A novel salviadione derivative, compound 15a, attenuates diabetes-induced renal injury by inhibiting NF-κB-mediated inflammatory responses
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Patients with unresolving acute respiratory distress syndrome (ARDS) have persistently elevated levels of proinflammatory cytokines in the lungs and circulation and increased rates of bacterial infections. Phagocytic cells hyperactivated with lipopolysaccharide (LPS), which induces high levels of proinflammatory cytokines in monocytic cells, are inefficient in killing ingested bacteria despite having intact phagocytic activity. On the other hand, phagocytic cells that are activated with an analogue of LPS that does not induce the expression of proinflammatory cytokines effectively ingest and kill bacteria. We hypothesized that in the presence of high concentrations of proinflammatory cytokines, bacteria may adapt and utilize cytokines to their growth advantage. To test our hypothesis, we primed a human monocytic cell line (U937) with escalating concentrations of the proinflammatory cytokines tumor necrosis factor alpha, interleukin-1beta (IL-1beta), and IL-6 and with LPS. These cells were then exposed to fresh isolates of three common nosocomial pathogens: Staphylococcus aureus, Pseudomonas aeruginosa, and an Acinetobacter sp. In human monocytes primed with lower concentrations of proinflammatory cytokines (10 to 250 pg) or LPS (1 and 10 ng), intracellular bacterial growth decreased. However, when human monocytes were primed with higher concentrations of proinflammatory cytokines (1 to 10 ng) or LPS (1 to 10 micrograms), intracellular growth of the tested bacteria increased significantly (P <0.0001). These results were reproduced with peripheral blood monocytes obtained from normal healthy volunteers. The specificity of the cytokine activity was demonstrated by neutralizing the cytokines with specific antibodies. Our findings provide a possible mechanism to explain the frequent development of bacterial infections in patients with an intense and protracted inflammatory response.
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Oxidative stress is hypothesized to play a role in the development of diabetes with and without nephropathy. In addition, it has been suggested that some metabolic abormalities associated with diabetes may be due to cytokine overproduction. In the light of this knowledge, we aimed to measure MDA levels as a marker of oxidative stress and the IL-6 level in diabetes with and without different stages of nephropathy. Plasma MDA levels in the group of NIDDM patients with advanced nephropathy were significantly higher than in the group of NIDDM patients without nephropathy, which had significantly higher levels compared with the control group. Although IL-6 levels were elevated in diabetic groups with and without nephropathy in comparison with the control, no significant difference was found between patient groups. As a conclusion, oxidative stress may play an important role in diabetes with and without nephropathy, but the IL-6 level may not be useful in the evaluation of diabetic nephropathy.
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Proinflammatory cytokines traditionally thought to be derived exclusively from the immune system and were therefore considered to be primarily responsible for initiating inflammatory in the myocardium. The effects of Proinflammatory Cytokines in the heart were discussed.
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Proinflammatory cytokines such as tumor necrosis factor-alpha (TNF) and interleukin-1beta (IL-1) have been found to be elevated in bronchoalveolar lavage (BAL) fluid and in plasma from patients with acute respiratory distress syndrome (ARDS). In order to measure the balance of proinflammatory cytokines and their inhibitors, we quantified the upregulation of intercellular adhesion molecules (ICAM-1) induced by ARDS BAL fluids in human alveolar type II-like (A459) cells, and defined proinflammatory activity as the amount of ICAM-1 induced by the SAL fluids. Proinflammatory activity was detected in 77% of the SAL fluids sampled during the first week of ARDS, was found maximal during the 3 first days after onset of ARDS, and was significantly greater than in BAL specimens from at risk patients. Blocking experiments with specific inhibitors of TNF and IL-1 added to the BAL fluids indicated that the bioactivity measured was mainly due to IL-1. In contrast, proinflammatory activity of conditioned supernates from endotoxin-treated alveolar macrophages was mostly due to TNF. Using a bioassay that measures balance of cytokines with their inhibitors, our results indicate that the net proinflammatory activity in ARDS BAL fluids is attributable to IL-1 and not to TNF.
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Abstract Objectives The study was to explore the influence of microRNA (miR)-345-3p on proinflammatory cytokines in patients with rheumatoid arthritis (RA). Methods A total of 32 RA patients and 32 healthy patients were enrolled. Proinflammatory factors in patients’ serum were detected by ELISA, and miR-345-3p was detected by RT-qPCR. The correlation between miR-345-3p expression and proinflammatory factors in RA patients was analyzed. The diagnostic value of miR-345-3p and proinflammatory factors in RA patients was analyzed by receiver operating curve diagnosis. The predictive value of miR-345-3p levels and proinflammatory factors in RA patients was analyzed by multivariate Cox regression. HFLS-RA and HFLS cells were cultured, in which miR-345-3p and proinflammatory cytokines were detected by RT-qPCR. Cell proliferation and apoptosis were determined by CCK-8 and flow cytometry, respectively. Results MiR-345-3p was lowly expressed in the serum of RA patients. MiR-345-3p and proinflammatory factors were of diagnostic and predictive values in RA. Elevated miR-345-3p restrained the production of proinflammatory factors of HFLS-RA cells, improved cell proliferation, and reduced apoptosis. Conclusion MiR-345-3p is a potential biomarker and ameliorates RA by reducing the release of proinflammatory cytokines.
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Our study1 found that rats with or without perioperative fentanyl injections demonstrated a significant hyperalgesia for several days after plantar incision and significant increases in proinflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNFα), in the spinal cord and bilateral dorsal root ganglia (DRG) but not in cerebrospinal fluid (CSF). The main reason that we assayed IL-1β and TNFα in CSF was to find an explanation for why the proinflammatory cytokines significantly increased in contralateral DRG as well as the ipsilateral DRG. The lack of translatable IL-1β and TNFα in CSF suggested that the increase of proinflammatory cytokines in contralateral DRG might be the connection between spinal microglia and DRG by cellular junction or other unclear mechanism rather than proinflammatory cytokines diffused into CSF. Our study did not eliminate the possibility that other cytokines, chemokines, or neurotrophic factors may diffuse into CSF and may contribute to the increase of proinflammatory cytokines in contralateral DRG after treatments. Dr Srinivas2 suggested that an efflux component may develop immediately after treatments and explain the increase of proinflammatory cytokines in contralateral DRG. We agree that it might happen. However, we collected the spinal cord, DRG, and CSF samples almost at the same time. Second, the increase of proinflammatory cytokines in the spinal cord was significant and persistent. If proinflammatory cytokines in the spinal cord diffused into CSF sufficiently, we should have detected them in CSF, but we did not detect any change of cytokines concentrations in CSF after treatments. This may imply that the cellular junction between spinal microglia and DRG may be a reasonable route, although the true mechanism is unclear. Inflammation, trauma, drug, or various diseases may induce an increase of proinflammatory cytokines, chemokines, or neurotrophic factors in the spinal cord or brain, along with pain behavior in animals.1,3 However, if we want to use cytokines such as IL-1β, IL-6, or TNFα as biomarkers for predicting and diagnosing pain in patients, we must collect CSF or blood as a sample for assay. A comprehensive review3 demonstrated that some proinflammatory cytokines increased in CSF in patients suffering from chronic pain, for example, a significant increase of IL-6 in lumbar radiculopathy patients, an increase of IL-8 in postherpetic neuralgia patients, and upregulation of IL-6, IL-8, and prostaglandin E2 in CSF after major orthopedic surgery. It also suggested that these changes correlated with pain severity and/or pain duration and that cytokines in the CSF could serve as biomarkers for predicting and diagnosing chronic or postoperative pain.3 However, the results were not always consistent in the same disease. Lundborg et al4 demonstrated an increased IL-8 in both CSF and blood, an increased IL-1β in CSF, and an increased IL-6 in blood in osteoarthritis patients. However, the study by Yeager et al5 demonstrated no significant differences of IL-6 level between osteoarthritis patients and healthy patients in CSF and blood. Thus, we are not yet able to use specific inflammatory factors as biomarkers to diagnose and prognose pain. Haihua Shu, PhD, MDLu Chang, MDDepartment of AnesthesiologyGuangdong Second Provincial General HospitalGuangzhou, Guangdong, China[email protected]
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The brain's response to ischemic injury is an acute and long-term inflammatory process. This process involves activation of resident cells (mainly microglia, hematogenous macrophages), production of proinflammatory mediators and infiltration of various proinflammatory cells (mainly neutrophils and lymphocytes). These cells play an essential role in ischemic brain tissue by releasing either proinflammatory or anti-inflammatory mediators at different time points. However, the exact pathogenesis of proinflammatory or anti-inflammatory genes in this process has not yet been elucidated. This review aims to investigate the inflammatory process of stroke, especially the role of proinflammatory and anti-inflammatory genes in the pathogenesis of stroke. We also summarize the current clinical trials of drugs that target the inflammatory mechanism for intervention.
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Proinflammatory reaction by the body occurs acutely in response to injury that is considered primarily beneficial. However, sustained proinflammatory cytokines observed with chronic pathologies such as metabolic syndrome, cancer, and arthritis are detrimental and in many cases is a major cardiovascular risk factor. Proinflammatory cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor α (TNFα) have long been implicated in cardiovascular risk and considered to be a major underlying cause for heart failure (HF). The failure of the anti-TNFα therapy for HF indicates our elusive understanding on the dichotomous role of proinflammatory cytokines on acutely beneficial effects versus long-term deleterious effects. Despite these well-described observations, less is known about the mechanistic underpinnings of proinflammatory cytokines especially TNFα in pathogenesis of HF. Increasing evidence suggests the existence of an active cross-talk between the TNFα receptor signaling and G-protein-coupled receptors such as β-adrenergic receptor (βAR). Given that βARs are the key regulators of cardiac function, the review will discuss the current state of understanding on the role of proinflammatory cytokine TNFα in regulating βAR function.
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