IL-6/STAT3 signaling pathway induces prostate apoptosis response protein-4(PAR-4) to stimulate malignant behaviors of hepatocellular carcinoma cells.

INTRODUCTION AND OBJECTIVES: Prostate apoptosis response protein-4 (PAR-4) is considered a tumor suppressor. However, the role of PAR-4 in hepatocellular carcinoma (HCC) has rarely been reported. The study explores the role of PAR-4 in the malignant behaviors of HCC cells. MATERIALS AND METHODS: TCGA database was applied to analyze the expression of PAR-4 in HCC. Evaluated PAR-4 relationship with clinical parameters and prognosis by tissue microarray; expression of STAT3, p-STAT3, Src and Ras was detected by Western blotting or laser confocal microscopy. Cell scratch and flow cytometry assays were used to observe IL-6 regulation of the malignant behaviors of HCC cells. The tumorigenic potential of HCC cells in vivo was evaluated in a nude mouse tumor model. RESULTS: Analysis indicated that the expression of PAR-4 in HCC tissues was significantly higher than that in normal liver tissues; and PAR-4 interacted with STAT3. KEGG analysis showed that PAR-4 plays a role in the Janus kinase (JAK)/STAT signaling pathway. The positive expression rate of PAR-4 in HCC tissues was significantly higher than that in adjacent tissues. Positive correlation between IL-6 and PAR-4 expression in the HCC tissues. Exogenous IL-6 significantly promoted the proliferation and migration of HCC cells and up-regulated the expression of PAR-4 and p-STAT3 in HCC cells. Interference of the expression of PAR-4 could reduce the malignant behaviors of HCC cells and inhibit tumorigenesis in a nude mouse tumor model. CONCLUSIONS: PAR-4 expression is positively correlated with HCC; PAR-4 promotes malignant behavior of HCC cells mediated by the IL-6/STAT3 signaling pathway.

Role of Proinflammatory Cytokines and Genetic Factors Related to Metabolic Alterations in People Living with HIV/AIDS.

Metabolic alterations are a common problem in people living with HIV (PLHIV), as a result of a stage of chronic inflammation that affects the homeostasis of the organism. Prolonged exposure to antiretroviral therapy has been associated with developing lipodystrophies that modify lipoprotein metabolism and inflammatory markers such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), which are mediators of the immune response. The study aimed to associate TNF-α and IL-6 levels with their polymorphisms and metabolic alterations in PLIHV. We hypothesized that TNF-α and IL-6 levels and their polymorphisms are associated with metabolic alterations. In total, 185 PLHIV and 51 HIV-negative people were included. Biochemical parameters were determined by colorimetric assay, cytokine levels by immunoassay, and allelic discrimination by quantitative polymerase chain reaction. A correlation was found between TNF-α levels and the variables cholesterol (r = -0.171, P = 0.020) and high-density lipoprotein (HDL) (r = -0.245, P = 0.001). There are associations between HDL levels (P = 0.011) and GG genotype of rs1800629. The results suggest a metabolic alteration related to the constant immune response, especially the production of proinflammatory cytokines such as TNF-α and IL-6. It was observed that genetic factors may influence metabolism alteration, mainly in lipids.

Analysis of Ferritin, Hepcidin, Zinc, C-Reactive Protein and IL-6 Levels in COVID-19 in Patients Living at Different Altitudes in Peru.

BACKGROUND: Despite great scientific efforts, understanding the role of COVID-19 clinical biomarkers remains a challenge. METHODS: A cross-sectional descriptive study in two Peruvian cities at different altitudes for comparison: Lima and Huaraz. In each place, three groups were formed, made up of 25 patients with COVID-19 in the ICU, 25 hospitalized patients with COVID-19 who did not require the ICU, and 25 healthy subjects as a control group. Five biomarkers were measured: IL-6, hepcidin, ferritin, C-reactive protein, and zinc using ELISA assays. RESULTS: Ferritin, C-reactive protein, and IL-6 levels were significantly higher in the ICU and non-ICU groups at both study sites. In the case of hepcidin, the levels were significantly higher in the ICU group at both study sites compared to the non-ICU group. Among the groups within each study site, the highest altitude area presented statistically significant differences between its groups in all the markers evaluated. In the lower altitude area, differences were only observed between the groups for the zinc biomarker. CONCLUSION: COVID-19 patients residing at high altitudes tend to have higher levels of zinc and IL-6 in all groups studied compared to their lower altitude counterparts.

The impact of interleukin-6 (IL-6) and mesenchymal stem cell-derived IL-6 on neurological conditions.

Interleukin-6 (IL-6) is a versatile cytokine crucial for immune response modulation, inflammation regulation, and various physiological processes in the body. Its wide-ranging functions underscore its importance in maintaining health. Dysregulated IL-6 is closely associated with many diseases, making it a key research and therapeutic target. Elevated IL-6 levels in the central nervous system worsen neuroinflammation in neurodegenerative diseases by activating microglia and astrocytes and releasing pro-inflammatory cytokines and neurotoxic molecules. Moreover, dysregulated IL-6 weakens the blood-brain barrier, exacerbating neuroinflammation and neuronal damage by allowing peripheral immune cells and inflammatory mediators to enter the brain. Mesenchymal stem cells (MSCs) show promise in modulating neuroinflammation by regulating IL-6 levels. They effectively suppress pro-inflammatory cytokines, including IL-6, while promoting anti-inflammatory factors. This therapeutic approach highlights the importance of targeting IL-6 and other inflammatory mediators to alleviate neuroinflammation and its adverse effects on neurological disorders. This review provides a comprehensive overview of IL-6's involvement in neurological disorders, examining endogenous IL-6 and IL-6 derived from MSCs. We explore IL-6's mechanisms affecting neuronal function, survival, and immune modulation in the central nervous system. Additionally, we discuss the potential of MSC-derived IL-6 in neuroregeneration and neuroprotection. By elucidating IL-6's interplay with neurological pathologies, this review offers insights into novel therapeutic strategies targeting IL-6 signaling pathways for neurological disorders.

Idiopathic Multicentric Castleman Disease With Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis/Renal Insufficiency, and Organomegaly (TAFRO) Syndrome in a Liver Transplant Recipient.

Idiopathic multicentric Castleman disease is a rare lymphoproliferative disorder that can be potentially fatal without timely diagnosis and treatment. We describe the first-ever reported occurrence of idiopathic multicentric Castleman disease with thrombocytopenia, anasarca, fever, reticulin fibrosis/renal insufficiency, and organomegaly syndrome in a liver transplant recipient. The diagnosis was challenging as the clinical presentation closely mimicked decompensated cirrhosis, and the profound thrombocytopenia limited tissue diagnosis. However, we were able to establish the diagnosis and treat it effectively. This case report signifies that a high index of suspicion and aggressive treatment can be lifesaving in liver transplant recipients presenting with this rare disorder.

Effects of association between resveratrol and ketamine on behavioral and biochemical analysis in mice.

Resveratrol (3,5,4'-trihydroxy-trans-stilbene), a phenol commonly found in grapes and wine, has been associated as protective in experimental models involving alterations in different neurotransmitter systems. However, studies are reporting that resveratrol could have adverse effects. This study evaluated if the association of a low dose of ketamine and resveratrol could induce behavioral manifestations associated with biochemical alterations. Moreover, the effects of treatment with resveratrol and/or ketamine on monoamine oxidase (MAO) activity, oxidative stress markers, and IL-6 levels in the brain were also investigated. Male Swiss mice received a low dose of ketamine (20 mg/kg) for 14 consecutive days, and resveratrol (10, 30, or 100 mg/kg) from day 8 up to day 14 of the experimental period, intraperitoneally. Locomotor, stereotyped behavior, Y-maze, novel recognition object test (NORT), and social interaction were quantified as well as ex vivo analysis of MAO activity, IL-6 levels, and oxidative stress markers (TBARS and total thiol levels) in brain tissues. Ketamine per se reduced the number of bouts of stereotyped behavior on day 8 of the experimental period. Resveratrol per se reduced the locomotor and exploratory activity in the open field, the time of exploration of new objects in the NORT, MAO-A activity in the striatum and increased the IL-6 levels in the cortex. These effects were attenuated when the mice were co-treated with ketamine and resveratrol. There was a decrease in MAO-A activity in the cortex of mice treated with ketamine + resveratrol 100 mg/kg. No significant alterations were found in oxidative stress markers. Resveratrol does not appear to cause summative effects with ketamine on behavioral alterations. However, the effect of resveratrol per se, mainly on locomotor and exploratory activity, should be better investigated.

Bone Remodeling and Bone Structural Genes in Legg-Calvé-Perthes Disease: The OPG rs2073618 and IL-6 rs1800795 Are Associated with High Risk in Mexican Patients.

Legg-Calve-Perthes disease (LCPD) is an idiopathic avascular necrosis of the pediatric femoral head. Bone remodeling and bone structural genes have the potential to contribute to the progression of LCPD when there is disequilibrium between bone resorption and bone formation. A case-control study was performed to search for associations of several common polymorphisms in the genes Receptor Activator for Nuclear Factor κappa B (RANK), Receptor Activator for Nuclear Factor κappa B Ligand (RANKL), osteoprotegerin (OPG), interleukin (IL)-6, and type 1 collagen (COL1A1) with LCPD susceptibility in Mexican children. A total of 23 children with LCPD and 46 healthy controls were genotyped for seven polymorphisms (rs3018362, rs12585014, rs2073618, rs1800795, rs1800796, rs1800012, and rs2586498) in the RANK, RANKL, OPG, IL-6, and COL1A1 genes by real-time polymerase chain reaction with TaqMan probes. The variant allele (C) of IL-6 rs1800795 was associated with increased risk of LCPD (odds ratio [OR]: 3.8, 95% confidence interval [CI]: [1.08-13.54], p = 0.033), adjusting data by body mass index (BMI) and coagulation factor V (FV), the association with increased risk remained (OR: 4.9, 95% CI: [1.14-21.04], p = 0.025). The OPG polymorphism rs2073618, specifically GC-GG carriers, was associated with a more than fourfold increased risk of developing LCPD (OR: 4.34, 95% CI: [1.04-18.12], p = 0.033) when data were adjusted by BMI-FV. There was no significant association between RANK rs3018362, RANKL rs12585014, IL-6 rs1800796, COL1A1 rs1800012, and rs2586498 polymorphisms and LCPD in a sample of Mexican children. The rs1800975 and rs2037618 polymorphisms in the IL-6 and OPG genes, respectively, are informative markers of increased risk of LCPD in Mexican children.

Cuban Policosanol (Raydel®) Exerts Higher Antioxidant and Anti-Glycation Activities than Chinese Policosanol (BOC Sciences) in Reconstituted High-Density Lipoproteins: In Vivo Anti-Inflammatory Activities in Zebrafish and Its Embryos.

The present study compares sugarcane-wax purified policosanols sourced from Cuba (Raydel®) and China (BOC Sciences) and utilized following the synthesis of reconstituted high-density lipoproteins (rHDL). The two policosanols exhibited distinctly different ingredient ratios of long-chain aliphatic alcohols, particularly 1-octacosanol (C28) and 1-tetratriacotanol (C34). After synthesizing rHDL with apolipoprotein A-I (apoA-I), the two policosanols bound well with phospholipid and apoA-I to form the discoidal rHDL. Notably, rHDL-1, containing Cuban policosanol, displayed the largest particle diameter at approximately 78 ± 3 nm. In contrast, both control rHDL (rHDL-0) and rHDL containing Chinese policosanol (rHDL-2) exhibited smaller particles, with diameters of approximately 58 ± 3 nm and 61 ± 2 nm, respectively. Furthermore, rHDL-1 demonstrated enhanced anti-glycation activity, safeguarding apoA-I from degradation within HDL, and displayed the antioxidant ability to inhibit LDL oxidation. A microinjection of each rHDL into zebrafish embryos in the presence of carboxymethyllysine (CML) revealed rHDL-1 to have the strongest antioxidant activity with the highest embryo survivability and normal developmental morphology. Dermal application to recover the wound revealed rHDL-1 to have the highest wound-healing activity (75%) and survivability (92%) in the cutaneous wound area in the presence of CML. In adult zebrafish, injecting CML (250 µg) caused acute death and hyperinflammation, marked by heightened neutrophil infiltration and interleukin (IL)-6 production in liver. However, co-administering rHDL-1 notably increased survival (85%) and exhibited strong anti-inflammatory properties, reducing IL-6 production while improving the blood lipid profile. However, a co-injection of rHDL-2 resulted in the lowest survivability (47%) with more hepatic inflammation. In conclusion, Cuban policosanol (Raydel®) has more desirable properties for the in vitro synthesis of rHDL with stronger anti-glycation and antioxidant activities than those of Chinese policosanol (BOC Sciences). Moreover, Raydel-policosanol-integrated rHDL demonstrates a noteworthy effect on accelerated wound healing and robust anti-inflammatory properties, leading to increased survivability in zebrafish embryos and adults by effectively suppressing CML-induced hyperinflammation.

Modulation of TNF-α, interleukin-6, and interleukin-10 by nebivolol-valsartan and nebivolol-lisinopril polytherapy in SHR rats.

Antihypertensive drug therapies have demonstrated their capacity to modulate the inflammatory processes associated with hypertension, leading to improvements in disease progression. Given the prevalent use of polytherapy in treating most hypertensive patients, comprehending the time-dependent effects of combination treatments on inflammation becomes imperative. In this study, spontaneously hypertensive rats (SHR) were divided into seven groups (n = 6): (i) SHR + vehicle, (ii) SHR + nebivolol, (iii) SHR + valsartan, (iv) SHR + lisinopril, (v) SHR + nebivolol-valsartan, (vi) SHR + nebivolol-lisinopril, and (vii) WKY + vehicle. Blood pressure was measured using the tail-cuff method. Temporal alterations in inflammatory cytokines TNF-α, IL-6, and IL-10 were assessed in serum through ELISA and mRNA expression in aortic tissue via qPCR after 1, 2, and 4 weeks of treatment with nebivolol, lisinopril, valsartan, and their respective combinations. Histological alterations in the aorta were assessed. The findings indicated that combined treatments reduced systolic and diastolic blood pressure in SHR. The nebivolol and lisinopril combination demonstrated a significant decrease in IL-6 serum and mRNA expression at both 1 week and 4 weeks into the treatment. Additionally, TNF-α mRNA expression also showed a reduction with this combination at the same time points. Particularly, nebivolol-valsartan significantly decreased TNF-α serum and mRNA expression after one and four weeks of treatment. Furthermore, an elevation in serum IL-10 levels was observed with both combination treatments starting from the second week onwards. This study provides compelling evidence that concurrent administration of nebivolol with lisinopril or valsartan exerts time-dependent effects, reducing proinflammatory cytokines TNF-α and IL-6 while modifying IL-10 levels in an experimental hypertensive model.

Redistribution of ASIC1a channels triggered by IL-6: Potential role of ASIC1a in neuroinflammation.

Cytokines, particularly IL-6, play a crucial role in modulating immune responses in the central nervous system (CNS). Elevated IL-6 levels have been observed in neuroinflammatory conditions, as well as in the sera and brains of patients with neurodegenerative diseases such as Parkinson's, Huntington's, Multiple Sclerosis, and Alzheimer's. Additionally, alterations in regional brain pH have been noted in these conditions. Acid-sensing ion channels (ASICs), including ASIC1a, activated by low pH levels, are highly abundant in the CNS and have recently been associated with various neurological disorders. Our study examined the impact of IL-6 on ASIC1a channels in cell cultures, demonstrating IL-6-induced the redistribution of cytosolic ASIC1a channels to the cell membrane. This redistribution was accompanied by increased ASIC1a current amplitude upon activation, as well as elevated levels of phosphorylated CaMKII and ERK kinases. Additionally, we observed posttranslational modifications on the ASIC1a channel itself. These findings provide insight into a potential link between inflammatory processes and neurodegenerative mechanisms, highlighting ASIC1a channels as promising therapeutic targets in these conditions.

Clinical significance of serum microRNA-146a and inflammatory factors in children with Mycoplasma pneumoniae pneumonia after azithromycin treatment.

OBJECTIVE: This study aimed to investigate the clinical significance of serum microRNA-146a and pro-inflammatory factors in children with Mycoplasma pneumoniae pneumonia after azithromycin treatment. microRNA-146a is known to regulate inflammatory responses, and excessive inflammation is a primary characteristic of MPP. METHODS: Children with MPP received conventional symptomatic therapy along with intravenous administration of azithromycin for one week. Serum levels of microRNA-146a and pro-inflammatory factors were measured using RT-qPCR and ELISA kits, respectively. The correlation between microRNA-146a and pro-inflammatory factors was analyzed by the Pearson method. Pulmonary function indexes were assessed using a pulmonary function analyzer, and their correlation with microRNA-146a and pro-inflammatory factors after treatment was evaluated. Children with MPP were divided into effective and ineffective treatment groups, and the clinical significance of microRNA-146a and pro-inflammatory factors was evaluated using receiver operating characteristic curves and logistic multivariate regression analysis. RESULTS: Serum microRNA-146a was downregulated in children with MPP but upregulated after azithromycin treatment, contrasting with the trend observed for pro-inflammatory factors. MicroRNA-146a showed a negative correlation with pro-inflammatory cytokines. Pulmonary function parameters were initially reduced in children with MPP, but increased after treatment, showing positive/inverse associations with microRNA-146a and pro-inflammatory factors. Higher microRNA-146a and lower pro-inflammatory factors predicted better efficacy of azithromycin treatment. MicroRNA-146a, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), and forced expiratory volume in the first second/forced vital capacity (FEV1/FVC) were identified as independent factors influencing treatment efficacy. CONCLUSION: Azithromycin treatment in children with MPP upregulates microRNA-146a, downregulates pro-inflammatory factors, and effectively improves pulmonary function.

IL-6, IL-10 and TNF-α gene polymorphisms in preeclampsia: a case-control study in a Mexican population.

OBJECTIVES: We focused our study on examining the genotype and allele frequency of IL-6 (rs1800795), TNF-α (rs1800629) and IL-10 (rs1800872) single nucleotide polymorphisms (SNP) on preeclampsia (PE) diagnosed Mexican pregnant women. MATERIAL AND METHODS: A case-control study was designed including 86 preeclampsia patients and 100 normotensives pregnancies from Women's Hospital of Culiacan, Mexico. Genotyping of IL-6, TNF-α and IL-10 was performed using TaqMan SNP Genotyping. RESULTS: Not significant association was found between development of PE and genotypic (p > 0.05) and allelic (p > 0.05) frequencies of IL-6, TNF-α and IL-10 SNPs. Genotype distributions of IL-6 (p = 0.599), TNF-α (p = 0.721) and IL-10 (p = 0.761) polymorphisms in the two groups were in agreement with Hardy-Weinberg equilibrium. CONCLUSIONS: According to the findings, the IL-6, TNF-α and IL-10 SNPs are not exponents of susceptibility to developing PE.

Clinical significance of serum microRNA-146a and inflammatory factors in children with Mycoplasma pneumoniae pneumonia after azithromycin treatment

Abstract Objective This study aimed to investigate the clinical significance of serum microRNA-146a and pro-inflammatory factors in children with Mycoplasma pneumoniae pneumonia after azithromycin treatment. microRNA-146a is known to regulate inflammatory responses, and excessive inflammation is a primary characteristic of MPP. Methods Children with MPP received conventional symptomatic therapy along with intravenous administration of azithromycin for one week. Serum levels of microRNA-146a and pro-inflammatory factors were measured using RT-qPCR and ELISA kits, respectively. The correlation between microRNA-146a and pro-inflammatory factors was analyzed by the Pearson method. Pulmonary function indexes were assessed using a pulmonary function analyzer, and their correlation with microRNA-146a and pro-inflammatory factors after treatment was evaluated. Children with MPP were divided into effective and ineffective treatment groups, and the clinical significance of microRNA-146a and pro-inflammatory factors was evaluated using receiver operating characteristic curves and logistic multivariate regression analysis. Results Serum microRNA-146a was downregulated in children with MPP but upregulated after azithromycin treatment, contrasting with the trend observed for pro-inflammatory factors. MicroRNA-146a showed a negative correlation with pro-inflammatory cytokines. Pulmonary function parameters were initially reduced in children with MPP, but increased after treatment, showing positive/inverse associations with microRNA-146a and pro-inflammatory factors. Higher microRNA-146a and lower pro-inflammatory factors predicted better efficacy of azithromycin treatment. MicroRNA-146a, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-8 (IL-8), and forced expiratory volume in the first second/forced vital capacity (FEV1/FVC) were identified as independent factors influencing treatment efficacy. Conclusion Azithromycin treatment in children with MPP upregulates microRNA-146a, downregulates pro-inflammatory factors, and effectively improves pulmonary function.

Evaluation of a prepared combined inactivated vaccine against hemorrhagic disease virus 2 and Clostridium perfringens type A infections in rabbit

Rabbit hemorrhagic disease virus 2 and Clostridium perfringens type A cause infections in rabbit. Vaccines are considered an effective strategy for fighting these infections. Nowadays, the demand for using a nanoparticle adjuvant as (Montanide IMS) is increased due to its ability for enhancing both humoral and cell mediated immunity and, in addition, it can be administrated through different routes. An inactivated vaccine against rabbit hemorrhagic disease virus 2 and Clostridium perfringens type A which adjuvanted by Montanide; IMS 1313 N VG PR (IMS 1313) was developed. The prepared vaccine was evaluated in rabbits for sterility, safety and potency via two different routes of vaccination. Oral administration of inactivated vaccine was evaluated as an alternative route to subcutaneous vaccination. The results revealed that rabbits vaccinated by subcutaneous route exhibited satisfactory antibody and antitoxin titer against rabbit hemorrhagic disease virus 2 and Clostridium perfringens type A, respectively, from 2nd week post vaccination and reached the peak at 3th week post vaccination. On the other hand, antibody and antitoxin titer of orally vaccinated rabbits didn't reach the satisfactory level. Rabbits vaccinated orally were not protected against virulent rabbit hemorrhagic disease virus 2, with 30percent protection, while rabbits vaccinated subcutaneously showed satisfactory protection (90percent). Serum nitric oxide and lysozyme activity had significant differences between vaccinated and control rabbits. The level of nitric oxide and lysozyme in sera of subcutaneously vaccinated rabbits was higher than that of orally vaccinated rabbits. Interleukin-6 and tumor necrosis factor-ɑ were determined in the spleen of vaccinated rabbits, significant differences were obtained between subcutaneously and orally vaccinated rabbits. It was concluded that the combined vaccine is potent when inoculated by subcutaneous route in contrast to the oral route. The Montanide; IMS 1313 adjuvant is a product that can be used for rabbit vaccine preparation(AU)

El virus de la enfermedad hemorrágica del conejo tipo 2 y el Clostridium perfringens tipo A causan infecciones en conejos. Las vacunas se consideran una estrategia eficaz para combatir estas infecciones. Hoy en día, la demanda para el uso de un adyuvante de nanopartículas como Montanide; IMS es cada vez mayor debido a su capacidad para mejorar la inmunidad humoral y la mediada por células, y a la posibilidad de administrarla por diferentes vías. En este estudio se desarrolló una vacuna inactivada contra el virus de la enfermedad hemorrágica del conejo tipo 2 y el Clostridium perfringens tipo A, adyuvada con Montanide™ IMS 1313 N VG PR (IMS 1313). Se evaluó la vacuna preparada en cuanto a esterilidad, seguridad y potencia en conejos mediante dos vías diferentes de vacunación. Se evaluó la administración oral de la vacuna inactivada como vía alternativa a la vacunación subcutánea. Los resultados revelaron que los conejos vacunados por vía subcutánea presentaban títulos satisfactorios de anticuerpos y antitoxinas contra el virus 2 de la enfermedad hemorrágica del conejo y el Clostridium perfringens tipo A, respectivamente, a partir de la segunda semana de vacunación y alcanzaron el máximo en la tercera semana. En cambio, los títulos de anticuerpos y antitoxinas de los conejos vacunados por vía oral no alcanzaron un nivel satisfactorio. Los conejos vacunados por vía oral no mostraron protección contra el virus virulento de la enfermedad hemorrágica del conejo tipo 2, con un 30 por ciento de protección, mientras que los conejos vacunados por vía subcutánea mostraron una protección satisfactoria (90 por ciento). El óxido nítrico sérico y la actividad de la lisozima presentaron diferencias significativas entre los conejos vacunados y los controles. El nivel de óxido nítrico y lisozima en el suero de los conejos vacunados por vía subcutánea fue superior al de los conejos vacunados por vía oral. Se determinaron la interleucina-6 y el factor de necrosis tumoral; en el bazo de los conejos vacunados, y se obtuvieron diferencias significativas entre los conejos vacunados por la vía subcutánea y la oral. Se concluyó que la vacuna combinada es potente cuando se inocula por vía subcutánea en contraste con la vía oral. El adyuvante Montanide; IMS 1313 es un producto que puede utilizarse para la preparación de vacunas para conejos(AU)

Tetrahydrocurcumin Derivatives Enhanced the Anti-Inflammatory Activity of Curcumin: Synthesis, Biological Evaluation, and Structure-Activity Relationship Analysis.

Tetrahydrocurcumin, the most abundant curcumin transformation product in biological systems, can potentially be a new alternative therapeutic agent with improved anti-inflammatory activity and higher bioavailability than curcumin. In this article, we describe the synthesis and evaluation of the anti-inflammatory activities of tetrahydrocurcumin derivatives. Eleven tetrahydrocurcumin derivatives were synthesized via Steglich esterification on both sides of the phenolic rings of tetrahydrocurcumin with the aim of improving the anti-inflammatory activity of this compound. We showed that tetrahydrocurcumin (2) inhibited TNF-α and IL-6 production but not PGE2 production. Three tetrahydrocurcumin derivatives inhibited TNF-α production, five inhibited IL-6 production, and three inhibited PGE2 production. The structure-activity relationship analysis suggested that two factors could contribute to the biological activities of these compounds: the presence or absence of planarity and their structural differences. Among the tetrahydrocurcumin derivatives, cyclic compound 13 was the most active in terms of TNF-α production, showing even better activity than tetrahydrocurcumin. Acyclic compound 11 was the most effective in terms of IL-6 production and retained the same effect as tetrahydrocurcumin. Moreover, acyclic compound 12 was the most active in terms of PGE2 production, displaying better inhibition than tetrahydrocurcumin. A 3D-QSAR analysis suggested that the anti-inflammatory activities of tetrahydrocurcumin derivatives could be increased by adding bulky groups at the ends of compounds 2, 11, and 12.

Differential gene expression of cytokines, receptors, and miRNAs in individuals living with HIV-1 and vaccinated against yellow fever.

Between 2016 and 2018, Brazil faced a yellow fever (YF) outbreak, which led to an expansion of vaccination coverage. The coexistence of the YF outbreak and the HIV-1 epidemic in Brazil raised concerns regarding the immune response and vaccine effectiveness in individuals living with HIV (PLWH). The aim of this study was to investigate the immune response to YF vaccination in PLWH and HIV-uninfected individuals as controls. Transcript levels of immunomodulatory molecules, including IL-6, IL-10, IL-21, TGF-ß, CD19, CD163, miR-21, miR-146, and miR-155, were measured using RTqPCR. TCD4+ cells were evaluated by cytometry, and neutralizing antibody (Nab) titers were detected by a micro plaque-reduction neutralization test. The findings of our study revealed several noteworthy observations. First, there was a notable reduction in the circulation of TCD4+ cells postvaccination. Among people living with HIV (PLWH), we observed an increase in the expression of IL-10 following vaccination, while IL-6 expression was diminished in PLWH with lower TCD4+ counts. Furthermore, we identified the downregulation of CD19 and TGF-ß, along with the upregulation of IL-21 and CD163. Notably, we observed positive correlations between the levels of IL-10/IL-21, IL-10/CD163, and IL-6/CD19. Additionally, there was a positive correlation between miRNAs 146 and 155. It is important to emphasize that all participants exhibited robust neutralizing antibody responses after receiving 17DD YF vaccination. In this context, the gene expression data presented can be useful for biomarker studies of protective antibodies induced by YF vaccination. This study sheds light on immune mechanisms in individuals living with HIV and YF vaccination.

Imipramine Administration in Brucella abortus 2308-Infected Mice Restores Hippocampal Serotonin Levels, Muscle Strength, and Mood, and Decreases Spleen CFU Count.

Brucellosis infection causes non-specific symptoms such as fever, chills, sweating, headaches, myalgia, arthralgia, anorexia, fatigue, and mood disorders. In mouse models, it has been associated with increased levels of IL-6, TNF-α, and IFN-γ, a decrease in serotonin and dopamine levels within the hippocampus, induced loss of muscle strength and equilibrium, and increased anxiety and hopelessness. Imipramine (ImiP), a tricyclic antidepressant, is used to alleviate neuropathic pain. This study evaluated the effects of ImiP on Balb/c mice infected with Brucella abortus 2308 (Ba) at 14- and 28-days post-infection. Serum levels of six cytokines (IFN-γ, IL-6, TNF-α, IL-12, MCP-1. and IL-10) were assessed by FACS, while the number of bacteria in the spleen was measured via CFU. Serotonin levels in the hippocampus were analyzed via HPLC, and behavioral tests were conducted to assess strength, equilibrium, and mood. Our results showed that mice infected with Brucella abortus 2308 and treated with ImiP for six days (Im6Ba14) had significantly different outcomes compared to infected mice (Ba14) at day 14 post-infection. The mood was enhanced in the forced swimming test (FST) (p < 0.01), tail suspension test (TST) (p < 0.0001), and open-field test (p < 0.0001). Additionally, there was an increase in serotonin levels in the hippocampus (p < 0.001). Furthermore, there was an improvement in equilibrium (p < 0.0001) and muscle strength (p < 0.01). Lastly, there was a decrease in IL-6 levels (p < 0.05) and CFU count in the spleen (p < 0.0001). At 28 days, infected mice that received ImiP for 20 days (Im20Ba28) showed preservation of positive effects compared to infected mice (Ba28). These effects include the following: (1) improved FST (p < 0.0001) and TST (p < 0.0001); (2) better equilibrium (p < 0.0001) and muscle strength (p < 0.0001); (3) decreased IL-6 levels (p < 0.05); and (4) reduced CFU count in the spleen (p < 0.0001). These findings suggest the potential for ImiP to be used as an adjuvant treatment for the symptoms of brucellosis, which requires future studies.

Modulation of JAK-STAT Signaling by LNK: A Forgotten Oncogenic Pathway in Hormone Receptor-Positive Breast Cancer.

Breast cancer remains the most frequently diagnosed cancer in women worldwide. Tumors that express hormone receptors account for 75% of all cases. Understanding alternative signaling cascades is important for finding new therapeutic targets for hormone receptor-positive breast cancer patients. JAK-STAT signaling is commonly activated in hormone receptor-positive breast tumors, inducing inflammation, proliferation, migration, and treatment resistance in cancer cells. In hormone receptor-positive breast cancer, the JAK-STAT cascade is stimulated by hormones and cytokines, such as prolactin and IL-6. In normal cells, JAK-STAT is inhibited by the action of the adaptor protein, LNK. However, the role of LNK in breast tumors is not fully understood. This review compiles published reports on the expression and activation of the JAK-STAT pathway by IL-6 and prolactin and potential inhibition of the cascade by LNK in hormone receptor-positive breast cancer. Additionally, it includes analyses of available datasets to determine the level of expression of LNK and various members of the JAK-STAT family for the purpose of establishing associations between expression and clinical outcomes. Together, experimental evidence and in silico studies provide a better understanding of the potential implications of the JAK-STAT-LNK loop in hormone receptor-positive breast cancer progression.

NO-IL-6/10-IL-1ß axis: a new pathway in steatotic and non-steatotic liver grafts from brain-dead donor rats.

Introduction: Brain death (BD) and steatosis are both risk factors for organ dysfunction or failure in liver transplantation (LT). Material and methods: Here, we examine the role of interleukin 6 (IL- 6) and IL-10 in LT of both non-steatotic and steatotic liver recovered from donors after brain death (DBDs), as well as the molecular signaling pathways underlying the effects of such cytokines. Results: BD reduced IL-6 levels only in nonsteatotic grafts, and diminished IL-10 levels only in steatotic ones. In both graft types, BD increased IL-1ß, which was associated with hepatic inflammation and damage. IL-6 administration reduced IL-1ß only in non-steatotic grafts and protected them against damage and inflammation. Concordantly, IL-1ß inhibition via treatment with an IL-1 receptor antagonist caused the same benefits in non-steatotic grafts. Treatment with IL-10 decreased IL-1ß only in steatotic grafts and reduced injury and inflammation specifically in this graft type. Blockading the IL-1ß effects also reduced damage and inflammation in steatotic grafts. Also, blockade of IL-1ß action diminished hepatic cAMP in both types of livers, and this was associated with a reduction in liver injury and inflammation, then pointing to IL-1ß regulating cAMP generation under LT and BD conditions. Additionally, the involvement of nitric oxide (NO) in the effects of interleukins was evaluated. Pharmacological inhibition of NO in LT from DBDs prompted even more evident reductions of IL-6 or IL-10 in non-steatotic and steatotic grafts, respectively. This exacerbated the already high levels of IL-1ß seen in LT from DBDs, causing worse damage and inflammation in both graft types. The administration of NO donors to non-steatotic grafts potentiated the beneficial effects of endogenous NO, since it increased IL-6 levels, and reduced IL-1ß, inflammation, and damage. However, treatment with NO donors in steatotic grafts did not modify IL-10 or IL-1ß levels, but induced more injurious effects tan the induction of BD alone, characterized by increased nitrotyrosine, lipid peroxidation, inflammation, and hepatic damage. Conclusion: Our study thus highlights the specificity of new signaling pathways in LT from DBDs: NO-IL-6-IL-1ß in non-steatotic livers and NO-IL-10-IL-1ß in steatotic ones. This opens up new therapeutic targets that could be useful in clinical LT.