In the article the function of nitric oxide (·NO) cycle in rat’s gastric mucosa was assessed under excessive combined chronic fluoride and nitrate intake during 30 days. It was estimated that general nitric oxide synthase activity (NOS) was increased during excessive sodium fluoride intake meanwhile influence on gene­ral nitrate reduction was not statistically significant, but general nitrite reduction was increased. General arginase activity decreased. Excessive sodium nitrate intake decreased NOS activity, but increased nitrate, nitrite reduction and general arginase activity. Combined sodium nitrate and fluoride intake increased NOS by 18.9%, nitrate reduction by 71.7%, nitrite by 161.5%, arginase activity increase by 61.4%. The highest amounts of peroxynitrite were obtained from excessive sodium fluoride intake group, excessive sodium nitrate intake showed the lowest levels and combined excessive sodium nitrate and fluoride intake levels had intermediate results. Summarizing the data obtained, the authors have made a conclusion that combined excessive sodium nitrate and fluoride intake creates optimal conditions for functioning of nitrate-nitrite reductases.

Glutathione S-transferases (GSTs) have been widely studied in relation to their role in herbicide tolerance and detoxification. However, a detailed characterization of GSTs from herbicide tolerant and sensitive maize cultivars is still lacking. In this study, we determined the mechanism of differential tolerance between two maize cultivars which had 4-fold difference tolerance to metolachlor. The metabolism rate of metolachlor was more rapid in the tolerant cultivar (Zea mays L. cv Nongda86) than the susceptible one (Zea mays L. cv Zhengda958). Addition of the GST inhibitor ethacrynic acid reduced the metabolism of metolachlor indicating the involvement of GSTs in the differential detoxification of metolachlor. The expression profiles of 32 GST isozymes were measured using quantitative RT-PCR. The results showed the expression of GST genes were slightly up-regulated in Nongda86, but severely inhibited in Zhengdan958 24h after metolachlor treatment. The genes GSTI, GSTIII, GSTIV, GST5, GST6 and GST7, which can detoxify chloroacetanilide herbicides, were all expressed higher in Nongda86 compared to Zhendgan958. The result of GST activity was consistent with the gene expression profiles. Collectively, higher-level expression of GST genes, leading to higher GST activity and faster herbicide detoxification, appears to be responsible for the difference in tolerance to metolachlor in two maize cultivars.

Hexavalent chromium (Cr (VI)) is a common environmental pollutant. Cr (VI) exposure can lead to severe damage to the liver, but the preventive measures to diminish Cr (VI)-induced hepatotoxicity need further study. S-allyl cysteine (SAC) is a constituent of garlic ( Allium sativum) and has many beneficial effects to humans and rodents. In this study, we intended to analyze the mechanistic role of SAC during Cr (VI)-induced hepatotoxicity. Male Wistar albino rats were induced with 17 mg/kg body weight to damage the liver. The Cr (VI)-induced rats were treated with 100 mg/kg body weight of SAC as an optimum dosage to treat hepatotoxicity. We observed that the levels of oxidants, lipid peroxidation and hydroxyl radical (OH•) were increased, and enzymatic antioxidants such as superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase were found to be decreased in Cr (VI)-induced rats. While treated with SAC, the levels of oxidants were decreased and enzymatic antioxidants were significantly ( p < 0.05) increased. Lysosomal enzyme activities were increased in Cr (VI)-induced rats and on treatment with SAC, the activities were significantly decreased. The expressions of nuclear factor-kappa B (p65-NF-κB), tumor necrosis factor α (TNF-α), and inducible nitric oxide synthase (iNOS) were increased during induction with Cr (VI). Subsequent administration of SAC to animals showed a decrease in the expressions of NF-κB, TNF-α, and iNOS. Results obtained from this study clearly demonstrated that SAC protects the liver cells from the Cr (VI)-induced free radical damage.

Coenzyme Q10 (CoQ10) has antioxidant and anti-inflammatory activity. The aim of this study was to investigate the effects of CoQ10 on the inhibition of nuclear factor-kappa B (NF-κB) activation during ischemia-reperfusion (I/R) of skeletal muscle.

Oxysterol sulfation plays a fundamental role in the regulation of many biological events. Its products, 25-hydroxycholesterol 3-sulfate (25HC3S) and 25-hydroxycholesterol 3, 25-disulfate (25HCDS), have been demonstrated to be potent regulators of lipid metabolism, inflammatory response, cell apoptosis, and cell survival. In the present study, we tested these products' potential to treat LPS-induced acute liver failure in a mouse model.

High plasma concentration of low-density lipoprotein cholesterol (LDL-c) plays a significant role in the incidence of atherosclerosis and coronary heart diseases (CHD).

To undertake a systematic review and meta-analysis of randomized controlled trials of the effect of glucagon-like peptide-1 receptor agonist (GLP-1 RAs) therapy on serum C-reactive protein (CRP) concentrations.

Elevated apoptosis of intestinal epithelial cells (IECs) greatly impairs the epithelial barrier integrity and contributes to the pathogenesis of Crohn's Disease (CD). Overproduction of pro-inflammatory cytokine Interferon-γ (IFN-γ) induces the excessive apoptosis of IECs and is involved in CD development. PRDM5 (PR domain containing 5 PFM2) a member of PRDM family, reportedly acts as a transcriptional regulator involved in tissue specific differentiation and tumor development. In this study, we investigated PRDM5 expression and its potential functions in both human CD (Crohn's disease) and TNBS (2,4,6-trinitrobenzenesulfonic acid sol)-induced mice experimental colitis. As shown by western blot and immunohistochemistry, significant up-regulation of PRDM5 was found in the inflamed intestinal tissues of CD patients and TNBS-treated mice, and the molecule was mainly located in IECs. To explore the biological functions of PRDM5 in IEC apoptosis, we established the interferon-γ (IFN-γ) induced cellular apoptosis model on human IEC line HT29 in vitro. IFN-γ significantly increased the expression of PRDM5 in a both time-dependent and concentration-dependent manner in HT29 cells, which was accompanied with an up-regulated expression of apoptotic markers (active caspase-3 and cleaved PARP(poly (ADP-ribpse) polymerase)). Inhibiting PRDM5 expression by siRNA attenuated the IFN-γ-triggered accumulation of active caspase-3 and cleaved PARP in IECs. Moreover, flow cytometry assay and CCK-8 analysis revealed that PRDM5 knockdown significantly alleviated the IFN-γ-induced cellular apoptosis in HT29 cells. Taken together, these data suggest that highly expressed PRDM5 may promote the IFN-γ-induced IEC apoptosis in the progression of CD.

Interferon-β 1a (IFN-β 1a) is a common strategy therapy for multiple sclerosis (MS) with unknown mechanisms. S100A12 (S100 calcium-binding protein A12) is a damage-associated molecular pattern molecule which binds to its receptor, RAGE (receptor for advanced glycation end products), and activates nuclear factor-κB (NF-κB). NF-κB is transcribed from proinflammatory molecules, which may participate in the pathogenesis of MS. Therefore, the aims of this study were to compare mRNA levels of S100A12, RAGE, and NF-κB in newly diagnosed MS patients with healthy controls and determine whether IFN-β 1a therapy affects the expression of the molecules.

Aquaporin-4 (AQP4), a key molecule for water homeostasis in the brain, is associated with adult neurogenesis, but its mechanisms regulating adult neural stem cells (aNSC) remain largely unexplored. Neuroinflammation has a relevant influence on adult neurogenesis, which is a common feature in various neurodegenerative diseases. Considering the possible link between neuroinflammation and AQP4, we speculate that AQP4 may mediate the synthesis and release of proinflammatory cytokines in glia and then indirectly regulate adult hippocampal neurogenesis.

Mesial temporal lobe epilepsy (MTLE) is the most common type of refractory epilepsy. It is often associated with hippocampal sclerosis, which is histopathologically characterized by selective neuron loss, mossy fiber sprouting, and synapse reconstruction, and is the primary cause of refractory epilepsy. Its mechanism has not been fully elucidated. Substantial evidence now supports that inflammatory pathways are activated in epilepsy foci. We have confirmed that the interleukin-1β (IL-1β) level is involved in the epileptogenesis of MTLE, and we further investigated how it works in its chronicity in this study.

The neuropeptide SP has physiologic and pathophysiologic roles in CNS and peripheral tissues and is involved in crosstalk between nervous and immune systems in various conditions, including HIV and SIV infection. Increased SP levels were demonstrated in plasma of HIV+ individuals as well as in the CNS of SIV-infected, nonhuman primates. SP increases HIV infection in macrophages through interaction with its receptor, NK1R. The SP effect on immune system is both pro- and anti-inflammatory and includes up-regulation of a number of cytokines and cell receptors. The main goal of this study was to determine whether there is interplay between monocyte exposure to SP and recruitment into sites of inflammation. We now demonstrate that exposure of either human macrophages or PBMCs to SP leads to increased production of chemokines, including MCP-1, for which expression is limited to cells of the myeloid lineage. This effect is inhibited by the NK1R antagonist, aprepitant. Exposure to conditioned medium derived from SP-treated PBMCs resulted in increased monocyte migration through semipermeable membranes and an in vitro human BBB model. Monocyte migration was blocked by anti-MCP-1 antibodies. Our results suggest that increased SP levels associated with HIV and other inflammatory conditions may contribute to increased monocyte migration into the CNS and other tissues through a MCP-1-dependent mechanism.

This study investigated the transcriptomic response of Streptococcus pneumoniae D39 to methionine. Transcriptome comparison of the S. pneumoniae D39 wild-type grown in chemically defined medium with 0-10 mM methionine revealed the elevated expression of various genes/operons involved in methionine synthesis and transport (fhs, folD, gshT, metA, metB-csd, metEF, metQ, tcyB, spd-0150, spd-0431 and spd-0618). Furthermore, β-galactosidase assays and quantitative RT-PCR studies demonstrated that the transcriptional regulator, CmhR (SPD-0588), acts as a transcriptional activator of the fhs, folD, metB-csd, metEF, metQ and spd-0431 genes. A putative regulatory site of CmhR was identified in the promoter region of CmhR-regulated genes and this CmhR site was further confirmed by promoter mutational experiments.

This work evaluated biological effect of nC60 on Scenedesmus obliquus. The cells were exposed to various concentrations of nC60 for 7days. Low-dose of nC60 was found to have a minor growth inhibitory effect. The transcriptomics and metabolomics were integrated to examine intricate molecular and cellular effects of nC60 on Scenedesmus obliquus. We found that Scenedesmus obliquus cells exposed to nC60 had several significant alterations in cellular transcription and biochemical processes. During the 7-day exposure to nC60, 2234 and 2,448 unigenes were differentially expressed by 0.1mg/L and 1mg/L nC60-treated groups compared with the control, including 2085 or 2247 up-regulated genes and 149 or 201 down-regulated genes, respectively. We successfully identified 22 metabolites, including 6 significantly changed metabolites, such as sucrose, d-glucose, and malic acid. The citrate cycle (TCA cycle) (ko00020) was the main target of both differentially expressed genes and metabolic change. However, accumulation of sucrose (end-product) could have induced feedback inhibition of photosynthesis in Scenedesmus obliquus, explaining the slight growth inhibition observed. The results provided a mechanistic understanding of the growth inhibition of nC60 toxicity. These genes and metabolites are useful biomarkers for future studies and offer new insights into the early detectable changes in Scenedesmus obliquus with nC60 exposure.

Exposures to metal toxicants in the environment disrupt normal physiological functions and have been linked to the development of a myriad of human diseases. While the molecular and cellular mechanisms underlying metal toxicities remain to be fully understood, it is well appreciated that metal toxicants induce cellular stresses and that how cells respond to the stresses plays an important role in metal toxicity. In this review, we focus on how metal exposures induce stresses in the endoplasmic reticulum (ER) to elicit the unfolded protein response (UPR). We document the emerging evidence that induction of ER stress and UPR in the development of human diseases is associated with metal exposures. We also discuss the role of the interplay between ER stress and oxidative stress in metal toxicity. Finally, we review recent advances in functional genomics approaches and discuss how applications of these new tools could help elucidate the molecular mechanisms underlying cellular stresses induced by environmental metal toxicants.

This study investigated the role of PDK1 in inflammatory response which is initiated by TNF-α and analyzed the association between PDK1 and RSK2. TNF-α were added into MH7A cells to induce inflammation condition. Through overexpressing or suppressing PDK1 in MH7A cells, the role of PDK1 in cell invasiveness and inflammatory factors was determined. Levels of MMPs protein and inflammatory cytokines were assessed with PDK1 siRNA and TNF-α treatment. Inhibition of RSK2 was used to investigate the function of RSK2 on PDK1-induced inflammation. The phosphorylation of RSK2 was detected when PDK1 was inhibited. Luciferase reporter assay was performed to detect the transcriptional activity of NF-κB. We found highly expressed PDK1 could promote cell invasion and secretion of IL-1β and IL-6 in MH7A cells. Inhibition of RSK2 reduced the PDK1-induced cell invasion and cytokines secretion in MH7A cells. In response to TNF-α, PDK1 could phosphorylate RSK2 and activated RSK2, then promoting the activation of NF-κB. This may be a possible therapeutic option of rheumatoid arthritis.

The renin-angiotensin-aldosterone system has become known as a prerequisite for tumor angiogenesis that is now recognized as a crucial step in the development of tumors, including cervical cancer. The Ang II-AT1R pathway is known to play an important role in tumor angiogenesis. MicroRNAs (miRNAs) are a class of small, regulating RNAs that participate in tumor genesis, differentiation and proliferation. The current study focused on the anti-tumor mechanism of olmesartan, a novel angiotensin II antagonist, on cervical cancer cells.

Cardiac cells are subjected to mechanical and electrical forces, which regulate gene expression and cellular function. Therefore, in vitro electromechanical stimuli could benefit further integration of therapeutic cells into the myocardium. Our goals were (a) to study the viability of a tissue-engineered construct with cardiac adipose tissue-derived progenitor cells (cardiac ATDPCs) and (b) to examine the effect of electromechanically stimulated cardiac ATDPCs within a myocardial infarction (MI) model in mice for the first time. Cardiac ATDPCs were electromechanically stimulated at 2-millisecond pulses of 50 mV/cm at 1 Hz and 10% stretching during 7 days. The cells were harvested, labeled, embedded in a fibrin hydrogel, and implanted over the infarcted area of the murine heart. A total of 39 animals were randomly distributed and sacrificed at 21 days: groups of grafts without cells and with stimulated or nonstimulated cells. Echocardiography and gene and protein analyses were also carried out. Physiologically stimulated ATDPCs showed increased expression of cardiac transcription factors, structural genes, and calcium handling genes. At 21 days after implantation, cardiac function (measured as left ventricle ejection fraction between presacrifice and post-MI) increased up to 12% in stimulated grafts relative to nontreated animals. Vascularization and integration with the host blood supply of grafts with stimulated cells resulted in increased vessel density in the infarct border region. Trained cells within the implanted fibrin patch expressed main cardiac markers and migrated into the underlying ischemic myocardium. To conclude, synchronous electromechanical cell conditioning before delivery may be a preferred alternative when considering strategies for heart repair after myocardial infarction. Stem Cells Translational Medicine 2017;6:970-981.

Glioma is the most frequent primary central nervous system tumor. Although the current first-line medicine, temozolomide (TMZ), promotes patient survival, drug resistance develops easily. Thus, it is important to investigate novel therapeutic reagents to solidify the treatment effect. β-Elemene (bELE) is a compound from a Chinese herb whose anticancer effect has been shown in various types of cancer. However, its role in the inhibition of glioma stem-like cells (GSLCs) has not yet been reported. We studied both the in vitro and the in vivo inhibitory effect of bELE and TMZ in GSLCs and parental cells and their combined effects. The molecular mechanisms were also investigated. We also optimized the delivery methods of bELE. We found that bELE selectively inhibits the proliferation and sphere formation of GSLCs, other than parental glioma cells, and TMZ exerts its effects on parental cells instead of GSLCs. The in vivo data confirmed that the combination of bELE and TMZ worked better in the xenografts of GSLCs, mimicking the situation of tumorigenesis of human cancer. Notch1 was downregulated with bELE treatment. Our data also demonstrated that the continuous administration of bELE produces an ideal effect to control tumor progression. Our findings have demonstrated, for the first time, that bELE could compensate for TMZ to kill both GSLCs and nonstem-like cancer cells, probably improving the prognosis of glioma patients tremendously. Notch1 might be a downstream target of bELE. Therefore, our data shed light on improving the outcomes of glioma patients by combining bELE and TMZ. Stem Cells Translational Medicine 2017;6:830-839.

Although astragaloside IV exhibits anti-inflammation, immunoregulatory, and anticancer properties, the chemosensitization effects of astragaloside IV in colorectal cancer have never been reported. Our study tested whether astragaloside could increase cisplatin sensitivity in colorectal cancer. CCK-8 assay was used to measure the cell viability of colorectal cancer cells. Quantitative real-time PCR and Western blot were performed to determine the mRNA and protein expression, respectively. Our data revealed that astragaloside IV administration significantly suppressed the cell growth of colorectal cancer cells, whereas no obvious cytotoxicity of astragaloside IV was observed in nonmalignant colonic cells. In addition, combined treatment with astragaloside IV dramatically elevated the chemosensitivity of colorectal cancer cells to cisplatin. Mechanical investigation revealed that the mRNA and protein expression of NOTCH3 was significantly lower in cisplatin and astragaloside IV-treated cells compared with cells treated with cisplatin alone. On the contrary, no obvious changes in tumor cell growth were shown after upregulation of NOTCH3 whether in the presence or absence of astragaloside IV. Thus, our data demonstrate that astragaloside IV increases the chemosensitivity of colorectal cancer cells to cisplatin, at least partly, through inhibition of NOTCH3. This study suggests that combined therapy with astragaloside IV might be a novel therapeutic approach for colorectal cancer.