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Doxorubicin (DOX) is a widely used antitumor drug that causes severe neurotoxicity in patients. Diallyl trisulfide (DATS) is an organosulfur compound with established potent antioxidant and anti-inflammatory properties. Herein, we investigated the neuroprotective efficacy of DATS in preventing DOX-induced neurotoxicity in a rat model. Specifically, DATS (40 mg/kg) was administered to rats 24 h after DOX treatment, once a week for 8 weeks. Our results showed that DATS treatment led to a decrease in plasma levels of tumor necrosis factor-alpha (TNF-α) induced by DOX. DATS restored cerebral cortex and hippocampus histopathological architecture and neuronal loss. Immunohistochemical staining indicated that DATS decreased the expression of glial fibrillar acidic protein (GFAP) in DOX treated rats. Components of stress-related inflammatory proteins (TNF-α, phospho nuclear factor kappa B (NF-κB), inducible nitricoxide synthase (iNOS) and cyclooxygenase-2 (COX-2)) were all significantly increased in the DOX group, in comparison with the control group, whereas they were decreased after DATS treatment. In addition, the mRNA of antioxidant enzymes (superoxide dismutase 2 (SOD2), catalase, glutathione peroxidase 1, 4 (GPx1 and GPx4)) and antioxidant proteins (heme oxygenase-1 (HO-1), superoxide dismutase 1, 2 (SOD1 and SOD2), Γ-glutamylcysteine synthase (Γ-GCSc)) were markedly increased in DOX group compared with the control group, which were significantly attenuated by DATS treatment. The upregulation of antioxidants enzymes in DOX group was probably a compensatory effect against elevated oxidative stress induced by DOX. DATS treatment could ameliorate this oxidative stress in brain. Our results suggested that DATS has potential clinical applications in the prevention of DOX-induced neurotoxicity by ameliorating inflammatory insults and oxidative stress., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Type 2 diabetes mellitus (T2DM) had been reported to be associated with tendinopathy. However, the underlying mechanisms of diabetic tendinopathy still remain largely to be discovered. The purpose of this study was to develop insulin resistance (IR) model on primary human tenocytes (hTeno) culture with tumour necrosis factor-alpha (TNF-α) treatment to study tenocytes homeostasis as an implication for diabetic tendinopathy., Methods: hTenowere isolated from human hamstring tendon. Presence of insulin receptor beta (INSR-β) on normal tendon tissues and the hTeno monolayer culture were analyzed by immunofluorescence staining. The presence of Glucose Transporter Type 1 (GLUT1) and Glucose Transporter Type 4 (GLUT4) on the hTeno monolayer culture were also analyzed by immunofluorescence staining. Primary hTeno were treated with 0.008, 0.08, 0.8 and 8.0 µM of TNF-α, with and without insulin supplement. Outcome measures include 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-d-glucose (2-NBDG) assay to determine the glucose uptake activity; colourimetric total collagen assay to quantify the total collagen expression levels; COL-I ELISA assay to measure the COL-I expression levels and real-time qPCR to analyze the mRNA gene expressions levels of Scleraxis (SCX), Mohawk (MKX), type I collagen (COL1A1), type III collagen (COL3A1), matrix metalloproteinases (MMP)-9 and MMP-13 in hTeno when treated with TNF-α. Apoptosis assay for hTeno induced with TNF-α was conducted using Annexin-V FITC flow cytometry analysis., Results: Immunofluorescence imaging showed the presence of INSR-β on the hTeno in the human Achilles tendon tissues and in the hTeno in monolayer culture. GLUT1 and GLUT4 were both positively expressed in the hTeno. TNF-α significantly reduced the insulin-mediated 2-NBDG uptake in all the tested concentrations, especially at 0.008 µM. Total collagen expression levels and COL-I expression levels in hTeno were also significantly reduced in hTeno treated with 0.008 µM of TNF-α. The SCX, MKX and COL1A1 mRNA expression levels were significantly downregulated in all TNF-α treated hTeno, whereas the COL3A1, MMP-9 and MMP-13 were significantly upregulated in the TNF-α treated cells. TNF-α progressively increased the apoptotic cells at 48 and 72 h., Conclusion: At 0.008 µM of TNF-α, an IR condition was induced in hTeno, supported with the significant reduction in glucose uptake, as well as significantly reduced total collagen, specifically COL-I expression levels, downregulation of candidate tenogenic markers genes (SCX and MKX), and upregulation of ECM catabolic genes (MMP-9 and MMP-13). Development of novel IR model in hTeno provides an insight on how tendon homeostasis could be affected and can be used as a tool for further discovering the effects on downstream molecular pathways, as the implication for diabetic tendinopathy., Competing Interests: The authors declare there are no competing interests., (©2020 Tan et al.)

Objective: To explore the clinical efficacy of acupuncture combined with Jingtong granule for nerve-root type cervical spondylosis and its effects on serum interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β) and hemorheological indexes., Methods: A total of 114 patients with nerve-root type cervical spondylosis were randomly divided into an observation group and a control group, 57 cases in each group. The patients in both groups were treated with traction. The patients in the control group were treated with oral administration of Jingtong granule, 4 g each time, 3 times a day, while based on the treatment of control group, the patients in the observation group were treated with acupuncture at Dazhui (GV 14), Tianzhu (BL 10), Houxi (SI 3), cervical Jiaji (EX-B 2), Quchi (LI 11), Hegu (LI 4) and Waiguan (TE 5), once a day. Both groups were treated for 4 weeks. The simplified McGill pain questionnaire (MPQ), neck disability index (NDI), numbness score, levels of IL-6, TNF-α, IL-1β in serum and hemorheological indexes were observed before and after treatment, and the clinical efficacy was compared between the two groups., Results: The total effective rate was 91.2% (52/57) in the observation group, which was higher than 71.9% (41/57) in the control group ( P <0.05). Compared before treatment, the scores of MPQ, NDI and numbness in the two groups were reduced after treatment ( P <0.05). After treatment, the scores of MPQ, NDI and numbness in the observation group were lower than those in the control group ( P <0.05). After treatment, the serum levels of IL-6, TNF-α and IL-1β in the two groups were reduced ( P <0.05), and those in the observation group were lower than the control group ( P <0.05). After treatment, the plasma viscosity, fibrinogen, low shear rate of whole blood viscosity and high shear rate of whole blood viscosity in the two groups were lower than before treatment ( P <0.05), and those in the observation group were lower than the control group ( P <0.05)., Conclusion: Acupuncture combined with Jingtong granule have significant clinical efficacy for nerve-root type cervical spondylosis, which could reduce the serum levels of IL-6, TNF-α and IL-1β and improve hemorheology.

Background: Osteoarthritis (OA) is a familiar joint degenerative disease. Long non-coding RNAs (lncRNAs) play vital roles in the pathogenesis of OA. Nevertheless, the regulatory impacts of lncRNA highly up-regulated in liver cancer (lncRNA-HULC) on OA remain dimness. The study tried to probe the protective effect of HULC on ATDC5 cells against tumor necrosis factor-alpha (TNF-α)-induced inflammatory injury., Methods: Relative expression levels of pro-inflammatory cytokines (IL-6, IL-8 and MCP-1) and HULC in OA cartilage tissues and normal cartilage tissues were determined by RT-qPCR. TNF-α induced inflammatory injury model in ATDC5 cells was constructed, and the biological functions of HULC overexpression or suppression in TNF-α-injured ATDC5 cells were assessed. The relevancy between miR-101 and HULC was investigated by utilizing bioinformatics prediction, luciferase reporter assay, RNA pull-down and immunoprecipitation. MiR-101 mimic and inhibitor were transfected into ATDC5 cells, and its regulatory effect on TNF-α-injured ATDC5 cells was examined. Further, NF-κB and MAPK signaling pathways were finally detected by western blot., Results: Enhancement of IL-6, IL-8 and MCP-1 were observated in OA cartilage tissues, but repression of HULC was discovered in OA cartilage tissues. HULC expression was decreased by TNF-α treatment, and overexpressed HULC significantly relieved TNF-α-induced ATDC5 cells injury. Additionally, miR-101 was mutual repressed with HULC, and overexpressed miR-101 reversed the protective effect of HULC in TNF-α-injured ATDC5 cells. Besides, HULC blocked NF-κB and MAPK pathways via repression of miR-101., Conclusions: The discoveries testified that HULC protected ATDC5 cells against TNF-α-induced inflammatory injury by repression of miR-101., (Copyright © 2019. Published by Elsevier B.V.)

Introduction: Since the synthesis of acetylsalicylic acid by Hoffmann in 1897, new classes of NSAIDs have been introduced; however, their side effects have limited their clinical applications. Consequently, our team has recently synthesized a novel bipyrazole compound that showed a satisfactory efficacy and safety profile. The aim of the current study was to elucidate the molecular mechanism of this bipyrazole compound., Method: The anti-inflammatory efficacy of the compound was assessed using formalin-induced paw edema test. Computer-assisted simulation docking experiments were carried out. Cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), neuronal nitric oxide synthase (nNOS), tumor necrosis factor-alpha (TNFα), interleukin-1 (IL1) and interleukin-10 (IL10) gene expression were quantified with real-time polymerase chain reaction (RT-PCR) using SYBR Green technology. The samples were taken from the plantar paw of mice after formalin local injection., Results: The efficacy of the bipyrazole compound was similar to that of indomethacin, diclofenac, and celecoxib, as proven by the formalin-induced paw edema. Docking study indicated a superior binding score for the studied compound relative to celecoxib, indomethacin, and diclofenac. RT-PCR assessment revealed a significant decrease in iNOS, COX-2, and TNFα gene expression in the bipyrazole-treated group. Moreover, a reduction in IL1 and nNOS gene expression levels and an increase in IL10 level were detected despite being insignificant compared to the control group., Conclusion: These findings revealed the superiority of the newly synthesized bipyrazole compound not only on the binding site, but also by inhibiting most of the inflammatory mediators including TNF-α.

Alpha-Lipoic Acid (ALA) is a natural antioxidant compound which is naturally found in plant sources. New evidence revealed that ALA can reduce inflammation. Our objective in this meta-analysis was to conduct a systematic review and meta-analysis on randomized controlled trials to indicate ALA effects on serum inflammatory mediators concentration such as tumor necrosis factor-alpha (TNF-α), c-reactive protein (CRP), and interleukin-6 (IL-6). In order to find relevant articles we performed a systematic research up to June 2018 using EMBASE, ISI web of science, Scopus, PubMed, and Google scholar. The overall treatment effect for each inflammatory marker was calculated as weighted mean differences (WMD) and corresponding 95% of confidence interval (CI) between changes in intervention and control groups. Changes for each parameter were calculated by subtracting baseline values from the final mean values. The I 2 statistic was used to examine between-study heterogeneity. When heterogeneity was > 25%, random effect model was run to estimate pooled effect size. There had been nineteen articles in our meta-analysis and twenty-one articles in systematic review. Our meta-analysis results indicated that ALA significantly decreased serum CRP levels (WMD= -0.29, 95% CI: -0.46, -0.12; I 2 =97.6%, P < 0.0001), IL-6 (WMD= -3.02, 95% CI: -4.03, -2.01; I 2 =99.7%, P < 0.0001) and TNF-α levels (WMD= -1.71, 95% CI: -2.30, -1.13; I 2 =99.0%, P < 0.0001). Our results indicated possible decreasing effect of ALA on inflammatory mediators especially in high dose. More randomized clinical trials (RCTs) are necessary with different intervention duration and on women and men separately., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: In hepatocellular carcinoma (HCC), inflammatory factors play an important role, but their effects on the prognosis of patients with HCC are still not very clear., Methods: Immunohistochemical staining was used to detect the expression of tumor necrosis factor-alpha (TNF-α) and nuclear factor-kappa B (NF-κB) in tumour tissues of Barcelona Clinic Liver Cancer-0-B stage (BCLC-0-B) patients with HCC. The relationship between TNF-α and NF-κB expression and clinicopathological features was analysed by χ 2 test. Kaplan-Meier analysis and the log-rank test were used to compare the prognoses of TNF-α and NF-κB high and low-expression groups among HCC patients. The Cox proportional hazard model was used to analyse HCC prognosis by univariate and multivariate analysis., Results: Patients with HCC had significantly longer survival times in the TNF-α/NF-κB high-coexpression group (P<0.05). High expression of TNF-α and NF-κB is an independent prognostic factor predicting postoperative survival and recurrence in patients with HCC (P<0.05)., Conclusions: High expression of TNF-α and NF-κB in the HCC microenvironment can predict survival, and patients with high expression have longer survival times and slowing the recurrence time than those in the low-expression group., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2019.03.09). The authors have no conflicts of interest to declare., (2019 Translational Cancer Research. All rights reserved.)

The exact mechanism of the migraine pathophysiology remained unclear. Although there are some reports showing low-grade inflammation in migraineurs, further studies are needed in this field. Thus, we designed a study to evaluate the serum levels of two main proinflammatory markers in migraine patients. In this case-control research, 43 migraine patients (23 chronic and 20 episodic migraineurs) and 40 age-sex-matched headache-free controls were studied. Demographic, dietary, and anthropometric data, headache characteristics, and serum C-reactive proteins (CRP) and tumor necrosis factor-alpha (TNF-α) assessments were collected. The mean ± SD age of the case and control groups were 36.98 ± 9.91 and 34.84 ± 9.75 years respectively. Compared to control subjects, both episodic and chronic migraineurs had significantly higher median levels of TNF-α (0.24, 0.95, and 1.90 pg/ml, respectively; P value < 0.001). Also, we observed a positive association between the TNF-α levels and the odds of having migraine after considering gender, age, body mass index, and dietary intakes of energy, carbohydrate, protein, fat, and mono and poly unsaturated fatty acids in the multivariable regression models (OR = 2.15; 95% CI 1.31-3.52; P value < 0.001). However, no significant association was demonstrated between migraine and serum CRP (OR = 2.91; 95% CI 0.87-9.78; P value = 0.08). These findings supported that inflammatory state could be related to the pathogenesis of migraine and it can thus be suggested that this effect might be beyond migraine progression. Further detailed studies are needed to investigate the importance of these findings in the pathogenesis of migraine headache.

Traumatic brain injury (TBI) is closely associated with marked inflammation. Although alpha-Melanocyte-Stimulating Hormone (α-MSH) exerts powerful anti-inflammatory effects, changes in endogenous α-MSH levels following TBI remain poorly understood. We investigated the changes of α-MSH levels in the cerebrospinal fluid (CSF) and plasma of post-TBI patients and the association of these changes with the severity of TBI and inflammation. TBI severity was assessed by the GCS coma scale from which, patients were separated into three groups. Clinical data were collected on days 1, 3, 5, and 7 including levels of α-MSH, tumor necrosis factor (TNF-α), and intracranial pressure (ICP). α-MSH levels in CSF steadily increased for one week (peak at day 5) but plasma α-MSH decreased and remained low. These changes were more substantial in the Severe Group of TBI with lower GCS. TNF-α levels were similarly increased in both CSF and plasma (peak at day 3). In the early phase of TBI elevated TNF-α and ICP dominated, and CSF α-MSH displayed a slow and insufficient increase. In later phases of TBI, TNF-α and ICP levels were alleviated concordantly with sustained increases in central α-MSH, wherein an anti-inflammatory environment might predominate. The relationship between plasma α-MSH and TNF-α showed significant negative correlation, and the relationship between CSF α-MSH and TNF-α showed significant positive correlation with a two-day lag. In conclusion, plasma α-MSH levels decreased, but CSF levels increased slowly following TBI. These changes were more substantial in severe patients with a lower GCS. Increases in central α-MSH paralleled alleviation of inflammation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Adipose tissue is an enormously active endocrine organ, secreting various hormones, such as adiponectin, leptin, resistin and visfatin, together with classical cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). All these adipocytokines play significant roles in the regulation of energy metabolism, glucose and lipid metabolism, reproduction, cardiovascular function and immunity. Adipocytokines are significantly regulated by nutritional status and can directly influence other organ systems, including brain, liver and skeletal muscle. Adiponectin plays a key role as an anti-inflammatory hormone. Upregulated expression of resistin, vaspin, apelin and TNF-α plays a significant role in induction of insulin resistance linked with obesity and type 2 diabetes. Ghrelin, the circulating peptide, has been found to stimulate appetite and regulate energy balance. Thus, it can be considered 1 of the candidate genes for obesity and type 2 diabetes. Omentin is a novel adipokine produced by visceral adipose tissue. Circulating levels of omentin are decreased in insulin-resistant states, for example, in obesity and diabetes. IL-6 plays a vital role in regulating the accumulation of lipids intramyocardially. Based on the biologic relevance of these adipocytokines, they can no longer be considered as energy storage sites alone but must also be considered in metabolic control. Hence, the present review summarizes the regulatory roles of adipocytokines in diabetes linked with obesity., (Copyright © 2017 Diabetes Canada. Published by Elsevier Inc. All rights reserved.)

Background: Immune activation and suppression in patients with major depressive disorders (MDD) have been both reported in different studies. We assume that these findings may indicate innate immunological tolerance in MDD, with subclinical elevated level of proinflammatory cytokines and the decrease in innate immune response while encountering pathogens., Methods: Peripheral monocytes of 50 untreated patients with MDD and 40 healthy controls were isolated and cultured, with or without 10 ng/ml lipopolysacchride (LPS) for 6 h (6 h, LPS+/-), and with LPS for 18 h (18, LPS+). The cell culture supernatants were collected to measure concentrations of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and interleukin 1 beta (IL-1β)., Results: The baseline concentrations of IL-6 and IL-1β (6 h, LPS-) were significantly higher in the MDD group than those in the control group. There was no significant difference of TNF-α between the two groups. The fold changes of LPS-induced secretion of IL-6 and TNF-α from monocytes cultured for 6 and 18 h were all lower in the patient groups, and that was true for IL-1β as monocytes cultured for 18 h., Limitations: Given the gap between the results of in vitro experiments and the actual response that happens in vivo when the immune system encounters pathogens from the external world, future research should include in vivo methods to test the results of the current study., Conclusions: Patients with MDD may have subclinical inflammation during a depressive episode, and the reduced response to LPS in monocytes indicates innate immunological tolerance., (Copyright © 2018. Published by Elsevier B.V.)

Background and Aim: Secondary loss of response to adalimumab (ADA-LOR) commonly occurs in patients with Crohn's disease (CD) treated with adalimumab (ADA). We evaluated the efficacy of concomitant elemental diet (ED) therapy to reduce ADA-LOR in adult CD patients., Methods: Patients were divided into either an ED (≥900 kcal/day) or a non-ED group (<900 kcal/day). Cumulative non-ADA-LOR rates were compared between groups. The effects of ED intake to reduce ADA-LOR were also assessed in antitumor necrosis factor-alpha (TNF-α)-naïve and infliximab (IFX)-intolerant or refractory CD patients. Serum ADA and TNF-α levels were measured., Results: We enrolled 117 CD patients into the ED (n = 25) or non-ED (n = 92) groups. Although the cumulative non-ADA-LOR rate was higher in the ED group than in the non-ED group, ED intake was not an independent reducing factor for ADA-LOR (adjusted hazard ratio = 0.725; 95% confidence interval: 0.448-1.180; P = 0.196) in all patients. ED intake was significantly more effective in reducing ADA-LOR in IFX-intolerant or refractory patients than in anti-TNF-α-naïve patients in a dose-related manner (P for interaction <0.20). Serum ADA levels did not differ between the groups. Serum TNF-α levels were significantly lower in the ED group than in the non-ED group at week 28 (P = 0.044) and week 52 (P = 0.043)., Conclusions: Concomitant ED therapy reduced ADA-LOR in IFX-intolerant or refractory patients in a dose-related manner. Reductions in the TNF-α levels by concomitant ED intake may contribute to reduce ADA-LOR in CD patients., (© 2017 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Tumor necrosis factor (TNF)-α is responsible for expressions of several clock genes and affects joint symptoms of rheumatoid arthritis (RA) with diurnal fluctuation. We tried to determine the mechanism involved in over-expression of Bmal1, induced by TNF-α, in primary cultured rheumatoid synovial cells. Cells were incubated with intra-cellular Ca 2+ chelator BAPTA-AM, calcineurin inhibitor FK506 and p300/CBP (CREB binding protein) inhibitor C646, respectively, or transfected with p300 and CBP small interfering RNA (siRNA) before stimulation with TNF-α. Oscillation phase and amplitude of Bmal1, transcriptional activator Rorα, transcriptional repressor Rev-erbα, and histone acetyltransferases (p300 and Cbp) were evaluated by quantitative real-time PCR. As results, TNF-α did not influence the oscillation phase of Rev-erbα, while enhanced those of Rorα, resulting in over-expression of Bmal1. When Ca 2+ influx was inhibited by BAPTA-AM, TNF-α-mediated up-regulation of Rorα was cancelled, however, that of Bmal1 was still apparent. When we further explored another pathway between TNF-α and Bmal1, TNF-α suppressed the expression of Rev-erbα in the absence of Ca 2+ influx, as well as those of p300 and Cbp genes. Finally, actions of TNF-α, in increasing Bmal1/Rorα and decreasing Rev-erbα, were cancelled by C646 treatment or silencing of both p300 and Cbp. In conclusion, we determined a novel role of TNF-α in inducing Bmal1 via dual calcium dependent pathways; Rorα was up-regulated in the presence of Ca 2+ influx and Rev-erbα was down-regulated in the absence of that. Results proposed that inhibition of p300/CBP could be new therapeutic targets for RA., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Tumor necrosis factor-α is an important pro-inflammatory cytokine having a key role in hosts defensive process of immune systems and its over expression led to a diverse range of inflammatory diseases such as Rheumatoid arthritis, Cronh's disease, psoriasis, etc. This paper describes our medicinal chemistry efforts on imidazo[1,2-b]pyridazine scaffold: design, synthesis and biological evaluation. By the introducing sulfonamide functionality at 3 positions and substituting 6 positions with (hetero)-aryl groups', a small library of compounds was prepared. All synthesized compounds were screened for lipopolysaccharide (LPS) mediated TNF-α production inhibitory activity. Biological data revealed that the majority of the compounds of this series showed moderate to potent TNF-α production inhibitory activity. Compound 5u and 5v are the most potent compounds from the series with activity of IC 50  = 0.5 µM and 0.3 µM respectively. A short SAR demonstrates that 3-sulfonyl-4-arylpiperidine-4-carbonitrile moiety on imidazo[1,2-b]pyridazine showed better activity compared to the 3-(4-aryllpiperazin-1-yl) sulfonyl) in hPBMC assay. The molecular modeling studies revealed that the potent TNF-α production inhibitory activity 5v due to the extra stability of complex because of an extra pi-pi (π-π) stacking, hydrogen-bonding interactions., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Tumor necrosis factor-alpha (TNF-α) is a proinflammatory cytokine released by immune cells during inflammation process. Sodium arsenite (NaAsO 2 ) is an environmental toxic metal. The effects of excess NaAsO 2 on TNF-α response and its intracellular signaling are not well understood. We hypothesized that NaAsO 2 exposure might affect cellular response to TNF-α. Using HeLa cell model, we found that the combination of NaAsO 2 and TNF-α clearly decreased cell viability and mitochondrial membrane potential, but increased percentage of early and late apoptotic cells and cleaved-poly (ADP-ribose) polymerase (PARP). Moreover, the combination prolonged the phosphorylation of mitogen-activated protein kinase (MAPK) members, including c-Jun-N-terminal kinase (JNK), p38, and extracellular signal related kinases (ERK), and increased intracellular reactive oxygen species (ROS), in comparison to treatment of NaAsO 2 or TNF-α alone. We further investigated the role of ROS and MAPK signaling on this event by inhibiting ROS production and MAPK. An antioxidant N-acetylcysteine pretreatment diminished the apoptosis-inducing effect of NaAsO 2 and TNF-α combination and also inhibited MAPK signaling. Using specific inhibitor of p38 (SB203580) and siRNA-p38 surprisingly increased cell apoptosis and this effect was not observed by JNK and ERK inhibition. This study suggests that p38 may possibly be a survival mediator in response to environmental toxicant-related inflammation. In conclusion, NaAsO 2 exposure might amplify inflammation-related tissue injury by potentiating the apoptosis-inducing effect of TNF-α through ROS-dependent mechanism.

The skin-associated chemokine CCL27 and its receptor CCR10 mediate the immune response of skin-homing T cells. The CCL27 secreted from keratinocytes was reportedly involved in inflammatory skin diseases such as atopic dermatitis, contact dermatitis, and psoriasis. However, whether ionizing radiation increases the levels of CCL27 secretion still remains unclear. In HaCaT cells, a human keratinocyte cell line, CCL27 secretion was markedly increased after X-ray irradiation. We further found that irradiation boosted the generation of reactive oxygen species (ROS), which was concomitant with the release of tumor necrosis factor-alpha (TNF-α). Moreover, alteration of ROS in irradiated HaCaT cells correlated with TNF-α secretion, indicating a positive loop of TNF-α secretion and ROS generation. This positive loop regulated the secretion of CCL27 from irradiated cells. We therefore concluded that the cross talk between TNF-α and ROS after keratinocytes was exposed to radiation, triggered CCL27 secretion for subsequent inflammation response., (© 2016 Wiley Periodicals, Inc.)

Objective: Elevated levels of tumor necrosis factor- alpha (TNF-α) in the capsule of the temporomandibular joint (TMJ) are implicated in the underlying pathology of temporomandibular disorders (TMD). TMD are a group of conditions that result in pain in the TMJ and/or muscles of mastication, and are associated with significant social and economic burdens. The goal of this study was to investigate the effect of elevated TNF-α levels in the TMJ capsule on nocifensive behavioral response to mechanical stimulation of trigeminal neurons and regulation of cytokines within the trigeminal ganglion., Design: Male Sprague-Dawley rats were injected bilaterally in the TMJ capsule with TNF-α and changes in nocifensive head withdrawal responses to mechanical stimulation of cutaneous tissue directly over the capsule was determined using von Frey filaments. Cytokine levels in trigeminal ganglia were determined by protein array analysis at several time points post injection and correlated to nocifensive behavior., Results: TNF-α caused a significant increase in the average number of nocifensive responses when compared to naive and vehicle treated animals 2h post injection, but levels returned to control levels at 24h. Based on array analysis, the levels of eight cytokines were significantly elevated above vehicle control levels at 2h following TNF-α injection, but all eight had returned to the vehicle control levels after 24h., Conclusions: Our findings provide evidence that elevated levels of TNF-α in the joint capsule, which is reported to occur in TMD, promotes nociception in trigeminal ganglia neurons via a mechanism that temporally correlates with differential regulation of several cytokines., Competing Interests: None., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: Olfactory dysfunction is a common finding in head trauma due to injury to the olfactory nerve. We previously reported that anti-inflammatory treatment with steroids improves recovery outcome in olfactory nerve injury models. Clinically, however, steroid administration is not recommended in the acute phase of head injury cases because of concerns regarding its side effects. Tumor necrosis factor (TNF-α) is known to play a key role in inflammatory response to injury. The present study examines if the inhibition of TNF-α can facilitate functional recovery in the olfactory system following injury., Materials and Methods: Olfactory nerve transection (NTx) was performed in olfactory marker protein (OMP-tau-lacZ) mice to establish injury models. We measured TNF-α gene expression in the olfactory bulb using semi-quantitative and real time polymerase chain reaction (PCR) assays and found that they increase within hours after NTx injury. A TNF-α antagonist (etanercept) was intraperitoneally injected immediately after the NTx and histological assessment of recovery within the olfactory bulb was performed at 5-70 days. X-gal staining labeled OMP in the degenerating and regenerating olfactory nerve fibers, and immunohistochemical staining detected the presence of reactive astrocytes and macrophages/microglia., Results: Etanercept-injected mice showed significantly smaller areas of injury-associated tissue, fewer astrocytes and macrophages/microglia, and an increase in regenerating nerve fibers. Olfactory function assessments using both an olfactory avoidance behavioral test and evoked potential recordings showed improved functional recovery in etanercept-injected animals., Conclusion: These findings suggest that inhibition of TNF-α could provide a new therapeutic strategy for the treatment of olfactory dysfunction following head injuries., (Copyright © 2016. Published by Elsevier B.V.)

Adrenomedullin (AM), a member of the calcitonin gene-related peptide (CGRP) family, has been demonstrated to be a pain peptide. This study investigated the possible involvement of AM in tumor necrosis factor-alpha (TNF-α)-induced responses contributing to neuronal plasticity in the dorsal root ganglia (DRG). Exposure of the DRG explant cultures to TNF-α (5nM) for 48h upregulated the expression of AM mRNA. The treatment with TNF-α also increased the level of CGRP, CCL-2 and MMP-9 mRNA in the cultured DRG. This increase was attenuated by the co-treatment with the selective AM receptor antagonist AM22-52 (2μM). The blockade of AM receptors inhibited TNF-α-induced increase of the glial fibrillary acidic protein (GFAP), interleukin-1β (IL-1β), phosphorylated cAMP response element binding protein (pCREB) and nuclear factor kappa B (pNF-κB) proteins. On the other hand, the treatment with the AM receptor agonist AM1-50 (10nM) for 96h induced an increase in the level of GFAP, IL-1β, pCREB and pNF-κB proteins. The inhibition of AM activity did not change TNF-α-induced phosphorylation of extracellular signal-related kinase (pERK) while the treatment with AM1-50 still increased the level of pERK in the cultured DRG. Immunofluorescence assay showed the colocalization of AM-like immunoreactivity (IR) with TNF-α-IR in DRG neurons. The present study suggests that the increased AM receptor signaling mediated the many, but not all, TNF-α-induced activities, contributing to peripheral sensitization in neuropathic pain., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Unlabelled: Ionizing radiation has attracted a lot of attention due to its beneficial and possible harmful effects to the human population. The brain displays numerous biochemical and functional alterations after exposure to irradiation, which induces oxidative-stress through generation of reactive oxygen species (ROS). The present study evaluated the neuro-protective role of fermented Ginkgo biloba (FGb) leaf extract, compared to non-fermented G. biloba (Gb) leaf extract against γ-irradiation (6Gy) in the rats' brain. The changes of the Gb phytochemical constituents after fermentation, using Aspergillus niger were evaluated by Gas Chromatography-Mass Spectrometry. The results showed a significant decrease in superoxide dismutase (SOD), glutathione peroxidase (GPx) activities and elevation of the calcium level in the brain cytosolic fraction of γ-irradiated rats. Further, significant increases in the malondialdehyde (MDA), the stress hormones (catecholamines); epinephrine (EN), norepinephrine (NE) and dopamine (DA) levels and the interleukin-1-beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) gene expression relative ratio in parallel with a significant decrease in the glutathione (GSH) content and DNA fragmentation in the brain tissues of the γ-irradiated rats were observed. The pre-treatment with Gb extract significantly amended these biochemical parameters. Meanwhile, the pre-treatment with the FGb showed more improvement, compared to Gb, of these biochemical parameters in the brain of γ-irradiated rats, which could be attributed to the enhancement of its antioxidant activity after fermentation. These findings suggested that fermentation enhances the protective effect of Gb in the brain on the neuroinflammation, release of the stress hormones, apoptosis and oxidative damage induced by γ-irradiation., In Conclusion: fermentation improved the bio-activities of Gb leaf extract and thus enhanced the in-vivo antioxidant, anti-apoptotic and anti-inflammatory activities, leading to amelioration of the stress hormones and Ca level. Accordingly, the fermentation enhances the protective role of Gb against γ-irradiation induced physiological disturbance in the rat's brain., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Sepsis is a potentially fatal syndrome mediated by an early [e.g., tumor necrosis factor-alpha (TNF-α)] and late [high mobility group box-1 (HMGB-1)] proinflammatory cytokine response to infection. Sepsis-induced acute kidney injury (AKI) is associated with a high mortality. C-Fos/activator protein-1 (AP-1) controls the transactivation of proinflammatory cytokines via AP-1 binding in the promoter region. T-5224 is a de novo small molecule inhibitor of c-Fos/AP-1 that controls gene expression of multiple proinflammatory cytokines. We investigated whether T-5224, a selective inhibitor of c-Fos/AP-1, improves survival in lethal lipopolysaccharide (LPS)-induced AKI by inhibiting early (TNF-α) and late (HMGB-1) proinflammatory cytokine response., Methods: Mice were divided into four groups (control, LPS, LPS + T-5224, and T-5224 only). Control mice were administered polyvinylpyrrolidone (PVP) solution orally, immediately after intraperitoneal (i.p.) saline injection. LPS mice were administered PVP solution orally immediately after i.p. LPS (10 mg/kg) injection. LPS + T-5224 mice were administered T-5224 orally (300 mg/kg) immediately after i.p. LPS injection. T-5224 mice were administered T-5224 orally (300 mg/kg) after i.p. saline injection. Serum concentrations of TNF-α, HMBG-1, and interleukin (IL)-10 were measured by enzyme-linked immunosorbent assay (ELISA). Serum blood urea nitrogen (BUN) and creatinine concentrations were commercially analyzed. Finally, histological examination was performed on the kidney., Results: Treatment with T-5224 decreased serum TNF-α and HMGB-1 levels and increased survival after LPS injection. Furthermore, T-5224 treatment decreased serum BUN and creatinine concentrations but increased serum IL-10 concentration. LPS-induced pathological changes in kidney were attenuated by T-5224 treatment., Conclusions: These results suggest that T-5224, a selective inhibitor of c-Fos/AP-1, inhibits expression of early and late proinflammatory cytokines, protecting mice from LPS-induced lethality. T-5224 is a potential approach for decreasing lethality in sepsis-induced AKI.

Tumor necrosis factor-alpha (TNF-α) antagonists have shown remarkable efficacy in psoriasis; however, the precise mechanisms of action of TNF-α blocking agents mainly focus on their neutralizing TNF-α and its anti-inflammatory effects. In this study, we generated a humanized anti-TNF-α monoclonal antibody (IBI303) and suggested a potential mechanism of anti-TNF-α therapy for psoriasis. The results of SPR and ELISA indicated that IBI303 has a good affinity to TNF-α. In vitro, it could suppress TNF-α-induced cytotoxicity in WEHI164 cells. In vivo, administration of IBI303 to K14-VEGF transgenic mice led to a significant treatment efficiency in psoriasis in a dose-dependent manner. IHC staining and cytokines-ELISA indicated that TNF-α inhibition strongly reduced inflammatory cells infiltration and pro-inflammatory cytokines release, accompanied by suppression of inflamed dermal blood vessels. Mechanistically, in order to explain the anti-angiogenesis effect of anti-TNF-α antibody, the production of cytokine in macrophage conditional medium was measured by ELISA. The result indicated that the massive secretion of TNF-α stimulated by LPS in RAW264.7 cell supernatant was markedly neutralized in a dose-response manner by IBI303, moreover, the expression of NF-κB p65 was down-regulated. Mouse endothelial cell tube formation assay showed that anti-TNF-α could inhibit blood vessels formation directly and indirectly. Collectively, our study suggested a kind of antipsoriatic mechanism of TNF-α inhibitors that is the dual inhibition of inflammation and angiogenesis., (Copyright © 2015. Published by Elsevier B.V.)

Background: Monitoring tuberculosis (TB) treatment response remains challenging due to lack of reliable laboratory markers. In recent years, increased efforts have been exerted toward development of new biomarkers reflecting treatment response appropriately. While performance of interferon-gamma release assays (IGRAs) to monitor anti-TB treatment has been extensively evaluated, there is no data about post-treatment changes in Mycobacterium tuberculosis (MTB) antigen-stimulated tumor necrosis factor-alpha (TNF-α) release in active TB patients. Herein, we explored whether the MTB antigen-stimulated TNF-α release would be useful for monitoring responses to anti-TB treatment., Methods: We compared unstimulated (TNF-αNil), MTB antigen-stimulated (TNF-αAg), and MTB antigen-stimulated minus unstimulated TNF-α levels (TNF-αAg-Nil) in supernatants from QuantiFERON-TB Gold In-Tube tests before and after treatment in 16 active TB patients, 25 latent TB infection (LTBI) subjects, and 10 healthy controls (HC)., Results: TNF-αAg and TNF-αAg-Nil levels decreased significantly after treatment in patients with active TB. In addition, TNF-αNil, TNF-αAg, and TNF-αAg-Nil levels were significantly higher in untreated active TB patients compared to LTBI subjects and HC., Conclusions: This finding cautiously suggests that MTB Ag-stimulated TNF-α response may be a potential adjunctive marker for monitoring treatment response in active TB patients.

Garlic (Allium sativum) is known to have many beneficial attributes such as antimicrobial, antiatherosclerotic, antitumorigenetic, and immunomodulatory properties. In the present study, we investigated the effects of an aqueous garlic extract on macrophage cytokine production by challenging the macrophage J774A.1 cell line with the garlic extract in the absence or presence of lipopolysaccharide (LPS) under different conditions. The effect of allicin, the major component of crushed garlic, was also investigated. Using enzyme-linked immunosorbent assay and reverse transcriptase-quantitative polymerase chain reaction, it was found that garlic and synthetic allicin greatly stimulated tumor necrosis factor-alpha (TNF-α) production in macrophages treated with LPS. The TNF-α secretion levels peaked earlier and were sustained for a longer time in cells treated with garlic and LPS compared with cells treated with LPS alone. Garlic acted in a time-dependent manner. We suggest that garlic, at least partially via its allicin component, acts downstream from LPS to stimulate macrophage TNF-α secretion., (© 2014 The Authors. Phytotherapy Research published by John Wiley & Sons, Ltd.)

Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) is considered to be the major one contributing to the process of development of endothelial dysfunction. Exposure to TNF-α induces the expression of a number of proinflammatory chemokines, such as monocyte chemotactic protein-1 (MCP-1), and adhesion molecules, including vascular adhesion molecule-1 (VCAM-1) and E-selectin, which mediate the interaction of invading monocytes with vascular endothelial cells. Glatiramer acetate (GA) is a licensed clinical drug for treating patients suffering from multiple sclerosis (MS). The effects of GA in vascular disease have not shown before. In this study, we found that GA significantly inhibited TNF-α-induced binding of monocytes to endothelial cells. Mechanistically, we found that GA ameliorated the upregulation of MCP-1, VCAM-1, and E-selectin induced by TNF-α. Notably, this process is mediated by inhibiting the nuclear translocation and activation of NF-κB. Our results also indicate that GA pretreatment attenuates the up-regulation of COX-2 and iNOS. These data suggest that GA might have a potential benefit in therapeutic endothelial dysfunction related diseases., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) is considered to be the major one contributing to the process of development of osteoarthritis (OA).Interferon regulatory factor 1 (IRF-1) is an important transcriptional factor accounting for inflammation response induced by TNF-α. The physiological function of IRF-1 in OA is still unknown. In this study, we reported that the expression levels of IRF-1 in OA chondrocytes were significantly higher compared to those in normal chondrocytes, which was reversed by treatment with Glatiramer acetate (GA), a licensed clinical drug for treating patients suffering from multiple sclerosis (MS). We also found that GA is able to attenuate the upregulation of IRF-1 induced by TNF-α. Matrix metalloproteinase13 (MMP-13) is one of the downstream target genes of IRF-1, which can induce the degradation of collagen II. Importantly, our results indicated that GA suppressed the expression of MMP-13 as well as the degradation of collagen II. In addition, GA also suppressed TNF-α-induced production of NO and expression of iNOS. Finally, we found that the inhibition of STAT1 activation played a critical role in the inhibitory effects of GA on the induction of IRF-1 and MMP-13. These data suggest that GA might have a potential effect in therapeutic OA., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Tumor necrosis factor-alpha (TNF-α) is a highly pleiotropic cytokine involved in a spectrum of physiological processes that control inflammation, anti-tumor responses and homeostasis through two receptors, TNF-R1 and TNF-R2. In general, TNF-R1 mediates cytotoxicity, resistance to infection and stimulation of NF-κB. By contrast, TNF-R2 has been implicated in proliferation of T-cell line, thymocytes and human mononuclear cells. Hematological malignancies are the types of cancer that affect normal hematopoiesis, have a speedy development, high lethal rate and until now still have no effective treatment. Several studies have shown that inflammatory cytokines play an important role in the onset and progress of these diseases. In this review, we summarize the recent studies and evaluate the positive or negative role of TNF-α in some hematological malignancies or diseases with a malignant tendency.

Objective: We evaluated the levels of cerebrospinal fluid concentrations of tumor necrosis factor-α, interleukin-6, and interleukin-8 in bacterial meningitis in children., Methods: The study included children up to 14 years of age admitted to a pediatric ward with fever, headache, vomiting, and seizures. The diagnosis of bacterial meningitis was based on clinical features: physical examination, blood and cerebrospinal fluid cytochemical findings, Gram stain, and bacterial culture. The cerebrospinal fluid levels of tumor necrosis factor-α, interleukin-6, and interleukin-8 were measured in 57 children with bacterial meningitis, 15 with viral meningitis, and 15 controls by enzyme-linked immunosorbent assay methods., Results: The mean concentrations of cerebrospinal fluid, tumor necrosis factor-α, interleukin-6, and interleukin-8 were 1108 ± 183, 652 ± 287, and 442 ± 120 pg/mL, respectively, in children with bacterial meningitis and were significantly increased in those in the viral meningitis group (tumor necrosis factor-α : 711 ± 105, IL-6 : 272 ± 161, IL-8 : 175 ± 62 pg/mL; P < 0.001) or control (390 ± 37, 59 ± 17, 19 ± 13 pg/mL, respectively, P < 0.001). At optimum cutoff level based on the receiver operating characteristic curve, cerebrospinal fluid cytokines (tumor necrosis factor-α, interleukin-6, and interleukin-8) showed sensitivity and specificity of 100% for the diagnosis of bacterial meningitis. For differentiation of bacterial from viral meningitis, cerebrospinal fluid level of tumor necrosis factor-α, IL-6, and IL-8 showed sensitivity and specificity of 94.7% and 86.7%, 80.7% and 53.3%, and 89.5% and 86.7%, respectively., Conclusion: The increased concentration of cerebrospinal fluid tumor necrosis factor-α, interleukin-6, and interleukin-8 in children with meningitis suggests a role in the pathogenesis of bacterial meningitis and these levels might prove to be useful in children whose diagnosis is in question., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Pothos scandens L. was used in Indian traditional medicine as an antiasthmatic drug. The ethanolic and aqueous extracts were prepared with aerial parts of P. scandens (PSE & PSA). ESI MS/MS of PSE ethanolic extract was carried out for the determination of chemical constituents. CP1 is isolated from the PSE, structurally confirmed with NMR and LCMS/MS. PSE, PSA and CP1 are evaluated against ovalbumin (OVA) induced airway hyperresponsiveness (AHR) in balb/c mice. The test drugs are administered p.o. prior to challenge with aerosolized 2.5% w/v OVA. Total and differential leucocyte count, nitrite (NO2), nitrate (NO3), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-13 (IL-13) are estimated in bronchoalveolar lavage fluid (BALF). Similarly, myeloperoxidase (MPO), malonaldehyde (MDA) and total lung protein (TLP) are estimated in the lungs. The results reveal a significant increase in total and differential leucocyte count, NO2, NO3, TNF-α, IL-6, and IL-13 in OVA induced AHR. However, these parameters are significantly decreased in PSE and PSA tested doses (PSE 100 & 200mg/kg). While, treatment with CP1 is less effective at 5 & 10mg/kg doses. Similar observations obtain for MPO and MDA in lungs. However, the mean value indicated that the PSE at 200mg/kg showed a significant restoration in all the parameters. Pro-inflammatory mediators are known to be responsible for AHR. Histopathology revealed justifies the effectiveness. The present investigations suggest PSE are interesting molecules for further research for asthma, with an approach through pro-inflammatory inhibitory pathway. P. scandens is a potential herbal medicine for allergy induced asthma., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: Previous studies have investigated the role of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and tumor necrosis factor-alpha (TNF-α) in carcinogenesis of osteosarcoma, but their results were inconsistent. We aimed to clarify the associations between CTLA-4, TNF-α polymorphism and osteosarcoma risk by using meta-analysis., Methods: We searched relevant studies without language restriction in PubMed, EMbase, Cochrane Library, Google Scholar databases, Chinese National Knowledge Infrastructure (CNKI) and conference literature in humans published prior to March 2013. The strengths of the associations between genetic variants and osteosarcoma risk were estimated by odds ratio (OR) with 95% confidence interval (95% CI)., Results: A total of seven studies with 1,198 osteosarcoma patients and 1,493 controls were selected. Four studies were eligible for CTLA-4 (1,003 osteosarcoma and 1,162 controls), and three studies for TNF-α (195 osteosarcoma and 331 controls). Pooled results showed that rs231775 polymorphism of CTLA-4 was associated with osteosarcoma risk (GG vs. AA: OR=1.63, 95% CI=1.24-2.13; GG + GA vs. AA: OR=1.56, 95% CI=1.21-2.01; AA + GA vs. GG: OR=0.83, 95% CI=0.71-0.97; G vs. A: OR=1.21, 95% CI=1.08-1.36). No significant heterogeneity was observed across the studies. No significant associations were found between rs5742909 polymorphism of CTLA-4 or rs1800629 polymorphism of TNF-α and osteosarcoma risk., Conclusions: These results suggest that the rs231775 polymorphism of CTLA-4 may play an important role in carcinogenesis of osteosarcoma.

Purpose: To determine if a serine protease inhibitor A3K (SA3K) reduces TNF-α-induced declines in rabbit corneal endothelial junctional barrier integrity., Methods: New Zealand rabbit corneas were incubated ex vivo for 24 hours in Dulbecco's modified Eagle's medium (DMEM) containing 10% FBS with or without TNF-α, in the presence or absence of SA3K at different concentrations. Corneal endothelial barrier function permeability was determined based on measurements of FITC-dextran tissue accumulation. Apical junctional complex (AJC) integrity was evaluated of zonula occludens-1 (ZO-1), vascular endothelial (VE)-cadherin, and filamentous actin (F-actin) and associated microtubules, as well as myosin light chain (MLC) by immunofluorescent staining, Western blot analysis, and/or RT-PCR., Results: TNF-α (20 ng/mL) increased corneal endothelial FITC-dextran permeability by 1.8-fold compared with the untreated control. SA3K (100-200 nM) dose dependently suppressed TNF-α-induced increases in permeability. SA3K nearly completely reversed TNF-α-induced disruptions of tight junctional ZO-1 and subjacent adherens junctions VE-cadherin integrity. Interestingly, SA3K reversed TNF-α-induced disruption of AJC linkage to the cytoskeletal F-actin array by restoring F-actin double-band structures. SA3K also attenuated TNF-α-induced microtubule disassembly. Furthermore, SA3K blocked increases in MLC phosphorylation status elicited by TNF-α., Conclusions: SA3K exposure markedly reduced TNF-α-induced disruption of barrier structure and function in the rabbit corneal endothelium by maintaining AJC integrity. These protective effects are due to suppression of MLC activation. SA3K may have, in vivo, a therapeutic potential to offset TNF-α-induced declines in endothelial barrier structural integrity and function.

Tumor necrosis factor-alpha (TNF-α), a member of the TNF superfamily, was the first cytokine to be evaluated for cancer biotherapy. However, the clinical use of TNF-α is severely limited by its toxicity. Currently, TNF-α is administered only through locoregional drug delivery systems such as isolated limb perfusion and isolated hepatic perfusion. To reduce the systemic toxicity of TNF-α, various strategies have been explored over the last several decades. This review summarizes current state-of-the-art targeted cancer therapy using TNF-α. Passive targeting, cell-based therapy, gene therapy with inducible or tissue-specific promoters, targeted polymer-DNA complexes, tumor pre-targeting, antibody-TNF-α conjugate, scFv/TNF-α fusion proteins, and peptide/TNF-α fusion proteins have all been investigated to combat cancer. Many of these agents are already in advanced clinical trials. Molecular imaging, which can significantly speed up the drug development process, and nanomedicine, which can integrate both imaging and therapeutic components, has the potential to revolutionize future cancer patient management. Cooperative efforts from scientists within multiple disciplines, as well as close partnerships among many organizations/entities, are needed to quickly translate novel TNF-α-based therapeutics into clinical investigation.