Tumor Necrosis Factor-alpha Receptor Research Articles

TNF-α–TNFR1 Signaling Mediates Inflammation and Bone Resorption in Apical Periodontitis

IntroductionThe aim of this study was to investigate the role of the proinflammatory axis TNF-α–TNFR1 in experimentally induced periapical inflammation and bone resorption in mice. MethodsAfter receiving Ethics Committee Approval (2019.1.139.58.0), experimental apical periodontitis was induced by means of inoculating oral microorganisms into the root canals of molars of mice. Genetically deficient tumor necrosis factor-α receptor-1 mice (TNFR1-/-; n = 50) response was compared with that of C57Bl6 wild-type mice (wild-type; n = 50) after 7, 14, 28, and 42 days. The analyses performed were micro–computed tomographic, histopathologic, histomicrobiological, and histometric evaluation, tartrate-resistant acid phosphatase staining, immunohistochemistry, and quantitative reverse transcriptase polymerase chain reaction. Data were analyzed by using one-way analysis of variance, followed by Tukey or Bonferroni tests (α = 5%). ResultsTNFR1-/- mice exhibited lower recruitment of neutrophils at 14, 28, and 42 days (P < .05), which resulted in reduced area and volume of apical periodontitis at 42 days (P < .05). The number of osteoclasts was also lower in TNFR1-/- animals at 14 and 42 days (P < .01), along with reduced synthesis of CTSK, MMP-9, and COX-2. Expression of RANKL, but not OPG, was reduced at 14 and 42 days (P < .001). The highest RANKL expression over OPG (ratio > 1) was found in wild-type animals at 7 (P < .0001) and 42 days (P < .001). ConclusionsPeriapical inflammation and bone resorption were exacerbated in wild-type animals compared with TNFR1-/- mice, demonstrating that the TNF-α–TNFR1 signaling pathway mediated catabolic events in bone after root canal contamination.

Golimumab for Polyarticular Juvenile Idiopathic Arthritis and Psoriatic Arthritis: Pharmacologic and Clinical Considerations.

Psoriatic arthritis is a chronic debilitating autoimmune condition, and when diagnosed in patients before the age of eighteen, it is considered pediatric polyarticular juvenile idiopathic arthritis. Monoarticular or polyarticular psoriatic arthritis can be distinguished from other arthropathies by its unique cutaneous manifestations. With numerous treatments already in clinical practice, there are numerous options for treatment. The current literature indicates an elevated level of tumor necrosis factor is present in the epidermis of patients with psoriatic arthritis when compared with the general population. For this reason, anti-tumor necrosis factor therapies have become a hallmark option for psoriatic arthritis patients. Golimumab, a human monoclonal antibody tumor necrosis factor-alpha (TNF-a) receptor antagonist, was chosen as the focus therapy for this investigation. The mechanism of action behind anti-tumor necrosis factor-alpha blockers involves the binding of human TNF-a soluble and transmembrane proteins to competitively inhibit TNF-a from binding to its cellular receptors. The present investigation evaluated current treatment options available for both juvenile- and adult-onset psoriatic arthritis and compared them with the efficacy seen with golimumab use. Pediatric patients included children ages 2-17, while adult populations included adults 18-83 years old. The Food and Drug Administration has approved golimumab for the treatment of rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and polyarticular juvenile idiopathic arthritis. The results of four different studies reporting on the therapeutic effects and adverse events of golimumab use in psoriatic arthritis, juvenile psoriatic arthritis, juvenile idiopathic arthritis, and juvenile polyarticular arthritis were used for comparison. The meta-analysis referenced studies including children ages 2-17 with no reference mentioning children less than age 2. Based on the results of each study, it can be concluded that golimumab, a human monoclonal antibody that prevents the activation of cellular inflammatory reactions when it binds to the TNF-a receptor, is an effective option for patients with active psoriatic arthritis and psoriatic juvenile idiopathic arthritis and for patients who are no longer responding to their current treatment with adalimumab. Each study also reported minimal adverse events associated with golimumab use, and the drug can be safely used in the pediatric population.

Can sulforaphane alter growth performance, innate immunity and antioxidant capability of common carp (Cyprinus carpio Huanghe var)?

Sulforaphane (SFN) is a plant extract with demonstrated immunity, anti-inflammatory and antioxidant properties. However, its research on aquatic animals is still lacking. Herein, this study aimed to investigate the effects of SFN on growth performance, innate immunity and antioxidant capability of common carp (Cyprinus carpio Huanghe var). Fish (76.17 ± 0.23 g) were fed diets supplemented with five levels (0, 5 mg kg−1, 10 mg kg−1,15 mg kg−1 and 20 mg kg−1) of SFN for 8 weeks. The results indicated that fish fed 10 mg kg−1 SFN showed higher weight gain rate (P < 0.05) than the control group and the group of 15 mg kg−1 SFN. Feed conversion ratio was significantly lower (P < 0.05) in fish fed 10 mg kg−1 SFN than the group of 15 mg kg−1 SFN. Plasma complement component 4 and interleukin-10 (IL-10) contents, acid phosphatase activity, and liver superoxide dismutase, glutathione peroxidase and catalase activities, glutathione content, and interleukin-1β, IL-10, tumor necrosis factor-α (TNF-α) and toll-like receptor 2 mRNA expressions all increased (P < 0.05) in response to dietary SFN levels from 0 to 10 mg kg−1, then decreased with further increasing SFN levels. Plasma TNF-α content increased (P < 0.05) in response to dietary SFN levels from 0 to 15 mg kg−1, then decreased with further increasing SFN levels. Plasma lysozyme and myeloperoxidase activities both increased (P < 0.05) in response to dietary SFN levels from 0 to 5 mg kg−1, then decreased with further increasing SFN levels. Liver malonaldehyde content was significantly lower (P < 0.05) in fish fed 10 mg kg−1 SFN than other groups except for the 5 mg kg−1 SFN. Overall, these findings suggested that dietary SFN could promote growth, enhance immunity and antioxidant capacity, and the best benefit was obtained in fish fed 10 mg kg−1. These results encouraged further research of SFN as feed additive in aquaculture and provided basic data for the future application of SFN in aquatic animals.

Extracorporeal removal of soluble tumor necrosis factor receptors for the treatment of advanced refractory solid tumors.

e14593 Background: Tumor necrosis factor-alpha (TNF) has well-established anti-tumor effects including cytotoxicity against tumor vasculature. Past use of recombinant TNF to treat solid tumors resulted in unacceptable toxicities when given systemically but is successfully used in localized limb perfusion to treat melanoma and sarcomas. An alternative to promote endogenous TNF-mediated anticancer activity involves therapeutic apheresis to reduce the high concentrations of soluble TNF receptors (sTNF-Rs) produced by tumors, which sequester TNF and inhibit its tumoricidal effects. Methods: The LW-02 Column contains recombinant single-chain TNF, a capture ligand that selectively removes sTNF-Rs from plasma, covalently linked to a bead matrix. LW-02 Column Immunopheresis was evaluated in heavily pretreated patients with metastatic melanoma, renal cell carcinoma or triple negative breast cancer [NCT04142931]. LW-02 Column Immunopheresis was performed 3x/week, processing up to two plasma volumes for approximately 12 weeks as monotherapy (Cohort A, n = 6) or combined with nivolumab (Cohort B, n = 5). The study evaluated column performance, safety, clinical efficacy, and immunological biomarkers in the tumor microenvironment and blood. Results: The LW-02 Column effectively reduced sTNF-R plasma concentrations with capture efficiencies of 95.6% and 82.8% for sTNF-R1 and sTNF-R2, respectively, at the 30-minute procedural time point. At the data cut-off (Sept 30, 2022), median overall survival (OS) was 34.7 and 44.4 weeks for all patients (n = 11) and patients treated for ≥4 weeks (n = 8) (the latter group was prespecified in the protocol), respectively. For Cohorts A and B, median OS was 34.7 weeks and 45.4 weeks, respectively, for patients treated for ≥4 weeks. Evaluation of safety showed that only 2 adverse events (AEs) of 95 total AEs (including 7 SAEs) were deemed possibly related to LW-02 Column treatment. Immunohistochemical evaluation of tumor biopsies obtained 10-14 weeks after initiating LW-02 Column Immunopheresis revealed increased tumor-infiltrating lymphocytes (CD8+, HLA-DR+, and/or PD-1+ cells; 5/5 patients examined), and a reduced presence of tumor-associated macrophages (CD68+; 4/5 patients) compared to pretreatment biopsies. Preliminary immune profiling of peripheral blood mononuclear cells (5 patients) revealed increased expression levels of transmembrane TNF-R1 and TNF-R2, suggestive of increased cellular TNF responsiveness, and increased expression of activation molecules HLA-DR and CD86 after 4 weeks of LW-02 Column monotherapy compared to pretreatment levels. Conclusions: LW-02 Column Immunopheresis achieved safe and effective depletion of sTNF-Rs from plasma of patients with solid tumors. Further studies will assess the clinical benefit profile of the LW-02 Column for resensitizing tumors to respond to immunotherapy. Clinical trial information: NCT04142931 .

Associations between circulating cell-free mitochondrial DNA, inflammatory markers, and cognitive and physical outcomes in community dwelling older adults

BackgroundDementia and frailty are common age-related syndromes often linked to chronic inflammation. Identifying the biological factors and pathways that contribute to chronic inflammation is crucial for developing new therapeutic targets. Circulating cell-free mitochondrial DNA (ccf-mtDNA) has been proposed as an immune stimulator and potential predictor of mortality in acute illnesses. Dementia and frailty are both associated with mitochondrial dysfunction, impaired cellular energetics, and cell death. The size and abundance of ccf-mtDNA fragments may indicate the mechanism of cell death: long fragments typically result from necrosis, while short fragments arise from apoptosis. We hypothesize that increased levels of necrosis-associated long ccf-mtDNA fragments and inflammatory markers in serum are linked to declines in cognitive and physical function, as well as increased mortality risk.ResultsOur study of 672 community-dwelling older adults revealed that inflammatory markers (C-Reactive Protein, soluble tumor necrosis factor alpha, tumor necrosis factor alpha receptor 1 [sTNFR1], and interleukin-6 [IL-6]) positively correlated with ccf-mtDNA levels in serum. Although cross-sectional analysis revealed no significant associations between short and long ccf-mtDNA fragments, longitudinal analysis demonstrated a connection between higher long ccf-mtDNA fragments (necrosis-associated) and worsening composite gait scores over time. Additionally, increased mortality risk was observed only in individuals with elevated sTNFR1 levels.ConclusionIn a community dwelling cohort of older adults, there are cross-sectional and longitudinal associations between ccf-mtDNA and sTNFR1 with impaired physical and cognitive function and increased hazard of death. This work suggests a role for long ccf-mtDNA as a blood-based marker predictive of future physical decline.

Circulating markers of intestinal barrier injury and inflammation following exertion in hypobaric hypoxia

ABSTRACT Hypoxia induced intestinal barrier injury, microbial translocation, and local/systemic inflammation may contribute to high-altitude associated gastrointestinal complications or symptoms of acute mountain sickness (AMS). Therefore, we tested the hypothesis that six-hours of hypobaric hypoxia increases circulating markers of intestinal barrier injury and inflammation. A secondary aim was to determine if the changes in these markers were different between those with and without AMS. Thirteen participants were exposed to six hours of hypobaric hypoxia, simulating an altitude of 4572 m. Participants completed two 30-minute bouts of exercise during the early hours of hypoxic exposure to mimic typical activity required by those at high altitude. Pre- and post-exposure blood samples were assessed for circulating markers of intestinal barrier injury and inflammation. Data below are presented as mean ± standard deviation or median [interquartile range]. Intestinal fatty acid binding protein (Δ251 [103-410] pg•mL−1; p = 0.002, d = 0.32), lipopolysaccharide binding protein (Δ2 ± 2.4 μg•mL−1; p = 0.011; d = 0.48), tumor necrosis factor-α (Δ10.2 [3-42.2] pg•mL−1; p = 0.005; d = 0.25), interleukin-1β (Δ1.5 [0-6.7] pg•mL−1 p = 0.042; d = 0.18), and interleukin-1 receptor agonist (Δ3.4 [0.4-5.2] pg•mL−1 p = 0.002; d = 0.23) increased from pre- to post-hypoxia. Six of the 13 participants developed AMS; however, the pre- to post-hypoxia changes for each marker were not different between those with and without AMS (p > 0.05 for all indices). These data provide evidence that high altitude exposures can lead to intestinal barrier injury, which may be an important consideration for mountaineers, military personnel, wildland firefighters, and athletes who travel to high altitudes to perform physical work or exercise.

Anti-nucleolin aptamer, iSN04, inhibits the inflammatory responses in C2C12 myoblasts by modulating the β-catenin/NF-κB signaling pathway

A myogenetic oligodeoxynucleotide, iSN04, is the 18-base single-stranded DNA that acts as an anti-nucleolin aptamer. iSN04 has been reported to restore myogenic differentiation by suppressing inflammatory responses in myoblasts isolated from patients with diabetes or healthy myoblasts exposed to cancer-releasing factors. Thus, iSN04 is expected to be a nucleic acid drug for the muscle wasting associated with chronic diseases. The present study investigated the anti-inflammatory mechanism of iSN04 in the murine myoblast cell line C2C12. Tumor necrosis factor-α (TNF-α) or Toll-like receptor (TLR) ligands (Pam3CSK4 and FSL-1) induced nuclear translocation and transcriptional activity of nuclear factor-κB (NF-κB), resulting in upregulated expression of TNF-α and interleukin-6. Pre-treatment with iSN04 significantly suppressed these inflammatory responses by inhibiting the nuclear accumulation of β-catenin induced by TNF-α or TLR ligands. These results demonstrate that antagonizing nucleolin with iSN04 downregulates the inflammatory effect mediated by the β-catenin/NF-κB signaling pathway in C2C12 cells. In addition, the anti-inflammatory effects of iSN04 were also observed in the rat smooth muscle cell line A10 and the murine adipocyte-like fibroblast cell line 3T3-L1, suggesting that iSN04 may be useful in preventing inflammation induced by metabolic disorders.

Effects of Different Combinations of Sodium Butyrate, Medium-Chain Fatty Acids and Omega-3 Polyunsaturated Fatty Acids on the Reproductive Performance of Sows and Biochemical Parameters, Oxidative Status and Intestinal Health of Their Offspring.

The aim of the study was to investigate the comparative effects of different combinations of sodium butyrate (SB), medium-chain fatty acids (MCFAs), and omega-3 polyunsaturated fatty acids (n-3 PUFAs) on the reproductive performances of sows, as well as on the biochemical parameters, oxidative statuses, and intestinal health of the sucking piglets. A total of 30 sows were randomly allocated to five treatments: (1) control diet (CON); (2) CON with 1 g/kg of coated SB and 7.75 g/kg of coated MCFAs (SM); (3) CON with 1 g/kg of coated SB and 68.2 g/kg of coated n-3 PUFAs (SP); (4) CON with 7.75 g/kg of coated MCFAs and 68.2 g/kg of coated n-3 PUFAs (MP); (5) CON with 1 g/kg of coated SB, 7.75 g/kg of coated MCFAs and 68.2 g/kg of coated n-3 PUFA (SMP). The results showed that sows fed the SP, MP, and SMP diets had shorter weaning-to-estrus intervals than those fed the CON diet (p < 0.01). The piglets in the SM, SP, and MP groups showed higher increases in the plasma catalase and glutathione peroxidase activities than those of the CON group (p < 0.01). The diarrhea incidence of piglets in the SM, SP and SMP groups was lower than that of piglets in the CON group (p < 0.01). Additionally, the addition of SM, SP, MP, and SMP to the sow diets increased the contents of immunoglobulin A, immunoglobulin G, fat, and proteins in the colostrum (p < 0.01), as well as the plasma total superoxide dismutase activities (p < 0.01) in the suckling piglets, whereas it decreased the mRNA expressions of tumor necrosis factor-α, interleukin-1β, and toll-like receptor 4 in the jejunum mucosa of the piglets. The relative abundances of Prevotella, Coprococcus, and Blautia in the colonic digesta of the piglets were increased in the SM group (p < 0.05), and the relative abundances of Faecalibacterium increased in the SMP group (p < 0.05), compared with the CON group. The relative abundances of Collinsella, Blautia, and Bulleidia in the MP group were higher than those in the CON group (p < 0.05). Collectively, dietary combinations of fatty acids with different chain lengths have positive effects on the growth performances and intestinal health of suckling piglets.

Abstract P4-03-14: Proinflammatory Dietary Patterns and Risk of Total and Subtypes of Breast Cancer Among US Women

Abstract Background: Dietary patterns promoting chronic inflammation, including the empirical dietary inflammatory pattern (EDIP), have been shown to strongly influence risk of weight gain, type 2 diabetes, cardiovascular disease, and colorectal cancer. However, it is unclear if this dietary pattern is associated with other tumors in which the mechanisms are not totally understood such as breast cancer. Methods: We prospectively followed 76,295 women from the Nurses’ Health Study (NHS, 1984-2016) and 91,078 women from the Nurses’ Health Study II (NHSII, 1991-2017). Diet was assessed by food frequency questionnaires (FFQs) every 4 years. The inflammatory potential of diet was evaluated using the previously established EDIP based on plasma C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor alpha receptor 2 (TNF-αR2). Higher scores indicate higher inflammatory potential of the diet. Results: During 4,153,676 person-years of follow-up, we documented 10,632 invasive breast cancer cases (6,807 NHS; 3,825 NHSII). In the pooled multivariable-adjusted analyses, women in the highest, compared with the lowest, EDIP quintile were at higher breast cancer risk (HRQ5vsQ1=1.12; 95% CI 1.05, 1.20; P-trend&amp;lt; 0.001). This association was attenuated after adjusting for weight change since age 18 y, although it remained significant (HRQ5vsQ1=1.07; 95% CI 1.00, 1.14; P-trend=0.01). In subtype analyses, we found evidence that the inflammatory potential of diet influenced breast cancer risk differentially by ER status (P-heterogeneity=0.038) and by molecular phenotype (P-heterogeneity=0.007), with the association between EDIP and breast cancer limited to ER-negative tumors (HRQ5vsQ1=1.31; 95% CI: 1.11, 1.55; P-trend=0.002; for ER-positive tumors, HR Q5vsQ1=1.03; 95% CI, 0.96, 1.12;P-trend=0.10) and basal-like tumors (HRQ5vsQ1=1.78; 95% CI: 1.19, 2.65; P-trend=0.004). Further adjustment for weight change since age 18 y did not materially alter the association for these subtypes. Conclusions: Dietary patterns with high potential to contribute to chronic systemic inflammation, based on higher EDIP scores, were associated with a modestly increased risk of breast cancer, which was more pronounced for ER-negative and basal-like breast tumors. Citation Format: Andrea Romanos-Nanclares, Walter C Willett, Bernard A Rosner, Daniel G Stover, Sarah Asad, Sagar Sardesai, Michelle D Holmes, Wendy Y Chen, Rulla M. Tamimi, Fred K Tabung, A Heather Eliassen. Proinflammatory Dietary Patterns and Risk of Total and Subtypes of Breast Cancer Among US Women [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-14.

Relationship between traffic-related air pollution and inflammation biomarkers using structural equation modeling

BackgroundEvidence suggests that exposure to traffic-related air pollution (TRAP) and social stressors can increase inflammation. Given that there are many different markers of TRAP exposure, socio-economic status (SES), and inflammation, analytical approaches can leverage multiple markers to better elucidate associations. In this study, we applied structural equation modeling (SEM) to assess the association between a TRAP construct and a SES construct with an inflammation construct. MethodsThis analysis was conducted as part of the Community Assessment of Freeway Exposure and Health (CAFEH; N = 408) study. Air pollution was characterized using a spatiotemporal model of particle number concentration (PNC) combined with individual participant time-activity adjustment (TAA). TAA-PNC and proximity to highways were considered for a construct of TRAP exposure. Participant demographics on education and income for an SES construct were assessed via questionnaires. Blood samples were analyzed for high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), and tumor necrosis factor-α receptor II (TNFRII), which were considered for the construct for inflammation. We conducted SEM and compared our findings with those obtained using generalized linear models (GLM). ResultsUsing GLM, TAA-PNC was associated with multiple inflammation biomarkers. An IQR (10,000 particles/cm3) increase of TAA-PNC was associated with a 14 % increase in hsCRP in the GLM. Using SEM, the association between the TRAP construct and the inflammation construct was twice as large as the associations with any individual inflammation biomarker. SES had an inverse association with inflammation in all models. Using SEM to estimate the indirect effects of SES on inflammation through the TRAP construct strengthened confidence in the association of TRAP with inflammation. ConclusionOur TRAP construct resulted in stronger associations with a combined construct for inflammation than with individual biomarkers, reinforcing the value of statistical approaches that combine multiple, related exposures or outcomes. Our findings are consistent with inflammatory risk from TRAP exposure.

Screening of Optimal CpG-Oligodeoxynucleotide for Anti-Inflammatory Responses in the Avian Macrophage Cell Line HD11.

) have been shown to possess immunostimulatory features in both mammals and birds. However, compared to their proinflammatory effects, little is known about the anti-inflammatory responses triggered by CpG-ODN in avian cells. Hence, in this study, the anti-inflammatory response in the chicken macrophage cell line HD11 was characterized under stimulation with five types of CpG-ODNs: CpG-A1585, CpG-AD35, CpG-B1555, CpG-BK3, and CpG-C2395. Single-stimulus of CpG-B1555, CpG-BK3, or CpG-C2395 induced interleukin (IL)-10 expression without causing cell injury. The effects of pretreatment with CpG-ODNs before subsequent lipopolysaccharide stimulation were also evaluated. Interestingly, pretreatment with only CpG-C2395 resulted in high expression levels of IL-10 mRNA in the presence of lipopolysaccharide. Finally, gene expression analysis of inflammation-related cytokines and receptors revealed that pre-treatment with CpG-C2395 significantly reduced the mRNA expression of tumor necrosis factor-α, IL-1β, IL-6, and Toll-like receptor 4. Overall, these results shed light on the anti-inflammatory responses triggered by CpG-C2395 stimulation through a comparative analysis of five types of CpG-ODNs in chicken macrophages. These results also offer insights into the use of CpG-ODNs to suppress the expression of proinflammatory cytokines, which may be valuable in the prevention of avian infectious diseases in the poultry industry.

Functional Study of TNFR2 Signaling and Drug Discovery Using a Protein Engineering Approach

Tumor necrosis factor-α (TNF), a proinflammatory cytokine, is critical to the pathogenesis of various inflammatory diseases. There are two subtypes of receptors for TNF, namely type I TNF receptor (TNFR1) and type II TNF receptor (TNFR2). Previous studies using animal models of diseases have demonstrated the predominant role of TNFR1 in the pathogenesis of inflammation. It has recently been proposed that TNFR2 is associated with anti-inflammatory function. This intriguing function of TNFR2 has implications from an immunological and pharmacological perspective. However, the mechanism of the TNFR2-mediated anti-inflammatory effect is not fully understood. In this context, we attempted to elucidate the TNFR2-mediated anti-inflammatory effect and other unknown biological functions of TNFR2 by utilizing our protein engineering technology to generate functional mutant cytokines. Our findings reveal the following. (1) TNFR2 is expressed on regulatory T cells (Tregs) but not conventional T cells (Tconvs) and TNFR2-mediated signals promote proliferation and activation of Tregs. (2) The crystal structure of TNF/TNFR2 complex was solved, which suggests a possible signal initiation mechanism via TNF/TNFR2 cluster formation on the cellular membrane. (3) A novel TNFR2-mediated signal molecule, aminopeptidase P3 (APP3/XPNPEP3), was identified that interacts with TNFR2 as an intracellular adaptor protein. APP3 is required for c-Jun N-terminal kinase (JNK) phosphorylation, the downstream molecule of TNFR2 signal transduction. These results are key to understanding the mechanism of immune regulation and will assist in the identification of immunomodulatory drugs targeting the TNFR2 signaling cascade as well as the function of Tregs.

The Medawar Prize Acceptance Speech 2022.

The Medawar Prize Acceptance Speech 2022.

Neohesperidin Alleviates the Neuropathic Pain Behavior of Rats by Downregulating the P2X4 Receptor.

Neuropathic pain (NP) is a type of chronic pain affecting 6-8% of human health as no effective drug exists. The purinergic 2X4 receptor (P2X4R) is involved in NP. Neohesperidin (NH) is a dihydroflavonoside compound, which has anti-inflammatory and antioxidative properties. This study aimed to investigate whether NH has an effect on P2X4R-mediated NP induced by chronic constriction injury (CCI) of the sciatic nerve in rats. In this study, the CCI rat model was established to observe the changes of pain behaviors, P2X4R, and satellite glial cells (SGCs) activation in dorsal root ganglion (DRG) after NH treatment by using RT-PCR, immunofluorescence double labeling and Western blotting. Our results showed CCI rats had mechanical and thermal hyperalgesia with an increased level of P2X4R. Furthermore, SGCs were activated as indicated by increased expression of glial fibrillary acidic protein and increased tumor necrosis factor-alpha receptor 1and interleukin-1β. In addition, phosphorylated extracellular regulated protein kinases and interferon regulatory factor 5 in CCI rats increased. After NH treatment in CCI rats, the levels of above protein decreased, and the pain reduced. Overall, NH can markedly alleviate NP by reducing P2X4R expression and SGCs activation in DRG.

Dipeptidyl peptidase-4 inhibitor: Sitagliptin down-regulated toll-like receptor 4 signaling pathway to reduce uterine injury in rats.

Uterine ischemia is a common problem with ongoing controversy about its pathogenesis and prevention. The present study aimed to investigate the protective role of sitagliptin against uterine ischemia-reperfusion injury (IRI). Rats were allocated into 4 groups: control, sitagliptin (SIT) (5 mg/kg), IR; ischemia was induced followed by reperfusion, and IR+SIT; SIT was administered 1 hr before IRI. Uteri were removed for histopathological and biochemical observations. Malondialdehyde (MDA), total nitrites (NOx), reduced glutathione (GSH), superoxide dismutase (SOD) activity, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and toll-like receptor 4 (TLR4) were all measured. Hematoxylin and eosin (H&E) stain, Periodic acid-Schiff stain (PAS), and caspase-3 immunostaining were applied. In the IR+SIT group; NOx, GSH, and SOD activities increased significantly. Meanwhile, the levels of MDA, TNF-α, IL-6, TLR4, and caspase-3 immunoexpression showed a significant reduction, as compared with the IR group. In the IR+SIT group, an improvement in the histopathological picture was noticed. The results showed that sitagliptin confers protection against uterine IRI through anti-oxidant, anti-inflammatory, and anti-apoptotic effects with a possible role for TLR4.

A Bitter Experience That Enlightens the Future: COVID-19 Neurological Affection and Perspectives on the Orexigenic System

The history of coronaviruses revealed that these viruses caused multiple outbreaks in the past, including a previous severe acute respiratory syndrome (SARS) outbreak in 2003. In 2019, a novel SARS virus, SARS-CoV-2, started a drastic pandemic that, up till now, keeps peaking in successive waves owing to the mutational ability of the virus versus the short-term immunity against it. Although the angiotensin-converting enzyme 2 (ACE2) is the gate through which the virus gets access to human cells, yet ACE2 is deemed protective in lung injury yielding vasodilator, anti-fibrotic, and anti-inflammatory peptides. The viral-provoked ACE2 downregulation aggravated a subsequent potentially lethal cytokine storm. Both the tumor necrosis factor-alpha (TNF-α) receptor (TNFR), activated by the proinflammatory cytokine, TNF-α, released during coronavirus disease 2019 (COVID-19), and ACE2 are cleaved by tumor necrosis convertase enzyme (TACE) to render respective soluble decoy mediators. Several risk factors were linked to COVID-19 morbidity and neurological affection, including obesity and diabetes mellitus (DM), attributed toACE2 overexpression in obesity, a low-grade inflammatory state with both obesity and DM, and defective lung reparative machinery, added to low tissue-to-lung ACE2 expression in DM. The ACE2 shedding by SARS-CoV-2 upon its entry into the brain, together with the inflammatory cytokines invading the brain, predispose to such neurological affection. However, ACE2 was not sufficient to justify the occurrence of neurological disorders with COVID-19, owing to its lower brain expression, relative to other tissues. Other mediators should have contributed to such neurological disorders, of which, orexins (OXs) are discussed, owing to multiple functional similarities to ACE2. Eventually, this review highlights such similarities selected according to their possible relevance to COVID-19 symptomatology and pathology. Both ACE2 and OXs confer anti-inflammatory benefits, reduce cerebral endothelial dysfunction, promote neuronal survival and neurogenesis, and add to their therapeutic potentiality in sepsis. Both ACE2 and OXs assist in moderating the stress responses and the stress-activated hypothalamic-pituitary-adrenal axis. Both ACE2 and OXs are affected by obesity and DM. The loss of ACE2 and OXs signaling was suggested in neuro-inflammatory and neurodegenerative diseases. Of interest is the abundance of OXs in the dissemination routes to the brain, namely, the peripheral olfactory and the enteric systems. The presumptive role of OXs as analgesics and antipyretics might add to their favorable profile. Advantageously, the availability of OXs agonists and antagonists makes it applicable to corroborate or abrogate the future utility of targeting the orexigenic system in terms of COVID-19 neurological affection. Elaborative work, exploring in vitro and in vivo models, is recommended to identify or deny such perspective involvement.

A longitudinal study of the association between pro-inflammatory cytokines and mood symptoms in bipolar disorder.

Because of a relative dearth of longitudinal studies, the directionality of the relationship between mood and inflammation among patients with bipolar disorder (BD) is still unclear. We aimed to investigate the longitudinal associations of pro-inflammatory markers with mood symptom severity in BD. Hundred and thirty-two adult patients with BD were enrolled. At the baseline and 1-year follow-up visit, all participants received mood assessment with Montgomery Åsberg depression rating scale (MADRS) and Young mania rating scale, and underwent blood draws to quantify metabolic profile and serum levels of the pro-inflammatory markers, including soluble interleukin-6 receptor, soluble tumor necrosis factor-α receptor type 1 (sTNF-αR1), monocyte chemoattractant protein-1, and C-reactive protein. A four-factor model of MADRS, consisting of sadness, negative thoughts, detachment, and neurovegetative symptoms, were applied. At baseline, 65 patients with BD were in depressed state, and 67 patients with BD were in euthymic state. Among patients in depressed state, baseline MADRS total score positively correlated with sTNF-αR1 level at follow-up. While baseline sTNF-αR1 level positively predicted sadness symptom in euthymic patients with BD who later developed depression (n=22), sadness in patients with bipolar depression predicted later increase in serum sTNF-αR1 level even after remission (n=17). Moreover, lithium had a stronger effect of lowering peripheral sTNF-αR1 level as compared with other mood stabilizers. Our results indicate the bidirectional inflammation-depression relationship in BD.

Systemic inflammation and oxidative stress contribute to acute kidney injury after transcatheter aortic valve implantation.

BackgroundAcute kidney injury (AKI) is a frequent complication of transcatheter aortic valve implantation (TAVI) and has been linked to preexisting comorbidities, peri-procedural hypotension, and systemic inflammation. The extent of systemic inflammation after TAVI is not fully understood. Our aim was to characterize the inflammatory response after TAVI and evaluate its contribution to the mechanism of post-procedural AKI.MethodsOne hundred and five consecutive patients undergoing TAVI at our institution were included. We analyzed the peri-procedural inflammatory and oxidative stress responses by measuring a range of biomarkers (including C-reactive protein [hsCRP], cytokine levels, and myeloperoxidase [MPO]), before TAVI and 6, 24, and 48 hours post-procedure. We correlated this with changes in renal function and patient and procedural characteristics.ResultsWe observed a significant increase in plasma levels of pro-inflammatory cytokines (hsCRP, interleukin 6, tumor necrosis factor alpha receptors) and markers of oxidative stress (MPO) after TAVI. The inflammatory response was significantly greater after transapical (TA) TAVI compared to transfemoral (TF). This was associated with a higher incidence of AKI in the TA cohort compared to TF (44% vs. 8%, respectively, p < 0.0001). The incidence of AKI was significantly lower when N-acetylcysteine (NAC) was given peri-procedurally (12% vs. 38%, p < 0.005). In multivariate analysis, only the TA approach and no use of NAC before the procedure were independent predictors of AKI.ConclusionsTAVI creates a significant post-procedural inflammatory response, more so with the TA approach. Mechanisms of AKI after TAVI are complex. Inflammatory response, hypoperfusion, and oxidative stress may all play a part and are potential therapeutic targets to reduce/prevent AKI.

Patterns of Daily Physical Movement, Chronic Inflammation, and Frailty Incidence.

Low physical activity is a criterion of phenotypic frailty defined as an increased state of vulnerability to adverse health outcomes. Whether disengagement from daily all-purpose physical activity is prospectively associated with frailty and possibly modified by chronic inflammation-a pathway often underlying frailty-remains unexplored. Using the Study to Understand Fall Reduction and Vitamin D in You data from 477 robust/prefrail adults (mean age = 76 ± 5 yr; 42% women), we examined whether accelerometer patterns (activity counts per day, active minutes per day, and activity fragmentation [broken accumulation]) were associated with incident frailty using Cox proportional hazard regression. Baseline interactions between each accelerometer metric and markers of inflammation that include interleukin-6, C-reactive protein, and tumor necrosis factor-alpha receptor 1 were also examined. Over an average of 1.3 yr, 42 participants (9%) developed frailty. In Cox regression models adjusted for demographics, medical conditions, and device wear days, every 30 min·d -1 higher baseline active time, 100,000 more activity counts per day, and 1% lower activity fragmentation was associated with a 16% ( P = 0.003), 13% ( P = 0.001), and 8% ( P < 0.001) lower risk of frailty, respectively. No interactions between accelerometer metrics and baseline interleukin-6, C-reactive protein, or tumor necrosis factor-alpha receptor 1 were detected (interaction P > 0.06 for all). Among older adults who are either robust or prefrail, constricted patterns of daily physical activity (i.e., lower total activity minutes and counts, and higher activity fragmentation) were prospectively associated with higher risk of frailty but not modified by frailty-related chronic inflammation. Additional studies, particularly trials, are needed to understand if this association is causal.

The Effect of Stereotactic Body Radiation Therapy for Hepatocellular Cancer on Regional Hepatic Liver Function

To investigate direct radiation dose-related and inflammation-mediated regional hepatic function losses after stereotactic body radiation therapy (SBRT) in patients with hepatocellular carcinoma (HCC) and poor liver function. Twenty-four patients with HCC enrolled on an IRB-approved adaptive SBRT trial had liver dynamic gadoxetic acid-enhanced magnetic resonance imaging and blood sample collections before and 1 month after SBRT. Gadoxetic acid uptake rate (k1) maps were quantified for regional hepatic function and coregistered to both 2-Gy equivalent dose and physical dose distributions. Regional k1 loss patterns from before to after SBRT were analyzed for effects of dose and patient using a mixed-effects model and logistic function and were associated with pretherapy liver-function albumin-bilirubin scores. Plasma levels of tumor necrosis factor α receptor 1 (TNFR1), an inflammation marker, were correlated with mean k1 losses in the lowest dose regions by Spearman rank correlation. The whole group had a k1 loss rate of 0.4%/Gy (2-Gy equivalent dose); however, there was a significant random effect of patient in the mixed-effect model (P < .05). Patients with poor and good liver functions lost 50% of k1 values at 12.5 and 57.2 Gy and 33% and 16% of k1 values at the lowest dose regions (<5 Gy), respectively. The k1 losses at the lowest dose regions of individual patients were significantly correlated with their TNFR1 levels after SBRT (P < .02). The findings suggest that regional hepatic function losses after SBRT in patients with HCC include both direct radiation dose-dependent and inflammation-mediated effects, which could influence how to manage these patients to preserve their liver function after SBRT.