Changes In Cytokines Research Articles

Inflammatory cytokine levels and changes during omalizumab treatment in chronic spontaneous urticaria

While several studies have examined the role of T cells and related cytokines in the development of chronic spontaneous urticaria (CSU), there is a limited amount of research focusing on the changes in cytokine levels during omalizumab treatment. The primary objective of this study was to investigate the inflammatory cytokine profile (including IL-4, IL-5, IL-10, IL-13, IL-17, IL-31, IL-33, and TNFα) among CSU patients undergoing to omalizumab treatment. Plasma levels of cytokines were measured using ELISA. Measurements were taken before CSU treatment, at the 3rd and 6th months of omalizumab treatment, and once in the control group. The severity of the patients’ disease was assessed using the weekly Urticaria Activity Score(UAS7), and disease control was evaluated using the Urticaria Control Test(UCT). Thirty-one CSU patients and 56 age- and gender-matched healthy controls were included. Plasma levels of IL-4 and IL-33 were significantly lower in patients with CSU compared to healthy controls (p = 0.001; p = 0.038, respectively). During omalizumab treatment, IL-4 levels showed a significant increase in the 3rd month compared to baseline (p = 0.01), and IL-5 levels significantly decreased in the 6th month compared to both the 3rd month and baseline (6th month vs. baseline; p = 0.006, 6th month vs. 3rd month; p = 0.001). One potential mechanism of action for omalizumab may involve its regulatory effects on type 2 inflammatory cytokines in CSU patients. This finding partially explains the efficacy of anti-IL-4/13 treatments in chronic spontaneous urticaria. Further investigations on drugs targeting type 2 inflammatory cytokines in CSU are warranted.

Effects of sEH inhibition on the eicosanoid and cytokine storms in SARS-CoV-2-infected mice.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection involves an initial viral infection phase followed by a host-response phase that includes an eicosanoid and cytokine storm, lung inflammation and respiratory failure. While vaccination and early anti-viral therapies are effective in preventing or limiting the pathogenic host response, this latter phase is poorly understood with no highly effective treatment options. Inhibitors of soluble epoxide hydrolase (sEH) increase levels of anti-inflammatory molecules called epoxyeicosatrienoic acids (EETs). This study aimed to investigate the impact of sEH inhibition on the host response to SARS-CoV-2 infection in a mouse model with human angiotensin-converting enzyme 2 (ACE2) expression. Mice were infected with SARS-CoV-2 and treated with either vehicle or the sEH inhibitor 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU). At day 5 post-infection, SARS-CoV-2 induced weight loss, clinical signs, a cytokine storm, an eicosanoid storm, and severe lung inflammation with ~50% mortality on days 6-8 post-infection. SARS-CoV-2 infection induced lung expression of phospholipase A2 (PLA2), cyclooxygenase (COX) and lipoxygenase (LOX) pathway genes, while suppressing expression of most cytochrome P450 genes. Treatment with the sEH inhibitor TPPU delayed weight loss but did not alter clinical signs, lung cytokine expression or overall survival of infected mice. Interestingly, TPPU treatment significantly reversed the eicosanoid storm and attenuated viral-induced elevation of 39 fatty acids and oxylipins from COX, LOX and P450 pathways, which suggests the effects at the level of PLA2 activation. The suppression of the eicosanoid storm by TPPU without corresponding changes in lung cytokines, lung inflammation or mortality reveals a surprising dissociation between systemic oxylipin and cytokine signaling pathways during SARS-CoV-2 infection and suggests that the cytokine storm is primarily responsible for morbidity and mortality in this animal model.

Amiloride lowers plasma TNF and interleukin-6 but not interleukin-17A in patients with hypertension and type 2 diabetes.

Interleukin (IL)-17A contributes to hypertension in preclinical models. T helper 17 and dendritic cells are activated by NaCl, which could involve the epithelial Na+ channel (ENaC). We hypothesized that the ENaC blocker amiloride reduces plasma IL-17A and related cytokines in patients with hypertension. Concentrations of IL-17A, IFN-γ, TNF, IL-6, IL-1β, and IL-10 were determined by immunoassays in plasma from two patient cohorts before and after amiloride treatment: 1) patients with type 2 diabetes mellitus (T2DM) and treatment-resistant hypertension (n = 69, amiloride 5-10 mg/day for 8 wk) and 2) patients with hypertension and type 1 diabetes mellitus (T1DM) (n = 29) on standardized salt intake (amiloride 20-40 mg/day, 2 days). Plasma and tissue from ANG II-hypertensive mice with T1DM treated with amiloride (2 mg/kg/day, 4 days) were analyzed. The effect of amiloride and benzamil on macrophage cytokines was determined in vitro. Plasma cytokines showed higher concentrations (IL-17A ∼40-fold) in patients with T2DM compared with T1DM. In patients with T2DM, amiloride had no effect on IL-17A but lowered TNF and IL-6. In patients with T1DM, amiloride had no effect on IL-17A but increased TNF. In both cohorts, blood pressure decline and plasma K+ increase did not relate to plasma cytokine changes. In mice, amiloride exerted no effect on IL-17A in the plasma, kidney, aorta, or left cardiac ventricle but increased TNF in cardiac and kidney tissues. In lipopolysaccharide-stimulated human THP-1 macrophages, amiloride and benzamil (from 1 nmol/L) decreased TNF, IL-6, IL-10, and IL-1β. In conclusion, inhibition of ENaC by amiloride reduces proinflammatory cytokines TNF and IL-6 but not IL-17A in patients with T2DM, potentially by a direct action on macrophages.NEW & NOTEWORTHY ENaC activity may contribute to macrophage-derived cytokine release, since amiloride exerts anti-inflammatory effects by suppression of TNF and IL-6 cytokines in patients with resistant hypertension and type 2 diabetes and in THP-1-derived macrophages in vitro.

Cytokine and Microbiome Changes in Adolescents with Anorexia Nervosa at Admission, Discharge, and One-Year Follow-Up.

Anorexia nervosa (AN) is a severe eating disorder that predominantly affects females and typically manifests during adolescence. There is increasing evidence that serum cytokine levels are altered in individuals with AN. Previous research has largely focused on adult patients, assuming a low-grade pro-inflammatory state. The serum levels of the cytokine tumour necrosis factor-alpha (TNF-α), interleukin (IL)-1β, IL-6 and IL-15, which are pro-inflammatory, were examined in 63 female adolescents with AN and 41 age-matched healthy controls (HC). We included three time points (admission, discharge, and 1-year follow-up) and investigated the clinical data to assess whether the gut microbiota was associated with cytokine alterations. Relative to the HC group, serum levels of IL-1β and IL-6 were significantly lower during the acute phase (admission) of AN. IL-1β expression was normalised to control levels after weight recovery. TNF-α levels were not significantly different between the AN and HC groups. IL-15 levels were significantly elevated in patients with AN at all time points. We found associations between cytokines and bodyweight, illness duration, depressive symptoms, and the microbiome. In contrast to most findings for adults, we observed lower levels of the pro-inflammatory cytokines IL-1β and IL-6 in adolescent patients, whereas the level of IL-15 was consistently increased. Thus, the presence of inflammatory dysregulation suggests a varied rather than uniform pro-inflammatory state.

Bronchoalveolar Lavage and Oleic Acid Two-hit Model for Inducing Acute Respiratory Distress Syndrome in Swine Models.

Acute respiratory distress syndrome (ARDS) is a widespread and often fatal clinical syndrome marked by the acute onset of pulmonary edema and inflammatory-mediated disruptions in alveolar-capillary permeability resulting in impaired gas exchange and tissue oxygenation with subsequent acute respiratory failure that accounts for 10.4% of all intensive care unit admissions worldwide and boasts a mortality rate of 38.5%. The current treatment for ARDS remains largely supportive. This is largely because of the many challenges of achieving a stable and sustainable animal model that recreates the pathophysiology of ARDS experimentally in a controlled setting to allow research to elucidate potential treatments of ARDS moving forward. The bronchoalveolar lavage and oleic acid models are currently the 2 most frequently used experimental models in inducing ARDS in animal models. This study demonstrated that combining them into a "two-hit model" can produce sustained ARDS in swine models per the Horowitz index (PaO2/FiO2 ratio of ≤300 mmHg). Additionally, expected changes in pH, pCO2, lung compliance, cytokines, and tissue histopathology were observed and add to our confidence and reliability that the "two-hit model" produces symptomatic ARDS in a manner very similar to that observed in humans. In conclusion, we demonstrated a viable animal model of human ARDS that is maintained for a prolonged period, suitable for continuous monitoring of the progression, and evaluation of potential future treatments and procedures to reduce patient morbidity and mortality. To carry out this two-hit model, lung injury was induced through a combination of bronchoalveolar lavage and oleic acid administration and the disease process of ARDS is subsequently tracked through clinically relevant parameters such as respiratory mechanics, cytokine response, aretrial blood gas (ABG) changes, and observation of postmortem histopathologic changes. This promising new model has the capacity to successfully replicate human ARDS which is a well-known and notoriously multifactorial pathogenic process to reproduce experimentally for an extended period of time. The "two-hit model" is a viable and appropriate model for the research of novel treatments for ARDS.

Phase II trial of vaccination with autologous, irradiated melanoma cells engineered by adenoviral mediated gene transfer to secrete granulocyte-macrophage colony stimulating factor in patients with stage III and IV melanoma.

In the era of immune checkpoint blockade, the role of cancer vaccines in immune priming has provided additional potential for therapeutic improvements. Prior studies have demonstrated delayed type hypersensitivity and anti-tumor immunity with vaccines engineered to secrete granulocyte-macrophage colony-stimulating factor (GM-CSF). The safety, efficacy and anti-tumor immunity of GM-CSF secreting vaccine in patients with previously treated stage III or IV melanoma needs further investigation. In this phase II trial, excised lymph node metastases were processed to single cells, transduced with an adenoviral vector encoding GM-CSF, irradiated, and cryopreserved. Individual vaccines were composed of 1x106, 4x106, or 1x107 tumor cells, and were injected intradermally and subcutaneously at weekly and biweekly intervals. The primary endpoints were feasibility of producing vaccine in stage III patients and determining the proportion of patients alive at two years in stage IV patients. GM-CSF vaccine was successfully developed and administered in all 61 patients. Toxicities were restricted to grade 1-2 local skin reactions. The median OS for stage III patients (n = 20) was 71.1 (95% CI, 43.7 to NR) months and 14.9 (95%CI, 12.1 to 39.7) months for stage IV patients. The median PFS in stage III patients was 50.7 (95%CI, 36.3 to NR) months and 4.1 (95% CI, 3.0-6.3) months in stage IV patients. In the overall population, the disease control rate was 39.3% (95%CI, 27.1 to 52.7%). In stage III patients, higher pre-treatment plasma cytokine levels of MMP-1, TRAIL, CXCL-11, CXCL-13 were associated with improved PFS (p<0.05 for all). An increase in post-vaccination levels of IL-15 and TRAIL for stage III patients was associated with improved PFS (p=0.03 for both). Similarly, an increase in post-vaccination IL-16 level for stage IV patients was associated with improved PFS (p=0.02) and clinical benefit. Vaccination with autologous melanoma cells secreting GM-CSF augments antitumor immunity in stage III and IV patients with melanoma, is safe, and demonstrates disease control. Luminex data suggests that changes in inflammatory cytokines and immune cell infiltration promote tumor antigen presentation and subsequent tumor cell destruction. Additional investigation to administer this vaccine in combination with immune checkpoint inhibitors is needed.

Bronchom assuages airway hyperresponsiveness in house dust mite-induced mouse model of allergic asthma and moderates goblet cell metaplasia, sub-epithelial fibrosis along with changes in Th2 cytokines and chemokines.

Asthma is a common obstructive airway disease with an inflammatory etiology. The main unmet need in the management of asthma is inadequate adherence to pharmacotherapy, leading to a poorly-controlled disease state, necessitating the development of novel therapies. Bronchom is a calcio-herbal formulation, which is purported to treat chronic asthma. The objective of the current study was to examine the in-vivo efficacy of Bronchom in mouse model of allergic asthma. Ultra high performance liquid chromatography was utilized to analyze the phytocompounds in Bronchom. Further, the in-vivo efficacy of Bronchom was evaluated in House dust mite (HDM)-induced allergic asthma in mice. Mice were challenged with aerosolized methacholine to assess airway hyperresponsiveness. Subsequently, inflammatory cell influx was evaluated in bronchoalveolar lavage fluid (BALF) followed by lung histology, wherein airway remodeling features were studied. Simultaneously, the levels of Th2 cytokines and chemokines in the BALF was also evaluated. Additionally, the mRNA expression of pro-inflammatory and Th2 cytokines was also assessed in the lung along with the oxidative stress markers. Phytocompounds present in Bronchom included, gallic acid, protocatechuic acid, methyl gallate, rosmarinic acid, glycyrrhizin, eugenol, 6-gingerol and piperine. Bronchom effectively suppressed HDM-induced airway hyperresponsiveness along with the influx of leukocytes in the BALF. Additionally, Bronchom reduced the infiltration of inflammatory cells in the lung and it also ameliorated goblet cell metaplasia, sub-epithelial fibrosis and increase in α-smooth muscle actin. Bronchom decreased Th2 cytokines (IL-4 and IL-5) and chemokines (Eotaxin and IP-10) in the BALF. Likewise, it could also suppress the mRNA expression of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-6 and IL-33), and IL-13. Moreover, Bronchom restored the HDM-induced diminution of endogenous anti-oxidants (GSH and SOD) and the increase in pro-oxidants (GSSG and MDA). Furthermore, Bronchom could also decrease the nitrosative stress by lowering the observed increase in nitrite levels. Taken together, the results of the present study data convincingly demonstrate that Bronchom exhibits pharmacological effects in an animal model of allergic asthma. Bronchom mitigated airway hyperresponsiveness, inflammation and airway remodeling evoked by a clinically relevant allergen and accordingly it possesses therapeutic potential for the treatment of asthma.

Early administration of umbilical cord blood cells following brief high tidal volume ventilation in preterm sheep: a cautionary tale

BackgroundUmbilical cord blood (UCB) cells are a promising treatment for preterm brain injury. Access to allogeneic sources of UCB cells offer the potential for early administration to optimise their therapeutic capacities. As preterm infants often require ventilatory support, which can contribute to preterm brain injury, we investigated the efficacy of early UCB cell administration following ventilation to reduce white matter inflammation and injury.MethodsPreterm fetal sheep (0.85 gestation) were randomly allocated to no ventilation (SHAM; n = 5) or 15 min ex utero high tidal volume ventilation. One hour following ventilation, fetuses were randomly allocated to i.v. administration of saline (VENT; n = 7) or allogeneic term-derived UCB cells (24.5 ± 5.0 million cells/kg; VENT + UCB; n = 7). Twenty-four hours after ventilation, lambs were delivered for magnetic resonance imaging and post-mortem brain tissue collected. Arterial plasma was collected throughout the experiment for cytokine analyses. To further investigate the results from the in vivo study, mononuclear cells (MNCs) isolated from human UCB were subjected to in vitro cytokine-spiked culture medium (TNFα and/or IFNγ; 10 ng/mL; n = 3/group) for 16 h then supernatant and cells collected for protein and mRNA assessments respectively.ResultsIn VENT + UCB lambs, systemic IFNγ levels increased and by 24 h, there was white matter neuroglial activation, vascular damage, reduced oligodendrocytes, and increased average, radial and mean diffusivity compared to VENT and SHAM. No evidence of white matter inflammation or injury was present in VENT lambs, except for mRNA downregulation of OCLN and CLDN1 compared to SHAM. In vitro, MNCs subjected to TNFα and/or IFNγ displayed both pro- and anti-inflammatory characteristics indicated by changes in cytokine (IL-18 & IL-10) and growth factor (BDNF & VEGF) gene and protein expression compared to controls.ConclusionsUCB cells administered early after brief high tidal volume ventilation in preterm fetal sheep causes white matter injury, and the mechanisms underlying these changes are likely dysregulated responses of the UCB cells to the degree of injury/inflammation already present. If immunomodulatory therapies such as UCB cells are to become a therapeutic strategy for preterm brain injury, especially after ventilation, our study suggests that the inflammatory state of the preterm infant should be considered when timing UCB cells administration.

Multi-cohort study on cytokine and chemokine profiles in the progression of COVID-19

Various substances in the blood plasma serve as prognostic indicators of the progression of COVID-19. Consequently, multi-omics studies, such as proteomic and metabolomics, are ongoing to identify accurate biomarkers. Cytokines and chemokines, which are crucial components of immune and inflammatory responses, play pivotal roles in the transition from mild to severe illness. To determine the relationship between plasma cytokines and the progression of COVID-19, we used four study cohorts to perform a systematic study of cytokine levels in patients with different disease stages. We observed differential cytokine expression between patients with persistent-mild disease and patients with mild-to-severe transformation. For instance, IL-4 and IL-17 levels significantly increased in patients with mild-to-severe transformation, indicating differences within the mild disease group. Subsequently, we analysed the changes in cytokine and chemokine expression in the plasma of patients undergoing two opposing processes: the transition from mild to severe illness and the transition from severe to mild illness. We identified several factors, such as reduced expression of IL-16 and IL-18 during the severe phase of the disease and up-regulated expression of IL-10, IP-10, and SCGF-β during the same period, indicative of the deterioration or improvement of patients’ conditions. These factors obtained from fine-tuned research cohorts could provide auxiliary indications for changes in the condition of COVID-19 patients.

The chronic leukocyte and inflammatory cytokine responses of older adults to resistance training in normobaric hypoxia; a randomized controlled trial

Trial designOlder adults experience chronic dysregulation of leukocytes and inflammatory cytokines, both at rest and in response to resistance training. Systemic hypoxia modulates leukocytes and cytokines, therefore this study characterized the effects of normobaric hypoxia on the leukocyte and cytokine responses of older adults to resistance training.Methods20 adults aged 60–70 years performed eight weeks of moderate-intensity resistance training in either normoxia or normobaric hypoxia (14.4% O2), consisting of two lower body and two upper body exercises. Venous blood was drawn before and after the training intervention and flow cytometry was used to quantify resting neutrophils, lymphocytes, monocytes, eosinophils and basophils, in addition to the subsets of lymphocytes (T, B and natural killer (NK) cells). Inflammatory cytokines were also quantified; interleukin 1 beta (IL-1β), IL-4, IL-6, IL-8, IL-10 and tumor necrosis factor alpha (TNF-α). Acute changes in leukocytes and cytokines were also measured in the 24 h following the last training session.ResultsAfter the intervention there was a greater concentration of resting white blood cells (p = 0.03; 20.3% higher) T cells (p = 0.008; 25.4% higher), B cells (p = 0.004; 32.6% higher), NK cells (p = 0.012; 43.9% higher) and eosinophils (p = 0.025; 30.8% higher) in hypoxia compared to normoxia, though the cytokines were unchanged. No acute effect of hypoxia was detected in the 24 h following the last training session for any leukocyte population or inflammatory cytokine (p < 0.05).ConclusionsHypoxic training caused higher concentrations of resting lymphocytes and eosinophils, when compared to normoxic training. Hypoxia may have an additional beneficial effect on the immunological status of older adults.Trial registrationAustralian New Zealand Clinical Trials Registry (ANZCTR). Trial number: ACTRN12623001046695. Registered 27/9/2023. Retrospectively registered. All protocols adhere to the COSORT guidelines.

Changes of Inflammatory Cytokines after 4-week and 8-week Aerobic Exercise in Hispanic Obese Females

Recent studies have insuffcient data to support the effects of exercise on inflammatory cytokines independent from weight loss. Thus, a reduction in fat mass is required to induce decreases in markers of pro-inflammatory cytokines. PURPOSE: Changes in inflammatory cytokines following 4-weeks and 8-weeks of aerobic exercise were measured in this study to find if exercise is an independent determinant on changes in inflammatory cytokines in middle-aged Hispanic obese females. Methods: 35 obese females were randomly assigned to either exercise (EX, N=16) or control (CON, N=19) group. The exercise group performed moderate intensity aerobic exercise on the treadmill for 60 minutes at 55% of VO2max for 8 weeks (3 days/week). Body composition measurement with dual-energy X-ray absorptiometry and blood collection were conducted before and after the 4th week and 8th week of the intervention (PRE, 4W, and 8W). Blood samples were used to measure levels of tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), and adiponectin. Two-way repeated measures ANOVA and Tukey post hoc tests were used for data analysis. RESULTS: Following 8 weeks of aerobic exercise intervention, participants had significantly reduced body mass index (34.2±4.6 mean±SD → 33.7±4.7, P=.035), %body fat (42.1±5.2% → 41.4±5.3, P=.014) and TNF-α (4.57±.24pg/mL mean±SE → 4.14±.31, P=.019) as compared to PRE. EX also observed a decrease in TNF-α (4.57±.24 → 4.29±.28, P=.033) when changes in body weight and %body fat were not observed after 4 weeks of aerobic exercise. CRP and adiponectin were unaltered in EX. CON showed no significant changes in any variables at 4W and 8W. CONCLUSION: It is suggested reductions in inflammatory cytokines are associated with fat loss; however, significant change in TNF- α at 4W when no change in %body fat is observed this indicates that moderate aerobic exercises may reduce level of inflammation independent from fat loss. This change is further improved when fat loss occurs at 8W. Therefore, it is plausible that moderate aerobic exercises may independently reduce risks of obesity-associated disorders in middle-aged Hispanic obese females. Results of this study suggest that longer periods of exercise training with fat loss may be required to induce significant changes in CRP and adiponectin in middle-aged obese females. TAMIU University Research Grant. 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.

The effects of repeat mild traumatic brain injuries on choroid plexus endothelial cells in-vitro

Chronic Traumatic Encephalitis (CTE) is a degenerative brain disorder seen in college and professional football players, and those that play other contact sports like hockey and soccer. It is characterized by a dementia-like phenotype and declination in memory, executive dysfunction, and mood and is associated with repetitive head trauma, as seen in those contact sports. Even with rule changes to protect the players, it is predicted that, on average, college football players experience 1,400-1,500 head impact exposures per year, or roughly 14 per game (Crisco et al., 2010). This is significant because existing literature provides evidence that it is the accumulation of repetitive head trauma, even mild, that eventually leads to lasting and irreparable damage seen in CTE. This study sought to characterize cytokine signaling in repeat mild traumatic brain injuries (rTBI) in choroid plexus endothelial cells (CPECs), the endothelial barrier of the blood-CSF barrier (BCSFB). We hypothesized that regulatory and pro-inflammatory cytokines and chemokines play a role in exacerbating post-rTBI symptomology even days after initial injury. Identifying key cytokines and their respective timepoints post-injury is important to allow us to better treat TBIs, while also preventing subsequent damage that might progress to CTE. To study this hypothesis, primary human CPECs were subjected to a 12% repetitive mechanical elongation strain using the FlexCell Tension system to mimic mild axonal stretching injury. The elongation mechanical strain was repeated 14 times over a 1-hour period, which is roughly the average number of impacts experienced by players during a one-hour college football game. We collected supernatant over 24-, 48-, 72-, and 96-hours post-injury and examined 36 different cytokines using RND microarrays following manufacturer’s instructions. Controls included cells subjected to no mechanical strain and cells that only received one total mechanical strain. Several notable cytokines and chemokines were altered during this period, including RANTES (CCL5), CXCL12, and macrophage migration inhibitory factor (MIF). RANTES is highly correlated with Alzheimer’s disease, a neurodegenerative disease and CTE relative, and CXCL12 and MIF are highly correlated with inflammatory processes. Many cytokine changes were more pronounced in the period between 24- and 48-hours after injury. However, there were lasting changes compared to the controls up to 96-hours later. These findings can be used to begin to understand the complexity of human CPEC cytokine signaling at the BCSFB when these cells react to the strain forces of repeat mild TBIs like those seen in college football players. This also gives us further insight into the lasting effects of rTBIs and the possible relation to CTE. With these results in mind, we plan to continue to monitor cytokines and chemokines up to two weeks post injury to determine if, and when, cytokine values return to baseline values post-injury. This project was funded by a Senior Research Grant from the Indiana Academy of Science and from a Faculty Research Development Grant from Marian University College of Osteopathic Medicine. 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.

Dihydroartemisinin breaks the immunosuppressive tumor niche during cisplatin treatment in Hepatocellular carcinoma

ObjectiveHepatocellular carcinoma, characterized by high mortality rates, often exhibits limited responsiveness to conventional treatments such as surgery, radiotherapy, and chemotherapy. Therefore, identifying a sensitizer for cisplatin has become crucial. Dihydroartemisinin, known for its potent role of tumor treatment, arises as a prospective candidate for cisplatin sensitization in clinical settings. MethodsA mouse model of liver tumor was established through chemical induction of DEN/TCPOBOP. Upon successful model establishment, ultrasound was employed to detect tumors, Hematoxylin and eosin staining was conducted for observation of liver tissue pathology, and ELISA was utilized to assess cytokine changes (IFN-γ, IL-2, IL-4, IL-10, TGF-β, IL-1β, CCL2, and CCL21) in peripheral blood, para-tumor tissues, and tumor tissues. The infiltration of CD8+T cells and macrophages in tumor tissue sections was detected by immunofluorescence. ResultsDihydroartemisinin combined with cisplatin obviously restrained the growth of liver tumors in mice and improved the weight and spleen loss caused by cisplatin. Cisplatin treatment of liver tumor mice increased the content of CCL2 and the number of macrophages in tumor tissues and promoted the formation of an immunosuppressive microenvironment. The combination therapy decreased the content of TGF-β in tumor tissues while increasing CCL2 levels in para-tumor tissues. Both combination therapy and cisplatin alone increased the number of CD8+T cells in tumor tissue, but there was no difference between them. ConclusionDihydroartemisinin combined with cisplatin obviously prevented the deterioration of liver tumor in hepatocellular carcinoma mice and improve the therapeutic effect of cisplatin by improving the immunosuppressive microenvironment induced by cisplatin. Our findings provide a theoretical basis for considering dihydroartemisinin as an adjuvant drug for cisplatin in the treatment of hepatocellular carcinoma in the future.

Oral beta-hydroxybutyrate alleviates COVID-19 related acute respiratory distress syndrome: A randomized, single-blind, placebo-controlled trial

BackgroundAcute respiratory distress syndrome (ARDS) is a lung complication of COVID-19 that requires intensive care and ventilation. Beta-hydroxybutyrate (BHB) is a ketone body that can modulate metabolism and inflammation in immune cells and lung tissues. We hypothesized that oral BHB could alleviate COVID-19 related ARDS by reducing pro-inflammatory cytokines and increasing anti-inflammatory cytokines. MethodsWe randomized 75 patients with mild (as per Berlin criteria) ARDS symptoms to receive oral 25 g twice daily or placebo for five days. The primary outcome was the change in pro-inflammatory cytokines (Interleukin-1β, Interleukin-6, interleukin-18, tumour necrosis factor-alpha) and anti-inflammatory cytokine (interleukin-10) from baseline to day 5. The secondary outcomes were the change in BHB levels from baseline to day 5, the number of hospitalization days, and the occurrence of adverse events. ResultsTreatment with formulated BHB resulted in a significant decrease in pro-inflammatory cytokines; Interleukin-1β (p = 0.0204), Interleukin-6 (p = 0.0309), interleukin-18 (p = 0.0116), tumour necrosis factor-alpha (p = 0.0489) and increase in interleukin-10 (p = 0.0246) compared treatment with placebo. Importantly, higher BHB levels (p = 0.0001) were observed after supplementation; additionally, patients who underwent this approach were hospitalized for fewer days. No serious adverse events were reported. ConclusionBeta-hydroxybutyrate, an oral adjunct therapy, has shown promising results in ameliorating symptoms of ARDS. This includes reduced inflammation, oxidative stress, and decreased patient fatigue levels. Further study with a large sample size is warranted to assess the potential of BHB therapy's effectiveness in reducing the development of severe illness. Clinical trial registration(http://ctri.nic.in/CTRI/2021/03/031790)

Effects of Exercise Intensities on Changes in Pro-/Anti-inflammatory Cytokines following 8-weeks of Aerobic Exercise Training

Inflammatory cytokines are useful biomarkers in predicting the development of metabolic and cardiovascular diseases and may be positively affected by physical activity and weight loss. Despite much interest in chronic low-level inflammation in the obese population, effects of aerobic training intensity on inflammatory cytokines remain elusive. PURPOSE: The purpose of this study was to investigate effects of 8-week aerobic exercise training at high and low intensities on changes in pro-/anti-inflammatory cytokines. Methods: Fifty three inactive obese Hispanic females (mean BMI = 34.5 kg/m2, aged 34-46 years) were divided into one of three groups: low intensity training group (LT: walking at 55% VO2max, n=16), high intensity training group (HT: running at 70% VO2max, n=18), and control group (CON: no intervention, n=19). LT and HT performed aerobic exercises three times per week at the given intensities. Exercise volume for two exercise groups was equated relative to kilograms of body weight by adjusting duration of exercise session (approximately 60 minutes for LT and 40 minutes for HT per session). Blood samples were collected before and after 8 weeks of intervention to measure levels of adiponectin, C-reactive protein (CRP) and tumor necrosis factor-alpha (TNF-α). Two-way repeated measures ANOVA and Tukey post hoc tests were used for data analysis. Results: Level of adiponectin showed no significant change in any groups after 8 weeks of aerobic exercise intervention. A significant decrease in CRP was observed in the HT group only (4.12 ±.26mg/L mean±SE → 3.89±.37, P=.041), but levels of TNF-a were significantly decreased in both LT (4.57±.24pg/mL → 4.14±.31, P=.019) and HT (4.54±.25 → 4.02±.41, P=.011). No changes were observed in CON. CONCLUSIONS: Significant decreases in CRP and TNF-a were found following high intensity aerobic exercise training while low intensity training reduced TNF-a only. The greater changes of pro-inflammatory cytokines in HT indicates high intensity aerobic exercise training may be more beneficial than low intensity training. Specifically, for controlling low-grade inflammation and immune function in obese Hispanic females. This study confirmed results of previous studies suggesting that longer period of exercise training with distinct fat loss may be required to induce significant changes in adiponectin in obese adults. TAMIU university research grant. 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.

Effectiveness of Low Molecular Weight Fucoidan and High Stability Fucoxanthin (LMF- HSFX) in Phaeophyta as Bioactivity in Emergency Therapy of Non-Alcoholic Fatty Liver Disease (NAFLD)

Indonesia is a maritime nation with a rich marine ecosystem and biodiversity. The waters are abundant in Phaeophyta (brown algae), which are a significant source of bioactive compounds such as fucoidan and fucoxanthin. These compounds have shown potential in treating Non-Alcoholic Fatty Liver Disease (NAFLD), a metabolic disorder characterized by excessive fat accumulation in the liver, leading to complications such as fibrosis, cirrhosis, and hepatocellular carcinoma. The objective of this study is to evaluate the effectiveness of Low Molecular Weight Fucoidan (LMF) and High Stability Fucoxanthin (HSFx) in the curative treatment of NAFLD. Specifically, the study aims to assess the bioactivity and biocompatibility of LMF-HSFx and compare its efficacy with a placebo group in the treatment of NAFLD. The study used a non-invasive Fibroscan to test Controlled Attenuation Parameter (CAP) and Transient Elastography on NAFLD patients. It included 42 NAFLD patients, divided into two groups: the LMF-HSFx group and the placebo group. The LMF-HSFx group received oral supplementation of 825 mg LMF fucoidan and 825 mg HSFx twice daily for six months. The effectiveness of the treatment was measured through changes in hepatic lipotoxicity, serum markers, and pro-inflammatory cytokines. The results showed significant reductions in hepatic lipotoxicity, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol, and triglycerides in the LMF-HSFx group. The study also observed significant reductions in pro-inflammatory cytokines (IL-6 and IFN-γ) and improvements in adiponectin and leptin levels. These findings suggest that the LMF-HSFx combination effectively reduces hepatic inflammation and improves metabolic parameters in NAFLD patients.

Immune Responses of Healthy Pregnant Women following an Elective Cesarean Section: Effects of Anesthetic Procedures.

A weakened immune system and more inflammatory cytokines being released are possible effects of the surgical stress that a cesarean section induces. This kind of reaction, in addition to the altered reaction to catecholamines, has the potential to significantly affect the immune system of the mother and the patients' general postoperative course. This prospective study compared the plasma levels of catecholamines and cytokines in healthy pregnant patients having cesarean sections under spinal anesthesia versus general anesthesia. A total of 30 pregnant women undergoing elective cesarean sections were divided into two groups: 15 who received general anesthesia (GA) and 15 who received spinal anesthesia (SA). Blood samples were collected from all subjects before anesthesia induction (pre-OP), 6 h postoperatively (6 h post-OP), and 12 h (12 h post-OP), to measure levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-8, IL-4, IL-10, norepinephrine (NE), and epinephrine (EPI). When we compared the two groups, we discovered that only IL-6 and IL-4 had significantly higher levels pre-OP, whereas all studied cytokines exhibited an increase in the GA versus SA group at 6 and 12 h post-OP. In the case of catecholamines, we discovered that serum levels are positively related with pro-inflammatory or anti-inflammatory cytokines, depending on the time of day and type of anesthetic drugs. Compared to SA, GA has a more consistent effect on the inflammatory response and catecholamine levels. The findings of this study confirm that the type of anesthesia can alter postoperative immunomodulation to various degrees via changes in cytokine and catecholamine production. SA could be a preferable choice for cesarean section because it is an anesthetic method that reduces perioperative stress and allows for less opioid administration, impacting cytokine production with proper immunomodulation.

Differential changes in expression of inflammatory mRNA and protein after oleic acid-induced acute lung injury

Background: Acute Respiratory Distress syndrome (ARDS) is a clinical syndrome of noncardiac pulmonary edema and inflammation leading to acute respiratory failure. We used the oleic acid infusion pig model of ARDS resembling human disease to explore cytokine changes in white blood cells (WBC) and plasma proteins, comparing baseline to ARDS values. Methods: Nineteen juvenile female swine were included in the study. ARDS defined by a PaO2/FiO2 ratio < 300 was induced by continuous oleic acid infusion. Arterial blood was drawn before and during oleic acid infusion, and when ARDS was established. Cytokine expression in WBC was analyzed by RT-qPCR and plasma protein expression by ELISA. Results: The median concentration of IFN-γ mRNA was estimated to be 59% (p = 0.006) and of IL-6 to be 44.4% (p = 0.003) of the baseline amount. No significant changes were detected for TNF-α, IL-17, and IL-10 mRNA expression. In contrast, the concentrations of plasma IFN-γ and IL-6 were significantly higher (p = 0.004 and p = 0.048 resp.), and TNF-α was significantly lower (p = 0.006) at ARDS compared to baseline. Conclusions: The change of proinflammatory cytokines IFN-γ and IL-6 expression is different comparing mRNA and plasma proteins at oleic acid-induced ARDS compared to baseline. The migration of cells to the lung may be the cause for this discrepancy.

Cytokine Dynamics in Acute Pancreatitis: The Quest for Biomarkers from Acute Disease to Disease Resolution.

Background: Acute pancreatitis (AP) is an inflammatory disease of the pancreas with incompletely known pathogenic mechanisms. This study aimed to explore the temporal changes in serum cytokines in patients with AP and to assess the association of these changes with disease severity. Methods: Fifty patients hospitalized with AP were enrolled, and their serum cytokine levels were analyzed at four different time points. A healthy control (HC) group of 30 outpatients was included. Results: AP patients showed increased levels of interleukin (IL)-6, IL-8, IL-10, vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-alpha, and monocyte chemoattractant protein (MCP)-1 at admission when compared with HC. IL-6, VEGF, and EGF remained elevated 1 month after hospitalization and 6 months after discharge. Conclusions the Bedside Index of Severity in Acute Pancreatitis (BISAP) and severity classification of the revised Atlanta classification system, IL-6 and VEGF, determined 48 h after hospitalization, were the two cytokines consistently elevated in the most severe patients. Increased levels of IL-4, IL-6, IL-10, and TNF-alpha at admission and MCP-1 48 h after admission are also related to the length of hospital stay. Conclusions: Our study highlights the role cytokines play in the pathogenesis of AP and can be useful in the development of future drug trials for AP.

Long-Term Immunomodulatory Impact of VNS on Peripheral Cytokine Profiles and Its Relationship with Clinical Response in Difficult-to-Treat Depression (DTD).

Vagus nerve stimulation (VNS) represents a long-term adjunctive treatment option in patients with difficult-to-treat depression (DTD). Anti-inflammatory effects have been discussed as a key mechanism of action of VNS. However, long-term investigations in real-world patients are sparse. In this naturalistic observational study, we collected data on cytokines in peripheral blood in n = 6 patients (mean age 47.8) with DTD and VNS treatment at baseline and at 6 months follow-up. We have identified clusters of peripheral cytokines with a similar dynamic over the course of these 6 months using hierarchical clustering. We have investigated cytokine changes from baseline to 6 months as well as the relationship between the cytokine profile at 6 months and long-term response at 12 months. After 6 months of VNS, we observed significant correlations between cytokines (p < 0.05) within the identified three cytokine-pairs which were not present at baseline: IL(interleukin)-6 and IL-8; IL-1β and TNF-α; IFN-α2 and IL-33. At 6 months, the levels of all the cytokines of interest had decreased (increased in non-responders) and were lower (5-534 fold) in responders to VNS than in non-responders: however, these results were not statistically significant. VNS-associated immunomodulation might play a role in long-term clinical response to VNS.