Serum TNF Research Articles

Serum TNF alpha concentration and arterial age of patients with acute cerebral infarction

Serum TNF alpha concentration and arterial age of patients with acute cerebral infarction

Gardenia jasminoides extract mitigates acetaminophen-induced liver damage in mice

BackgroundAcetaminophen (APAP)-induced hepatotoxicity is a potentially life-threatening condition. Gardenia jasminoides fruit extract (GJE), which contains geniposide (Gen) as its major active constituent, possesses anti-inflammatory and antioxidant properties and may help address the underlying pathogenesis of APAP-induced hepatotoxicity. This study aimed to evaluate the effects of GJE in a mouse model of APAP-induced hepatotoxicity.MethodsTwenty-four male ICR mice were divided into 4 groups (n = 6/group): [1] Control group, mice were given distilled water; [2] APAP group, mice received a single dose of 600 mg/kg APAP; [3] APAP + low-dose GJE group, mice received APAP followed 30 min later by 2 doses of low-dose GJE (0.44 g/kg/dose, containing Gen 100 mg/kg/dose) 8 h apart; [4] APAP + high-dose GJE group, mice received APAP followed by 2 doses of high-dose GJE (0.88 g/kg/dose, containing Gen 200 mg/kg/dose). All mice were euthanized 24 h after APAP administration. Liver tissue was used for histological examination and to measure glutathione (GSH) and malondialdehyde (MDA) levels. Serum was used to determine levels of ALT and inflammatory cytokines (tumor necrosis factor- α (TNF-α) and interleukin-6 (IL-6)).ResultsLiver histopathology showed moderate to severe hepatic necroinflammation in the APAP group, whereas only mild necroinflammation was observed in both treatment groups. Serum ALT levels were significantly elevated in the APAP group compared to the control group but were significantly reduced after low- and high-dose GJE treatment. Serum TNF- α levels were significantly higher in the APAP group than in the control group and were significantly lower after high-dose GJE treatment (135.5 ± 477.2 vs. 35.5 ± 25.8 vs. 74.7 ± 47.2 vs. 41.4 ± 50.8 pg/mL, respectively). Serum IL-6 followed a similar pattern. Hepatic GSH levels were significantly lower in the APAP group compared to the control group but significantly increased after both low- and high-dose GJE treatment (19.9 ± 4.5 vs. 81.5 ± 12.4 vs. 71.4 ± 7.8 vs. 82.6 ± 6.6 nmol/mg protein, respectively). Conversely, hepatic MDA levels were significantly elevated in the APAP group compared with the control group but significantly decreased after high-dose GJE treatment (108.6 ± 201.5 vs. 40.5 ± 18.0 vs. 40.5 ± 16.8 nmol/mg protein, respectively).ConclusionsTreatment with G. jasminoides fruit extract can alleviate APAP-induced hepatotoxicity, likely through its anti-inflammatory and antioxidant properties.

EFFECT OF SUPPLEMENTATION OF ACACIA HONEY AND PIOGLITAZONE ON INFLAMMATORY MEDIATORS AND OXIDATIVE STRESS IN STREPTOZOTOCIN INDUCED DIABETIC RATS

Background: Diabetes mellitus (DM) has emerged as a major health threat worldwide. There is an increasing advocacy of natural products in the treatment of DM and its complications. Objective of this study was to see the effect of supplementation of Pioglitazone and Acacia honey on inflammatory mediators and oxidative stress in streptozotocin (STZ) induced diabetic rats. Methods: The study was conducted in Al-Nafees Medical College in association with National Institute of Health, Islamabad. There were 150 male Sprague Dawley rats divided into 5 equal groups. Group-I was taken as normal control whereas Group-II was diabetic control. The Groups-II?V were given STZ through intraperitoneal route. Group-III received Acacia honey for 3 weeks. Group-IV was given intra-peritoneal injection of pioglitazone plus Acacia honey, and Group-V was administered pioglitazone through intraperitoneal route for same dose and duration. Serum catalase, hydrogen peroxide, CRP and TNF-? were measured after three weeks. Statistical analysis was done on SPSS-22. The values were presented as Mean±SEM and p?0.05 was considered significant. Results: On day 25 compared to Group-II, serum TNF-? and hydrogen peroxide levels were significantly decreased in Groups-III, IV and V. The mean serum CRP levels were significantly decreased in Group-III and IV while Group-II and III had significantly raised serum catalase levels. Conclusion: Acacia honey along with pioglitazone decreases oxidative stress as predicted by increase in levels of catalase. This combination also reduces inflammation as measured by decreased levels of CRP and TNF-? in STZ induced diabetic rats. Pak J Physiol 2024;24(3):18?22, DOI: https://doi.org/10.69656/pjp.v20i3.1536

UFMylation is involved in serum inflammatory cytokines generation and splenic T cell activation induced by lipopolysaccharide

UFMylation, a novel ubiquitin-like protein modification system, has been recently found to be activated in inflammation. However, the effects of UFMylation activation on inflammation in vivo remains unclear. In the present study, we generated a UFMylation activated mice using transgenic (TG) techniques. Lipopolysaccharide (LPS) was used to induce systemic inflammation in both TG and non-transgenic (NTG) mice. Serum cytokines were detected using a Mouse Cytokine Array, and the proportions of splenic NK, B and T cells were determined by using flow cytometry. We found that TG mice showed increased serum G-CSF, TNF RII and decreased serum TCA-3, CD30L, bFGF, IL-15 and MIG compared with NTG mice at baseline. Furthermore, serum cytokines in TG mice exhibited different responses to LPS compared to NTG mice. LPS up-regulated serum TNF RII, G-CSF, MCP-5, RANTES, KC, BLC, MIG and down-regulated IL-1b, IL-2, IL-3, IL-4, IL-5, IL-7, IL-10, IL-12p40, IL-15, IL-17, IFN-γ, TCA-3, Eotaxin-2, LIX, MCP-1, TNFα, GM-CSF in NTG mice, whereas LPS up-regulated G-CSF, MCP-5, RANTES, KC, BLC, MIG, ICAM-1, PF4, Eotaxin, CD30L, MIP-1a, TNFRI and down-regulated IL-1b, IL-3, LIX, MCP-1, TNFα, GM-CSF in TG mice. Data from flow cytometry indicated that LPS significantly reduced the percentages of NK and NKT cells in NTG mice, whereas UFMylation activation inhibited LPS-induced NKT cell decrease. The proportions of B cells, total CD4+ and total CD8+ T cells were comparable between TG and NTG mice in response to LPS treatment, whereas the percentages of CD4+CD69+ and CD8+CD69+T cells were lower in TG mice. These findings suggest that UFMylation may alter LPS-induced serum cytokine profile and participate in splenic T cell activation in vivo.

Single and Mixed Strains of Probiotics Reduced Hepatic Fat Accumulation and Inflammation and Altered Gut Microbiome in a Nonalcoholic Steatohepatitis Rat Model.

As gut dysbiosis has been implicated in the pathogenesis of nonalcoholic steatohepatitis (NASH), probiotic supplementation might be a potential treatment for this condition. The aim of this study was to evaluate the effects of single- and mixed-strain probiotics on the severity of NASH induced by a high-fat, high-fructose (HFHF) diet and their mechanisms of action. Male Sprague-Dawley rats were divided into four groups (n = 7 per group): control group, NASH group, NASH + single-strain group, and NASH + mixed-strain group. In the single-strain and mixed-strain groups, rats received Lactobacillus plantarum B7 and Lactobacillus rhamnosus L34 + Lactobacillus paracasei B13 by oral gavage once daily, respectively. The duration of the study was 6 weeks. Liver tissue was used for histopathology, hepatic fat content was assessed by Oil Red O staining and hepatic free fatty acid (FFA), and hepatic TLR4 and CD14 expression were assessed by immunohistochemistry. Fresh feces was collected for gut microbiota analysis. Liver histology revealed a higher degree of fat accumulation, hepatocyte ballooning, and lobular inflammation in the NASH group, which improved in probiotics-treated groups. The amounts of hepatic fat droplets and hepatic FFA levels were more pronounced in the NASH group than in the control and treatment groups. Serum TNF- α levels were significantly higher in the NASH group than in control and probiotic groups. The expression of CD14 and TLR4 increased in the NASH group as compared with the control and probiotics-treated groups. Alpha diversity was reduced in the NASH group, but increased in both treatment groups. The relative abundance of Lactobacillus significantly decreased in the NASH group, but increased in both treatment groups. The relative abundance of Akkermansia significantly increased in the NASH group, but decreased in both treatment groups. In conclusion, both single-strain and mixed-strain probiotics could improve NASH histology by suppressing inflammatory responses in the liver, with this improvement potentially being associated with changes in the gut microbiota.

Analysis of the expression of cytokines and chemokines, platelet-leukocyte aggregates, sCD40L and sCD62P in cutaneous melanoma.

Cutaneous melanoma (CM) is a malignancy with a variable incidence worldwide and a poor advanced-stage prognosis. Melanoma growth is closely associated with the immune system. A cross-sectional study was performed on CM patients admitted at the Hospital de Cancer de Pernambuco (HCP) between 2015 and 2018. Fifty-one CM patients were included, and 30 healthy individuals. The study aimed to evaluate the association of platelet activation mechanisms and inflammatory response in patients with cutaneous melanoma. Elevated serum IL10 and low serum TNF levels in CM patients compared to controls (p < 0.05). High IL6 levels in patients with negative lymph nodes LN (-) compared to positive lymph nodes group (LN +, p = 0.0005). Low RANTES levels in patients compared to controls (p < 0.05). Elevated levels of platelet-lymphocyte (PLA), platelet-monocytes (PMA), and platelet-neutrophils (PNA) aggregates were observed in patients compared to controls (p < 0.05). CM patients with stage II had lower PMA levels than stages I and III (p < 0.05). High PMA levels were observed in patients with LN (+) compared to the LN (-) group (p < 0.0001). Patients with SSM had high levels of sCD40L and sCD62P compared to controls (p < 0.05)). High sCD40L levels in stage II compared to the stage III group, and sCD62P in stages I and II compared to the stage III group (p < 0.05). High sCD62P levels in patients with LN (-) compared to the group LN (+) (p < 0.05). It was observed the immunosuppressive profile in CM may favor tumor progression. High levels of platelet-leukocyte aggregates, sCD40L, and sCD62P may be associated with the worst prognosis.

Differences in Eotaxin Serum Levels between Polytraumatized Patients with and without Concomitant Traumatic Brain Injury-A Matched Pair Analysis.

Background/Objectives: Early detection of traumatic brain injury (TBI) is crucial for minimizing secondary neurological damage. Our study aimed to assess the potential of IL-4, IL-6, IL-7, IL-8, IL-10, TNF, and eotaxin serum levels-as a single clinical tool or combined into a panel-for diagnosing TBI in multiple injured patients. Methods: Out of 110 prospectively enrolled polytrauma victims (median age, 39 years; median ISS, 33; 70.9% male) admitted to our level I trauma center over four years, we matched 41 individuals with concomitant TBI (TBI cohort) to 41 individuals without TBI (non-TBI cohort) based on age, gender, Injury Severity Score (ISS), and mortality. Patients' protein levels were measured upon admission (day 0) and on days 1, 3, 5, 7, and 10 during routine blood withdrawal using one separation gel tube each time. Results: The median serum levels of IL-4, IL-6, IL-7, IL-8, IL-10, and TNF exhibited non-similar time courses in the two cohorts and showed no significant differences on days 0, 1, 3, 5, and 7. However, the median eotaxin levels had similar trend lines in both cohorts, with consistently higher levels in the TBI cohort, reaching significance on days 0, 3, and 5. In both cohorts, the median eotaxin level significantly decreased from day 0 to day 1, then significantly increased until day 10. We also found a significant positive association between day 0 eotaxin serum levels and the presence of TBI, indicating that for every 20 pg/mL increase in eotaxin level, the odds of a prevalent TBI rose by 10.5%. ROC analysis provided a cutoff value of 154 pg/mL for the diagnostic test (sensitivity, 0.707; specificity, 0.683; AUC = 0.718). Conclusions: Our findings identified the brain as a significant source, solely of eotaxin release in humans who have suffered a TBI. Nevertheless, the eotaxin serum level assessed upon admission has limited diagnostic value. IL-4, IL-6, IL-7, IL-8, IL-10, and TNF do not indicate TBI in polytraumatized patients.

Mechanism analysis of essential oil from Radix Bupleuri for the treatment of asthma through regulation of ectopic olfactory receptor

Ethnopharmacological relevanceRadix Bupleuri is the root of Bupleurum chinense DC. (BC) and a classic aromatic traditional Chinese medicine. The traditional pharmacological effects of Radix Bupleuri are alleviating bronchial spasms, dilating airways, and promoting the resolution of respiratory inflammation, thereby reducing asthma symptoms. Aim of the studyStudies have demonstrated the efficacy of water extracts from BC in asthma treatment. However, the potential role of volatile oil, another active constituent in BC, remains unexplored with asthma. Notably, volatile oil is renowned for its ease of absorption and direct targeting of affected areas, offering distinct advantages in alleviating airway inflammation. This study aims to explain the anti-asthmatic mechanism of BC-oil through in vivo and in vitro pharmacological experiments. Materials and methodsFirstly, the OVA-induced SD rat asthma model was utilized to evaluate the pharmacological effect of BC-oil by lung function monitoring, HE staining, flow cytometry, ELISA, and RT-qPCR. The anti-asthmatic mechanism was further analyzed by combining transcriptomic analysis of lung tissue from rat model and airway smooth muscle tissue from public database. Initially, GC-MS was used to analyze the components of BC-oil. The anti-asthmatic activity was evaluated in 16-HBE, RBL-2H3, and ASMC cells using CAMKII inhibitors to explore of the critical signal transduction regulated by BC-oil. Furthermore, molecular docking and calcium flow assay were utilized to screen and identify the active components from BC-oil. ResultsOral administration of BC-oil significantly enhanced pulmonary function in asthmatic SD rats by reducing airway resistance and elastic resistance. Additionally, BC-oil inhibited inflammatory cytokines, including serum IL-2, pulmonary Il1b, Tnf, and Cxcl13, demonstrating potent anti-inflammatory and immunomodulatory effects. In this study, we analyzed the significant role of OR2W3 in asthma using public transcriptomic data. Furthermore, we indicated that BC-oil regulated the expression of Olr1433 and GNAL in rat lung tissue. BC-oil reduced degranulation and inhibited gene expression of Il3 and Tnf in RBL-2H3 cells and suppressed gene expression of IL8 and TNF in 16-HBE cells. BC-oil also attenuated airway smooth muscle cell proliferation and expression of Acta2 and Ccnd1. Furthermore, BC-oil regulates asthma-related cellular processes by activating CAMKII. GC-MS analysis identified 11 components of BC-oil, and n-hexadecanoic acid, linoleic acid and oleic acid from BC-oil were identified to interact with OR2W3 by molecular docking. The calcium flow assay revealed linoleic acid as a significant activator of OR2W3 and indicated that BC-oil alleviated asthma through the ectopic olfactory signaling pathway. ConclusionsThe mechanism of BC-oil in treating asthma through signal transduction of OR2W3 is revealed at the molecular and cellular levels.

The Hepatoprotective Effect of Glycyrrhiza glabra Roots Extract Against Amiodarone Induced Hepatotoxicity in Male Rats

Amiodarone (AMD), a powerful antidysrhythmic medication, can cause hepatotoxicity when used long-term or in high doses. It affects both mitochondrial and lysosomal function because of its lipophilic nature and accumulation in tissues. It also has direct production of ROS. Glycyrrhiza glabra is one of the medicinal plants that have been commonly used for thousands of years. It possesses anti-ulcer, anti-inflammatory and antioxidant properties. In this study, the antihepatotoxic effect of Gg was evaluated against AMD liver toxicity in rats model, thirty rats were taken and divided evenly into five groups given daily doses by gastric gavage oral tube for 3 weeks as follows: the 1st group acted as a control group given D.W., and the 2nd group received AMD at a dose of 300mg/kg for 2 weeks. 3rd, 4th, and 5th groups were pretreated with Gg in doses of 200, 400, and 800 mg, respectively, for one week, then along with AMD for 2 weeks. Hepatic damage, revealed by histology and the increased activities of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and serum phospholipase A2 (PLA2) was decreased in the AMD group. Gg extract significantly reduced the elevated AST and ALT levels caused by AMD intoxication, rendering PLA2 to its normal level. It also enhanced liver superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA) levels. Gg extract markedly reverses the increased serum TNF levels induced by AMD; therefore, it may be considered a good hepatoprotective agent.

Study of the Effect of Tumor Necrosis Factor Alpha (TNF-α) Antagonist (Adalimumab) on Giardiasis in Mice

Abstract Giardia lamblia (G. lamblia) is the most common worldwide intestinal protozoal. Serum TNF-α contributes to the recovery from Giardia lamblia infection especially in the first and second week of infection. TNF-α antagonists are biologics used to treat many inflammatory diseases as rheumatoid arthritis. The present study aimed to study the effect of TNF-α antagonist (Adalimumab) on experimental giardiasis in mice by parasitological and histopathological examination. A total of 45 parasite-free laboratory-bred Swiss albino mice included into 2 main groups: test group and control group were used. Test group included mice infected with G. lamblia and receiving three intraperitoneal Adalimumab injections from days 9 till 15 post infection (pi). This group was further subdivided into 3 subgroups (Ia, Ib, Ic) according to Adalimumab doses which were 1.5, 3 and 6 mg/kg BW, received, respectively. Control group (non-Adalimumab-treated group) included a non-infected healthy group and Giardia -infected group. Monitoring the serum TNF-α level in all mice was done on two occasions (day 16 and 28 pi) by ELISA to follow variation in its level with and without administration of the drug. Infection outcome was assessed by following cyst shedding in stools of infected mice on intermittent days, counting trophozoites in intestinal wash, registering weight of animals, and recording pathological changes occurring in histopathological sections from small intestine. Highly significant increase in serum TNF-α was recorded in infected control mice on day 16 post-infection than in normal control group. Similarly, a significant increase in TNF-α level in the 3 test subgroups but attaining significant lower levels. On day 28 post infection, serum TNF- α level decreased in all infected mice with no significant differences being higher in infected control group than in non-infected control group. On assessing the effect of decreased serum TNF-α by the drug on infection outcome, highly significant increases in cyst shedding were recorded in the test group specifically group receiving 3 mg/kg BW than in control infected group on day 16 pi, and in trophozoite counts on day 28 pi. Mice weight gain was highly significant being more in control non-infected group than in control infected group. It was significantly lower in test group than normal infection control. The intestinal sections of test subgroups showed moderate to severe inflammatory reaction with more inflammatory cellular infiltration in the lamina propria causing villous shortening and blunting more than that observed in infection control group. Furthermore, lymphoid follicles and sloughing of the epithelium were only observed in test subgroups on day 16 p.i. It was concluded that TNF-α antagonist (Adalimumab) led to increased parasitic load as evidenced by cyst shedding, trophozoite count, less weight gains with moderate to severe histopathological damage in test subgroups.

A randomized trial of the inflammatory cytokines levels and the blood transfusion rate between miniaturized tubing group and conventional tubing group in congenital heart disease open heart surgeries.

We aimed to compare the inflammatory cytokines levels of the miniaturized and conventional extracorporeal circuit system. The miniaturized extracorporeal circuit system may be fewer possible inflammation-induced or blood transfusion-related complications. We performed a prospective randomized controlled trial (RCT) of 101 patients undergoing congenital heart surgery with CPB (cardiopulmonary bypass, weight ≤15kg, age ≤2years). Patients were divided into two different CPB groups randomly by random data form. Blood samples at five different time points and the ultrafiltration fluid before and after CPB were collected in all patients. IL-6, IL-8, and TNF alpha were respectively tested with Abcam ELISA kit. The IL-6 level of blood serum in two groups had no statistical differences between the two groups at all time points. The IL-8 level of blood serum in two groups had no statistical differences right after anesthesia and 5min after CPB. However, IL-8 level was significantly higher in conventional extracorporeal circuit group than that in miniaturized extracorporeal circuit group at 6h, 12h and 24h after CPB. Blood serum TNF alpha in conventional extracorporeal circuit group was significantly higher at 6h after CPB than that in miniaturized extracorporeal circuit group. No statistical differences in TNF alpha were found between two groups right after anesthesia and at 5min after CPB, 12h and 24h after CPB. In ultrafiltration fluid, no statistical differences were found in IL-6, IL-8 nor TNF alpha between two groups in all time. No statistical differences were found in ICU (intensive care unit) stay and mechanical ventilation time between the two groups. The blood transfusion rate was significantly lower in miniaturized extracorporeal circuit group. Implementing the miniaturized extracorporeal circuit system could decrease the inflammatory cytokines at a certain level. The blood transfusion rate is significantly lower in miniaturized extracorporeal circuit group This indicates the miniaturized extracorporeal circuit system might be a safer CPB strategy with fewer possible inflammation-induced or blood transfusion-related complications.

Regulation of Inflammation, Without Impacting Heart Rate, via Electrical Stimulation of the Dorsal Motor Nucleus of the Vagus

The vagus nerve plays an important role in neuroimmune interactions and in the regulation of inflammation. Recently, using optogenetics it has been demonstrated that the brainstem’s dorsal motor nucleus of the vagus (DMN) is a significant source of efferent vagus nerve fibers that control inflammation. In contrast to optogenetics, electrical neuronal stimulation is an approved therapeutic approach. However, the anti-inflammatory effectiveness of electrical stimulation of the DMN (eDMNS) and the possible heart rate (HR) alterations associated with this approach have not been investigated. Here, we examined the effects of eDMNS on the HR and cytokine levels in murine endotoxemia as well as the cecal ligation and puncture (CLP) model of sepsis. C57BL/6 mice (8-10 weeks old), under anesthesia and secured in a stereotaxic frame, received eDMNS via a concentric bipolar electrode in the left or right DMN, or sham treatment. eDMNS (50, 250 or 500 μA and 30 Hz, for 1 min) was performed and HR recorded. In endotoxemia experiments, mice underwent sham or 5-minute eDMNS (250 μA or 50 μA) followed by LPS (0.5 mg/kg) i.p. injection. eDMNS was also studied on mice with cervical unilateral vagotomy or sham surgery. In CLP experiments sham or left eDMNS was performed immediately post CLP. Cytokines and corticosterone were measured 90 mins after LPS administration or 24h after CLP. CLP survival was monitored for 14 days. Both left and right eDMNS at 250 μA and 500 μA significantly reduced HR, compared with pre- and post-stimulation, while 50 μA did not. Left-side eDMNS at 50 μA decreased serum and splenic TNF levels, and increased serum IL-10 during endotoxemia. The anti-inflammatory effect of eDMNS was abrogated in mice with ipsilateral unilateral vagotomy, which was also not associated with serum corticosterone alterations. Right-side eDMNS lowered serum TNF levels and increased IL-10 but had no impact on splenic cytokines. In CLP, left eDMNS decreased serum TNF and IL-6 levels, lowered splenic IL-6 and increased splenic IL-10, and improved survival in mice. For the first time, we demonstrate that an eDMNS regimen, which does not cause bradycardia, mitigates LPS-induced inflammation. These effects are dependent on an intact vagus nerve and are unrelated to corticosteroid alterations. Additionally, eDMNS reduces inflammation and enhances survival in a polymicrobial sepsis model. These findings hold promise for further research into bioelectronic anti-inflammatory strategies aimed at the brainstem DMN. This work was partially funded by NIGMS. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

PROLONGED ENDOTHELIAL DYSFUNCTION IN POST-COVID-19 HYPERTENSIVE PATIENTS

Objective: to investigate the endothelial function in hypertensive patients after 1.5 ± 0.4 years after COVID-19 recovery. Design and method: We studied 64 treated hypertensive patients divided into 2 groups: 39 patients recovered from mild to moderate COVID-19 in 2020-2022 years (1st group) and 25 patients were not ill with COVID-19 (2nd group). All patients were vaccinated against COVID-19. The clinical characteristics and laboratory finding measurements were evaluated. Results: There were no significant differences in sex, duration of hypertension, frequency of family history of premature CVD, smoking, alcohol consumption, BMI, and presence of concomitant DM, CAD, stroke/TIA, atrial fibrillation, heart failure, office BP between the 2 groups. The patients in 1st group were younger and had higher GFR than patients in 2nd group (respectively, 57.9 ± 1.0 vs 61.1 ± 1.5 years, P = 0.03 and 83.2 ± 3.4 vs 71.9 ± 3.7 ml/ min/1.73m2, P = 0.03). The levels of anti-spike IgG antibodies by 21.3% were higher in vaccinated patients with prior COVID-19 than in patients without prior COVID-19. Serum IL-10 and TNF- α concentrations did not differ between groups. However, serum levels of asymmetric dimethylarginine (ADMA) (0.64 ± 0.02 vs 0.53 ± 0.02 μmol/l, P = 0.047), CRP (8.6 ± 2.5 vs 4.3 ± 0.6 mg/l, P = 0.049), 24-h albuminuria (28.1 ± 3.8 vs 14.1 ± 2.3 mg/day, P = 0.048) were higher in post-COVID-19 patients than in patients of 2nd group. Conclusions: After 1.5 ± 0.4 years of recovery from COVID-19, the hypertensive patients who received the vaccine were found to have greater activation of systemic inflammation, higher levels of albuminuria, and higher blood ADMA concentrations compared to vaccinated individuals who did not have COVID-19. This fact may indicate a long-lasting dysfunction of the endothelium after suffering from COVID-19 and the absence of such an effect after vaccination without a history of COVID-19.

Noninvasive focused ultrasound stimulation of the celiac-superior mesenteric ganglion complex regulates inflammation in murine endotoxemia

The nervous system has an important role in the regulation of cytokines and inflammation ( Nature, 2002). The celiac-superior mesenteric ganglion complex (CSMGC) is an important component of the vagus nerve based inflammatory reflex, which controls inflammation ( Nat Neuroscience 2017). In addition to receiving cholinergic innervations from the efferent vagus nerve, the CSMGC is innervated by preganglionic sympathetic splanchnic nerves, which also are involved in the inflammatory regulation. Both neuronal types - vagal and preganglionic sympathetic - interact with catecholaminergic neurons, which reside in this ganglionic complex and innervate the liver, spleen, and other abdominal organs. Despite being a prominent locus of neuronal interactions, the possibilities of directly targeting the CSMGC to regulate cytokine responses and inflammation remains unexplored. To provide insight, we subjected the CSMGC in mice to focused ultrasound stimulation (FUS) - a non-invasive approach, which has been increasingly utilized in neuromodulation. We used ultrasound imaging and doppler to localise the complex in anesthetized 10–14-week-old male C57BL/6J mice. To perform stimulation, the FUS transducer was placed on the abdominal surface over the CSMGC and FUS (1.1MHz and 200mV per pulse, 150 burst cycles, 500μs burst period) or sham stimulation was delivered for 2 mins or 5 mins. Five mins post FUS, mice were injected with lipopolysaccharide (endotoxin, 0.25mg/kg, i.p.) and euthanized after 90 mins. Blood and liver were collected and processed for cytokine analysis. Compared to sham stimulation, FUS of the CSMGC for 5mins (n=11,12/group) significantly decreased serum TNF levels (1,875 ± 750 pg/ml vs 672.9 ± 335 pg/ml, P&lt; 0.0001) and hepatic TNF levels (27.8 ± 8.6 pg/mg vs 16.0 ± 7.1 pg/mg, P= 0.0018) in endotoxemic mice. In contrast, FUS of CSMGC for 2 mins (n=15/group) did not significantly alter serum TNF levels (1,458 ± 599.9 pg/ml vs 1,120 ± 332.5 pg/ml, P=0.1607). These results demonstrate the anti-inflammatory effcacy of noninvasive FUS of the CSMGC. Our findings also identify the CSMGC as an easily targetable new therapeutic site for controlling systemic and hepatic inflammation with a potential for clinical translation. This work was partially supported by NIGMS. R01GM128008. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Electrical stimulation of the dorsal motor nucleus of the vagus in male mice can regulate inflammation without affecting the heart rate

BackgroundThe vagus nerve plays an important role in neuroimmune interactions and in the regulation of inflammation. A major source of efferent vagus nerve fibers that contribute to the regulation of inflammation is the brainstem dorsal motor nucleus of the vagus (DMN), as recently shown using optogenetics. In contrast to optogenetics, electrical neuromodulation has broad therapeutic implications. However, the anti-inflammatory effectiveness of electrical stimulation of the DMN (eDMNS) and the possible heart rate (HR) alterations associated with this approach have not been investigated. Here, we examined the effects of eDMNS on HR and cytokine levels in mice administered with lipopolysaccharide (LPS, endotoxin) and in mice subjected to cecal ligation and puncture (CLP) sepsis. MethodsAnesthetized male 8–10-week-old C57BL/6 mice on a stereotaxic frame were subjected to eDMNS using a concentric bipolar electrode inserted into the left or right DMN or sham stimulation. eDMNS (500, 250 or 50 μA at 30 Hz, for 1 min) was performed and HR recorded. In endotoxemia experiments, sham or eDMNS utilizing 250 μA or 50 μA was performed for 5 mins and was followed by LPS (0.5 mg/kg) i.p. administration. eDMNS was also applied in mice with cervical unilateral vagotomy or sham operation. In CLP experiments sham or left eDMNS was performed immediately post CLP. Cytokines and corticosterone were analyzed 90 mins after LPS administration or 24 h after CLP. CLP survival was monitored for 14 days. ResultsEither left or right eDMNS at 500 μA and 250 μA decreased HR, compared with baseline pre-stimulation. This effect was not observed at 50 μA. Left side eDMNS at 50 μA, compared with sham stimulation, significantly decreased serum and splenic levels of the pro-inflammatory cytokine TNF and increased serum levels of the anti-inflammatory cytokine IL-10 during endotoxemia. The anti-inflammatory effect of eDMNS was abrogated in mice with unilateral vagotomy and was not associated with serum corticosterone alterations. Right side eDMNS in endotoxemic mice suppressed serum TNF and increased serum IL-10 levels but had no effects on splenic cytokines. In mice with CLP, left side eDMNS suppressed serum IL-6, as well as splenic IL-6 and increased splenic IL-10 and significantly improved the survival rate of CLP mice. ConclusionsFor the first time we show that a regimen of eDMNS which does not cause bradycardia alleviates LPS-induced inflammation. These eDMNS anti-inflammatory effects require an intact vagus nerve and are not associated with corticosteroid alterations. eDMNS also decreases inflammation and improves survival in a model of polymicrobial sepsis. These findings are of interest for further studies exploring bioelectronic anti-inflammatory approaches targeting the brainstem DMN.

Clinical efficacy of recombinant human basic fibroblast growth factor combined with ranitidine in the treatment of recurrent oral ulcer and its effect on serum TNF, IL-2 and T-lymphocyte subsets.

To evaluate the clinical efficacy of recombinant human basic fibroblast growth factor (rh-bFGF) combined with ranitidine in the treatment of recurrent oral ulcer and its effects on serum TNF, IL-2 and T-lymphocyte subsets. This was a retrospective study. Eighty patients with oral ulcers admitted to First Medical Center, Chinese PLA General Hospital from July 2021 to June 2022 were randomly divided into the control group and the experimental group (n=40). Patients in the control group were given topical treatment with rh-bFGF gel, while those in the experimental group were given oral treatment combined with ranitidine based on the control group, and both groups were treated continuously for 14 days. The therapeutic effect, pain relief time, ulcer healing time, as well as the differences in the levels of inflammatory factors and T-lymphocyte subsets were compared and analyzed between the two groups. The overall response rate of the experimental group was 92.5%, while that of the control group was 75%, with a statistically significant difference(P=0.03). After treatment, inflammatory factors indexes in the experimental group were significantly lower than those in the control group, with statistically significant differences (P=0.00). The indexes of T-lymphocyte subsets in the experimental group were significantly higher than those in the control group after treatment, with statistically significant differences (P=0.00). Recombinant human basic fibroblast growth factor combined with ranitidine is effective in the treatment of recurrent oral ulcers, boasting various benefits such as effectively promoting ulcer healing, reducing pain and inflammatory response, and enhancing immune function.

P803 iGenoMed-MTT: A prospective multiomic study of response to molecularly targeted therapies in IBD

Abstract Background No tools exist to individualize treatment selection in Inflammatory bowel disease (IBD) to optimize outcomes. We prospectively recruited patients prior to initiation of molecularly targeted (advanced) therapy (MTT) to identify predictive biomarkers of response and define pathways impacted by successful treatment. Methods Serum was collected before initiation of treatment in all patients, and at visit 1 (V1~16 wks) for a subset of patients. Serum samples were analyzed for &amp;gt;140 protein biomarkers (OLINK) and &amp;gt;1200 lipid metabolites. Whole exome sequencing and GWAS data was generated for all participants. Initial data outline proteomic data. Results Of the first 166 IBD patients analyzed, therapies initiated included TNF antagonists (n=85), ustekinumab (n=43), vedolizumab (n=28) and janus kinase inhibitors (n=10). Bio-naïve (n=96) and patients using baseline corticosteroids (n=77) were included. Sixty-three patients achieved remission. In TNF-antagonist initiations, serum TNF concentrations increased between baseline and V1 (p=4E-3), while it decreased for other MTTs (p=0.07). In bio-naïve patients, serum TNF concentration had a strong correlation with CXCL10 (r=0.58, P=3E-10). From the Principal Component Analysis of analytes correlated to TNF in bio-naïve patients, we built a proxy for the level of active TNF. At baseline, compared to TNF antagonist naïve patients, significantly higher serum TNF concentrations existed in patients with prior TNF-antagonist exposure &amp;gt;1-month post-cessation and a markedly high TNF concentration with cessation &amp;lt;1 month prior to baseline (p&amp;lt; 2E-16). In patients with prior TNF-antagonist exposure, serum TNF concentrations did not correlate with other cytokines (incl. CXCL10). In these patients, elevated serum TNF were found at V1, suggesting accumulation of inactive (complexed) TNF with treatment. A similar pattern was observed for IL-12 after ustekinumab treatment (elevated serum IL-12 with recent ustekinumab (p= 8E-13), large increase in IL-12 after ustekinumab (p=9E-5)). Reduced IL-12 concentrations existed in current corticosteroid users, compared to previous users and those who never used (p=4E-8). In baseline samples in bio-naive patients prior to therapy initiation, serum concentrations of six analytes provided a discriminant model of corticosteroid use, whith an area under (AUC) the receiver operation characteristic (ROC) curve showed excellent discrimination (AUC=0.91). Conclusion These data uniquely characterize proteomic data in patients with various advanced therapies and will enable development of predictive panels. Unique availability of multiple therapies linked to longitudinal proteomic data may allow personalized panels for treatment selection.

Effects of the Surgical Ligation of the Ureter in Different Locations on the Kidney over Time in the Rat Model.

To evaluate the effects of the surgical ligation of the ureter in different locations on the kidney over time in the rat model. A total of 155 rats were enrolled and randomly divided into the case (n = 150) and control (n = 5) groups. The case group included three separate groups (fifty rats in each group) that underwent surgical ureteral ligation at the proximal, middle, and distal ureter. The laboratory tests, and tumor necrosis factor α (TNF-α), were measured in groups. The pathological evaluation for glomerular changes, tubular dilation, interstitial fibrosis, and interstitial infiltration of the inflammatory cells following the obstruction was performed (severity of tubular atrophy categorized too mild (+), moderate (++), and severe (+++)). To compare the continuous variables between the groups and between the measurement times, the analysis of variance (ANOVA) was used. Our results revealed that the creatinine four weeks after the obstruction was significantly higher in the proximal group obstruction (p value: 0.046). The three groups had no significant differences regarding urine creatinine, serum sodium, and serum TNF (p value: 0.261). Obstruction did not change the glomerular morphology in three intervention groups after six weeks. The commencing of severe tubular atrophy in proximal, middle, and distal ureteral obstruction was at weeks three, four, and six, respectively. The location of ureteral obstruction is also crucial in deciding to intervene to relieve the complete ureteral obstruction. Severe tubular damage occurs in weeks three, four, and six in proximal, middle, and distal ureteral obstruction, respectively.

Evaluation of health risk associated with consumption of food crops from electronic waste dumpsite using albino Wistar rat’s model: Bayelsa state Nigeria case study

The alterations in some important health biomarkers associated with consumption of food crops harvested near E-waste dumpsite in Bayelsa State, Nigeria, was evaluated. Samples of soil, plant, water and sea foods were collected around E-waste dumpsites and control sites for laboratory screening. A standard animal feed was formulated (control group), and the feed formulated from plants harvested from e-waste dumpsites was used to feed the experimental animals (Test group) for a period of three months. The formulated feeds were screened for toxic metals using atomic absorption spectrometry. The study comprises of twenty-eight animals (fourteen each of male and female) of albino wistar strain, weighing 50-100g were divided into two groups of fourteen animals each. Health biomarkers such as C-reactive protein, TNF alpha, creatinine, alanine transaminase (ALT), aspartate transaminase (AST), alanine phosphatase (ALP), platelet count, and oxidative stress parameters were evaluated in both groups. Toxic metals content of samples collected from the E-waste dumpsite revealed significantly (p&lt;0.05) higher levels of Cd, Co, Ni and Pb, which exceeded WHO permissible limits, compared with the control (p&lt;0.05) site. Significant (p&lt;0.05) differences between the test and control group for serum C-reactive protein, TNF alpha, creatinine concentrations, ALT, AST, ALP activities, platelet count, and oxidative stress parameters of the test group were all significantly (p&lt;0.05) higher than the control group, suggesting the presence of oxidative stress trigger(s) among animals in the test group and these results were further affirmed by the histology results as presented. Conclusively, this study highlighted a strong correlation between consumption of food crops cultivated near E-wastes dumpsites and potential associated health risks. Hence, demands public awareness and a call on governments and concerned regulatory bodies to ensure and enforce ethical E-waste management and disposal practices to minimize E-waste exposure and toxicity.

Tumor necrosis factor α promotes clonal dominance of KIT D816V+ cells in mastocytosis: role of survivin and impact on prognosis

AbstractSystemic mastocytosis (SM) is defined by the expansion and accumulation of neoplastic mast cells (MCs) in the bone marrow (BM) and extracutaneous organs. Most patients harbor a somatic KIT D816V mutation, which leads to growth factor–independent KIT activation and accumulation of MC. Tumor necrosis factor α (TNF) is a proapoptotic and inflammatory cytokine that has been implicated in the clonal selection of neoplastic cells. We found that KIT D816V increases the expression and secretion of TNF. TNF expression in neoplastic MCs is reduced by KIT-targeting drugs. Similarly, knockdown of KIT or targeting the downstream signaling cascade of MAPK and NF-κB signaling reduced TNF expression levels. TNF reduces colony formation in human BM cells, whereas KIT D816V+ cells are less susceptible to the cytokine, potentially contributing to clonal selection. In line, knockout of TNF in neoplastic MC prolonged survival and reduced myelosuppression in a murine xenotransplantation model. Mechanistic studies revealed that the relative resistance of KIT D816V+ cells to TNF is mediated by the apoptosis-regulator BIRC5 (survivin). Expression of BIRC5 in neoplastic MC was confirmed by immunohistochemistry of samples from patients with SM. TNF serum levels are significantly elevated in patients with SM and high TNF levels were identified as a biomarker associated with inferior survival. We here characterized TNF as a KIT D816V-dependent cytokine that promotes clonal dominance. We propose TNF and apoptosis-associated proteins as potential therapeutic targets in SM.