TNF Levels Research Articles

Treatment with tofacitinib attenuates muscle loss through myogenin activation in the collagen-induced arthritis.

Sarcopenia is a muscle disease characterized by reduction of muscle strength and muscle mass. In RA, 25.9 to 43.3% of the patients present sarcopenia. The loss of muscle mass observed in RA patients occurs either by activation of catabolic pathways or by inhibition of anabolic pathways. Despite having a list of drugs capable of treating RA inflammation, their effect on muscle is unclear. Our objective was to evaluate the tofacitinib effect on the muscle mass of collagen-induced arthritis (CIA) mice. CIA was induced in male DBA/1J mice by subcutaneous injection of Type 2 Collagen plus Freund Adjuvant. Animals were randomized into 3 groups: CIA + tofacitinib; CIA + vehicle; and healthy controls. Treatment was administered twice a day, between days 18 and 45 after induction. Clinical score, edema, and body weight were evaluated during the experimental period. After euthanasia, tibiotarsal joints were collected for assessment of disease histopathological score, and tibialis anterior (TA) and gastrocnemius (GA) muscles were weighed to assess muscle mass. Muscle atrophy was evaluated by measurement of TA myofiber cross-sectional area (CSA). Protein expression was evaluated by western blot using GA homogenates. Serum inflammatory markers were evaluated by ELISA. Statistical analysis included ANOVA followed by Tukey's or with Kruskal-Wallis. The statistical difference was assumed for p < 0.05. Tofacitinib treatment decreased arthritis severity by reducing clinical score, and hind paw edema in comparison with the vehicle group. Tofacitinib showed weight gain, higher TA and GA weights, and increased CSA compared to the vehicle group. On day 45, Tofacitinib presented increased muscle strength compared to the vehicle group, however, no difference was found in muscle fatigue. Pax7 expression was unchanged, while MyoD expression showed an increasing trend, and myogenin expression was significantly increased in Tofacitinib compared to vehicle and control groups. The treatment didn't modify Murf-1 expression. Tofacitinib mice showed decreased serum levels of TNF and increased IL-6 serum levels. Tofacitinib attenuated muscle loss in arthritic mice, increased muscle weight and muscle CSA. Activation of satellite cell regeneration, based on the increased expression of myogenin, is a potential mechanism involved in tofacitinib action against muscle loss.

Immune checkpoints PD1/PDL1, TIM3/GAL9 and key immune mediators landscape reveal differential expression dynamics on imatinib response in chronic myeloid leukemia.

The immune system of chronic myeloid leukemia (CML) patients is severely impaired, hampering anti-tumor responses, and maximal immune recovery occurs after achieving deep molecular responses to tyrosine kinase inhibitors. This study aimed to discern the expression patterns of NCR2, IL2, IL4, EOMES, FOXP3, GATA3, RORGT, PD1/PDL1 and TIM3/GAL9, expanding our previous dataset up to 19 key immune mediators, during the initial year on imatinib. Gene expression dynamics were evaluated in 171 peripheral blood samples from 89 CML patients, including 43 longitudinally monitored individuals, and 52 healthy donors. Univariate and unsupervised analyses confirmed diminished expression of most studied immune mediators, except for TNF, ARG1 and IL4, differentiating between baseline and 3-month samples. Most of the studied mediators normalized along treatment, with a transient increase of TNF and IL6 levels at 3-months, especially in optimal responders (BCR::ABL1 < 0.1%). Univariate and multivariate analyses showed heightened ARG1 levels and a transition from PD1/PDL1 dominance at 3 months to TIM3/GAL9 at 12 months in non-optimal responders (BCR::ABL1 ≥ 0.1%). Our longitudinal design offers a deeper exploration of immune gene expression dynamics in CML patients on imatinib, highlighting its potential implications for therapy outcomes.

Successful Treatment of Pediatric Generalized Pustular Psoriasis (GPP) with Spesolimab: 5 Case Reports and Evaluations of Circulating IL-36 Levels.

Generalized pustular psoriasis (GPP) is a rare, severe, and potentially life-threatening inflammatory cutaneous disease. IL-36 is a key treatment target in GPP. Spesolimab, a humanized monoclonal antibody of the IL-36 receptor, has demonstrated a good efficacy and a favorable safety profile in adults with GPP. However, data on its use in children are scarce. We treated patients aged 4-12 years with GPP with a single dose of spesolimab. The Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) total score, GPPGA pustulation sub-score, Generalized Pustular Psoriasis Area and Severity Index (GPPASI), and the Japanese Dermatological Association severity index for GPP were evaluated. The levels of IL-36α, IL-36β, and IL-36γ were detected by the magnetic bead-based immunoassays, and the levels of IL-17A, IL-17C, IFN-γ, TNF, IL-6, and IL-8 were measured by the Olink proximity extension assay technology. We included five patients (four boys and one girl) with a median age was 6.9 years old (range: 4.8 to 10.6 years), and a median age of onset of 1.7 years (range: 3 months-10 years and 5 months). After 1week of spesolimab administration, all patients had a total GPPGA score of 0/1 and pustulation subscore of 0, all patients had a GPPASI of 50, and four patients had a GPPASI of 75. Meanwhile, plasma levels of IL-36α, IL-36β, IL-36γ, IL-17A, IL-17C, IFN-γ, TNF, IL-6, IL-8 all decreased, and those of IL-36α, IL-36β, IL-17A, IL-17C, and IL-6 were statistically significant. There was no recurrence after 2 to 8 months of treatment. No other adverse event was recorded apart from one patient who experienced an upper respiratory infection in the first week. Spesolimab might be a prospective option for children aged 4 to 12 years.

Evaluation of the Activity of Olibanum Oil as an Immune Booster in Rats

The applications of herbal medicine have recently acquired growing interest in range of the prophylaxis and treatment of diseases. Olibanum has been used since ancient eras and several reports studied the pharmacological characteristics of boswellic acid, particularly their effect on the inflammatory response, analgesic properties, and anti-arthritic activity mostly in cell lines, but new approaches include animal models to assess these natural derivatives effects taking into consideration of being safer than synthetic preparations. The impact of olibanum oil on several parameters was studied in rats during this study. These included white blood cell (WBC) count, lactate dehydrogenase (LDH), and C reactive protein (CRP), as well as other pro-inflammatory cytokines like tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), and the cytokine interleukin -10 (IL-10) that is anti-inflammatory. Total WBCs in addition to IL-10 levels significantly increased in the oil-treated group in comparison with the control one, while the rats treated with olibanum oil revealed a significant reduced level of LDH, CRP, IL-6 and TNF- α compared with the controls (p &lt; 0.05). These outcomes indicate that olibanum oil treatment are manifested by cytokine changes, it can improve the anti-inflammatory response and down-regulate the pro-inflammatory cytokines. So, the promising impact of olibanum oils as an immunomodulator could be used in alternative therapies.

RIP1 inhibition protects retinal ganglion cells in glaucoma models of ocular injury

AbstractReceptor-interacting protein 1 (RIP1, RIPK1) is a critical mediator of multiple signaling pathways that promote inflammatory responses and cell death. The kinase activity of RIP1 contributes to the pathogenesis of a number of inflammatory and neurodegenerative diseases. However, the role of RIP1 in retinopathies remains unclear. This study demonstrates that RIP1 inhibition protects retinal ganglion cells (RGCs) in preclinical glaucoma models. Genetic inactivation of RIP1 improves RGC survival and preserves retinal function in the preclinical glaucoma models of optic nerve crush (ONC) and ischemia–reperfusion injury (IRI). In addition, the involvement of necroptosis in ONC and IRI glaucoma models was examined by utilizing RIP1 kinase-dead (RIP1-KD), RIP3 knockout (RIP3-KO), and MLKL knockout (MLKL-KO) mice. The number of RGCs, retinal thickness, and visual acuity were rescued in RIP1-kinase-dead (RIP1-KD) mice in both models, while wild-type (WT) mice experienced significant retinal thinning, RGC loss, and vision impairment. RIP3-KO and MLKL-KO mice showed moderate protective effects in the IRI model and limited in the ONC model. Furthermore, we confirmed that a glaucoma causative mutation in optineurin, OPTN-E50K, sensitizes cells to RIP1-mediated inflammatory cell death. RIP1 inhibition reduces RGC death and axonal degeneration following IRI in mice expressing OPTN-WT and OPTN-E50K variant mice. We demonstrate that RIP1 inactivation suppressed microglial infiltration in the RGC layer following glaucomatous damage. Finally, this study highlights that human glaucomatous retinas exhibit elevated levels of TNF and RIP3 mRNA and microglia infiltration, thus demonstrating the role of neuroinflammation in glaucoma pathogenesis. Altogether, these data indicate that RIP1 plays an important role in modulating neuroinflammation and that inhibiting RIP1 activity may provide a neuroprotective therapy for glaucoma.

Prophylactic clemastine treatment improves influenza A virus-induced cognitive dysfunction in mice

Respiratory infection by influenza A virus (IAV) is known to cause systemic inflammation, neuroinflammation, and cognitive impairment. We previously found that experimental infection with IAV affected oligodendrocyte homeostasis, which was associated with altered expression of genes involved in myelin maintenance as well as the lipidome. In this study, we sought to determine if clemastine, an antihistamine with myelin promoting properties, could reverse the effects of IAV on oligodendrocyte (OL) specific genes, as well as mitigate infection-induced cognitive impairment. Male and female C57BL/6J mice were randomized into experimental groups based on clemastine treatment, infection, and sex. Treatment with vehicle or clemastine (10 mg/kg/d) commenced seven days prior to inoculation with either saline or IAV and continued throughout the experiment. Body weight was measured throughout the infection. Spatial learning and memory were assessed by Morris water maze. Sickness behavior was assessed by measuring burrowing response. Immune cell responses were determined by flow cytometry, RT-qPCR, antigen recall assays and ELISA, and viral load assessed by RT-qPCR. Hippocampal levels of neuroinflammatory (Tnf, Cdkn1a) and myelin (Plp1, Mag, Ugt8a) genes were determined by RT-qPCR. Mice infected with IAV developed weight loss, impaired cognitive flexibility, reduced burrowing behavior, altered lung immune cell infiltration, increased circulating anti-viral IgM and IgG levels and increased T cell responses to IAV epitopes. Infection increased hippocampal levels of genes associated with neuroinflammation and decreased levels of genes involved in myelination. Clemastine treatment resulted in earlier recovery of weight loss in males and increased IgM levels for both sexes, but neither affected expression levels of Tnf or Cdkn1a, nor rescued changes to oligodendrocyte genes. However, treatment mitigated infection-induced neurocognitive impairment.

Genetic signatures of AKT1 variants associated with worse COVID-19 outcomes - a multicentric observational study.

The COVID-19, triggered by the SARS-CoV-2 virus, has varied clinical manifestations, ranging from mild cases to severe forms such as fatal pneumonia and acute respiratory distress syndrome (ARDS). Disease severity is influenced by an exacerbated immune response, characterized by high pro-inflammatory cytokine levels. Inhibition of AKT can potentially suppress pathological inflammation, cytokine storm and platelet activation associated with COVID-19. In this study, we aimed to investigate the rs2494746 and rs1130214 variants in the AKT1 gene associated with severe COVID-19 outcomes. Peripheral blood samples and sociodemographic data from 508 individuals with COVID-19, measuring plasma cytokine concentrations using ELISA and genotyped the AKT1 variants. The rs2494746-C allele was associated with severity, ICU admission, and death from COVID-19. The C allele at rs1130214 was linked to increased TNF and D-dimer levels. Moreover, both variants exhibited an increased cumulative risk of disease severity, ICU admission, and mortality caused by COVID-19. In the predictive analysis, the rs2494746 obtained an accuracy of 71%, suggesting a high probability of the test determining the severity of the disease. Our findings contribute to understanding the influence of the AKT1 gene variants on the immunological damage in individuals infected with SARS-CoV-2.

Polystyrene nanoplastics induce apoptosis, histopathological damage, and glutathione metabolism disorder in the intestine of juvenile East Asian river prawns (Macrobrachium nipponense)

Nanoplastics (NPs) are widely distributed in the aquatic environment and have become a global concern as a new type of pollutant. Many researchers have studied the physiological effects of NPs on aquatic organisms, but relatively little is known about their effects on intestinal immune function in crustaceans. Therefore, we used NPs concentrations of 0, 5, 10, 20, 40 mg/L for 28 days of stress, evaluated the effects of NPs exposure on intestinal cell apoptosis, histopathological damage, and glutathione (GSH) metabolism of juvenile East Asian river prawns (Macrobrachium nipponense). As NPs concentration increased, the contents of total GSH and oxidized glutathione decreased gradually (P < 0.05), the concentration of GSH first increased and then decreased (P < 0.05), and the activities of lysozyme, acid phosphatase, phenoloxidase, and alkaline phosphatase first increased and then decreased (P < 0.05). Additionally, intestinal tissue structure was damaged, and the apoptosis rate significantly increased (P < 0.05). The expression of intestinal autophagy genes (CTL, ALF, Crustin, ATG8, and BCL-2) increased at first and then decreased, the expression levels of TNF and Wnt4 significantly decreased, and the expression of Beclin significantly increased with increasing NPs concentration. We also found that AP-1 and PTEN were highly expressed in the hepatopancreas and were involved in intestinal immune responses. Our results showed that exposure to NPs may induce apoptosis of intestinal tissue cells, induce autophagy, and inhibit GSH metabolism, thereby reducing intestinal immune function of M. nipponense. These findings provide a reference for healthy aquaculture and ecological risk assessment of prawns.

Evaluation of Drug Effects on IL-17 and TNF levels in Patients with Rheumatoid Arthritis

Evaluation of Drug Effects on IL-17 and TNF levels in Patients with Rheumatoid Arthritis

Integrated analysis of multi-omics data for the discovery of biomarkers and therapeutic targets for juvenile idiopathic arthritis

BackgroundJuvenile idiopathic arthritis (JIA) is a prevalent chronic rheumatic disease affecting children. Current medications merely alleviate symptoms rather than curing the disease. Hence, the identification and development of novel drug targets and biomarkers for JIA are imperative for enhancing treatment efficacy. MethodsWe employed two-sample Mendelian randomization (MR) analysis to investigate the causal effects of plasma proteins on JIA. Additionally, colocalization, bulk RNA-seq, and single-cell RNA-seq analyses were conducted to further investigate and validate the potential of candidate proteins as drug targets. ResultsThrough MR analysis, we successfully identified five plasma proteins that are causally linked to JIA. Genetically inferred lower levels of AIF1, TNF, and TNFSF11 were associated with an elevated risk of JIA, while higher levels of AGER and GP1BA proteins were positively correlated with JIA risk. Colocalization analysis further supported our findings on GP1BA (OR = 9.26, 95% CI: 2.30-37.20) and TNFSF11 (OR = 0.18, 95% CI: 0.07-0.45). Based on this evidence, we classified these five proteins into two tiers. Finally, we conducted a systematic evaluation of the druggability and current drug development progress for these identified candidate proteins. ConclusionsThis study employed MR analysis to reveal causal relationships between plasma proteins and JIA, identifying five potential candidate proteins as promising drug targets for JIA, particularly focusing on GP1BA and TNFSF11.

Role the (IL1, IL6, and TNF) with Chronic Autoimmune Diseases in Mosul City / Iraq

Objective: Our study examined the relationship of the levels of cytokines IL1, 6, and TNF in three different immune diseases with age and Sex. Material and methods: The samples of the study were obtained from in Mosul city hospitals for the period from October 2023 to February 29, 2024. The study included 90 different medical cases suffering from immune diseases, 50 of whom were suffering from rheumatoid arthritis, 16 were suffering from erythematosus, and 24 were suffering from Celiac disease. The ages of the study participants were between 10 years and 65 years. Outcomes: Serum samples were examined for IL1, 6, and TNF using the ELISA technique. The results of ELISA revealed that Concentrations of Interleukins and TNF were low in all patients because the patients in the chronic phase of Autoimmune Diseases take treatment to reduce the cytokines which is hyperactive Therefore, cytokines concentrations appeared lower than standard concentrations. However, the results show a significant association between measuring IL-1 for a CD and measuring IL-6, TNF for an SLE among Autoimmune disease patients and their sex, and age. Conclusion: significance and impact of study: IL1, 6, and TNF are one of the most common cytokines on the globe. It has been connected directly or indirectly with various disorders, including autoimmune diseases. However, the link between IL1, 6 - TNF and Autoimmune Diseases is still controversial. Our results indicate that they play a possible role in the development of autoimmune diseases; however, more studies on a larger scale are required to confirm the results.

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

The Potential Renoprotective Effect of Fedratinib in Renal Ischemia Reperfusion Injury in Male Rat Model

Renal Ischemia Reperfusion Injury (RIRI) is a serious condition that arises following kidney transplantation or other circumstances that result in decreased blood supply to the kidneys, these conditions cause a harm to the renal tissue. Gaining insight into the fundamental mechanisms of RIRI, including inflammation, cell death pathways, is essential for the development of successful therapeutic approaches. Objective: This study aimed to assess the effects of Fedratinib, a JAK2 inhibitor, in reducing RIRI in a rat model. The study involved rats divided into four groups: Sham group, control group, vehicle group, and Fedratinib group. Rats underwent anaesthesia and midline incision to expose renal pedicles, with blood flow halted using microvascular clamps. The wound was stitched, and the animals were left for 90 minutes to allow reperfusion. Blood samples were collected from the heart apex to assess serum urea and creatinine, and renal slices were used for PCR to detect the jak2/stat3 pathway. The Elisa was used to evaluate TNF, IL-6, NF-κB, Bax, Bcl2, and HMGB levels. Results: IL-6 and TNF-α, and HMGB1 were identified to have a role in the development of RIRI, inhibition of JAK2/STAT3 pathway by Fedratinib significantly decrease their concentration and minimizing RIRI. Suppression of JAK2/STAT3 pathway led to a significant inhibition in NF-κB and apoptosis. Conclusion: Fedratinib has a potential preventive effect against RIRI through their activity as JAK2 inhibitor and inhibition of the following downstream inflammatory pathways.

Relationship between fat embolism and endothelial glycocalyx

Fat embolism (FE) is acknowledged as one of the significant causes of sudden death following traumatic injury. To clarify the relevance of vascular endothelial glycocalyx (EGC) damage and FE, temporal changes in the mRNA levels of inflammatory cytokines associated with EGC components were investigated in an experimental fat embolization rat model. Nine-week-old rats were used as FE models through triolein injection (TO) and femoral fracture (FX), and physiological saline was administered to the control group. RT-qPCR and fat staining were performed. The target genes were Il6, Il10, Tnf, Elane, Sdc1, Sdcbp, Vcan, Hyal1, Fn1, and CD14. Notably, FE was detected in 100% and 5.6% of the TO and FX groups, respectively, using fat staining. Bimodal peaks in the mRNA expression levels of Sdc1, Tnf, Elane, IL6, and IL10 were observed 4 and 20 h after treatment in both groups. In the TO group, mRNA expression peaked at 4 h and then declined to the lowest level at 16 h. The incidence of fat emboli due to trauma was consistent with that reported in previous studies. Bimodal mRNA peaks may correspond to FE progression, in which physical obstructions are followed by biochemical reactions. The fluctuation in Sdc1 expression suggests that the initial peak resulted from physical EGC damage. The subsequent peak could be because of EGC damage caused by the secretion of inflammatory cytokines induced by oleic acid from lipid droplet decomposition. These results suggest that EGC disorders caused by lipid droplets may induce lung damage during FE.

Correlation analysis of serum Rac1 level with asthma control, airway inflammatory response and lung function in asthmatic children

ObjectiveTo investigate the correlation between serum Rac1 enzyme (Rac1) level with asthma control, airway inflammatory response and lung function in asthmatic children.MethodsA retrospective analysis was performed on 79 children with asthma who were diagnosed and treated in our hospital from June 2020 to January 2023. According to the severity of the disease, the children were divided into mild group (25 cases), moderate group (30 cases) and severe group (24 cases). 36 healthy children who underwent physical examination at the same period in our hospital were selected as the control group. The state of an illness, control level, serum mRNA Rac1, inflammatory factors, and lung function of the children in two groups were compared between the control group and the observation group.ResultsThe Rac1 mRNA levels, forced vital capacity (FVC), forced expiratory volume in one second/FVC (FEV1/FVC), peak expiratory flow (PEF), and maximum mid-expiratory flow (MMEF) in the observation group were significantly lower than these in the control group (P < 0.05). The tumor necrosis factor-alpha (TNF-α), interleukin-5 (IL-5), IL-6, and IL-33 in the observation group were markedly higher than these in the control group (P < 0.05). As the state of an illness worsened, the Rac1 mRNA levels, FVC, FEV1/FVC, PEF, and MMEF gradually reduced (P < 0.05), while the levels of TNF-α, IL-5, IL-6, and IL-33 increased (P < 0.05). As the degree of disease control improved, the Rac1 mRNA levels, FVC, FEV1/FVC, PEF, and MMEF gradually elevated (P < 0.05), and the levels of TNF- α, IL-5, IL-6, and IL-33 showed the opposite trend (P < 0.05). Rac1 was negatively related to the levels of TNF-α, IL-5, IL-6 and IL-33 (P < 0.05), and positively to the levels of FVC, FEV1/FVC, PEF and MMEF (P < 0.001). Rac1 mRNA levels, FVC, FEV1/FVC, PEF and MMEF were protective factors, while TNF-α, IL-5, IL-6 and IL-33 were risk factors for the prognosis of children with asthma (P < 0.05).ConclusionChildren with asthma have obviously lower serum Rac1 mRNA levels, higher inflammatory factor levels and lower lung function. Serum Rac1 mRNA level may be associated with better asthma control, lower airway inflammatory response, better lung function and lower disease severity. It has important reference value for the evaluation of the state of an illness, efficacy and prognosis of children with bronchial asthma.

Absence of TNFR1 promotes a protective response in the early phase of hepatic encephalopathy induced by thioacetamide in mice

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome with a wide spectrum of cognitive deficits, motor impairment, and psychiatric disturbances resulting from liver damage. The cytokine TNF has been considered the main cytokine in the development and progression of HE, with a pivotal role in the initiation and amplification of the inflammatory cascade. The aim of the present study was to evaluate the involvement of TNF type 1 receptor (TNFR1) in locomotor deficits and in the levels of TNF, IFN-γ, IL-6, IL-10, IL-12p70, CCL2, CX3CL1 and BDNF from the frontal cortex and hippocampus of TNFR1 knockout mice (TNFR1-/-) mice with HE induced by thioacetamide. Wild-type (WT) animals with HE developed locomotor deficit. The absence of TNFR1 absence of TNFR1 in HE animals attenuated the locomotor activity impairment in parallel with a balanced neuroinflammatory environment 24 h after the administration of thioacetamide. Taken together, the data suggests that the absence of TNFR1 promoted a protective response in the early phase of hepatic encephalopathy induced by thioacetamide in mice.

Ameliorative Effect of Lycopene on Follicular Reserve Depletion, Oxidative Damage, Apoptosis Rate, and Hormonal Profile during Repeated Superovulations in Mice.

Superovulation is a crucial step in assisted reproductive technology that involves the administration of gonadotrophins. Repeated superovulations result in severe ovarian damage. The present study investigated the effect of in vivo administration of lycopene on ovarian damage induced by four successive cycles of superovulation. Superovulated mice were simultaneously administered intraperitoneally with saline (R4) or 5 mg/kg lycopene (R4-Lyc). The evaluated parameters were the count of different types of follicles, expression of ovarian antioxidant- and apoptosis-related genes, and serum concentrations of estradiol, progesterone, and inhibin-B. Increased numbers of healthy follicles and a decreased count of atretic follicles were observed in mice of the R4-Lyc group compared to those of the R4 group. Moreover, significantly higher mRNA levels of Sod3, Cat, and Nrf2 and lower mRNA levels of Keap1, Tnf, Nfkb, and Casp3, together with decreased H2O2 concentrations and increased total antioxidant capacity, were detected in the ovaries of lycopene-treated mice. Regarding serum reproductive hormones, elevated concentrations of estradiol, progesterone, and inhibin-B were evident in lycopene-administered mice. The present study reports a significant role of lycopene in alleviating the ovarian damage induced by multiple hormonal superstimulations, which could help to improve the outcomes of in vitro embryo production.

Asymptomatic carriage of Plasmodium falciparum in children living in a hyperendemic area occurs independently of IgG responses but is associated with a balanced inflammatory cytokine ratio

BackgroundAsymptomatic carriage of infected red blood cells (iRBCs) can be prevalent in communities regardless of transmission patterns and can occur with infection of different Plasmodium species. Clinical immunity dampens the inflammatory responses leading to disease symptoms in malaria. The aim of this study was to define the immunological correlates of asymptomatic carriage of Plasmodium falciparum in a highly exposed population.Methods142 asymptomatic Plasmodium-infected individuals greater than 2 years of age without fever (body temperature <37.5 ℃) were followed weekly for 10 weeks before being treated with artemisinin-based combination therapy (ACT). Plasma levels of 38 cytokines were measured at baseline by Luminex and the quantity and growth inhibitory activities of circulating parasite-reactive antibodies measured. The Plasmodium antigen tested included P. falciparum merozoite extract (ME) and schizont extract (SE), and the recombinant proteins erythrocyte binding antigen 175 (EBA-175) and merozoite surface protein 1 (MSP-119).ResultsMedian levels of IgG against P. falciparum EBA-175 and MSP-119 at baseline were significantly higher in those older than 20 years of age compared with the younger age group and appeared to correlate with better parasite control. Amongst all participants there were no discernible changes in IgG levels over time. Parasite density was higher in the younger age group and associated with IL-10, TNF and MCP-1 levels. A balanced IL-10:TNF ratio was associated with asymptomatic malaria regardless of age, and balanced ratios of IL-10/TNF and IL-10/IFN-γ were the only significant correlate of maintenance of asymptomatic malaria over the course of the study in individuals 20 years of age and younger.ConclusionThe above findings indicate that asymptomatic carriage of P. falciparum in children living in a hyperendemic area occurs independently of IgG but is associated with a balanced inflammatory cytokine ratio.

The roles of genetic mutation and cytokines/chemokines in immune response and their association with uveal melanoma patient outcome

The impact of tumor mutations and the interplay of cytokines and chemokines on the immune response and clinical outcomes in uveal melanoma (UM) warrants further exploration. In our study, we delved into the correlation between genetic alterations and survival rates in a cohort of 188 UM patients, utilizing data from cBioPortal. We assessed the composition of immune cell populations within 80 UM tumors by examining RNA sequence-based gene expression data from The Cancer Genome Atlas (TCGA). Furthermore, we scrutinized the relationship between genetic mutations and the expression of cytokines and chemokines, as well as their influence on various immune cell subsets. Our investigation revealed a significant association between the presence of mutated GNAQ or SF3B1 genes and improved progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS) when compared to patients with non-mutated counterparts. In contrast, the presence of immune response gene mutations was associated with a detrimental effect on PFS, DSS, and OS. We also observed that the expression levels of cytokines and chemokines were positively linked to the infiltration of immune killer cells and inversely related to the populations of B cells and dendritic cells. Elevated expression levels of PDCD1, TNF, IL6, CXCL9, and CXCL10 were found to be correlated with reduced OS. Intriguingly, an increase in CD8+ T cell populations was associated with a poorer OS, a finding that warrants further investigation. These findings underscore the potential utility of cytokines/chemokines expression levels, immune cell subsets, and mutation status as critical biomarkers for the selection of patients who are most likely to benefit from immunotherapeutic interventions. Our research provides valuable insights that could guide the development of more targeted and effective treatment strategies for UM patients.

Mycobacterium tuberculosis cough aerosol culture status associates with host characteristics and inflammatory profiles

Interrupting transmission events is critical to tuberculosis control. Cough-generated aerosol cultures predict tuberculosis transmission better than microbiological or clinical markers. We hypothesize that highly infectious individuals with pulmonary tuberculosis (positive for cough aerosol cultures) have elevated inflammatory markers and unique transcriptional profiles compared to less infectious individuals. We performed a prospective, longitudinal study using cough aerosol sampling system. We enrolled 142 participants with treatment-naïve pulmonary tuberculosis in Kenya and assessed the association of clinical, microbiologic, and immunologic characteristics with Mycobacterium tuberculosis aerosolization and transmission in 129 household members. Contacts of the forty-three aerosol culture-positive participants (30%) are more likely to have a positive interferon-gamma release assay (85% vs 53%, P = 0.006) and higher median IFNγ level (P < 0.001, 4.28 IU/ml (1.77-5.91) vs. 0.71 (0.01-3.56)) compared to aerosol culture-negative individuals. We find that higher bacillary burden, younger age, larger mean upper arm circumference, and host inflammatory profiles, including elevated serum C-reactive protein and lower plasma TNF levels, associate with positive cough aerosol cultures. Notably, we find pre-treatment whole blood transcriptional profiles associate with aerosol culture status, independent of bacillary load. These findings suggest that tuberculosis infectiousness is associated with epidemiologic characteristics and inflammatory signatures and that these features may identify highly infectious persons.