot analysis were performed to assess angiogenesis-related factors at the mRNA and protein levels. HtrA4 deficiency inhibited IL-6 expression in trophoblasts, and the reduced secretion of IL-6 decreases VEGFA expression in HUVECs by modulating the JAK2/STAT3 signaling pathway to prevent tube formation. Moreover, rescuing HtrA4 expression restored the HUVEC tube formation ability. Interestingly, IL-6 expression was lower in supernatants with only cultured HUVECs than in co-cultured HUVECs with BeWo WT cells, but the HUVEC tube formation ability was similar. These findings suggest that the promoting angiogenesis-related signaling pathway differs between only HUVECs and co-cultured HUVECs, and that the deficiency of HtrA4 weakens the activation of the IL-6/JAK/STAT3/VEGFA signaling pathway, reducing the ability of tube formation in HUVECs. HtrA4 deficiency in trophoblasts hinders angiogenesis and may contribute to placental dysfunction.

Abstract P2127: A Novel Arnt Dependent Hif2a Singling In Protecting Against Cardiac Microvascular Endothelial Barrier Dysfunction Following Myocardial Infarction

Rationale: Cardiac microvascular leakage and inflammation are triggered during myocardial infarction (MI) and contribute to heart failure. Hypoxia-inducible factor 2α ( Hif2α ) is highly expressed in endothelial cells (ECs) and rapidly activated by myocardial ischemia, but its impact in microvascular endothelial barrier function during MI is unclear. Objective: To test our hypothesis that the expression of Hif2α in ECs regulates cardiac microvascular permeability in infarcted hearts, which is through its binding partner aryl hydrocarbon nuclear translocator. (ARNT). Methods and Results: Experiments were conducted with mice carrying an inducible EC-specific Hif2α -knockout ( ecHif2α -/- ) mutation, with mouse cardiac microvascular endothelial cells (CMVECs) isolated from the hearts of ecHif2α -/- mice after the mutation was induced, and with human CMVECs and umbilical-vein endothelial cells transfected with ecHif2α siRNA. After MI induction, echocardiographic assessments of cardiac function were significantly lower, while measures of cardiac microvascular leakage (Evans blue assay), plasma IL6 levels, and cardiac neutrophil accumulation and fibrosis (histology) were significantly greater, in ecHif2α -/- mice than in control mice, and RNA-sequencing analysis of heart tissues from both groups indicated that the expression of genes involved in vascular permeability and collagen synthesis was enriched in ecHif2α -/- hearts. In cultured ECs, ec Hif2α deficiency was associated with declines in endothelial barrier function (electrical cell impedance assay) and the reduced abundance of tight-junction proteins, as well as an increase in the expression of inflammatory markers, all of which were largely reversed by the overexpression of ARNT. We also found that ARNT, but not Hif2α, binds directly to the IL6 promoter and suppresses IL6 expression. Conclusions: Endothelial HIF-2a protects from hypoxia-induced cardiac microvascular barrier dysfunction, promotes inflammation damage and represents a potential therapeutic target for cardioprotection, and prevention of fibrosis following acute ischemic injury.

L-alanyl-L-glutamine modified perfusate improves human lung cell functions and extend porcine ex vivo lung perfusion.

The clinical application of normothermic ex vivo lung perfusion (EVLP) has increased donor lung utilization for transplantation through functional assessment. To develop it as a platform for donor lung repair, reconditioning and regeneration, the perfusate should be modified to support the lung during extended EVLP. Human lung epithelial cells and pulmonary microvascular endothelial cells were cultured, and the effects of Steen solution (commonly used EVLP perfusate) on basic cellular function were tested. Steen solution was modified based on screening tests in cell culture, and further tested with an EVLP cell culture model, on apoptosis, GSH, HSP70, and IL-8 expression. Finally, a modified formula was tested on porcine EVLP. Physiological parameters of lung function, histology of lung tissue, and amino acid concentrations in EVLP perfusate were measured. Steen solution reduced cell confluence, induced apoptosis, and inhibited cell migration, compared to regular cell culture media. Adding L-alanyl-L-glutamine to Steen solution improved cell migration and decreased apoptosis. It also reduced cold preservation and warm perfusion-induced apoptosis, enhanced GSH and HSP70 production, and inhibited IL-8 expression on an EVLP cell culture model. L-alanyl-L-glutamine modified Steen solution supported porcine lungs on EVLP with significantly improved lung function, well-preserved histological structure, and significantly higher levels of multiple amino acids in EVLP perfusate. Adding L-alanyl-L-glutamine to perfusate may provide additional energy support, antioxidant, and cytoprotective effects to lung tissue. The pipeline developed herein, with cell culture, cell EVLP, and porcine EVLP models, can be used to further optimize perfusates to improve EVLP outcomes.

Key genes and regulatory networks of hypoxic preconditioning on osteoblasts

The purpose of this study was to identify the key genes and pathways involved in hypoxic preconditioning of osteoblasts. Cells of the hypoxic-preconditioning group underwent 10 min of hypoxic cultivation/10 min normoxic cultivation three times before 4 h of hypoxic cultivation. The long-time hypoxia group underwent 4 h of hypoxic cultivation, and the control group cells underwent 4 h of normoxic cultivation. Differences in miRNAs expressed were analyzed by high-throughput sequencing. MiRwalk 3.0 was used to predict the target genes and conduct a Gene Set Enrichment Analysis. The STRING database and Cytoscape were used to explore the hub genes. A total of 8635 genes and 121 pathways are enriched in the hypoxic-preconditioning compared with the long-time hypoxia group, including the hub genes Utp6, Eif3a, Etf1, Rrp12 and Mkks. 8,476 target genes and 121 pathways are enriched in the hypoxic-preconditioning group compared with the control group, including the hub genes Chd7, Cebpa and Fosb, and 9,315 target genes and 131 pathways are enriched in the long-term hypoxia group compared with the control group, including the hub genes Dcun1d2, Ube2d1 and Frk. Hypoxia preconditioning improved cell viability (p < 0.01), enhanced ALP, IL10 and VEGF expression, and inhibited IL6 expression (p < 0.05). Hypoxic preconditioning is an effective method for promoting osteoblast activity.

Effect of lipoxin A4 methyl ester from arachidonic acid on JAK2/STAT3 pathway after cerebral ischemia-reperfusion injury

It was determined if lipoxin A4 methyl ester (LXA4 ME) affects JAK2/STAT3 pathway following transient focal cerebral ischemia-reperfusion injury (CIRI) in rats. Adult male SD rats were randomly assigned to sham-operated, CIRI group, DMSO + CIRI, AG490 + CIRI, and LXA4 ME + CIRI. Neurologic deficit was evaluated in rats after 24 h reperfusion. IL-6 levels of brain tissue were determined 6 and 24 h post-reperfusion using an ELISA assay. STAT3 and SOCS3 mRNA levels were analyzed via real-time quantitative PCR. P-JAK2, p-STAT3, and SOCS3 were measured via Western blotting, and localized by fluorescent immunohitochemistry. Transient cerebral ischemia in rats caused a significantly elevated concentration of IL-6, levels of STAT3 and SOCS3 mRNA, phosphorylation of JAK2 and STAT3, and immunoreactive glia of ipsilateral cortex 24 h post-reperfusion versus sham rats. The AG490 intervention downregulated cerebral ischemia-induced JAK2 and STAT3 phosphorylation, and their immunoreactive glia located in the ischemic cortex. LXA4 ME reduced the concentration of IL-6, increased SOCS3 expression, inhibited phosphorylation and immunoreactive glia of JAK2 and STAT3, as well as ameliorated neurologic dysfunction. In conclusions, LXA4 ME inhibited JAK2/STAT3 activation, perhaps via upregulating SOCS3, as well as suppressed IL-6 expression to ameliorate cerebral ischemic injury.

Biodentine but not MTA induce DSPP expression of dental pulp cells with different severity of LPS-induced inflammation.

To explore the inflammatory and differentiation response in inflamed dental pulp cells (DPCs) induced by lipopolysaccharide (LPS) under different conditions with Biodentine and mineral trioxide aggregate (MTA) treatment. DPCs were treated with 0.001-1µg/mL LPS for different periods to induce inflammation. Normal and inflamed DPCs were further treated with 0.14mg/mL Biodentine or 0.13mg/mL MTA for different periods. mRNA expression level of IL-6, IL-8 and ALP were analysed by qPCR. DSPP protein expression was detected by western blot. The data were analysed by the Mann-Whitney test, unpaired t test or two-way ANOVA. After treatment for different times and with different concentrations of LPS, different severity of pulp inflammation was revealed by the expressions of IL-6 and IL-8. Higher concentrations of LPS induced higher IL-6 and IL-8 expressions, and these expressions first increased and then decreased (p < 0.0001). At 96 and 192h, Biodentine significantly suppressed IL-6 expression in both normal and inflamed DPCs (p < 0.05). At 48 and 96h, Biodentine suppressed ALP expression in both normal and inflamed DPCs (p < 0.05). At 48 and 96h, Biodentine induced DSPP expressions in both normal and inflamed DPCs (p < 0.05). Biodentine enhanced more DSPP differentiation of both normal and inflamed DPCs under different treatment durations than MTA. The prognosis of vital pulp therapy may depend on the severity of pulp inflammation which is difficult to be determined in clinical settings. Therefore, Biodentine may enhance odontogenic differentiation in different severity of pulp inflammation imply its clinical indications.

Analysis of Anti-Cancer and Anti-Inflammatory Properties of 25 High-THC Cannabis Extracts.

Cannabis sativa is one of the oldest cultivated plants. Many of the medicinal properties of cannabis are known, although very few cannabis-based formulations became prescribed drugs. Previous research demonstrated that cannabis varieties are very different in their medicinal properties, likely due to the entourage effect—the synergistic or antagonistic effect of various cannabinoids and terpenes. In this work, we analyzed 25 cannabis extracts containing high levels of delta-9-tetrahydrocannabinol (THC). We used HCC1806 squamous cell carcinoma and demonstrated various degrees of efficiency of the tested extracts, from 66% to 92% of growth inhibition of cancer cells. Inflammation was tested by induction of inflammation with TNF-α/IFN-γ in WI38 human lung fibroblasts. The efficiency of the extracts was tested by analyzing the expression of COX2 and IL6; while some extracts aggravated inflammation by increasing the expression of COX2/IL6 by 2-fold, other extracts decreased inflammation, reducing expression of cytokines by over 5-fold. We next analyzed the level of THC, CBD, CBG and CBN and twenty major terpenes and performed clustering and association analysis between the chemical composition of the extracts and their efficiency in inhibiting cancer growth and curbing inflammation. A positive correlation was found between the presence of terpinene (pval = 0.002) and anti-cancer property; eucalyptol came second, with pval of 0.094. p-cymene and β-myrcene positively correlated with the inhibition of IL6 expression, while camphor correlated negatively. No significant correlation was found for COX2. We then performed a correlation analysis between cannabinoids and terpenes and found a positive correlation for the following pairs: α-pinene vs. CBD, p-cymene vs. CBGA, terpenolene vs. CBGA and isopulegol vs. CBGA. Our work, thus, showed that most of high-THC extracts demonstrate anti-cancer activity, while only certain selected extracts showed anti-inflammatory activity. Presence of certain terpenes, such as terpinene, eucalyptol, cymene, myrcene and camphor, appear to have modulating effects on the activity of cannabinoids.

Lycopene Inhibits IL-6 Expression by Upregulating NQO1 and HO-1 via Activation of Nrf2 in Ethanol/Lipopolysaccharide-Stimulated Pancreatic Acinar Cells.

In alcoholic pancreatitis, alcohol increases gut permeability, which increases the penetration of endotoxins, such as lipopolysaccharides (LPS). LPS act as clinically significant triggers to increase pancreatic damage in alcoholic pancreatitis. Ethanol or LPS treatment increases reactive oxygen species (ROS) production in pancreatic acinar cells. ROS induce inflammatory cytokine production in pancreatic acinar cells, leading to pancreatic inflammation. The nuclear erythroid-2-related factor 2 (Nrf2) pathway is activated as a cytoprotective response to oxidative stress, and induces the expression of NAD(P)H quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1). Lycopene exerts anti-inflammatory and antioxidant effects in various cells. We previously showed that lycopene inhibits NADPH oxidase to reduce ROS and IL-6 levels, and zymogene activation in ethanol or palmitoleic acid-treated pancreatic acinar cells. In this study, we examined whether lycopene inhibits IL-6 expression by activating the Nrf2/NQO1-HO-1 pathway, and reducing intracellular and mitochondrial ROS levels, in ethanol and LPS-treated pancreatic AR42J cells. Lycopene increased the phosphorylated and nuclear-translocated Nrf2 levels by decreasing the amount of Nrf2 sequestered in the cytoplasm via a complex formation with Kelch-like ECH1-associated protein 1 (Keap1). Using exogenous inhibitors targeting Nrf2 and HO-1, we showed that the upregulation of activated Nrf2 and HO-1 results in lycopene-induced suppression of IL-6 expression and ROS production. The consumption of lycopene-rich foods may prevent the development of ethanol and LPS-associated pancreatic inflammation by activating Nrf2-mediated expression of NQO1 and HO-1, thereby decreasing ROS-mediated IL-6 expression in pancreatic acinar cells.

The DPA-derivative 11S, 17S-dihydroxy 7,9,13,15,19 (Z,E,Z,E,Z)-docosapentaenoic acid inhibits IL-6 production by inhibiting ROS production and ERK/NF-κB pathway in keratinocytes HaCaT stimulated with a fine dust PM10

11 S, 17S-dihydroxy 7,9,13,15,19 (Z,E,Z,E,Z)-docosapentaenoic acid (DoPE) is a derivative of docosapentaenoic acid, a specialized pro-resolving mediator of inflammation such as lipoxins, resolvins, maresins, and protectins. PM10 is a fine dust particle that induces oxidative stress, DNA damage, inflammation, aging, and cancer. The anti-inflammatory mechanism of DoPE, however, has not yet been elucidated. In these studies, we investigated whether DoPE has anti-inflammatory effects in human keratinocyte HaCaT cells. We demonstrated that DoPE suppressed PM10-induced expressions of IL-6 mRNA and protein in human HaCaT keratinocytes. We also investigated the modulating effects of DoPE on reactive oxygen species (ROS) and mitogen-activated protein kinase (MAPK). ROS production, extracellular signal regulated kinase (ERK) phosphorylation, and translocation of nuclear factor-kappa B (NF-kB) p65 and NF-kB activity were suppressed by DoPE in PM10-stimulated HaCaT cells. Collectively, our results demonstrated that DoPE inhibited IL-6 expression by reducing ROS generation, suppressing ERK phosphorylation, and inhibiting translocation of NF-kB p65 and NF-kB activity in PM10-stimulated HaCaT cells, suggesting that DoPE can be useful for the resolution of the inflammation caused by IL-6.

MiR-197-3p reduces bortezomib resistance in multiple myeloma by inhibiting IL-6 expression in a MEAF6-dependent manner

ObjectiveThis study investigated the mechanism by which miR-197-3p regulated IL-6 expression and reduced bortezomib (BTZ) resistance in multiple myeloma (MM). MethodsThe expression of miR-197-3p, MEAF6 and IL-6 in BTZ-resistant MM cells was measured. The effects of miR-197-3p/IL-6 axis on drug resistance and cell apoptosis were evaluated in BTZ-resistant MM cells. The expression of JAK/STAT3 proteins was detected by Western blotting. The binding of miR-197-3p to MEAF6 mRNA was verified using molecular biology techniques. Chromatin immunoprecipitation was used to assess histone acetylation in IL-6 promoter. The effect of miR-197-3p on MM growth was investigated in a mouse model. ResultsMiR-197-3p was lowly expressed, and MEAF6 and IL-6 were highly expressed in BTZ-resistant MM cells. Overexpression of miR-197-3p increased drug sensitivity in BTZ-resistant MM cells, which was counteracted by overexpression of IL-6. Overexpression of miR-197-3p also inhibited MM growth in vivo. Mechanistically, miR-197-3p suppressed the expression of IL-6 by inhibiting MEAF6-mediated histone H3 acetylation in IL-6 promoter. The miR-197-3p/IL-6 axis also inhibited the activation of JAK/STAT3 signaling pathway. ConclusionmiR-197-3p reduces BTZ resistance in MM by inhibiting acetylation-mediated expression of IL-6 and by inactivating JAK/STAT3 signaling pathway.

Abstract 11618: Serum and Glucocorticoid Inducible Kinase-1 (SGK-1) Activity is Upregulated in Hypertension and Promotes IL-6 Expression to Drive Aortic Macrophage Accumulation

Introduction: The serum and glucocorticoid inducible kinase-1 (SGK-1) is a mechanosensitive kinase and it is hypothesized that SGK-1 activity is upregulated with elevated aortic tension to augment pro-inflammatory cytokine expression and promote macrophage accumulation to drive hypertensive remodeling. Methods: Hypertension (HTN) was induced in C57Bl/6 mice with AngiotensinII (AngII) infusion (1.46mg/kg/day x21days, n=4). Terminal procedure included blood pressure (SBP) quantification, aortic diameter (AoD) assessment, and harvest of infrarenal aorta. Abundance of SGK-1, pSGK-1, and the mature macrophage marker F4/80 was determined by immunoblot. The spontaneously hypertensive BPH/2 mice were also utilized and assessed for SBP, AoD, and target proteins (n=4). A subset of animals had systemic infusion of EMD638683, a selective SGK-1 inhibitor (2.5mg/kg/day x 21 days, n=4). Aortic VSMCs were subjected to 12% biaxial cyclic stretch for 3 and 12 hours +/- EMD638683 (10μM) with subsequent QPCR for IL-6 and MCP-1 expression. Statistical analysis included two-way ANOVA across treatment groups with significance at p&lt;0.05. Results: C57Bl/6+AngII mice and BPH/2 mice had significant elevation in SBP (p&lt;0.05) without change in AoD. The pSGK-1/SGK-1 and abundance F4/80 were increased in both models of HTN (p&lt;0.05) and decreased with systemic EMD638683 (p&lt;0.05), with no change in SBP. IL-6 expression was upregulated in VSMC that had Stretch for 3hrs (1.64 + 0.22 fold; p&lt;0.05) or 12hrs (1.99 + 0.33 fold; p&lt;0.05), and at both timepoints EMD638683 significantly inhibited IL-6 expression (p&lt;0.05 vs respective Stretch). MCP-1 expression was unchanged after 3hr Stretch, but it was significantly elevated following 12hr Stretch (2.05 + 0.38 fold; p&lt;0.05), and inhibited by EMD638683 (p&lt;0.05). This data suggests a biomechanical link between aortic VSMC mechanotransduction and cytokine production to promote macrophage accumulation, mediated in-part by SGK-1 activation. Conclusions: Mechanical stimuli can elevate SGK-1 activity and increase pro-inflammatory cytokine production to accumulate macrophages, which may lead to proteolytic aortic remodeling. Therefore, SGK-1 may represent a novel target to abrogate hypertensive aortic inflammation.

Investigation of the effects of hesperidin administration on abamectin-induced testicular toxicity in rats through oxidative stress, endoplasmic reticulum stress, inflammation, apoptosis, autophagy, and JAK2/STAT3 pathways.

In this study, the potential effects of hesperidin (HES) on chronic toxicity caused by abamectin (ABM) in the testicular tissue were investigated through oxidative stress, inflammation, endoplasmic reticulum stress (ERS), apoptosis, and autophagy pathways. Male Sprague Dawley rats were used in the study. Animals in the ABM group were orally administered 1 mg/kg ABM every other day for 28 days, while HES used against ABM was given at 100 or 200 mg/kg 30 min after ABM administration for 28 days. Markers of oxidative stress, inflammation, ERS, apoptosis, and autophagy in the testicular tissues removed after the animals are sacrificed were analyzed using biochemical, real-time polymerase chain reaction (RT-PCR), or western blot techniques. The results obtained showed that ABM caused oxidative stress, and triggered ERS, inflammation, apoptosis, and autophagy. On the other hand, HES showed antioxidant effect by increasing superoxide dismutase, catalase, glutathione peroxidase enzyme activities, and glutathione levels in testis tissue and attenuated lipid peroxidation. Accordingly, MAPK14 reduced the NF-κB, IL-1β, TNF-α, and IL-6 expression levels, presenting an anti-inflammatory effect. In addition, Bax protected against apoptosis and autophagy by reducing the caspase-3, beclin-1, LC3A, and LC3B expressions, and increasing Bcl-2 expression. It was observed that HES also interrupted the JAK2/STAT3 signaling pathway by suppressing IL-6 expression. Taken into consideration together, HES provided significant protection against the destruction caused by ABM in testicular tissue with antioxidant, anti-inflammatory, antiapoptotic, and anti-autophagic effects. Thus, it was revealed that HES has the potential to serve as an alternative treatment option in ABM toxicity.

Downregulation of amine oxidase copper containing 1 inhibits tumor progression by suppressing IL-6/JAK/STAT3 pathway activation in hepatocellular carcinoma.

Amine oxidase copper containing 1 (AOC1) is a copper-containing amine oxidase that catalyzes the deamination of polyamines. AOC1 functions as an oncogene in human gastric cancer. There is little information available regarding the function of AOC1 in hepatocellular carcinoma (HCC). In the present study, reverse transcription-quantitative PCR was used to detect the expression levels of AOC1 in HCC tissues, and the role of AOC1 in HCC progression was determined using western blot, Cell Counting Kit 8, clone formation, wound-healing and Transwell assays. An AOC1 survival curve was generated with data downloaded from The Cancer Genome Atlas, and Gene Set Enrichment Analysis was performed to investigate the potential biological mechanisms of AOC1 in HCC. AOC1 was found to be upregulated in HCC tissues, which was associated with a poor prognosis. Furthermore, AOC1-knockdown inhibited HCC cell proliferation, migration and invasiveness, suppressed IL-6 expression, as well as decreasing JAK2 and STAT3 phosphorylation. Ultimately, the results of the present study illustrate that AOC1 promoted the proliferation, migration and invasiveness of HCC cells by regulating the IL-6/JAK/STAT3 pathway.

Isotretinoin-Delonix polymeric nanoparticles: Potentials for skin follicular targeting in acne treatment

In acne management, oral isotretinoin (IST) is associated with various untoward systemic effects, while its topical formulation has irritation side effects. Delonix (DLX) is a natural galactomannan derived from Delonix regia seed that can fabricate nanoparticles for topical skin delivery. This study aims to develop IST-DLX nanoparticles and assess their prospects for acne treatment. Fluorescent-DLX nanoparticles (made with a lipophilic BODIPY dye) or IST-DLX nanoparticles were prepared and characterized. BODIPY-DLX nanoparticles’ skin distribution and IST-DLX nanoparticles’ in-vitro targeting were assessed in pig ear skin, inflammatory modulation was assessed in AMJ-2 macrophage cells, while skin penetration and irritation were assessed in Wistar rats. IST-DLX nanoparticles had ≈230 nm, negative zeta potential, and ≈30% encapsulation efficiency. Confocal showed BODIPY in DLX nanoparticles accumulated in hair follicles as compared to BODIPY solution. IST-DLX nanoparticles released ≈37% IST over 48 h and increased IST 3-fold in hair follicles compared to IST solution. IST-DLX nanoparticles suppressed IL-6 expression in cells and reduced photo-irritation in Wistar rats compared to IST solution. In conclusion, IST-DLX nanoparticles may target and deliver adequate IST to skin layers associated with acne, avoid systemic penetration, modulate inflammatory pathogenic acne stage and prevent IST topical photo-irritation.

In vitro impact preliminary assessment of airborne particulate from metalworking and woodworking industries

Inhalation is the main route of exposure to airborne pollutants. To evaluate the safety and assess the risks of occupational hazards different testing approaches are used. 3D airway epithelial tissues allow to mimic exposure conditions in vitro, generates human-relevant toxicology data, allows to elucidate the mode of action of pollutants. Gillian3500 pumps were used to collect the airborne particulate from woodworking and metalworking environments. EpiAirway tissues were used to model half working day (4 h), full working day (8 h), and 3 working day exposures to occupational pollutants. Tissue viability was assessed using an MTT assay. For preliminary assessment, RT-qPCR analyses were performed to analyze the expression of gelsolin, caspase-3, and IL-6. Tissue morphology was assessed by hematoxylin/eosin staining. An effect on the proliferation of lung epithelial cell line A549 was assessed. Acute exposure to workspace pollutants slightly affected tissue viability and did not change the morphology. No inhibiting effect was observed on the proliferation of A549 cells. Preliminary analysis showed that both types of particles suppressed the expression of gelsolin, with the effect of metalworking samples being more pronounced. A slight reduction in caspase-3 expression was observed. Particles from metalworking suppressed IL-6 expression.