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Hydroxytyrosol (HT) and oleuropein (OL), the most abundant of the phenolic compounds in olives, have anticancer properties against breast cancer (BC). However, little attention has been paid to the mechanism of HT or OL in BC cells. The objective of this study was to identify the underlying molecular mechanisms of these compounds. ER-positive BC MCF7 and T47D cells were treated with HT and OL in combination with hepatocyte growth factor (HGF), rapamycin (Rapa, an agonist of autophagy) or 3-methyladenine (3-MA, an inhibitor of autophagy). Cell viability, metastasis capability and autophagy-related proteins were evaluated by wound healing assays, Transwell assays and Western blot. HT and OL reduced the cell viability of MCF-7 and T47D cells in a dose-dependent manner. Both cells were more sensitive to HT than OL. In addition, Rapa significantly inhibited HGF-induced migration and invasion, indicating that metastases of both BC cells could be inhibited by suppression of autophagy. Moreover, HT and OL significantly blocked HGF- or 3-MA-induced cell migration and invasion by reversing LC3II/LC3I and Beclin-1 downregulation and p62 upregulation. These findings revealed that HT and OL could suppress migration and invasion by activating autophagy in ER-positive BC cells, which might be a promising therapeutic strategy. [ABSTRACT FROM AUTHOR]

Objectives: Therapeutic approaches for multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), are accompanied by various undesirable side effects. Owing to the anti-inflammatory and antioxidant effects of walnut, we investigated its effects on the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. Methods: After EAE induction in mice, the treated group was gavaged daily with walnut oil. The weights and clinical symptoms were monitored daily for 21 days following the onset of symptoms. The spleens and brains of the mouse were removed and used for ELISA and histological studies. Results: The average disease severity and plaque formation in the brains of the walnut oil-treated group were significantly lower (P < 0.05) than those of the untreated group. Stimulated splenocytes of the treated group expressed significantly less INF-γ and interleukin (IL)-17 than the untreated group with no significant differences in IL-10 or IL-5 production. In serum from the treated group, IL-17 expression was also significantly less than in the untreated group, while IL-10 was greater (P < 0.05). Conclusion: Walnut oil significantly reduced disease severity, inhibited plaque formation, and altered cytokine production. More studies are required to identify the mechanism of action of walnut oil as a valuable supplement in the treatment of MS. [ABSTRACT FROM AUTHOR]

Introduction: Diabetic macular edema is a sight-threatening disease and a major cause for blindness for people in working age. The pathogenesis or pathophysiology of this condition is multifactorial and different pathways have been identified, such as inflammation, the modulation of vascular integrity and tractional forces at the vitreomacular interface. Considering the significance of these pathogenetic mechanisms as the main targets in the modern treatment of diabetic macular edema, the current review aims to provide a detailed insight in the current understanding regarding these pathways. Areas covered: This review discusses original research articles including basic science and clinical studies as well as review articles focusing on inflammation, the vascular endothelial growth factor (VEGF) pathway and the role of the vitreomacular interface. The literature was searched using Medline/PubMed and articles were selected given their relevance for the topic to be discussed. Expert commentary: In recent years, knowledge regarding the pathophysiology of diabetic macular edema has significantly increased. Several interacting pathways with multiple growth factors, cytokines, cellular responses and so on, have been identified. Some of these insights have been successfully transferred into current treatment strategies already, such as VEGF suppression or anti-inflammatory treatments using steroids. It will be a future challenge not only to further identify additional pathophysiological aspects, but also to better understand their interactions and relevance as potential treatment targets and potential combinations. [ABSTRACT FROM AUTHOR]

Background:Psoriasis is mediated by a T helper 17 (Th17) cell inflammatory process. This study describes the changes in serum levels of IL-17, 22 and 23 in patients of psoriasis vulgaris treated with narrow band ultraviolet B (NBUVB). Methods:The serum levels of IL-17, 22 and 23 were compared with a control group (n = 30) before and after NBUVB. In addition, post-NBUVB levels were compared with healthy controls. Psoriasis Area Severity Score (PASI) and Body Surface Area scoring were used to evaluate severity of disease. Results:When compared with the non-psoriasis control group, IL-17, 22 and 23 were higher in psoriasis patients (p < 0.05,p < 0.001,p < 0.001, respectively). The serum levels of all three interleukins strongly correlated with severity of disease. Although IL-17, 22 and 23 decreased after NBUVB, decline in IL-17 was not significant after phototherapy as compared to controls (p = 0.634). IL-22 and 23 continued to remain elevated post-phototherapy when compared with control group (p < 0.05,p < 0.0001, respectively). Conclusions:The serum levels of IL-17, 22 and 23 decrease after phototherapy in psoriasis. Post-phototherapy only the IL-17 levels decrease to that of non-psoriasis controls. Our study supports the role of T helper 17 cell specific cytokines in psoriasis and a possible mechanism of action of NBUVB via inhibition of these cytokines. [ABSTRACT FROM AUTHOR]

ContextThe antioxidative properties of plants or plant derivative products are well known for their free radical scavenging effects.Flagellaria indicaL. (Flagellariaceae) (FI) is a tropical medicinal plant used by the natives of Sabah as medication for semi-paralysis. ObjectiveThis study evaluates the hepatoprotective mechanism of FI against carbon tetrachloride (CCl4)-mediated liver damage. Materials and methodsAqueous extract of FI leaves was orally administered to adult Sprague–Dawley rats once daily for 14 consecutive days at 300, 400, and 500 mg/kg b.w. prior to CCl4treatment (1.0 mL/kg b.w.) on the 13th and 14th days. ResultsTotal phenolic content in the aqueous extract of FI leaves was 65.88 ± 1.84 mg gallic acid equivalent/g. IC50value for free radical scavenging activity of FI aqueous extract was reached at the concentration of 400 μg/mL. Biochemical studies show that the aqueous extract of FI was able to prevent the increase in levels of serum transaminases, alanine aminotransferase, and aspartate aminotransferase (38–74% recovery), and malondialdehyde formation (25–87% recovery) in a dose-dependent manner. Immunohistochemical results evidenced the suppression of oxidative stress markers (4-hydroxynonenal and 8-hydroxydeoxyguanosine) and pro-inflammatory markers (tumour necrosis factor-α, interleukin-6, prostaglandin E2). Histopathological and hepatocyte ultrastructural alterations proved that there were protective effects in FI against CCl4-mediated liver injury. Signs of toxicity were not present in rats treated with FI alone (500 mg/kg b.w.). Discussion and conclusionIt can be concluded that the presence of phenolic constituents and their antioxidative effects can be credited to the hepatoprotective activity of FI. [ABSTRACT FROM AUTHOR]

This study investigated whether oxymatrine (OMT) treatment can ameliorate renal interstitial fibrosis in unilateral ureteral obstruction (UUO) mice model. Moreover, the potential mechanisms of such treatment were analyzed. Twenty-four C57/BL6 mice were randomly divided into three groups, namely sham group, vehicle plus unilateral ureteral obstruction (UUO)-treated group, and 100 mg/kg/d OMT plus UUO-treated group. All mice were euthanized seven days after surgery, and their kidneys were harvested. Renal injury, fibrosis, expression of proinflammatory cytokines, and the transforming growth factor-β1/Smads (TGF-β/Smads) and nuclear factor-kappa B (NF-κB)-signaling pathways were assessed. The results showed OMT significantly prevented kidney injury and fibrosis, as evidenced by decreased expression of collagen-1 and fibronectin. Furthermore, OMT administration inhibited the release of inflammatory factors including tumor necrosis factor-α, (TNF-α) interleukin-1β (IL-1β), and interleukin-6 (IL-6), as well as phosphorylated NF-κB p65. In addition, OMT blocked the activation of myofibroblasts by inhibiting the TGF-β/Smad3-signaling pathway. The findings indicate that OMT-attenuated renal fibrosis and inflammation, and this renoprotective effect may be ascribed to the inactivation of the TGF-β/Smad3 and NF-κB p65 pathways. [ABSTRACT FROM PUBLISHER]

Neuroblastoma (NB) is the most common extra cranial solid tumor of childhood, with 60% of patients presenting with high risk (HR) NB by means of clinical, pathological and biological features. The 5-year survival rate for HR-NB remains below 40%, with the majority of patients suffering relapse from chemorefractory tumor. Immunotherapy is the main strategy against minimal residual disease and clinical experience has mostly focused on monoclonal antibodies (MoAb) against the glycolipid disialoganglioside GD2. Three anti-GD2 antibodies have been tested in the clinic including murine 14G2a, human-mouse chimeric ch14.18 and 3F8. Anti-GD2 MoAb induces cellular cytoxicity against NB and is most effective when effector cells like natural killer cells, granulocytes and macrophages are amplified by cytokines. The combination of cytokines IL-2 and GM-CSF with the anti-GD2 MoAb ch14.18 (Dinutuximab) has shown a significant improvement in outcome for HR-NB. The FDA and EMA approved dinutuximab (UnituxinR) in 2015 for the treatment of patients with HR-NB who achieved at least a partial response after multimodality therapy. [ABSTRACT FROM PUBLISHER]

Background: Autoimmune hepatitis (AIH) is a chronic long-lasting hepatocellular inflammation associated with circulating auto antibodies. In addition to the genetic component, several cytokines have been implicated to be involved in AIH. This study was performed to investigate potential associations of AIH with IL4 gene variants. Method: The studied alleles and genotypes included: IL4G/T allele polymorphisms at position -1098 and C/T allele polymorphisms at two positions (-33 and -590) on the IL4 gene, in addition to the A/G allele polymorphisms at position +1902 on the IL4RA gene. Result: The IL4 C allele and CC genotype at position -590 and TT genotype at position -33 had a significantly higher frequency in AIH patients. Conclusion: This study identified the IL4 C allele and CC genotype susceptibility gene in AIH, which will provide better insights into the mechanisms of AIH and potential therapeutic interventions. [ABSTRACT FROM AUTHOR]

Context:Nepenthes mirabilis(Lour.) Rafarin (Nepenthaceae) is a carnivorous plant used as a folk medicine in the treatment of jaundice, hepatitis, gastric ulcers, ureteral stones, diarrhea, diabetes, and high blood pressure. Neither the phytochemical content nor biological activities ofN. mirabilishave been reported. Objective: The anti-inflammatory activity from theN. mirabilismethanolic extract led to the isolation of compounds (1–26). Materials and methods: Chromatographic methods were used to isolate compounds from the methanol extract ofN. mirabilisbranches and leaves.The anti-inflammatory activity of these isolated compounds was investigated in lipopolysaccharide (LPS)-stimulated bone marrow-derived dendritic cells (BMDCs) using ELISA. Primary BMDCs were used to examine the production of pro-inflammatory cytokines (IL-12 p40, IL-6, and TNF-α, at concentrations of 0.1, 0.2, and 1.0 μM) as compared with a positive control, SB203580 (1.0 μM). MTT assays showed that isolated compounds (1–26) did not exhibit significant cytotoxicity at concentrations up to 20.0 μM. Results: Compound9showed potent inhibition of IL-12 p40, IL-6, and TNF-α production (IC50 = 0.17 ± 0.02, 0.46 ± 0.01, and 8.28 ± 0.21 μM, respectively). Compound4showed potent inhibition of IL-12 p40 and IL-6 production (IC50 = 1.17 ± 0.01 and 2.15 ± 0.04 μM). In addition, IL-12 p40 inhibition by naphthalene derivatives (1–7,9, and10), phenolic compounds (11–15), lupeone (18), and flavonoids (22,25, and26) was more potent than with the positive control. The isolated compounds exhibited little and/or no inhibitory effects on TNF-α production in LPS-stimulated BMDCs. Discussion and conclusion: Taken together, these data suggest that the isolated components have significant inhibitory effects on pro-inflammatory cytokine production and warrant further study concerning their potential medicinal use. [ABSTRACT FROM AUTHOR]

The richly innervated corneal tissue is one of the most powerful pain generators in the body. Corneal neuropathic pain results from dysfunctional nerves causing perceptions such as burning, stinging, eye-ache, and pain. Various inflammatory diseases, neurological diseases, and surgical interventions can be the underlying cause of corneal neuropathic pain. Recent efforts have been made by the scientific community to elucidate the pathophysiology and neurobiology of pain resulting from initially protective physiological reflexes, to a more persistent chronic state. The goal of this clinical review is to briefly summarize the pathophysiology of neuropathic corneal pain, describe how to systematically approach the diagnosis of these patients, and finally summarizing our experience with current therapeutic approaches for the treatment of corneal neuropathic pain. [ABSTRACT FROM AUTHOR]

We examined the hypothesis that antioxidant substances and enzymes in lung, heart and in bronchoalveolar lavage fluid (BALF) are altered in response to O3in cardiovascular disease and/or metabolic syndrome (CVD)-prone rat models. CVD strains [spontaneously hypertensive (SH), SH stroke-prone (SHSP), SHHF/Mcc heart failure obese (SHHF), insulin-resistant JCR:LA-cp obese (JCR) and Fawn-Hooded hypertensive (FHH)] were compared with normal strains [Wistar, Sprague–Dawley (SD) and Wistar Kyoto (WKY)]. Total glutathione (GSH + GSSG or GSx), reduced ascorbate (AH2), uric acid (UA) and antioxidant enzymes were determined in lung, heart and BALF immediately (0 h) or 20-h post 4-h nose-only exposure to 0.0, 0.25, 0.5 and 1.0 ppm O3. Basal- and O3-induced antioxidant substances in tissues varied widely among strains. Wistar rats had a robust O3-induced increase in GSx and AH2 in the lung. Two CVD strains (JCR and SHHF) had high basal levels of AH2 and GSx in BALF as well as high basal lung UA. Across all strains, high BALF GSx was only observed when high BALF AH2 was present. CVD rats tended to respond less to O3than normal. High-basal BALF AH2 levels were associated with decreased O3toxicity. In summary, large differences were observed between both normal and CVD rat strains in low-molecular weight antioxidant concentrations in lung, BALF and heart tissue. Wistar (normal) and JCR and SHHF (CVD) rats appeared to stand out as peculiar in terms of basal- or O3-induced changes. Results elucidate interactions among antioxidants and air pollutants that could enhance understanding of cardiopulmonary disease. [ABSTRACT FROM AUTHOR]

The molecular bases for variability in air pollutant-induced pulmonary injury due to underlying cardiovascular (CVD) and/or metabolic diseases are unknown. We hypothesized that healthy and genetic CVD-prone rat models will exhibit exacerbated response to acute ozone exposure dependent on the type and severity of disease. Healthy male 12–14-week-old Wistar Kyoto (WKY), Wistar (WS) and Sprague Dawley (SD); and CVD-compromised spontaneously hypertensive (SH), Fawn-Hooded hypertensive (FHH), stroke-prone spontaneously hypertensive (SHSP), obese spontaneously hypertensive heart failure (SHHF) and obese JCR (JCR) rats were exposed to 0.0, 0.25, 0.5, or 1.0 ppm ozone for 4 h; pulmonary injury and inflammation were analyzed immediately following (0-h) or 20-h later. Baseline bronchoalveolar lavage fluid (BALF) protein was higher in CVD strains except for FHH when compared to healthy. Ozone-induced increases in protein and inflammation were concentration-dependent within each strain but the degree of response varied from strain to strain and with time. Among healthy rats, SD were least affected. Among CVD strains, lean rats were more susceptible to protein leakage from ozone than obese rats. Ozone caused least neutrophilic inflammation in SH and SHHF while SHSP and FHH were most affected. BALF neutrophils and protein were poorly correlated when considering the entire dataset (r = 0.55). The baseline and ozone-induced increases in cytokine mRNA varied markedly between strains and did not correlate with inflammation. These data illustrate that the degree of ozone-induced lung injury/inflammation response is likely influenced by both genetic and physiological factors that govern the nature of cardiovascular compromise in CVD models. [ABSTRACT FROM AUTHOR]

Objectives. Repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral-prefrontal cortex (DLPFC) exerts antidepressant effects. In this randomised controlled clinical trial we aimed to test the safety and therapeutic efficacy of bilateral theta-burst stimulation (TBS) as an add-on therapy to standard treatment of major depression. Methods. Fifty-six patients diagnosed with a moderate to severe depressive episode received 15 daily treatments of either rTMS (110% motor-threshold; rightDLPFC, 1000 stimuli at 1 Hz + leftDLPFC, 1000 stimuli at 10 Hz), theta-burst stimulation (80% motor-threshold; rightDLPFC, continuous TBS, 1200 stimuli + leftDLPFC, intermittent TBS, 1200 stimuli), or sham TMS ( N = 17, sham coil with the TBS protocol). Results. There was no significant effect in the primary outcome measures (change of the 21-item Hamilton Rating Scale for Depression). However, there was a tendency towards an increased responder rate at the end of the follow-up period for both active treatments as compared to sham, and this tendency was most pronounced for the TBS group. Conclusions. This pilot study did not reveal significant advantages of bilateral TBS or rTMS over sham treatment as an add-on treatment for major depression. A tendency towards a superior effect of bilateral TBS at the end of the follow-up period may warrant further studies. [ABSTRACT FROM AUTHOR]

Alpinetin, a flavonoid compound extracted from the seeds of Alpinia katsumadai Hayata, has been known to possess antibacterial, anti-inflammatory and other important therapeutic activities. In the current study, we investigated alpinetin for its immunosuppressive effect on activation and cytokines secretion of murine T lymphocytes. The data showed that alpinetin markedly suppressed ConA-induced murine splenocyte proliferation, Th1/Th2 cytokines production, CD4+ T-cell populations and ratio of CD4+/CD8+. This inspired us to further study the effects of alpinetin in vivo. The results showed that administration of alpinetin suppressed T-cell-mediated delayed-type hypersensitivity reaction in mice. In addition, we studied signal transduction pathways about T-cell activation on puried murine T lymphocytes by Western-blot assay. The data revealed that alpinetin could shock the activation of NF-κB, NFAT2 signal transduction pathways. These observations indicated that alpinetin have potential effects in downregulating the immune system and might be developed as a useful immunosuppressive agent in treating undesired immune responses. [ABSTRACT FROM AUTHOR]

Pro-inflammatory cytokines have been associated with chronic inflammation and inflammatory diseases. Increased levels of interleukins (ILs) have been associated with inflammatory disease exacerbation. ILs levels have been observed to be associated with advance stage cancer for several types of cancer and a poor prognostic maker for malignant disease. Moreover; increased levels of cytokines induce tumorigenesis. There are several paradigms such as the hepatocellular carcinoma induced from chronic inflammation of an underlying hepatitis. In the current review, we will focus on IL-8 and -17. These two ILs as in the case of others, induce neo-angiogenesis through activation of the vascular endothelial growth (VEGF) factor pathway. Additionally, they enhance the activity of matrix metalloproteinase-2 and -9 (MMP-2,-9) which in turn increase the metastatic activity of the underlying malignancy. Inhibition of cytokine production could be a potential treatment both for chronic inflammatory diseases and tumor modulation. Local microenvironment modulation could be applied in surgery resected patients as in the case of lung cancer in order to enhance the local immune activity. [ABSTRACT FROM AUTHOR]

Inducible heat shock protein (HSP)70 (HSP70-1A and HSP70-1B proteins) is a chaperone responsible for assisting proper protein folding. Following stress conditions, HSP70 is highly up-regulated to mediate cytoprotective functions. In addition, HSP70 is able to trigger innate and adaptive immune responses that promote the immune recognition of antigens and to act as a cytokine when it is released. The data in the literature are controversial with regard to expression studies in peripheral blood mononuclear cells (PBMCs). In the present study, we aimed to examine if alterations of HSP70-1A/B expression are involved in the autoimmune pathogenesis of multiple sclerosis (MS). We determined both mRNA and protein expression in PBMCs of MS patients and healthy donors (HDs). We found a baseline increased expression of the HSPA1A gene in PBMCs from MS patients compared with HDs. Gene expression findings were associated with an increased protein expression of HSP70-1A/B in T lymphocytes (CD4+ and CD8+) and monocytes from MS patients under basal conditions that may reflect the immunological activation occurring in MS patients. We also provided evidence that heat shock (HS) stimulus induced HSP70-1A/B protein expression in HDs and MS patients, and that HS-induced HSP70-1A/B protein expression in monocytes correlated with the number of T2 lesions at baseline in MS patients. However, after lipopolysaccharide inflammatory stimulus, monocytes from MS patients failed to induce HSP70-1A/B protein expression. Our data hint at altered immune responses in MS and may indicate either a state of chronic stress or increased vulnerability to physiological immune responses in MS patients. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy aims to generate long-lived, tumour-specific adaptive immunity to limit dysregulated tumour progression and metastasis. Tumour vasculature has emerged as a critical checkpoint controlling the efficacy of immunotherapy since it is the main access point for cytotoxic T cells to reach tumour cell targets. Therapeutic success has been particularly challenging to achieve because of the local, cytokine-rich inflammatory milieu that drives a pro-tumourigenic programme supporting the growth and survival of malignant cells. Here, we focus on recent evidence that systemic thermal therapy can switch the activities of the inflammatory cytokine, interleukin-6 (IL-6), to a predominantly anti-tumourigenic function that promotes anti-tumour immunity by mobilising T cell trafficking in the recalcitrant tumour microenvironment. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the neuroprotective and immunomodulatory effects of mesenchymal stem cells (MSCs) engineered to secrete CX3CL1 on the light-injured retinal structure and function. Methods: Normal MSCs and CX3CL1-expressing MSCs (CX3CL1-MSCs) were transplanted into the subretinal space of light-injured rats. By ERG and TUNEL methods, their rescue effect of the host retina was compared with untreated light-injured and vehicle-injected rats. Activated microglia in the retina were stained by ED-1 antibody, and Western blot was performed to quantify cytokines secreted by the retina post-transplantation. Results: ERG analysis showed better function in CX3CL1-MSC-injected group than other groups at 21 days after transplantation ( p < 0.05). CX3CL1-MSCs inhibited apoptosis of the retinal cells and microglial activation. Neurotrophic factors expression in host retina that received CX3CL1-MSCs was stronger than in the retina that received normal MSCs. Conversely, the expression of proinflammatory factors was downregulated. Conclusions: CX3CL1-MSCs subretinal transplantation may enhance protective effect against light-induced retinal degeneration. [ABSTRACT FROM AUTHOR]

Background: Interferon-gamma (IFN-γ) release assays (IGRAs) are suboptimally sensitive to diagnose tuberculosis (TB) and latent TB infection (LTBI) in young children. In this study we compared Mycobacterium tuberculosis antigen-stimulated IFN-γ inducible protein 10 (IP-10) responses in children with active TB and LTBI to responses from children with non-tuberculous mycobacterial (NTM) lymphadenopathy and respiratory tract infection (RTI). We also assessed test agreement between IP-10 and the QuantiFERON®-TB Gold In-Tube (QFT-IT) test results, and investigated whether IP-10 release upon mitogen stimulation is associated with age. Methods: We recruited 48 children (median age 54 months) diagnosed in Germany with either active TB ( n == 11), LTBI ( n == 14), NTM lymphadenopathy ( n == 8), or common RTI ( n == 15). IFN-γ levels were measured using the QFT-IT. These plasma supernatants were used to determine IP-10 concentrations using an in-house enzyme-linked immunosorbent assay (ELISA). Results: The median antigen-stimulated IP-10 levels in children with active TB, LTBI, NTM lymphadenopathy, and RTI were 12,702 pg/ml, 9109 pg/ml, 97 pg/ml, and 84 pg/ml, respectively. We observed a strong correlation between IP-10 and IFN-γ plasma concentration in children with active TB and LTBI ( r2 == 0.69). Overall agreement between IP-10 and QFT-IT assays was high (kappa == 0.95). IP-10 levels after mitogen stimulation showed no association with age. Conclusions: IP-10 and IFN-γ were both induced with antigen stimulation in blood from children in the TB and LTBI groups, in contrast to the NTM and RTI groups. Compared to IFN-γ the IP-10 levels were higher and IP-10 was released independently of age. IP-10 therefore may represent an additional biomarker in the paediatric population. [ABSTRACT FROM AUTHOR]

Cachexia is a metabolic syndrome that manifests with excessive weight loss and disproportionate muscle wasting. It is related to many different chronic diseases, such as cancer, infections, liver disease, inflammatory bowel disease, cardiac disease, chronic obstructive pulmonary disease, chronic renal failure and rheumatoid arthritis. Cachexia is linked with poor outcome for the patients. In this article, we explore the role of the hypothalamus, liver, muscle tissue and adipose tissue in the pathogenesis of this syndrome, particularly concentrating on the role of cytokines, hormones and cell energy-controlling pathways (such as AMPK, PI3K/Akt and mTOR). We also look at possible future directions for therapeutic strategies. [ABSTRACT FROM AUTHOR]

Until recently, cytokine therapy has been the only validated option for patients with advanced renal cancer. IFN-α is one of very few treatments that have demonstrated improved median survival compared with the appropriate control. In patients with synchronous metastases at diagnosis, debulking nephrectomy prior to interferon, further improves overall survival. High-dose IL-2 appears to be able to cure a small percentage of highly selected patients. There is potential to further improve patient selection for these options. The demonstrated value of cytokines should not be overlooked in the rust hot use new drugs. In the adjuvant setting, vaccine therapy has provided the only system at the molecular level, as well as the ingenuity and enthusiasm of immunotherapists, will undoubtedly lead to continuing attempts to identify and overcome obstacles to achieve the grail of human tumor rejection in clinical practice. Targets within the immune regulatory system and the use of vaccines as targeting agents may bring together the fields of immunotherapy and targeted therapy in the near future. [ABSTRACT FROM AUTHOR]

T-bet, a Th1-specific transcription factor, can promote the production of IFN-γ. IFN-γ is the principal Th1 effector cytokine and it has a crucial role in Th1 differentiation, which can drive the differentiation of naïve CD4+T cells into T-helper 1 (Th1) cells. In our study, a human T-bet gene was fused with a gene fragment encoding HIV-1 protein transduction domain in a bacterial expression vector to produce a Tat/T-bet fusion protein. The expressed and purified Tat/T-bet proteins were transduced efficiently into THP-1 cells in a time- and dose-dependent manner; when Tat/T-bet pretreated THP-1 cells were co-cultured with CD4+T cells, the IFN-γ level increased higher to about 7 pg/ml, 10-folds as compared with the normal level when tested at 48 hours. The results demonstrated that the Tat/T-bet fusion protein can be efficiently transduced into antigen-presenting cells (APCs) like THP-1 cells and then regulated Th1/Th2 balance, which may act as a potential tool for gene therapy. [ABSTRACT FROM AUTHOR]

The heterodimeric cytokine IL-12 (composed of a p35 and a p40 subunit) is produced primarily by monocytes, macrophages and B cells. In vitro and in vivo experiments have demonstrated the crucial role of IL-12 in initiating and establishing both innate immunity and T cell-mediated resistance to intracellular pathogens, including Leishmania donovani, Toxoplasma gondii, Listeria monocytogenes, and Mycobacterium tuberculosis. Assessment of cytokine expression has thus become crucial to understand host responses to infections. In this study, by using the reverse transcriptase-real time PCR we developed a highly specific and sensitive assay to quantitatively evaluate IL-12p40 mRNA transcription levels in peripheral blood mononuclear cells (PBMCs) stimulated with PHA vs. unstimulated cells. We also used the ELISA to evaluate bioactive IL-12 release in culture supernatants. We provide evidence that IL-12 p40 mRNA levels were significantly up-regulated in PHA-activated PBMCs. These results were correlated with data of IL-12 levels obtained by ELISA. [ABSTRACT FROM AUTHOR]

Biophytum sensitivum has been used in traditional folk medicine to treat numerous diseases. The molecular mechanism of B. sensitivum pharmacological and biochemical actions of macrophages in inflammation has not been clearly elucidated. We examined how the methanol extract of B. sensitivum regulates the production of interleukin (IL)-1β, tumor necrosis factor (TNF)-α, IL-6, and nitric oxide (NO) in vitro and in vivo. The extract inhibits the production of NO and proinflammatory cytokines in lipopolysaccharide (LPS) or Concanavalin (Con) A-stimulated primary macrophages. In vitro L929 bioassay revealed the inhibition of TNF-α production by B. sensitivum treatment. Moreover, the extract could suppress the inducible nitric oxide synthase and cyclo-oxygenase-2 mRNA expression in LPS or Con A-stimulated macrophages. These findings provide evidence that B. sensitivum possesses potential anti-inflammatory activity and may be beneficial for the treatment of endotoxin shock or sepsis. [ABSTRACT FROM AUTHOR]

Objective: Signal transducers and activators of transcription (STATs) are crucial mediators of cytokine signalling. Constitutive activation of STATs, especially STAT3, has been reported in several diseases. Primary Sjögren's syndrome (pSS) is associated with overproduction of cytokines such as interleukin-10 (IL-10), although the mechanism by which this occurs is unknown. As STAT3 is a potent inducer of IL-10, this study focused on determining the pattern of STAT3 activation in peripheral lymphocytes from patients with pSS. Methods: Twelve pSS patients and 12 healthy age-matched control subjects were studied. Peripheral blood mononuclear cells (PBMCs) were isolated by gradient centrifugation. Phosphorylated STAT3 (pSTAT3) and also STAT3 expression were determined by flow cytometry in gated CD3+ and CD19+ lymphocytes. Similarly, pJak1 and pTyk2 were also determined in gated CD3+ lymphocytes. Results: Although the protein expression of STAT3 was similar among controls and pSS patients, we found that STAT3 was constitutively activated in CD3+ lymphocytes from pSS patients. Neither Jak1 nor Tyk2 (the upstream activators of STAT3) was activated in pSS CD3+ lymphocytes, suggesting that the constitutive activation of STAT3 observed in pSS patients might not depend on cytokine stimulation but instead might be the result of an abnormal inactivation of pSTAT3. Conclusions: These data provide evidence of abnormal STAT3 signalling in T cells from pSS patients. [ABSTRACT FROM AUTHOR]

Background In the current study, we determined whether bovine dialyzable leukocyte extract (bDLE) modulates lipopolysaccharide (LPS)-induced nitric oxide and cytokine overproduction. Methods Human whole blood cells were treated with LPS (50 ng) + bDLE (1 U). Results The bDLE treatment decreased nitric oxide as well as TNF-α, IL-6 and IL-10 (P <0.01) cytokine production. In addition, it decreased TNF-α, IL-1β and IL-6 mRNA expression and suppressed IL-10 and IL-12p40 mRNA expression, but did not modulate IL-8 mRNA expression in LPS-stimulated human blood cells. Discussion Our results suggest that bDLE may effectively modulate the fatal symptoms of hypotensive shock associated with endotoxin (LPS)-induced nitric oxide and cytokine production, and this may offer therapeutic potential for the treatment of endotoxic shock. [ABSTRACT FROM AUTHOR]

Chronic renal failure (CRF) patients suffer from a chronic inflammation. They are at increased risk of cardiovascular disease. In order to investigate this inflammatory process and cardiovascular risk factors associated with haemodialysis (HD) and peritoneal dialysis (PD), we compared serum/plasma pro-inflammatory cytokines, C-reactive protein (CRP), and cardiac troponin T (cTnT) of 146 CRF patients treated or not treated with PD or HD. Serum cytokines and CRP as well as plasma cTnT were measured by enzyme-linked immunosorbent assay, chemiluminescence immunoassay, and electrochemiluminescence immunoassay, respectively. Results indicated that serum interleukin (IL)-18 concentrations were significantly higher in PD and low creatinine clearance pre-dialysis CRF (LCC) patients than HD patients (both p < 0.05). IL-6 and tumour necrosis factor (TNF)-α concentrations were significantly higher in PD patients than LCC patients (both p < 0.01). Serum hsCRP and plasma cTnT in HD were significantly higher than LCC (both p < 0.01). The elevation of pro-inflammatory cytokines should play an important role in the chronic inflammation and increased cardiovascular risk of CRF patients on dialysis. We are evaluating further the diagnostic and prognostic applications of pro-inflammatory cytokines and biochemical inflammatory markers for these patients. [ABSTRACT FROM AUTHOR]

The Korean genuine medicine “Seonghyangjeongkisan” (SHJKS) has long been used for various cerebrovascular diseases. However, very little scientific investigation has been carried out. Cytokines involved in the regulation of inflammatory reactions and immune responses may play a role in the pathogenesis of cerebral infarction (CI). The aim of the present study is to elucidate how SHJKS modulates the inflammatory reaction in lipopolysaccaride (LPS) plus phytohaemagglutinin (PHA)-stimulated peripheral mononuclear cells (PBMCs) from CI patients. The amount of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 in PBMC culture supernatant was significantly increased in the LPS plus PHA treated cells compared to unstimulated cells. SHJKS inhibited the TNF-α, IL-1β, IL-6, and IL-8 production in dose dependent manner. Maximal inhibition rate of the TNF-α, IL-1β, IL-6, and IL-8 by SHJGS (1.0 mg/ml) was 68.01 ± 0.28% (P < 0.01), 52.11 ± 0.56 % (P < 0.01), 53.42 ± 0.46 % (P < 0.01), and 46.70 ± 0.37% (P < 0.05), respectively. In addition, we show that SHJKS suppressed nuclear factor (NF)-κB activation induced by LPS plus PHA, leading to suppression of IκB-α phosphorylation and degradation. These results suggest that SHJKS might have regulatory effects on LPS plus PHA-induced cytokine production and NF-κB activation, which might explain its beneficial effect in the treatment of CI. [ABSTRACT FROM AUTHOR]

Psoriasis vulgaris and psoriatic arthritis are inflammatory diseases in which inflammation and sustained inducing lesions result from immune disorders associated with overactivity of T cells that produce multiple proinflammatory cytokines, including tumor necrosis factor alpha (TNF-α) and interleukin (IL): IL-2, IL-12, IL-17, IL-22 or IL-23. Modern treatment of these diseases is focused on reducing the inflammatory process responsible for the development of the disease. In recent years, the treatment of psoriasis is developing at a dynamic rate. Such therapeutic advances are contributed to the possibility of patient therapy through the use of some registered biologic agents, such as TNF-α inhibitors (infliximab, etanercept and adalimumab), and an inhibitor of the p40 subunit common to IL-12 and IL-23 (ustekinumab). In addition to the already registered medications for the indications mentioned above, there is a large group of preparations that are currently undergoing clinical trials in Europe, Canada and the United States, which provides hopes of therapy efficacy and safety. [ABSTRACT FROM PUBLISHER]

Describes the hematological and clinical therapeutic effect of cytokines and patients with myelodysplastic syndromes (MDS). Clinical trials with recombinant human granulocyte colony-stimulating factor (rhG-CSF) or rh granulocyte-macrophage colony-stimulating factor; Administration of cytokine combinations.

The author discusses anti-Tumor necrosis factors (TNF) therapy for chronic rheumatic diseases spondyloarthritis (SpA). It mentions about the use of TNF in the treatment of ankylosing spondylitis (AS). It states that cytokine Interleukin (IL)-6 is a potential target for biologic inhibitors because of its involvement in the inflammatory processes. It comments on the need of optimizing the use of current therapeutic options such as nonsteroidal anti-inflammatory drugs (NSAIDs).

The article discusses the possible use of IL-12 and IL-23 cytokines receptors as the therapeutic targets for inflammatory diseases such as psoriasis. The authors discuss a brief description and functions of these receptors based on various clinical studies presented. Moreover, they contend that the safety and efficacy of IL-12 and IL-13 inhibitors represent a relevant new advances for inflammatory diseases aside from being a new therapeutic target for psoriasis.

The article discusses the role of platelets in inflammation and innate immunity. Topics discussed include information on the formation of antimicrobial and procoagulant neutrophil extracellular traps (NETs); the effect of platelet-derived growth factors and cytokines in wound healing; and the use of platelet-rich plasma in regenerative medicine.

An editorial is presented in which the author discusses role of interleukin (IL)-21 a cytokine with pleiotropic effects on cells on a chronic autoimmune disease systemic lupus erythematosus. Topics discussed include production of autoantibodies against nuclear components, promotion of B-cell dysfunction in SLE patients, and role in the SLE-associated immune alterations.

Adoptive therapy with engineered T cells shows promising results in treating patients with malignant disease, but is challenged by incomplete responses and tumor recurrences. Here, we aimed to direct the tumor microenvironment in favor of a successful immune response by local secretion of interleukin (IL-) 12 and IL-18 by sadministered T cells. To this end, we engineered T cells with a melanoma-specific T cell receptor (TCR) and murine IL-12 and/or IL-18 under the control of a nuclear-factor of activated T-cell (NFAT)-sensitive promoter. These T cells produced IL-12 or IL-18, and consequently enhanced levels of IFNγ, following exposure to antigen-positive but not negative tumor cells. Adoptive transfer of T cells with a TCR and inducible (i)IL-12 to melanoma-bearing mice resulted in severe, edema-like toxicity that was accompanied by enhanced levels of IFNγ and TNFα in blood, and reduced numbers of peripheral TCR transgene-positive T cells. In contrast, transfer of T cells expressing a TCR and iIL-18 was without side effects, enhanced the presence of therapeutic CD8+T cells within tumors, reduced tumor burden and prolonged survival. Notably, treatment with TCR+iIL-12 but not iIL-18 T cells resulted in enhanced intra-tumoral accumulation of macrophages, which was accompanied by a decreased frequency of therapeutic T cells, in particular of the CD8 subset. In addition, when administered to mice, iIL-18 but not iIL-12 demonstrated a favorable profile of T cell co-stimulatory and inhibitory receptors. In conclusion, we observed that treatment with T cells engineered with a TCR and iIL18 T cells is safe and able to skew the tumor microenvironment in favor of an improved anti-tumor T cell response. [ABSTRACT FROM PUBLISHER]

Checkpoint inhibition has established immunotherapy as a major modality of cancer treatment. However, the success of cancer immunotherapy is still limited as immune regulation of tumor immunity is very complicated and mechanisms involved may also differ among cancer types. Beside checkpoints, other good candidates for immunotherapy are immunosuppressive cytokines. TGF-β is a very potent immunosuppressive cytokine involved in suppression of tumor immunity and also necessary for the function of some regulatory cells. TGF-β has three isoforms, TGF-β 1, 2 and 3. It has been demonstrated in multiple mouse tumor models that inhibition of all three isoforms of TGF-β facilitates natural tumor immunosurveillance and tumor vaccine efficacy. However, individual isoforms of TGF-β are not well studied yet. Here, by using monoclonal antibodies (mAbs) specific for TGF-β isoforms, we asked whether it is necessary to inhibit TGF-β3 to enhance tumor immunity. We found that blockade of TGF-β1 and 2 and of all isoforms provided similar effects on tumor natural immunosurveillance and therapeutic vaccine-induced tumor immunity. The protection was CD8+T cell-dependent. Blockade of TGF-β increased vaccine-induced Th1-type response measured by IFNγ production or T-bet expression in both tumor draining lymph nodes and tumors, although it did not increase tumor antigen-specific CD8+T cell numbers. Therefore, protection correlated with qualitative rather than quantitative changes in T cells. Furthermore, when combined with PD-1 blockade, blockade of TGF-β1 and 2 further increased vaccine efficacy. In conclusion, blocking TGF-β1 and 2 is sufficient to enhance tumor immunity, and it can be further enhanced with PD-1 blockade. [ABSTRACT FROM PUBLISHER]

Inflammation is one of the hallmarks of carcinogenesis. High mammographic density has been associated with increased risk of breast cancer but the mechanisms behind are poorly understood. We evaluated whether breasts with different mammographic densities exhibited differences in the inflammatory microenvironment. Postmenopausal women attending the mammography-screening program were assessed having extreme dense, n = 20, or entirely fatty breasts (nondense), n = 19, on their regular mammograms. Thereafter, the women were invited for magnetic resonance imaging (MRI), microdialysis for the collection of extracellular moleculesin situand a core tissue biopsy for research purposes. On the MRI, lean tissue fraction (LTF) was calculated for a continuous measurement of breast density. LTF confirmed the selection from the mammograms and gave a continuous measurement of breast density. Microdialysis revealed significantly increased extracellularin vivolevels of IL-6, IL-8, vascular endothelial growth factor, and CCL5 in dense breast tissue as compared with nondense breasts. Moreover, the ratio IL-1Ra/IL-1β was decreased in dense breasts. No differences were found in levels of IL-1β, IL-1Ra, CCL2, leptin, adiponectin, or leptin:adiponectin ratio between the two breast tissue types. Significant positive correlations between LTF and the pro-inflammatory cytokines as well as between the cytokines were detected. Stainings of the core biopsies exhibited increased levels of immune cells in dense breast tissue. Our data show that dense breast tissue in postmenopausal women is associated with a pro-inflammatory microenvironment and, if confirmed in a larger cohort, suggests novel targets for prevention therapies for women with dense breast tissue. [ABSTRACT FROM PUBLISHER]

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal stem cell disorders characterized by ineffective hematopoiesis frequently progressing into acute myeloid leukemia (AML), with emerging evidence implicating aberrant bone marrow (BM) microenvironment and inflammation-related changes. 5-azacytidine (5-AC) represents standard MDS treatment. Besides inhibiting DNA/RNA methylation, 5-AC has been shown to induce DNA damage and apoptosisin vitro. To provide insights intoin vivoeffects, we assessed the proinflammatory cytokines alterations during MDS progression, cytokine changes after 5-AC, and contribution of inflammatory comorbidities to the cytokine changes in MDS patients. We found that IL8, IP10/CXCL10, MCP1/CCL2 and IL27 were significantly elevated and IL12p70 decreased in BM of MDS low-risk, high-risk and AML patients compared to healthy donors. Repeated sampling of the high-risk MDS patients undergoing 5-AC therapy revealed that the levels of IL8, IL27 and MCP1 in BM plasma were progressively increasing in agreement within vitroexperiments using several cancer cell lines. Moreover, the presence of inflammatory diseases correlated with higher levels of IL8 and MCP1 in low-risk but not in high-risk MDS. Overall, all forms of MDS feature a deregulated proinflammatory cytokine landscape in the BM and such alterations are further augmented by therapy of MDS patients with 5-AC. [ABSTRACT FROM PUBLISHER]

Background & Aims: There is no generally accepted adjuvant therapy for hepatocellular carcinoma (HCC) after curative resection. Autologous cytokine-induced killer (CIK) cells therapy has been reported to improve outcomes of patients with HCC, but its role as an adjuvant therapy remains unclear. This study aimed to evaluate the efficacy and safety of CIK as an adjuvant therapy for HCC after curative resection. Methods: This is a single center, phase 3, open label, randomized controlled trial (RCT). Two hundred patients who were initially diagnosed with HCC of Barcelona Clinic Liver Cancer (BCLC) stage A or B, and underwent curative hepatectomy were randomly assigned to receive four cycles of CIK treatment (the CIK group, n = 100) or no treatment (the control group, n = 100). The primary outcome was time to recurrence. The secondary outcomes included disease-free survival (DFS), overall survival (OS) and adverse events. Results: All patients in the CIK group finished the treatment by protocol. The median time to recurrence (TTR) was 13.6 (IQR 6.5–25.2) mo in the CIK group and 7.8 (IQR 2.7–17.0) mo in the control group (p= 0.01). There were no significant differences between the groups in DFS and OS. All adverse events were grade 1 or 2. There were no significant differences in incidence between the two groups. Conclusions: Four cycles of CIK therapy were safe and effective to prolong the median TTR in patients with HCC after curative resection, but the treatment did not improve the DFS and OS. [ABSTRACT FROM PUBLISHER]

Recent extraordinary advances in cancer immunotherapy rely primarily on marshaling T cell responses. Here we discuss how NK cell responses can be amplified. We find that MHC I-deficient tumors induce anergy of NK cells but that cytokine therapy restores NK cell activity and increases the survival of mice bearing MHC I-deficient tumors. [ABSTRACT FROM PUBLISHER]

Tumor-targeting immune responses provide a significant contribution to (when they do not entirely account for) the clinical activity of diverse antineoplastic regimens, encompassing not only a large panel of immunotherapeutic strategies but also conventional cytotoxic molecules, targeted anticancer agents and irradiation. In line with this notion, several approaches have been devised to elicit novel or boost existing anticancer immune responses, including the administration of immunomodulatory cytokines. Such a relatively unspecific intervention suffices to mediate clinical effects in (at least a subset of) patients bearing particularly immunogenic tumors, like melanoma and renal cell carcinoma. More often, however, immunostimulatory cytokines are administered to boost the immunogenic potential of other agents, including (but not limited to) immune checkpoint-blocking antibodies, anticancer vaccines, oncolytic viruses and immunogenic chemotherapeutics. Here, we summarize the latest advances in the clinical development of recombinant cytokines as an immunomodulatory intervention for cancer therapy. [ABSTRACT FROM PUBLISHER]

Alpha interferon (IFN-α) controls homeostasis of hematopoietic stem cells, regulates antiviral resistance, inhibits angiogenesis, and suppresses tumor growth. This cytokine is often used to treat cancers and chronic viral infections. The extent of cellular responses to IFN-α is limited by the IFN-induced ubiquitination and degradation of the IFN-α/β receptor chain 1 (IFNAR1) chain of the cognate receptor. IFNAR1 ubiquitination is facilitated by the βTrcp E3 ubiquitin ligase that is recruited to IFNAR1 upon its degron phosphorylation, which is induced by the ligand. Here we report identification of protein kinase D2 (PKD2) as a kinase that mediates the ligand-inducible phosphorylation of IFNAR1 degron and enables binding of βTrcp to the receptor. Treatment of cells with IFN-α induces catalytic activity of PKD2 and stimulates its interaction with IFNAR1. Expression and kinase activity of PKD2 are required for the ligand-inducible stimulation of IFNAR1 ubiquitination and endocytosis and for accelerated proteolytic turnover of IFNAR1. Furthermore, inhibition or knockdown of PKD2 robustly augments intracellular signaling induced by IFN-α and increases the efficacy of its antiviral effects. The mechanisms of the ligand-inducible elimination of IFNAR1 are discussed, along with the potential medical significance of this regulation. [ABSTRACT FROM AUTHOR]

The article focuses on the study that discovers cytokines as tumor suppressor are misused in treating breast cancer in New York. The study is conducted at the Memorial Sloan-Kettering Cancer Center, New York aiming to examine the impact of cytokines in breast cancer metastasis. The study concludes that cytokines are essential for innovative therapeutic approach for cancer diseases.