Levels Of Nuclear Factor Research Articles

Cardioprotective Effects of Ursodeoxycholic Acid in Isoprenaline-Induced Myocardial Injury in Rats.

Patients suffering from cholelithiasis have an increased risk of developing cardiovascular complications, particularly ischemic myocardial disease. Ursodeoxycholic acid (UDCA), already used in clinical practice for the treatment of cholelithiasis and related conditions, has proven antioxidative, anti-inflammatory, and cytoprotective effects. Therefore, the aim of this study was to investigate the cardioprotective effect of UDCA pre-treatment on isoprenaline-induced myocardial injury in rats. Male Wistar albino rats were randomized into four groups. Animals were pre-treated for 10 days with propylene glycol + saline on days 9 and 10 (control), 10 days with propylene glycol + isoprenaline on days 9 and 10 (I group), 10 days with UDCA + saline on days 9 and 10 (UDCA group), and 10 days with UDCA + isoprenaline on days 9 and 10 (UDCA + I group). UDCA pre-treatment significantly reduced values of high-sensitivity troponin I (hsTnI) and aspartate aminotransferase (AST) cardiac markers (p < 0.001 and p < 0.01, respectively). The value of thiobarbituric acid reactive substances (TBARS) was also decreased in the UDCA + I group compared to the I group (p < 0.001). UDCA also significantly increased glutathione (GSH) levels, while showing a tendency to increase levels of superoxide dismutase (SOD) and catalase (CAT). The level of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression, a key regulatory gene of inflammation, was diminished when UDCA was administered. A reduction of cardiac damage was also observed in the UDCA pre-treated group. In conclusion, UDCA pre-treatment showed a cardioprotective effect on isoprenaline-induced myocardial injury in rats, primarily by reducing oxidative stress and inflammation.

Protective effect of tert-butylhydroquinone against cisplatin-induced hepatorenal injury via modulating oxidative stress, inflammation, and apoptosis

Context Cisplastin (CDDP) is a chemotherapeutic drug frequently used to manage a variety of cancers. However, its use is associated with hepatorenal toxicity resulting from elevated reactive oxygen species production. Objective Herein, the hepatorenal protective effect of tert-butylhydroquinone (tBHQ) in cisplatin (CDDP)-treated rats was examined. Methods Wistar male rats randomly divided into four groups: normal control, tBHQ, CDDP and tBHQ + CDDP received 50 mg/kg b.w./day of tBHQ orally for 14 days while 7 mg/kg b.w of CDDP was administered intraperitoneally on Day 8. Results CDDP increased serum biomarkers of hepatic (AST, ALP, ALT, GGT) and renal (creatinine, urea, uric acid, kidney injury molecule 1) function. The levels of nuclear factor erythroid-2-related factor 2 protein and the activities of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase activities were decreased in liver and kidney. Also, CDDP increased hepatic and renal levels of NF-κB, TNFα, Bax and caspase-3 proteins and decreased hepatorenal levels of Bcl-2 protein in the liver and kidney. Pre-treatment with tBHQ prevented these negative effects. Significance Pre-intervention with tBHQ attenuates hepatorenal toxicity of CDDP by dampening oxidative stress, inflammation and apoptosis.

Effects of Gap 26, a Connexin 43 Inhibitor, on Cirrhotic Cardiomyopathy in Rats.

Introduction Cirrhotic cardiomyopathy (CCM) is recognized by impaired cardiac responsiveness to stress, prolonged QT interval, and systolic and diastolic dysfunctions. Connexins are a family of transmembrane proteins that play a key role in cardiac physiology. Connexin 43 (Cx43) inhibition showed cardio-protective effects. Peptide drug Cx43 inhibitor, Gap 26, could inhibit gap junction 43. This study was designed to evaluate the effects of a connexin mimetic peptide, Gap 26, in the CCM model in rats. Methods The cirrhosis was induced through carbon tetrachloride (CCl4). On day 56, electrocardiography (ECG) was recorded, spleen weight was measured, and tissue and serum samples were collected. Further, Cx43 mRNA expression in heart tissue was checked. Results The chronotropic responses decreased in the CCl4/saline and increased in the CCl4/Gap. The spleen weight, QTc interval, and brain natriuretic peptide (BNP), tumor necrosis factor-alpha (TNF-α), aspartate aminotransferase (AST), alanine transaminase (ALT), and malondialdehyde (MDA) levels elevated in the CCl4/saline, and the spleen weight, QTc interval, and MDA and ALT levels were reduced by Gap 26 treatment. The level of nuclear factor (erythroid-derived 2) factor 2 (Nrf2) decreased in the CCl4/saline. The Cx43 expression was downregulated in the CCl4/saline and upregulated with the Gap 26 treatment. Conclusion Gap 26 not only alleviated the chronotropic hyporesponsiveness and the severity of liver damage and upregulated the atrial Cx43 expression, but it also had an antioxidant effect on the heart.

MiR-25 overexpression inhibits titanium particle-induced osteoclast differentiation via down-regulation of mitochondrial calcium uniporter in vitro

BackgroundMitochondrial calcium uniporter (MCU) is an important ion channel regulating calcium transport across the mitochondrial membrane. Calcium signaling, particularly via the Ca2+/NFATc1 pathway, has been identified as an important mediator of the osteoclast differentiation that leads to osteolysis around implants. The present study aimed to investigate whether down-regulation of MCU using microRNA-25 (miR-25) mimics could reduce osteoclast differentiation induced upon exposure to titanium (Ti) particles.MethodsTi particles were prepared. Osteoclast differentiation of RAW264.7 cells was induced by adding Ti particles and determined by TRAP staining. Calcium oscillation was determined using a dual-wavelength technique. After exposure of the cells in each group to Ti particles or control medium for 5 days, relative MCU and NFATc1 mRNA expression levels were determined by RT-qPCR. MCU and NFATc1 protein expression was determined by western blotting. NFATc1 activation was determined by immunofluorescence staining. Comparisons among multiple groups were conducted using one-way analysis of variance followed by Tukey test, and differences were considered significant if p < 0.05.ResultsMCU expression was reduced in response to miR-25 overexpression during the process of RAW 264.7 cell differentiation induced by Ti particles. Furthermore, osteoclast formation was inhibited, as evidenced by the low amplitude of calcium ion oscillation, reduced NFATc1 activation, and decreased mRNA and protein expression levels of nuclear factor-κB p65 and calmodulin kinases II/IV.ConclusionsRegulation of MCU expression can impact osteoclast differentiation, and the underlying mechanism likely involves the Ca2+/NFATc1 signal pathway. Therefore, MCU may be a promising target in the development of new strategies to prevent and treat periprosthetic osteolysis.

Ursolic acid mitigates cognitive dysfunction through amelioration of oxidative stress, inflammation and apoptosis in diabetic rats

&#x0D; &#x0D; &#x0D; &#x0D; Purpose: To determine the effect of ursolic acid (UA) on diabetes-induced cognitive defect, as well as its mechanism of action in streptozotocin (STZ)-induced diabetic rats.&#x0D; Methods: A rat model of diabetes was established by administration of STZ. The rats received UA via gastric perfusion for 56 successive days. Learning and memory functions were assessed using Morris water maze. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) levels in hippocampus tissues were determined spectrophotometrically. Tumor necrosis factor-a (TNF-a), interleukin-1β (IL-1β) and interleukin-6 (IL-6) levels were assayed by quantitative real-time polymerase chain reaction (qRT- PCR) and enzyme-linked immunosorbent assay (ELISA). The protein expression levels of nuclear factor erythroid-2-related factor-2 (Nrf-2), heme oxygenase-1 (HO-1), Bcl-2 and Bax were evaluated by western blotting.&#x0D; Results: Learning and memory impairment in STZ-induced diabetic rats was mitigated by UA (p &lt; 0.05). In hippocampus tissue, UA reduced oxidative stress by enhancing SOD activity and reducing MDA levels. Furthermore, UA reduced inflammatory response by downregulating TNF-α, IL-1β and IL-6 levels (p &lt; 0.05). Concomitantly, the lower protein concentrations of Nrf-2 and HO-1 were elevated by administration of UA. Furthermore, UA suppressed Bax/Bcl-2 ratio to ameliorate apoptosis (p &lt; 0.05).&#x0D; Conclusion: UA reduces diabetes-induced hippocampal oxidative stress, inflammation and apoptosis. Thus, it might be a potential drug candidate for delaying diabetes-associated cognitive decline (DACD).&#x0D; &#x0D; &#x0D; &#x0D;

Andrographolide Inhibits Proliferation and Promotes Apoptosis in Bladder Cancer Cells by Interfering with NF- κ B and PI3K/AKT Signaling In Vitro and In Vivo

To explore the influences of andrographolide (Andro) on bladder cancer cell lines and a tumor xenograft mouse model bearing 5637 cells. For in vitro experiments, T24 cells were stimulated with Andro (0-40 µmol/L) and 5637 cells were stimulated with Andro (0 to 80 µmol/L). Cell growth, migration, and infiltration were assessed using cell counting kit-8, colony formation, wound healing, and transwell assays. Apoptosis rate was examined using flow cytometry. In in vivo study, the antitumor effect of Andro (10 mg/kg) was evaluated by 5637 tumor-bearing mice, and levels of nuclear factor κ B (NF- κ B) and phosphoinositide 3-kinase/AKT related-proteins were determined by immunoblotting. Andro suppressed growth, migration, and infiltraion of bladder cancer cells (P⩽0.05 or P⩽0.01). Additionally, Andro induced intrinsic mitochondria-dependent apoptosis in bladder cancer cell lines. Furthermore, Andro inhibited bladder cancer growth in mice (P⩽0.01). The expression of p65, p-AKT were suppressed by Andro treatment in vitro and in vivo (P⩽0.05 or P⩽0.01). Andrographolide inhibits proliferation and promotes apoptosis in bladder cancer cells by interfering with NF- κ B and PI3K/AKT signaling in vitro and in vivo.

NFATc1/αA and Blimp-1 Support the Follicular and Effector Phenotype of Tregs.

CD4+CXCR5+Foxp3+ T-follicular regulatory (TFR) cells control the germinal center responses. Like T-follicular helper cells, they express high levels of Nuclear Factor of Activated T-cells c1 , predominantly its short isoform NFATc1/αA. Ablation of NFATc1 in Tregs prevents upregulation of CXCR5 and migration of TFR cells into B-cell follicles. By contrast, constitutive active NFATc1/αA defines the surface density of CXCR5, whose level determines how deep a TFR migrates into the GC and how effectively it controls antibody production. As one type of effector Treg, TFR cells express B lymphocyte-induced maturation protein-1 (Blimp-1). Blimp-1 can directly repress Cxcr5 and NFATc1/αA is necessary to overcome this Blimp-1-mediated repression. Interestingly, Blimp-1 even reinforces the recruitment of NFATc1 to Cxcr5 by protein-protein interaction and by those means cooperates with NFATc1 for Cxcr5 transactivation. On the contrary, Blimp-1 is necessary to counterbalance NFATc1/αA and preserve the Treg identity. This is because although NFATc1/αA strengthens the follicular development of Tregs, it bears the inherent risk of causing an ex-Treg phenotype.

Waterpipe smoke-induced hypercoagulability and cardiac injury in mice: Influence of cessation of exposure

Waterpipe tobacco smoking has gained worldwide popularity, particularly among youths. Several clinical and experimental studies have reported that waterpipe smoking (WPS) injures the cardiovascular system. However, the impact of smoking cessation (CS) on the cardiovascular toxicity induced by WPS received scant attention. Hence, we assessed, in C57BL/6 mice, the cardiovascular effects of WPS exposure for 3 months followed by 3 months of SC, as compared with mice exposed for either 3 months to WPS or air (control). WPS exposure induced hypertension, prothrombotic events both in vivo and in vitro and increased the plasma concentrations of tissue factor, fibrinogen and plasminogen activator inhibitor-1. These effects were significantly alleviated by SC. In heart tissue, the levels of troponin I, creatine kinase, lipid peroxidation, 8-isoprostane, tumor necrosis factor α, inteleukin 6, DNA damage and cleaved caspase-3 were significantly increased by WPS exposure. These actions were significantly reduced in the group of mice exposed to WPS followed by SC. Similarly, the increase in the level of nuclear factor κ-β induced by WPS exposure was significantly mitigated by SC. Immunohistochemical analysis of the hearts showed that WPS exposure increased the expression of nuclear factor erythroid-derived 2-like 2 by cardiomyocytes. The latter effect was significantly reduced by SC. Taken together, our data show that SC is associated with amelioration of WPS induced hypertension, prothrombotic events and cardiac oxidative stress, inflammation, DNA damage and apoptosis.

Protective effect of Geophila obvallata (Shumach) Didr leaf extract and its fractions against cadmium-induced nephrotoxicity in male Wistar rats

Cadmium (Cd) is a known nephro-toxicant. This research determined the ameliorative effects of Geophila obvallata crude methanol extract (Me70) and its fractions on Cd-induced nephrotoxicity in Wistar rats. Male rats were randomly allocated to nine (9) groups of six (6) rats each. Group I was given normal water and feed only. Group II received 0.3 mg Cd/L only for two weeks. Groups III, IV, V, VI and VII were pre-exposed to aqueous, ethyl acetate, hexane, butanol and chloroform fractions of Me70, each at a dose of 50 mg/kg bwt for fourteen (14) days prior to treatment with 0.3 mg Cd/L for a further two weeks. Group VIII was pre-exposed to Me70 at a dose of 50 mg/kg bwt for fourteen (14) days, prior to administration of 0.3 mg Cd/L for fourteen (14) days, while group IX received 50 mg/kg.bwt of Me70 only for fourteen (14) days. The treatments were administered daily for twenty-eight (28) days via oral gavage. Cadmium levels in the kidney tissues of Cd-treated rats increased significantly while their body weights decreased relative to control. The levels of kidney function markers in the plasma, lipid peroxidation levels, catalase activity, metallothionine (MT-1) and kidney injury molecule-1 (KIM-1) mRNA were increased significantly, while glutathione (GSH) levels, activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione-s-transferase (GST), and levels of nuclear factor erythroid-2-related factor 2 (Nrf-2), peroxisome proliferator-activated receptor –gamma coactivator- 1-alpha (PGC-1α), heme oxygenase-1 (HO-1) and NADH quinone oxidoreductase-1 (NQ-O1) were decreased significantly in rats treated with Cd-only. Overall, pre-treatment with Me70 produced better protection from the toxic effects of cadmium induction in experimental rats.

Vagus nerve stimulation modulates arachidonic acid production in the mesenteric lymph following intestinal ischemia-reperfusion injury.

Inflammatory lipid mediators in mesenteric lymph (ML), including arachidonic acid (AA), are considered to play an important role in the pathogenesis of multiple-organ dysfunction after hemorrhagic shock. A previous study suggested that vagus nerve stimulation (VNS) could relieve shock-induced gut injury and abrogate ML toxicity, resulting in the prevention of multiple-organ dysfunction. However, the detailed mechanism of VNS in lymph toxicity remains unclear. The study aimed to investigate the relationship between VNS and inflammatory lipid mediators in ML. Male Sprague-Dawley rats underwent laparotomy and superior mesenteric artery obstruction (SMAO) for 60 minutes to induce intestinal ischemia followed by reperfusion and observation. The ML duct was cannulated, and ML samples were obtained both before and after SMAO. The distal ileum was removed at the end of the observation period. In one group of animals, VNS was performed from 10 minutes before 10 minutes after SMAO (5 V, 0.5 Hz). Liquid chromatography-electrospray ionization-tandem mass spectrometry analysis of AA was performed for each ML sample. The biological activity of ML was examined using a monocyte nuclear factor κ-light-chain-enhancer of activated B cells activation assay. Western blotting of phospholipase A2 group IIA (PLA2-IIA) was also performed for ML and ileum samples. Vagus nerve stimulation relieved the SMAO-induced histological gut injury. The concentration of AA and level of nuclear factor κ-light-chain-enhancer of activated B cells activation in ML increased significantly after SMAO, whereas VNS prevented these responses. Western blotting showed PLA2-IIA expression in the ML and ileum after SMAO; however, the appearance of PLA2-IIA band was remarkably decreased in the samples from VNS-treated animals. The results suggested that VNS could relieve gut injury induced by SMAO and decrease the production of AA in ML by altering PLA2-IIA expression in the gut and ML.

Level of The Nuclear factor -Erythroid 2–related factor2 in Egyptian patients with cutaneous warts

A wart is a noncancerous growth that may arise in the skin and mucosa. These are benign lesions caused by human papillomavirus (HPV), and over 100 different strains of HPV have been found. Prevalent warts, genital warts, flat warts, deep palmoplantar warts, localised epithelial hyperplasia, epidermodysplasia verruciformis, and plantar cysts are the most common ways that infection manifests. In individuals with genital warts or who are immunocompromised, malignant transformation is often found. While oxidative stress is an intriguing and mostly unexplored option in HPV-mediated carcinogenesis, further investigation is needed. Aim: The goal of this research is to find out whether levels of Nuclear factor-erythroid 2-related factor 2 (Nrf2) are associated to cutaneous warts in Egyptian patients and whether there is a relationship between Nrf2 levels and the severity of the disease. Objectives and Processes: Enzyme-linked immunosorbent assay was used to detect the amounts of Nrf2 in 25 patients with warts and 25 healthy controls (ELISA). Warts are correlated with Nrf2 levels, and these levels were shown to be greater in patients with warts (P =0.001). The most likely conclusion is that higher levels of Nrf2 indicate a role in the development of warts.

LOW-DOSE FOLIC ACID PROTECTS AGAINST ADVERSE CARDIAC REMODELING IN SPONTANEOUSLY HYPERTENSIVE RATS WITH HYPERHOMOCYSTEINEMIA

Objective: The interaction between hypertension and hyperhomocysteinemia (Hhcy) leads to adverse myocardial and coronary vascular remodeling in the hypertensive heart, resulting in impaired diastolic function. Folic acid (FA) is a free radical scavenger with antioxidant properties that effectively reduces homocysteine (Hcy) levels. The aim of this study was to evaluate whether lowering plasma homocysteine (Hcy) with different dose of folic acid (FA) could against Hhcy-induced myocardial injury in spontaneously hypertensive rats (SHRs) and its possible mechanisms. Design and method: Thirty-two adult male SHRs were randomly divided into four groups (n = 8/group), namely control group, Hhcy intervention group, Hhcy + Low-dose FA treatment group (0.4 mg/Kg·d), Hhcy + High-dose FA treatment group (4 mg/Kg·d), and then three Hhcy groups were subcutaneously injected 2% DL- homocysteine 5 ml/Kg. FA intervention started after 4 weeks’ Hcy injection. The total duration of the trial was 16 weeks. Cardiac echocardiography was performed at the last week. The Systolic blood pressure (SBP), diastolic blood pressure (DBP), plasma Hcy, serum malondialdehyde (MDA), superoxide dismutase (SOD) were measured, and Masson's trichrome stain to enable evaluation of collagen deposition under a microscope. Furthermore, the levels of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase 1 (HO-1) protein were detected by extraction of nuclear protein from cardiac tissue. Results: Intragastric administration of FA significantly reduced plasma Hcy levels. Serum SOD was significantly increased and serum MDA were also significantly attenuated by FA. Low-dose folic acid is more effective than high-dose folic acid in relieving Hhcy-induced anomalies in the heart of SHRs, such as the decline in cardiac diastolic function, perivascular collagen accumulation, and arteriolar wall thickening. FA increased the expression of Nrf2 and HO-1, and exhibited a protective effect against Hhcy-induced oxidative stress (OS), and there were no significant difference between high-dose and low-dose FA groups. Conclusions: Low-dose FA treatment can better protect against Hhcy-induced myocardial injury in SHRs, which may be due to its inhibition of OS and upregulation of Nrf2/HO-1 pathway.

The Role of Thymoquinone in Mitigating Carbon Tetrachloride-Induced Hepatocellular Carcinoma in Rats: Targeting the CHOP-1/JNK/P38 MAPK, NFκB/TNF-α/IL-10, and Bax/Bcl-2/Caspase-3 Signalling Pathways

The present study was conducted to evaluate the effect of thymoquinone (TQ) on hepatocellular carcinoma (HCC) in rats. Our study has reported that TQ treatment of experimentally-induced HCC results in the up-regulation of the Jun-N-terminal kinase and p38 mitogen activated protein kinase pathway (JNK/p38 MAPK) and the enhancement of anti-inflammatory, anti-oxidant, and pro-apoptotic machineries. TQ resulted in a significant decrease in the levels of nuclear factor kappa-light-chain-enhancer of activated B-cells (NFκB), tumor necrosis factor-α (TNF-α), and a significant increase in the anti-inflammatory interleukin-10 (IL-10). The pro-apoptotic effect of TQ was demonstrated through stimulating the apoptotic Bcl-2-associated X (Bax) gene and inhibiting the anti-apoptotic B-cell lymphoma 2 (Bcl-2) gene together with increasing the level of caspase 3 and up-regulating the C/EBP homologous protein (CHOP-1) gene expression. TQ treatment also enhanced the activity of the ROS scavenger, superoxide dismutase (SOD), and decreased the level of the lipid peroxidation product malondialdehyde (MDA). TQ-dependent suppression of HCC was associated with the up-regulation of JNK/p38 MAPK, enhanced CHOP-1 expression, and subsequently increased Bax gene expression.

The identification of critical time windows of postnatal root elongation in response to Wnt/β-catenin signaling.

In this study, we attempted to define the precise window of time for molar root elongation using a gain-of-function mutation of β-catenin model. Both the control and constitutively activated β-catenin (CA-β-cat) mice received a one-time tamoxifen administration (for activation of β-catenin at newborn, postnatal day 3, or 5, or 7, or 9) and were harvested at the same stage of P21. Multiple approaches were used to define the window of time of postnatal tooth root formation. In the early activation groups (tamoxifen induction at newborn, or P3 or P5), there was a lack of molar root elongation in the CA-β-cat mice. When induced at P7, the root length was slightly reduced at P21. However, the root length was essentially the same as that in the control when β-cat activated at P9. This study indicates that root elongation occurs in a narrow time of window, which is highly sensitive to a change of β-catenin levels. Molecular studies showed a drastic decrease in the levels of nuclear factor I-C (NFIC) and osterix (OSX), plus sharp reductions of odontoblast differentiation markers, including Nestin, dentin sialoprotein (DSP), and dentin matrix protein 1 (DMP1) at both mRNA and protein levels. Murine molar root elongation is precisely regulated by the Wnt/β-catenin signaling within a narrow window of time (newborn to day 5).

Soluble cluster of differentiation 74 regulates lung inflammation through the nuclear factor-κB signaling pathway

The soluble form of the migration inhibitory factor receptor cluster of differentiation 74 (sCD74) has previously been shown to be elevated during the development of acute lung injury (ALI) in mice. However, the biological role of increased sCD74 in ALI remans poorly understood. Synthesized recombinant sCD74 protein was administered to mice intratracheally. Pro-inflammatory genes in lung tissue and the inflammatory factors in bronchoalveolar lavage fluid (BALF) were analyzed using RT-PCR and ELISA, respectively. Additionally, RAW264.7, A549, and human umbilical vein endothelial cells (HUVEC) were treated with sCD74, and the resulting pro-inflammatory factor protein and gene expression levels were analyzed in the supernatants and cell lysates. Meanwhile, the level of nuclear factor (NF)-κB components in cell lysates after stimulating macrophages with sCD74 was also assessed. After administration of 0.5 mg/kg body weight sCD74 to mice, the expression of Tnfa, Mip2, and Il6 increased in lung tissues after 2 h by 2.1-, 3.4-, and 2.8-fold, respectively. Moreover, the BALF concentrations of TNF-α and MIP-2 reached maximal levels of 560 and 107 pg/mL at 8 h compared to those in the saline group, respectively. Similarly, TNFA, MIP2, and IL6 expression increased by 4.0-, 11.8-, and 2.6-fold, respectively, 2 h after stimulating macrophages with 1000 ng/mL sCD74. The levels of phospho-IκB and phospho-p65 were also significantly increased in the cytoplasm and nucleus of macrophages following sCD74 stimulation. Taken together, these results suggest that sCD74 is a critical cellular factor involved in the lung acute inflammatory response through nuclear factor-κB signaling.

Relationships among pancreatic beta cell function, the Nrf2 pathway, and IRS2: a cross-sectional study

ABSTRACT Objectives This study aimed to investigate the relationships among islet function, the Nrf2 pathway, and insulin receptor substrate 2 (IRS2) in type 2 diabetes mellitus (T2DM), prediabetes mellitus (IGR), and normal glucose tolerance (NGT) populations. Methods Three hundred cases each were selected for the NGT, IGR, and T2DM groups; FBG, 2hPG, HbA1 c, FINS, TG, TC, HDL-C, and LDL-C levels and serum levels of nuclear factor in E2-related factor 2 (Nrf2), insulin receptor substrate 2 (IRS2), tumor necrosis factor alpha (TNF-α), and heme oxygenase 1 (HO-1) were evaluated. Results The T2DM group had lower islet β-cell function index and insulin sensitivity index than the NGT and IGR groups (P < 0.05). The Nrf2, IRS2, and HO-1 levels in the NGT, IGR, and T2DM groups followed a decreasing trend in the order mentioned, whereas the TNF-α levels followed an increasing trend. Conclusions Upon impairment of glucose regulation, the expression of TNF-α in the human body increased, which indicated the aggravation of oxidative stress (OS) and the inflammatory response. Islet function was maintained in the pre-diabetic population, and concurrently, the TNF-α, Nrf2, and HO-1 levels were moderately elevated, the expression of IRS2 was marginally inhibited, and the Nrf2 pathway was activated under mild OS stimulus to resist OS, inflammation, and injury, which may have been mediated through PI3 K/AKT. In patients with T2DM, islet function was significantly poorer, TNF-α amplification was enhanced significantly, and Nrf2, HO-1, and IRS2 expression reduced significantly; this suggested that, along with the aggravation of OS and the inflammatory response, Nrf2 pathway activation and HO-1 expression were both inhibited, the antioxidant capacity of the body was reduced, IRS2 degradation increased, and islet function was impaired.

\u03b2-catenin promotes MTX resistance of leukemia cells by down-regulating FPGS expression via NF-\u03baB

BackgroundAberrant activation of β-catenin has been shown to play important roles in the chemoresistance of acute lymphoblastic leukemia (ALL), but the involvement and mechanism of β-catenin in methotrexate (MTX) resistance is poorly understood. In the present study, we demonstrate a critical role of β-catenin-NF-κB-FPGS pathway in MTX resistance in the human T-lineage ALL cell lines.MethodsLentivirus sh-β-catenin was used to silence the expression of β-catenin. Flow cytometry was performed to detect apoptosis after MTX treatment. Western blot, real-time PCR, Co-immunoprecipitation (Co-IP), Chromatin immunoprecipitation (ChIP), Re-ChIP, and Luciferase assay were utilized to investigate the relationship among β-catenin, nuclear factor (NF)-κB, and folypoly-γ-glutamate synthetase (FPGS).ResultsDepletion of β-catenin significantly increased the cytotoxicity of MTX. At the molecular level, knockdown of β-catenin caused the increase of the protein level of FPGS and NF-κB p65. Furthermore, β-catenin complexed with NF-κB p65 and directly bound to the FPGS promoter to regulate its expression. In addition, β-catenin repression prolonged the protein turnover of FPGS.ConclusionsTaken together, our results demonstrate that β-catenin may contribute to MTX resistance in leukemia cells via the β-catenin-NF-κB-FPGS pathway, posing β-catenin as a potential target for combination treatments during ALL therapy.

Geranium koreanum, a medicinal plant Geranii Herba, ameliorate the gastric mucosal injury in gastritis-induced mice

Ethnopharmacological relevanceGeranii Herba, the traditional medicinal plants Korean and northeast China, has been used in the healing of a variety of gastrointestinal inflammation disorders. Geranium koreanum is a congeneric origin plant of Geranii Herba that can be used as medicinal plants with Geranium thunbergii, Geranium sibiricum, Geranium carolinianum, Geranium nepalense, and Geranium japonicam. However, research on the biological activity of Geranium koreanum is currently insufficient. Aim of the studyGastritis is typically characterized by inflammation and irritation, and it is commonly caused by factors such as stress, alcohol consumption, smoking, and the use of anti-inflammatory drugs. In particular, excessive ethanol ingestion is an important cause of gastric disease mediated by mucosal damage by inflammatory cells infiltration. In this study, we investigated whether Geranium koreanum, the well-known traditional medicinal plant, could have a protective effect on gastric mucosal damage in an HCl/EtOH-induced gastritis model by analyzing the inflammation response in gastric tissue. Material and methodsThe cytotoxicity and anti-inflammatory effects of Geranium koreanum were analyzed by determining cell viability and nitric oxide (NO) production, as well as the levels of nuclear factor (NF)-κB proteins in lipopolysaccharide (LPS)-induced cells. Additionally, we measured the damage ratio, conducted histopathological assay by H&E and PAS staining, and determined the levels of pro-inflammation mediator proteins in gastric tissue after induction of gastritis by HCl/EtOH administration in order to analyze the gastro-protective effects of Gerranium koreanum. ResultsThe ulcer ratio and inflammatory cell infiltration in gastric mucosa were reduced by treatment with Geranium koreanum. Additionally, the expression of inflammatory mediators in gastric tissue was effectively decreased by extracts administrated at 200 mg/kg, as compared to the gastritis control. ConclusionsWe demonstrated that Geranium koreanum could have ameliorating effects against HCl/EtOH-induced gastritis through the anti-inflammatory response, which indicates the potential use of this plant as a natural preventive medicine for gastritis treatment.

NEAT1 aggravates sepsis-induced acute kidney injury by sponging miR-22-3p.

Background and aimAcute kidney injury (AKI) is a common complication of sepsis. Long noncoding RNA nuclear-enriched abundant transcript 1 (NEAT1) plays a vital role in various diseases, including AKI. This study aimed to investigate the function and mechanism of NEAT1 in sepsis-induced AKI.Materials and methodsA septic AKI model was established by treating HK-2 cells with lipopolysaccharide (LPS). The levels of NEAT1 and miR-22-3p were measured by quantitative real-time PCR. Cell apoptosis was assessed by flow cytometry. The levels of apoptosis-related protein and autophagy-related factors were examined by the western blot assay. An enzyme-linked immunosorbent assay was used to calculate the contents of inflammatory factors. The interaction between NEAT1 and miR-22-3p was validated by dual-luciferase reporter assay, RNA immunoprecipitation assay, and RNA pull-down assay. The levels of nuclear factor (NF)-κB pathway-related proteins were evaluated by the western blot assay.ResultsNEAT1 was upregulated, while miR-22-3p was downregulated in patients with sepsis and in LPS-stimulated HK-2 cells. LPS treatment triggered cell apoptosis, autophagy, and inflammatory response in HK-2 cells. NEAT1 knockdown attenuated LPS-induced cell injury. NEAT1 modulated LPS-triggered cell injury by targeting miR-22-3p. Furthermore, NEAT1 regulated the NF-κB pathway by modulating miR-22-3p.ConclusionDepletion of NEAT1 alleviated sepsis-induced AKI via regulating the miR-22-3p/NF-κB pathway.

Anserine and glucosamine supplementation attenuates the levels of inflammatory markers in rats with rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disorder that affects the joint synovium. Anserine is a functional dipeptide containing methylhistidine and β-alanine, and is present in the brain and skeletal muscle of birds and mammals. Glucosamine is an amino sugar used in the synthesis of glycosylated proteins and lipids. We evaluated the effects of anserine and glucosamine on RA. Rats were assigned into the control group, RA group, anserine group (1 mg/kg), glucosamine group (200 mg/kg), or anserine plus glucosamine group (anserine, 1 mg/kg + glucosamine, 200 mg/kg). Treatment was continued for 45 consecutive days and was administered orally. The serum levels of catalase, glutathione peroxidase (Gpx), superoxide dismutase (SOD), reduced glutathione (GSH), lipid peroxidation, uric acid, nitric oxide, ceruloplasmin, zinc, copper, prostaglandin E2 (PGE2), matrix metalloproteinase (MMP)-3, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were assayed. The mRNA and protein levels of nuclear factor (NF)-κB and inducible nitric oxide synthase (iNOS) in synovial tissue were also determined. Anserine plus glucosamine significantly increased the catalase, SOD, Gpx, GSH, and zinc levels compared to the control, anserine, and glucosamine groups. Also, anserine plus glucosamine significantly reduced the PGE2, MMP-3, TNF-α, IL-1β, and IL-6 levels compared to the control, anserine, and glucosamine groups. Furthermore, anserine plus glucosamine significantly reduced the mRNA and protein levels of NF-κB and iNOS compared to the control, anserine, and glucosamine groups. Therefore, supplementation of anserine plus glucosamine shows therapeutic potential for RA.