Inducible Tumor Necrosis Factor-α Research Articles

The ameliorative effect of Acetylsalicylic acid plus Ascorbic acid against renal injury in Corn Syrup-fed rats

Dietary consumption of commercially prepared (often through processing) corn syrup can activate reactive oxygen species and the inflammatory pathways observed in kidney damage in humans and experimental animals. This study was designed to assess the effects of antioxidant properties of acetylsalicylic (ASA) and ascorbic acid (AA) on corn syrup (CS) induced renal injury. Forty male Sprague–Dawley rats (14–16 weeks) were randomly classified into 5 groups, each containing 8 rats: control group (C), CS group, CS+ASA group (ASA-10 mg/kg/day/po), CS+AA group (AA-200 mg/kg/day/po) and CS+ASA+AA group (combination treatment with ASA and AA doses). At the end of the experiment, blood and tissue samples were collected for biochemical, histopathological and immunohistochemical examinations. Malondialdehyde (p<0.001) levels were increased in the CS group compared with control group and were decreased in the ASA, AA and ASA+AA treated groups (p≤0.001 for all) compared with CS group. Catalase activities were decreased in the CS group (p≤0.001) compared with the control group (p<0.001) and significantly increased in AS+AA-treated group (p<0.001) compared with the CS group. Significant histopathological changes including tubular vacuoler degeneration, tubular dilatation, cortical and medullar haemorrhage, mononuclear cell infiltration, and increased inducible nitric oxide synthase and tumor necrosis factor-α staining were observed in the CS group. Combination theraphy reversed all these changes. The administration of ASA and AA for the treatment of kidney damage due to corn syrup consumption provides an ideal target for improving oxidative stress and potential therapeutic treatments.

Endothelin-1-mediated miR-let-7g-5p triggers interlukin-6 and TNF-α to cause myopathy and chronic adipose inflammation in elderly patients with diabetes mellitus.

Background: Diabetes and sarcopenia are verified as mutual relationships, which seriously affect the quality of life of the elderly. Endothelin-1 is well investigated, is elevated in patients with diabetes, and is related to muscle cellular senescence and fibrosis. However, the mechanism of ET-1 between diabetes and myopathy is still unclear. The aim of this study was to evaluate the prevalence of sarcopenia in the elderly with diabetes and to clarify its relationship with ET-1 molecular biological mechanism, progress as well as changes in muscle and fat.Methods: We recruited 157 type 2 diabetes patients over 55 years old and investigated the prevalence of sarcopenia in diabetes patients and examined the association of ET-1 alterations with HbA1c, creatinine, or AMS/ht2. Next, sought to determine how ET-1 regulates inflammation in muscle cells by western blot and qPCR assay. Using XF Seahorse Technology, we directly quantified mitochondrial bioenergetics in 3T3-L1 cells.Results: ET-1 was positively correlated with HbA1c, creatinine levels, and duration of disease, and negatively correlated with AMS/ht2. We found that ET-1 dose-dependently induces tumor necrosis factor-α (TNF-α) and interleukin (IL)-6β expression through the PI3K/AKT, and NF-κB signaling pathways in C2C12 cells. Also identified that TNF-α, IL-6β, and visfatin releases were found in co-cultured with conditioned medium of ET-1/C2C12 in 3T3-L1 cells. ET-1 also reduces the energy metabolism of fat and induces micro-environment inflammation which causes myopathy. ET-1 also suppresses miR-let-7g-5p expression in myocytes and adipocytes.Conclusion: We describe a new mechanism of ET-1 triggering chronic inflammation in patients with hyperglycemia.

Anti-Tumoral Effect and Action Mechanism of Exosomes Derived From Toxoplasma gondii-Infected Dendritic Cells in Mice Colorectal Cancer.

Toxoplasma gondii is an obligate intracellular protozoan with anti-tumor activity against a variety of cancers. However, the therapeutic effect of T. gondii on colorectal cancer is unclear, and using direct Toxoplasma infection in immunotherapy involves safety concerns. This study investigated the anti-tumoral effect and mechanism of exosomes derived from dendritic cells (DCs) infected with T. gondii (Me49-DC-Exo). We used differential ultracentrifugation to isolate exosomes from uninfected DCs (DC-Exo) and T. gondii Me49-infected DCs (Me49-DC-Exo). The isolated exosomes were identified by transmission electron microscopy, nanoparticle tracking analysis, and western blotting. Me49-DC-Exo significantly inhibited the tumor growth and reduced the proportion of M2 macrophages in the blood of tumor-bearing mice. In vitro, Me49-DC-Exo suppressed macrophage (RAW264.7) polarization to M2 phenotype. miRNA sequencing revealed that multiple miRNAs in Me49-DC-Exo were differentially expressed compared with DC-Exo, among which miR-182-5p, miR-155-5p, miR-125b-2-3p, and miR-155-3p were up-regulated, while miR-9-5p was significantly down-regulated. Transfecting mimics or inhibitors of these differential miRNAs into RAW264.7 cells showed that miR-155-5p promoted M1 macrophage polarization while inhibiting M2 macrophage polarization. Bioinformatics prediction and dual-luciferase reporter assay confirmed the suppressor of cytokine signaling 1 (SOCS1) as a direct target of miR-155-5p. Silencing SOCS1 gene expression in RAW264.7 cells increased CD86 + CD206 − M1 macrophage proportion, and inducible nitric oxide synthase and tumor necrosis factor-α mRNA levels. However, arginase-1 and transglutaminase 2 expression levels decreased. These results suggest that the exosomes inhibit macrophage polarization to M2 phenotype and regulate SOCS1 expression by delivering functional miR-155-5p. These findings provide new ideas for colorectal cancer immunotherapy.

BI 1015550 is a PDE4B Inhibitor and a Clinical Drug Candidate for the Oral Treatment of Idiopathic Pulmonary Fibrosis.

The anti-inflammatory and immunomodulatory abilities of oral selective phosphodiesterase 4 (PDE4) inhibitors enabled the approval of roflumilast and apremilast for use in chronic obstructive pulmonary disease and psoriasis/psoriatic arthritis, respectively. However, the antifibrotic potential of PDE4 inhibitors has not yet been explored clinically. BI 1015550 is a novel PDE4 inhibitor showing a preferential enzymatic inhibition of PDE4B. In vitro, BI 1015550 inhibits lipopolysaccharide (LPS)-induced tumor necrosis factor-α (TNF-α) and phytohemagglutinin-induced interleukin-2 synthesis in human peripheral blood mononuclear cells, as well as LPS-induced TNF-α synthesis in human and rat whole blood. In vivo, oral BI 1015550 shows potent anti-inflammatory activity in mice by inhibiting LPS-induced TNF-α synthesis ex vivo and in Suncus murinus by inhibiting neutrophil influx into bronchoalveolar lavage fluid stimulated by nebulized LPS. In Suncus murinus, PDE4 inhibitors induce emesis, a well-known gastrointestinal side effect limiting the use of PDE4 inhibitors in humans, and the therapeutic ratio of BI 1015550 appeared to be substantially improved compared with roflumilast. Oral BI 1015550 was also tested in two well-known mouse models of lung fibrosis (induced by either bleomycin or silica) under therapeutic conditions, and appeared to be effective by modulating various model-specific parameters. To better understand the antifibrotic potential of BI 1015550 in vivo, its direct effect on human fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) was investigated in vitro. BI 1015550 inhibited transforming growth factor-β-stimulated myofibroblast transformation and the mRNA expression of various extracellular matrix proteins, as well as basic fibroblast growth factor plus interleukin-1β-induced cell proliferation. Nintedanib overall was unremarkable in these assays, but interestingly, the inhibition of proliferation was synergistic when it was combined with BI 1015550, leading to a roughly 10-fold shift of the concentration–response curve to the left. In summary, the unique preferential inhibition of PDE4B by BI 1015550 and its anticipated improved tolerability in humans, plus its anti-inflammatory and antifibrotic potential, suggest BI 1015550 to be a promising oral clinical candidate for the treatment of IPF and other fibro-proliferative diseases.

Noncanonical Wnt5a/JNK Signaling Contributes to the Development of D-Gal/LPS-Induced Acute Liver Failure.

Acute liver failure (ALF) is a deadly clinical disorder with few effective treatments and unclear pathogenesis. In our previous study, we demonstrated that aberrant Wnt5a expression was involved in acute-on-chronic liver failure. However, the role of Wnt5a in ALF is unknown. We investigated the expression of Wnt5a and its downstream c-Jun N-terminal kinase (JNK) signaling in a mouse model of ALF established by coinjection of D-galactosamine (D-Gal) and lipopolysaccharide (LPS) in C57BL/6 mice. We also investigated the role of Box5, a Wnt5a antagonist, in vivo. Moreover, the effect of Wnt5a/JNK signaling on downstream inflammatory cytokine expression, phagocytosis, and migration in THP-1 macrophages was studied in vitro. Aberrant Wnt5a expression and JNK activation were detected in D-Gal/LPS-induced ALF mice. Box5 pretreatment reversed JNK activation and eventually decreased the mortality rate of D-Gal/LPS-treated mice, with reduced hepatic necrosis and apoptosis, serum ALT and AST levels, and liver inflammatory cytokine expression, although the latter was not significant. We further demonstrated that recombinant Wnt5a (rWnt5a)-induced tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) mRNA expression and increased THP-1 macrophage phagocytosis in a JNK-dependent manner, which could be restored by Box5. In addition, rWnt5a-induced migration of THP-1 macrophages was also reversed by Box5. Our findings suggested that Wnt5a/JNK signaling plays an important role in the development of ALF and that Box5 could have particular hepatoprotective effects in ALF.

Structural characterization of phenolic constituents from the rhizome of Imperata cylindrica var. major and their anti-inflammatory activity

As one of raw materials, the rhizome of Imperata cylindrica var. major (Nees) C.E. Hubb. is used in kinds of preparations curing inflammation related diseases, while its effective substances are not yet clear. In this paper, its chemical constituents and their anti-inflammatory activities were investigated. As results, ten compounds, named as imperphenoside A (1), imperphenols B (2) and C (3), imperphenosides D–F (4–6), and imperlignanosides A–D (7–10), along with previously reported thirty-seven known ones (11–47) were obtained from it. Their structures were ascertained basing on the extensive spectroscopic methods and electronic circular dichroism data analysis. Meanwhile, compounds 4, 11, 12, 24, 27, 31, 32, 37, 43, 45, and 47 exhibited nitric oxide inhibitory effects in concentration dependent at 3, 10, and 30 μM on lipopolysaccharides induced RAW 264.7 cells. Moreover, the western blot analysis indicated that compounds 4, 11, 43, and 47 could restrain the phosphorylation of nuclear factor kappa-B kinase to down-regulate the protein expression of inflammatory cytokines such as inducible nitric oxide synthase, interleukin-6 and tumor necrosis factor-α. In conclusion, they might play the anti-inflammatory effects through regulating NF-κB signaling pathway.

Structure and pro-inflammatory activities of bran polysaccharides from a novel wheat kernel.

In this study, the structure and pro-inflammatory activities of water-soluble wheat bran polysaccharides (WBP) were evaluated. WBP were heteropolysaccharides consisting 60.34% arabinoxylan as the main component and 31.80% mannose residues characterized with the instrumental analyses. The result of cellular experiment displayed that WBP had significant pro-inflammatory activities by increasing the concentration of nitric oxide (NO) and up-regulating the inflammatory cytokine expressions of inducible nitric oxide synthase (iNOS), interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2), and tumor necrosis factor-α (TNF-α). WBP mediated macrophages RAW 264.7 pro-inflammatory response through phosphatidylinositol 3 hydroxykinase/protein kinase B (PI3K/Akt) signaling pathway by significantly promoting Akt and phosphoinositide-dependent kinase 1 (PDK1) phosphorylations. Meanwhile, the expression of related phosphorylated proteins JNK and ERK1/2 was significantly up-regulated which suggested that WBP played pro-inflammatory roles by activating mitogen-activated protein kinases (MAPKs) signaling pathway. PRACTICAL APPLICATIONS: In recent years, wheat bran generally has the phenomenon of high yield and low utilization rate. Wheat bran has rich nutritional value and contains a lot of effective biologically active substances. Based on our findings, the water-soluble polysaccharides extracted from wheat bran have significant effects on regulating immunity and can be utilized as sources of natural immune modulators. The research can develop new functions of wheat bran polysaccharides, and improve processing utilization rate and product added value.

Phase 1b Results for Subcutaneous Talquetamab Plus Daratumumab in Patients with Relapsed/Refractory Multiple Myeloma

Phase 1b Results for Subcutaneous Talquetamab Plus Daratumumab in Patients with Relapsed/Refractory Multiple Myeloma

Reciprocal induction of hepatitis C virus replication and stimulation of hepatic profibrogenic cytokine release and cellular viability by YKL-40.

BackgroundPrevious studies have suggested the YKL-40/chitinase 3-like protein 1 protein is upregulated in chronic hepatitis C virus (HCV) infection with fibrosis. We sought to determine whether HCV regulates YKL-40 expression and to elucidate the mechanisms by which YKL-40 mediates the liver fibrosis caused by HCV infection.MethodsWe used purified protein, small molecule inhibitors and short-interfering RNAs to over-express or knock down certain kinases to explore the mechanisms underlying the regulation by HCV of YKL-40 expression in the Japanese fulminant hepatitis 1 (JFH1) model.ResultsHCV induced YKL-40 production in hepatic parenchymal cells. Further, HCV-mediated upregulation of YKL-40 through cooperative induction of tumor necrosis factor-α (TNF-α) and reactive oxygen species (ROS)-mitogen-activated protein kinase MAPKs, which are nuclear factor-κB (NF-κB)-dependent pathways. YKL-40 protein also mildly increased HCV replication, triggering hepatic profibrogenic cytokine release and cellular viability as feedback. Additionally, hepatic parenchymal cells were the sole source of YKL-40 production in the infectious JFH1 model, whereas YKL-40 was under-detected in hepatic stellate cells (HSCs) in the presence or absence of the JFH1 supernatant, which was not investigated so far.ConclusionsHCV induced and maintained secretion of YKL-40 through sustained activation of NF-κB via cooperative induction of the TNF-α and ROS-MAPKs pathways. HCV interacted with YKL-40 to enhance the progression of hepatic fibrosis. These findings support a potential role for blockade of YKL-40 as an antifibrotic strategy.

Probiotic Properties of Lactic Acid Bacteria with High Conjugated Linoleic Acid Converting Activity Isolated from Jeot-Gal, High-Salt Fermented Seafood.

Conjugated linoleic acid (CLA) isomers are potent health-promoting fatty acids. This study evaluated the probiotic properties of 10 strains of high CLA-producing lactic acid bacteria (LAB) isolated from Jeot-gal, a high-salt, fermented seafood. Two isolates, Lactiplantibacillus plantarum JBCC105683 and Lactiplantibacillus pentosus JBCC105676, produced the largest amounts of CLA (748.8 and 726.9 μg/mL, respectively). Five isolates, L. plantarum JBCC105675, L. pentosus JBCC105676, L. pentosus JBCC105674, L. plantarum JBCC105683, and Lactiplantibacillus paraplantarum JBCC105655 synthesized more cis-9, trans-11-CLA than trans-10, cis-12-CLA (approximately 80:20 ratio). All the strains survived severe artificial acidic environments and showed antimicrobial activity and strong adhesion capability to Caco-2 cells as compared to the commercial strain Lactocaseibacillus rhamnosus GG. Among them, Pediococcus acidilactici JBCC105117, L. paraplantarum JBCC105655, and L. plantarum JBCC105683 strongly stimulated the immunological regulatory gene PMK-1 and the host defense antimicrobial peptide gene clec-60 in Caenorhabditis elegans. Moreover, three strains showed a significant induction of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, IL-12, and IL-10 production in RAW 264.7 macrophages, indicating that they were promising candidates for probiotics with high CLA-converting activity. Our results indicate that the newly isolated CLA-producing LAB might be useful as a functional probiotic with beneficial health effects that modulate the immune system.

Oncostatin M promotes hepatic progenitor cell activation and hepatocarcinogenesis via macrophage-derived tumor necrosis factor-α

Hepatocellular carcinoma (HCC) usually occurs at the late stage of chronic liver injury. Oncostatin M (OSM) is a tumor-associated cytokine highly expressed in cirrhosis and HCC patients; however, its role in hepatocarcinogenesis has not been clearly elucidated. In this study, we investigated the effect of OSM on HCC occurrence in a rat model of N-diethylnitrosamine-induced HCC. OSM overexpression significantly increased the number of tumor nodules and shortened the overall survival of the rats. Notably, OSM promoted HPC activation in vivo but did not directly regulate the proliferation of the HPC cell line in vitro. Further, OSM induced tumor necrosis factor-α (TNF-α) secretion and CD68+ macrophage accumulation, which were positively correlated with HPC activation. Additionally, TNF-α or macrophage depletion inhibited the promoting effect of OSM on hepatocarcinogenesis and HPC activation. Furthermore, OSM expression in the peritumoral tissues of HCC was positively correlated with poor overall survival of patients. In conclusion, OSM plays an important role in hepatocarcinogenesis by regulating the liver inflammation environment. Hence, OSM could be used as a potential target for HCC prevention and therapy or as an indicator of HCC prognosis.

Anti-Inflammatory Effect of Liverwort (Marchantia polymorpha L.) and Racomitrium Moss (Racomitrium canescens (Hedw.) Brid.) Growing in Korea.

Bryophytes contain a variety of bioactive metabolites, but studies about the anti-inflammatory effect of bryophytes are meager. Therefore, the present study aimed to compare the anti-inflammatory effect of methanol extract of Marchantia polymorpha L. (liverwort) and Racomitrium canescens (Racomitrium moss) in lipopolysaccharide (LPS)-induced HaCaT cells. To evaluate the anti-inflammatory effect of liverwort and Racomitrium moss, the levels of nitric oxide (NO) production and the mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and tumor necrosis factor-α (TNF-α), and interleukin (IL)-6 and IL-1β in LPS-induced HaCaT cells were measured. The methanol extract of liverwort and Racomitrium moss significantly decreased LPS-induced NO production in HaCaT cells. When compared with Racomitrium moss extract, pre-treatment with methanol extract of liverwort markedly inhibited the expression of iNOS, COX-2, IL-6, and IL-1β at the concentration of 100 µg/mL with the exception of TNF-α. Further, liverwort extract markedly attenuated the production of TNF-α, IL-6, and IL-1β in the culture medium. In addition, ethyl acetate and butanol fractions obtained from the methanol extract of liverwort showed remarkable inhibitory activity against the production of NO in LPS-stimulated HaCaT cells. The LC-MS data revealed the presence of bisbibenzyl types of bioactive components in the methanol extract of liverwort. These data demonstrate that liverwort extract exhibits effective inhibitory activity against the production of inflammatory mediators in LPS-induced HaCaT cells and may be useful for the treatment of inflammation-mediated diseases.

Pathogenic Characterization of Clostridium perfringens Strains Isolated From Patients With Massive Intravascular Hemolysis.

Sepsis caused by Clostridium perfringens infection is rare but often fatal. The most serious complication leading to poor prognosis is massive intravascular hemolysis (MIH). However, the molecular mechanism underlying this fulminant form of hemolysis is unclear. In the present study, we employed 11 clinical strains isolated from patients with C. perfringens septicemia and subdivided these isolates into groups H and NH: septicemia with (n = 5) or without (n = 6) MIH, respectively. To elucidate the major pathogenic factors of MIH, biological features were compared between these groups. The isolates of two groups did not differ in growth rate, virulence-related gene expression, or phospholipase C (CPA) production. Erythrocyte hemolysis was predominantly observed in culture supernatants of the strains in group H, and the human erythrocyte hemolysis rate was significantly correlated with perfringolysin O (PFO) production. Correlations were also found among PFO production, human peripheral blood mononuclear cell (PBMC) cytotoxicity, and production of interleukin-6 (IL-6) and interleukin-8 (IL-8) by human PBMCs. Analysis of proinflammatory cytokines showed that PFO induced tumor necrosis factor-α (TNF-α), IL-5, IL-6, and IL-8 production more strongly than did CPA. PFO exerted potent cytotoxic and proinflammatory cytokine induction effects on human blood cells. PFO may be a major virulence factor of sepsis with MIH, and potent proinflammatory cytokine production induced by PFO may influence the rapid progression of this fatal disease caused by C. perfringens.

Recombinant Rv1654 protein of Mycobacterium tuberculosis induces mitochondria-mediated apoptosis in macrophage.

Mycobacterium tuberculosis contains diverse immunologically active components. This study investigated the biological function of a newly identified component, Rv1654, with the potential to induce apoptosis in macrophages. Recombinant Rv1654 induced macrophage apoptosis in a caspase-9/3-dependent manner through the production of reactive oxygen species (ROS) and interaction with Toll-like receptor 4. In addition, Rv1654 induced the production of tumor necrosis factor-α, interleukin-6, and monocyte chemoattractant protein-1 through the mitogen-activated protein kinase pathway. Furthermore, Rv1654-induced c-Jun N-terminal kinase (JNK) activation was inhibited by the ROS scavenger and Rv1654-induced apoptosis was inhibited by the JNK inhibitor. Moreover, it was found that treatment of macrophages with Rv1654 led to the loss of mitochondrial membrane potential, release of cytochrome c into the cytosol, and translocation of Bax into the mitochondria. Finally, Rv1654-mediated apoptosis was inhibited in macrophages transfected with Bax siRNA. These results suggest that Rv1654 induces macrophage apoptosis through a mitochondrial-dependent pathway and ROS-mediated JNK activation.

SOCS1/JAK2/STAT3 axis regulates early brain injury induced by subarachnoid hemorrhage via inflammatory responses.

The SOCS1/JAK2/STAT3 axis is strongly associated with tumor growth and progression, and participates in cytokine secretion in many diseases. However, the effects of the SOCS1/JAK2/STAT3 axis in experimental subarachnoid hemorrhage remain to be studied. A subarachnoid hemorrhage model was established in rats by infusing autologous blood into the optic chiasm pool. Some rats were first treated with JAK2/STAT3 small interfering RNA (Si-JAK2/Si-STAT3) or overexpression plasmids of JAK2/STAT3. In the brains of subarachnoid hemorrhage model rats, the expression levels of both JAK2 and STAT3 were upregulated and the expression of SOCS1 was downregulated, reaching a peak at 48 hours after injury. Simultaneously, the interactions between JAK2 and SOCS1 were reduced. In contrast, the interactions between JAK2 and STAT3 were markedly enhanced. Si-JAK2 and Si-STAT3 treatment alleviated cortical neuronal cell apoptosis and necrosis, destruction of the blood-brain barrier, brain edema, and cognitive functional impairment after subarachnoid hemorrhage. This was accompanied by decreased phosphorylation of JAK2 and STAT3 protein, decreased total levels of JAK2 and STAT3 protein, and increased SOCS1 protein expression. However, overexpression of JAK2 and STAT3 exerted opposite effects, aggravating subarachnoid hemorrhage-induced early brain injury. Si-JAK2 and Si-STAT3 inhibited M1-type microglial conversion and the release of pro-inflammatory factors (inducible nitric oxide synthase, interleukin-1β, and tumor necrosis factor-α) and increased the release of anti-inflammatory factors (arginase-1, interleukin-10, and interleukin-4). Furthermore, primary neurons stimulated with oxyhemoglobin were used to simulate subarachnoid hemorrhage in vitro, and the JAK2 inhibitor AG490 was used as an intervention. The in vitro results also suggested that neuronal protection is mediated by the inhibition of JAK2 and STAT3 expression. Together, our findings indicate that the SOCS1/JAK2/STAT3 axis contributes to early brain injury after subarachnoid hemorrhage both in vitro and in vivo by inducing inflammatory responses. This study was approved by the Animal Ethics Committee of Anhui Medical University and the First Affiliated Hospital of University of Science and Technology of China (approval No. LLSC-20180202) on March 1, 2018.

A "sandwich" cell culture platform with NIR-responsive dynamic stiffness to modulate macrophage phenotypes.

Considering the key roles of macrophages in tissue repair and immune therapy, designing smart biomaterials able to harness macrophage phenotypes on demand during the healing process has become a promising strategy. Here, a novel "sandwich" cell culture platform with near-infrared (NIR) responsive dynamic stiffness was fabricated to polarize bone marrow-derived macrophages (BMDMs) in situ for revealing the relationship between the macrophage phenotype and substrate stiffness dynamically. Under NIR irradiation, calcium ions (Ca2+) diffused through the middle layer of the IR780-mixed phase change material (PCM) due to the photothermal effect of IR780, resulting in an increase of hydrogel stiffness in situ by the crosslinking of the upper layer of the hyaluronic acid-sodium alginate hydrogel (MA-HA&SA). The up-regulation of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-α (TNF-α) was quantified by immunostaining and enzyme-linked immune sorbent assay (ELISA), respectively, indicating the transformation of macrophages from the anti-inflammatory to pro-inflammatory phenotype under dynamic stiffness. The nuclear Yes-associated-protein (YAP) ratio positively correlated with the shift of the macrophage phenotype. The modulation of macrophage phenotypes by stiffness-rise without the stimuli of cytokines offers an effective and noninvasive strategy to manipulate immune reactions to achieve optimized healing or therapeutic outcomes.

Taurine attenuates the damage of lupus nephritis mouse via inactivation of the NF-κB pathway

Taurine is an organic amino acid and a major constituent of bile. With its contribution to various cellular functions, it has demonstrated therapeutic effects in a wide range of diseases. Since there is a lack of literature investigating taurine as a treatment for lupus nephritis (LN), here we examined the potential of taurine as a treatment for LN. Experiments were carried out using MRL/lpr mice as a model of LN, and C57BL/6 mice were used as negative controls. At 12 weeks old, MRL/lpr mice were divided into four groups and treated with 0, 50 and 100 mg/kg body weight taurine for 5 days. Enalapril is used as a positive control drug. All animals were sacrificed after treatment. LN-induced damage was assessed by proteinuria, blood urea nitrogen (BUN) and serum creatinine (CRE) levels. The degree of inflammation was assessed by inducible nitric oxide synthase (iNOS), interleukin-4 (IL-4), IL-10, and tumor necrosis factor-α (TNF-α) levels. The degree of oxidative stress was assessed by malondialdehyde (MDA), reactive oxygen species (ROS), superoxide dismutase (SOD), and glutathione peroxidase (Gpx) levels. Hematoxylin and eosin (HE) staining and TUNEL staining assessed histopathological damage and apoptosis, respectively. The levels of Bcl-2, Bax, caspase-3, caspase-9, and NF-κB p65 were detected by western blot. The data indicated that taurine administration improved kidney functions, reversed cell death, suppressed oxidative stress, and importantly, adjusted the immune response of LN mice to a more balanced state. These results provide a novel strategy for LN therapy, which may overcome the disadvantages of traditional immunosuppression and hormone treatments with greater efficacy and fewer side effects.

A 'Sandwich' Cell Culture Platform with NIR-Responsive Dynamic Stiffness to Modulate Macrophage Phenotypes

Considering the key roles of macrophages in tissue repair and immune therapy, designing smart biomaterials able to harness macrophage phenotypes on demand during the healing process has become a promising strategy. Here, a novel “sandwich” cell culture platform with near-infrared (NIR) responsive dynamic stiffness was fabricated to polarize macrophage in situ for revealing the relationship between macrophages phenotype and substrate stiffness dynamically. Under NIR irradiation, calcium ions (Ca2+) were diffused through the middle layer of IR780-mixed phase change material (PCM) due to the photo-thermal effect of IR780, resulting in the increase of hydrogel stiffness in situ by the crosslinking of the upper layer of hyaluronic acid-sodium alginate hydrogel (MA-HA&SA). The up-regulation of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-α (TNF-α) were quantified by immunostaining and enzyme-linked immune sorbent assay (ELISA), respectively, indicating the transformation of macrophage from the anti-inflammatory to pro-inflammatory phenotype under dynamic stiffness. An increase of nuclear localization of Yes-associated-protein (YAP) confirmed that the mechanotransduction mechanism of the transition of macrophages phenotype. The modulation of macrophage phenotypes by dynamic stiffness without the stimuli of cytokines offers an effective and noninvasive strategy to manipulate immune reactions to achieve optimized healing or therapeutical outcomes.

Interleukin-6, Tumor Necrosis Factor-α Expression Levels in Prostate Cancer Tissues and Their Effects on Epithelial Interstitial Transformation, Migration and Invasion in Prostate Cancer Cells

Background: To investigate the expression of Interleukin-6, Interleukin-6 in prostate cancer tissues and its effect on migration and evasiveness of cancer cells. Material and Methods: The releasing of Interleukin-6, Tumor necrosis factor-α in prostate cancer cells was detected by ELISA method. For prostate cancer cells after knockout, additional Interleukin-6 or Tumor necrosis factor-α induction was given in vitro. After 12 h of culture, the effects of Interleukin-6, Tumor necrosis factor-α on the migration and evasiveness of prostate cancer cells were observed by Western blot method and matrices invasion experiment. Results: The expression of epithelial mesenchymal transition-related proteins, the migration and invasion ability of prostate cancer cells in each gene knockout group were significantly reduced. After induction of inflammatory factors (Interleukin-6 or Tumor necrosis factor-α) in the gene knockout group for 12 h, the expression levels of epithelial mesenchymal transition-related proteins, the migration and aggressiveness of prostate cancer were significantly higher than those after knockout. Conclusion: Interleukin-6 and Tumor necrosis factor-α can induce epithelial mesenchymal transition in LNCaP and PC3 cells, promote cell invasion and metastasis, and provide a new direction for future research.

Evaluation of serum and gingival crevicular fluid microRNA-223, microRNA-203 and microRNA-200b expression in chronic periodontitis patients with and without diabetes type 2

microRNA dysregulation is a reported feature of multiple pathologies, including periodontal disease, as demonstrated on cell lines, in animal models, and tissues biopsies, but serum and gingival crevicular fluid microRNA expression data in humans is scarce, especially with the diabetes (type 2) systemic complication. ObjectiveTo assess serum and gingival crevicular fluid relative quantification levels of miR-223, miR-203, and miR-200b in chronic periodontitis and type 2 diabetic chronic periodontitis patients to address their possible implication in chronic periodontitis pathogenesis and its systemic complications and also to correlate their differential expression with some inflammatory (serum tumor necrosis factor-α and interleukin-10) parameters. MethodsSixty subjects were recruited and divided into three groups; chronic periodontitis (n = 20), type 2 diabetic chronic periodontitis (n = 20), and healthy control (n = 20). Both serum and gingival crevicular fluid were collected from each participant for miRNA expression analysis and serum inflammatory parameters assessment. ResultsA significant increase in the relative quantification levels of miR-223 and miR-200b were detected in patient groups along with a positive correlation with tumor necrosis factor-α. However, miR-203 was significantly decreased in patient groups associated with a negative correlation with tumor necrosis factor-α. ConclusionsmiR-223 and miR-200b have a potential role in chronic periodontitis pathogenesis associated with type 2 diabetes, with the ability to induce tumor necrosis factor-α secretion, while miR-203 might have a protective and healing role due to the negative correlation with the serum tumor necrosis factor-α levels found. Therefore, they may be considered as a promising therapeutic target and effective serum disease biomarkers.