Enhanced anti-inflammatory effect of fish myofibrillar protein by introducing pectin oligosaccharide and its molecular mechanisms.

This study investigated the efficacy of glycation with edible uronic acid-containing oligosaccharides via the Maillard reaction to enhance the anti-inflammatory effect of fish myofibrillar protein (Mf). Lyophilized Mf was reacted with pectin oligosaccharide (PO, half of the total protein weight) at 60 °C and 35 % relative humidity for up to 12 h to produce glycated Mf (Mf-PO). After pepsin and trypsin digestion, the anti-inflammatory effect was assessed by measuring the secretions of proinflammatory cytokines in LPS-stimulated RAW 264.7 macrophages, and the anti-inflammatory effect of Mf was enhanced by PO-glycation without marked lysine loss and browning. The effects on the expressions of genes related to the LPS-stimulated signaling pathway in macrophages were also examined. PO-glycation suppressed LPS-stimulated inflammation by suppressing expression of cd14 and enhancing suppressive effect of Mf on the TLR4-MyD88-dependent inflammatory signaling pathway. Therefore, as an edible reducing sugar, PO could be an effective bioindustrial material for developing anti-inflammatory Mf.

Pro-inflammatory cytokines gene expression in liver and kidneys of rats exposed to a sub-lethal dose of Bitis arietans snake venom.

Bitis arietans (Puff adder) is a poisonous snake and its bite causes pain, edema, blistering, tissue damage and neutrophilia. There are limited studies on inflammatory process involved in Bitis arietans envenomation. We therefore investigated the role of proinflammatory cytokines in Bitis arietans venom (BAV)-induced liver and kidney toxicities in rats. Adult male Sprague Dawley rats were treated with BAV (0.5 mg/kg) and were sacrificed after specific time intervals (2 h, 24 h, 1 week). Blood samples were collected for liver and renal function tests and tissues were collected for histopathology and gene expression analysis of IL-1ß, IL-6, and TNF-α in liver and kidneys. There was no significant difference in serum ALT activities among different treatment groups. Serum AST was significantly increased at 24 h following BAV injection. In both organs, injection of BAV resulted in mild inflammatory cell infiltration at 2 h post-dosing which normalized after 1 week. In liver, there was a significant increase in IL-1ß expression in BAV-treated rats at 2 and 24 h post-dosing that reduced after one week. Significant increases in IL-6 and TNF-α were observed at 24 h and 1 week after BAV exposure. In kidneys, there were significant increases in IL-1ß and TNF-α expression at 24 h that subsided after 1 week. In conclusion, a single sub-lethal dose of BAV caused an acute phase inflammation in liver and kidneys. It is most probable that a higher dose of BAV may result in greater and irreversible damage to these organs.

Expression profile of Toll-like receptors and cytokines in the cecal tonsil of chickens challenged with Eimeria tenella.

Chicken coccidiosis, caused by Eimeria spp., seriously affects the development of the poultry breeding industry. Currently, extensive studies of chicken coccidiosis are mostly focused on acquired immune responses, while information about the innate immune response of chicken coccidiosis is lacking. Toll-like receptor (TLR), the key molecule of the innate immune response, connects innate and adaptive immune responses and induces an immune response against various pathogen infections. Therefore, the quantitative real-time PCR was used to characterize the expression profile of chicken TLRs (chTLRs) and associated cytokines in the cecal tonsil of chickens infected with Eimeria tenella. The results showed that the expression of chTLR1a, chTLR2a, and chTLR5 was significantly upregulated at 3 h post-infection, while chTLR1b, chTLR2b, chTLR3, chTLR7, chTLR15 and chTLR21 was significantly downregulated (p < 0.05). In addition, chTLR1a expression rapidly reached the peaked expression at 3 h post-infection, while chTLR2b and chTLR15 peaked at 168 h post-infection, and chTLR2a expression was highest among chTLRs, peaking at 48 h post-infection (p < 0.05). For cytokines, interleukin (IL)-6 and tumor necrosis factor (TNF)-α peaked at 96 h post-infection, IL-4 and IL-12 peaked at 144 h post-infection, and interferon-γ expression was highest among cytokines at 120 h post-infection. In addition, IL-12 and IL-17 were markedly upregulated at 6 h post-infection (p < 0.05). These results provide insight into innate immune molecules during E. tenella infection in chickens and suggest that innate immune responses may mediate resistance to chicken coccidiosis.

Circulating levels of cytokines and risk of urologic cancers: a two-sample Mendelian randomization study.

BACKGROUND: Chronic inflammation is associated with the etiology of various cancers. However, there is a lack of systematic research in urologic cancers. This study aims to use a two-sample Mendelian randomization (MR) approach to evaluate the role of circulating cytokines in the development of urologic cancers. METHODS: We obtained the summary-level data for bladder cancer (373,295 cases and 372,016 controls), prostate cancer (462,933 cases and 459,664 controls), and kidney cancer (463,010 cases and 461,896 controls) from the UK Biobank. Genetic variations linked to 41 circulating cytokines were used as instrumental variables (IVs) in meta-analyses of genome-wide association studies (GWASs) involving 8,293 individuals from Finland. We primarily used the inverse-variance weighted (IVW) method to assess the potential associations between the 41 cytokines and the risk of 3 common urologic cancers. Weighted-median method, weighted mode and simple-median method were used to assess the sensitivity. Heterogeneity and pleiotropic outlier were evaluated by Cochran's Q test and MR-Egger regression. Genetic correlation, colocalization analysis and multivariable MR analysis were used to further validate the potential pleiotropy. RESULTS: After the Bonferroni correction, there was an observed association between elevated genetically predicted levels of CCL27 and a heightened risk for bladder cancer. Conversely, IL-12p70 levels were found to have a protective association against the risk of bladder cancer. Sensitivity analyses utilizing various IV sets and MR approach remained robust. Furthermore, we found potential associations of 7 cytokines with urologic cancers (4.07 × 10-4 ≤ P < 0.05). CONCLUSION: Our study supported causal associations between CCL27, IL-12p70 and bladder cancer risk and potential associations of 7 cytokines with the risk of urologic cancers, helping us to further understand the pathogenesis of urologic cancers and providing clues for improving diagnostic accuracy and therapies.

Genetic and immunological implications in fibromyalgia: A Literature Review.

Fibromyalgia (FM), a musculoskeletal condition characterized by widespread pain and numerous associated symptoms, is a complex disorder with uncertain etiology and pathogenesis. Most of the patients suffering from this syndrome are undiagnosed due to a lack of standard diagnostic criteria. Recent studies have shown the involvement of immune dysfunction and various pro-inflammatory cytokines in FM. Since there is so much uncertainty regarding the pathogenesis of FM, treatment modalities are very limited and ineffective. This review aimed to analyze the immunological mechanisms behind FM, attempting to deepen the understanding of its pathogenesis. Additionally, the review elucidates FM's associations with autoimmune diseases, highlighting shared pathophysiological mechanisms and overlapping symptoms. We synthesized current literature available on Google Scholar, PubMed, Springer, and Web of Science, the review explored the intricate interactions between genetic predisposition, immune dysregulation, and environmental factors in FM pathogenesis. The inclusion criteria prioritized studies focusing on the immunological aspect of FM. In conclusion, immune dysfunction has a role to play in the pathogenesis of FM, and immunomodulatory therapies have proven to be beneficial in the treatment of FM. Genetic variants, epigenetic modifications, and gut microbiome alterations are potential triggers for immune system dysfunction, contributing to the manifestation and exaggeration of FM symptoms. This review provided a comprehensive resource for researchers and clinicians, a guide for future investigations and clinical management towards improved outcomes and enhanced quality of life for individuals with FM.

Screening of key genes related to M6A methylation in patients with heart failure.

OBJECTIVE: This study aims to identify m6A methylation-related and immune cell-related key genes with diagnostic potential for heart failure (HF) by leveraging various bioinformatics techniques. METHODS: The GSE116250 and GSE141910 datasets were sourced from the Gene Expression Omnibus (GEO) database. Correlation analysis was conducted between differentially expressed genes (DEGs) in HF and control groups, alongside differential m6A regulatory factors, to identify m6A-related DEGs (m6A-DEGs). Subsequently, candidate genes were narrowed down by intersecting key module genes derived from weighted gene co-expression network analysis (WGCNA) with m6A-DEGs. Key genes were then identified through the Least Absolute Shrinkage and Selection Operator (LASSO) analysis. Correlation analyses between key genes and differentially expressed immune cells were performed, followed by the validation of key gene expression levels in public datasets. To ensure clinical applicability, five pairs of blood samples were collected for quantitative real-time fluorescence PCR (qRT-PCR) validation. RESULTS: A total of 93 m6A-DEGs were identified (|COR| > 0.6, P < 0.05), and five key genes (LACTB2, NAMPT, SCAMP5, HBA1, and PRKAR2A) were selected for further analysis. Correlation analysis revealed that differential immune cells were negatively associated with the expression of LACTB2, NAMPT, and PRKAR2A (P < 0.05), while positively correlated with SCAMP5 and HBA1 (P < 0.05). Subsequent expression validation confirmed significant differences in key gene expression between the HF and control groups, with consistent expression trends observed across both training and validation sets. The expression trends of LACTB2, PRKAR2A, and HBA1 in blood samples from the qRT-PCR assay aligned with the results derived from public databases. CONCLUSION: This study successfully identified five m6A methylation-related key genes with diagnostic significance, providing a theoretical foundation for further exploration of m6A methylation's molecular mechanisms in HF.

Host cytokine genetic polymorphisms in a selected population of persons living with hepatitis B virus infection in the central region of Ghana.

BACKGROUND: Hepatitis B virus (HBV) infection is a public health concern in resource limited settings like Ghana. Over the past decades, it is noted that the natural course of HBV in persons infected are taking a worse turn leading to liver cirrhosis and cancer. The outcome of HBV infection is influenced by viral and host factors including genetics. Cytokine variations affect virus survival and progression and may even influence associated complications. Cytokines such as tumor necrosis factor alpha (TNF-α), interleukins (IL-4, IL-6, IL-8, IL-10, IL-18), interferon gamma (IFN)-γ, and tumor growth factor-beta (TGF-ß) have key roles in HBV infection and modulation. In this study, polymorphisms occurring in five cytokines were analysed to understand how they can influence prognosis of HBV infection. METHODS: The study is a single centre cross-sectional study involving 227 participants made up of HBV infected participants and HBV-negative controls. Recruitment was from March 2021 to April 2022. Blood samples were taken for full blood count, HBV antigen profile, liver function tests, HBV DNA quantification and cytokine genotyping. FIB score was calculated using available tools. Statistical analysis was undertaken with p < 0.05 set as statistically significant. RESULTS: The 20-39-year-old group formed majority of the HBV infected participants with 60% of all participants being classified as healthy HBsAg carriers. IL2 rs1479920 GG carriers ((1258.93; 0.00-5011.87) IU/mL had reduced HBV DNA in comparison to IL2 rs1479920 AA ((5011.87; 2113.49-5956.62) /AG (3548.13; 0.00-6309.57) IU/mL carriers. TNF-α rs1800629 AA carriers (1258.93; 0.00-3981.07) IU/mL had a reduction in HBV DNA levels in comparison to TNF-α rs1800629 GG carriers (1584.89; 0.00-5011.87) IU/mL. The results of univariate (OR = 0.08, 0.00-0.93; p = 0.043) and multivariate (OR = 0.02, 0.00-0.67; p = 0.029) analysis, showed that carrying TNF-α rs1800629 AA genotype reduce susceptibility to high FIB score compared with GG genotypes. In univariate analysis, subjects aged 20-39 years (OR = 5.00, 1.13-6.10; p = 0.034) and 40-59 years (OR = 41.99, 3.74-47.21; p = 0.0002) were more susceptible to high FIB score compared to subjects aged 1-19 years. Being female (OR = 2.42, 1.03-5.71; p = 0.043) in the univariate models showed higher odds of having high levels of HBV DNA in the multivariate model. There was a reduced likelihood of herbal medicine usage influencing HBV DNA levels significantly (OR = 0.29, 0.10-0.86; p = 0.025). CONCLUSION: In conclusion, variations in IL2 rs1479920 GG and IL2 rs1479921 AA could offer protective effects by reducing HBV DNA. TNF-α rs179924CT may also cause elevation in HBV DNA levels whiles TNF-α -308A/G, showed a potential protective effect on liver scarring in HBV infected participants. It is therefore important to take a further look at such variations for understanding of HBV modulation in the Ghanaian population.

Genetic associations of visfatin polymorphisms with clinicopathologic characteristics of prostate cancer in Taiwanese males.

The most general cancer in men is prostate cancer (PCa), with its risk increasing due to age and obesity. Visfatin, a member of adipokines, is related to cancer progression and metastasis, but its relationship in PCa remains undetermined. In addition, no knowledge is available regarding relations between visfatin polymorphisms and clinicopathological characteristics in PCa. We sought to investigate the functions of four visfatin gene polymorphisms and clinicopathological characteristics on the hazard of developing PCa in 695 Taiwanese males with PCa. Carriers of the GA+AA heterozygote of SNP rs61330082 were at a markedly higher risk of biochemical recurrence than those with the GG genotype. Visfatin rs61330082 and rs11977021 were related with a high risk of perineural invasion, lymphovascular invasion, and biochemical recurrence in prostate-specific antigen (PSA) > 10 PCa patients. The Cancer Genome Atlas database noted that visfatin mRNA level did not prominently differ with pathological T/N stage and overall survival. This finding is the first to document a connection between visfatin polymorphisms and clinicopathological characteristics of PCa in Taiwanese males.

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

Introduction: 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. Methods: Peripheral blood samples and sociodemographic data from 508 individuals with COVID-19, measuring plasma cytokine concentrations using ELISA and genotyped the AKT1 variants. Results: 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. Discussion: Our findings contribute to understanding the influence of the AKT1 gene variants on the immunological damage in individuals infected with SARS-CoV-2.

Cytokine gene polymorphisms and suicide risk in an Indian ancestral population: A case-control study.

BACKGROUND: India currently accounts for a majority of global suicide deaths. Research in European ancestry has established that suicide mortality has a significant genetic component, and suggests that inflammation may play a crucial role in the pathophysiology of suicide. Inflammation is also highly relevant in regions of increased pollution exposure, such as the megacities of India. To address the existing gaps in genetic research on suicide and possible association with inflammatory biomarkers, we examined genetic polymorphism and clinical risk phenotypes in a population-based suicide-death cohort, India. MATERIAL AND METHODS: Genotyping of IL-1ß(rs16944) & (rs1143627), IL-4(rs2070874), IL-6(rs1800795) and IL-10(rs1800896) was done in 234 post-mortem suicide-death cases and 256 post-mortem controls (N = 490) using PCR RFLP method. RESULTS: Our analyses identified three significant (p < 0.001) associations of cytokine variants with suicide death, including IL-1ß(rs16944), OR = 0.627; IL-4(rs2070874), OR = 0.524; and IL-6(rs1800795), OR = 2.509. Cases were more likely female and were more likely to have a history of psychiatric illness, though rate of psychiatric illness was low in suicide cases(9%). CONCLUSION: Our genetic results are generally consistent with previous research on risk for depression and suicidal behaviour, and both genetic and phenotypic results provide new insights into risk factors that may contribute to suicide in India.

Autoinflammation in patients with leukocytic CBL loss of heterozygosity is caused by constitutive ERK-mediated monocyte activation.

Patients heterozygous for germline CBL loss-of-function (LOF) variants can develop myeloid malignancy, autoinflammation, or both, if some or all of their leukocytes become homozygous for these variants through somatic loss of heterozygosity (LOH) via uniparental isodisomy. We observed an upregulation of the inflammatory gene expression signature in whole blood from these patients, mimicking monogenic inborn errors underlying autoinflammation. Remarkably, these patients had constitutively activated monocytes that secreted 10 to 100 times more inflammatory cytokines than those of healthy individuals and CBL LOF heterozygotes without LOH. CBL-LOH hematopoietic stem and progenitor cells (HSPCs) outgrew the other cells, accounting for the persistence of peripheral monocytes homozygous for the CBL LOF variant. ERK pathway activation was required for the excessive production of cytokines by both resting and stimulated CBL-LOF monocytes, as shown in monocytic cell lines. Finally, we found that about 1 in 10,000 individuals in the UK Biobank were heterozygous for CBL LOF variants and that these carriers were at high risk of hematological and inflammatory conditions.

Effect of peimisine on pulmonary interstitial fibrosis induced by bleomycin in mouse pulmonary fibrosis.

Peimisine has therapeutic effects on cough, asthma, acute lung injury and liver fibrosis. However, it has not been reported whether peimisine has an inhibitory effect on pulmonary fibrosis. In current study, a mouse pulmonary interstitial fibrosis model was established to investigate the efficacy of peimisine. Mice were categorized into six groups: Control, model, pirfenidone and three peimisine multi-dose groups. After the modelling, each group was given drugs for 21 days. Mice were euthanized and the histopathology changes of the lung were compared. The contents of cytokines in serum were determined. The mRNA expression levels of related genes in the lung tissue were detected. The contents of macrophages and neutrophils in the bronchoalveolar lavage fluid (BALF) were detected. The antifibrotic effect of peimisine was validated by using MRC-5 cells. The results demonstrated that peimisine could alleviate the destruction of alveolar structure and reduce the aggregation of inflammatory cells. Peimisine could reduce the protein expression levels of cytokines in serum. The mRNA levels of related genes were regulated. The contents of macrophages and neutrophils were decreased. Peimisine had a regulatory effect on the abnormal proliferation of MRC-5 cells. The mechanism was related to regulating extra cellular matrix (ECM) and epithelial-mesenchymal transition (EMT).

Investigation of parasite genetic variation and systemic immune responses in patients presenting with different clinical presentations of cutaneous leishmaniasis caused by Leishmania aethiopica.

BACKGROUND: Cutaneous leishmaniasis (CL) is a neglected tropical skin disease, caused by the protozoan parasite Leishmania. In Ethiopia, CL is mainly caused by Leishmania aethiopica and can present in different clinical forms. The aim of this study was to assess whether these different forms are associated with differences in parasite genetic and host systemic immune signatures. METHODS: Here we analysed the whole genome sequence data for 48 clinical parasite isolates and the systemic immune signature from a cohort of CL patients, who were recruited in Nefas Mewcha, Northern Ethiopia, from January 2019 to January 2022. RESULTS: Our results show that parasites from CL cases with different presentations in a single Ethiopian setting are from the same genetic population based on a permutation test of genome-wide similarity. Furthermore, a logistic regression test for genome wide association did not identify any individual genetic variants significantly associated with disease presentation. We also measured plasma chemokine and cytokine levels of 129 CL patients presenting with different forms of CL. None of the chemokine [eotaxin, eotaxin-3, interleukin (IL)-8, interferon (IFN)-γ-induced protein-10 (IP-10), monocyte chemoattractant protein (MCP)-1, MCP-4, macrophage-derived chemokines (MDC), macrophage inflammatory protein (MIP)-1α, MIP-1ß and thymus- and activation-regulated chemokine (TARC)] or cytokine (IFN-γ, IL-1ß, interleukin-2, IL-4, IL-6, IL-10, IL-12p70, IL-13, tumor necrosis factor-α) levels measured were significantly different between the different clinical presentations of CL, as measured by Kruskal-Wallis test. We also compared those with healthy nonendemic controls: our results show a chemokine (IP-10, MCP-1, MCP-4, MDC, MIP-1α, MIP-1ß and TARC) but not a cytokine immune signature in patients with CL as compared to healthy nonendemic controls, as measured by Mann-Whitney test. CONCLUSIONS: The results of our study did not identify a systemic immune signature or parasite genetic factors associated with different clinical presentation of CL.

Effect of Heat Stress on the Expression of Circulating Cyto(chemo)kine and Inflammatory Markers in Broiler Chickens Selected for High- or Low-water Efficiency.

BACKGROUND: Water scarcity is a current, significant global concern that will only increase under the pressure of climate change. Improving water efficiency of poultry is a new and promising area to help temper agriculture's future impact on fresh water availability. Here, we explored the effects of acute heat stress (HS) on circulating stress and inflammatory markers in 2 lines of broilers divergently selected for water efficiency. METHODS: Male chicks from low (LWE) and high water efficient (HWE) lines were raised in 12 environmental chambers (2 pens/chamber, 6 chambers/line, 20 birds/pen) under normal conditions until day 28. On day 29, birds were subjected to thermoneutral (TN, 25 °C) or HS (36 °C) conditions, resulting in four treatments (2 lines × 2 environmental conditions). After 3 h of HS, whole blood was collected (8 birds per line × environment) and analyzed for target gene expression and plasma cytokine levels. Data were analyzed by 2-way ANOVA, with line, environment, and their interaction as main factors, and means were compared using Tukey's multiple range test. RESULTS: Gene expression of heat shock protein (HSP) 27, HSP70, interleukin (IL)-6, IL-18, c-reactive protein (CRP), tumor necrosis factor-α (TNFα), C-C motif chemokine ligand 4 (CCL4), CCL20, nucleotide-binding domain, leucine-rich repeat (NLR) family pyrin domain containing 3 (NLRP3), NLR family CARD domain containing 5 (NLRC5), and NLR family member X1 (NLRX1) were increased by HS, with no differences between the lines. HSP70, IL-10, and NLRC3 were lower in the HWE as compared to the LWE lines. Additionally, there were interactive effects between line and environment for HSP90, IL-4, and CCL4, where HS induced HSP90 expression in the LWE only, and IL-4 and CCL4 in HWE only. Arginine vasopressin (AVP) gene expression was significantly lower in the whole blood of the HWE line; however, plasma protein levels were not different. CONCLUSIONS: Overall, most of the effects seen on cyto (chemokines) and inflammatory markers were due to acute HS, with only a few genes differentially regulated between the lines. This likely indicates that the divergent selection for water efficiency for four generations did not elicit changes in inflammation and stress molecular signatures.

Causal association of circulating inflammatory proteins on neurodegenerative diseases: Insights from a mendelian randomization study.

Neuroinflammation is increasingly recognized as a pivotal factor in the development and progression of neurodegenerative disorders. While correlations between inflammatory cytokines and these diseases are documented, the definitive causal dynamics remain to be elucidated. We explored the causal association between 91 circulating inflammatory cytokines and Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Parkinson's disease (PD) through Mendelian randomization analysis. Leveraging genetic variants from the most comprehensive genome-wide association studies (GWAS) available for these cytokines, AD, ALS, MS and PD, we sought to uncover the causality. Our study validated a causal influence of genetically determined cytokine levels on the susceptibility to AD, with notable cytokines including C-X-C motif chemokine 1 (OR = 0.9993, p = 0.0424), Interleukin-18 (OR = 0.9994, p = 0.0186), Leukaemia inhibitory factor receptor (OR = 0.9993, p = 0.0122) and Monocyte chemoattractant protein-1 (OR = 0.9992, p = 0.0026) in risk attenuation. Additionally, a positive causal relationship was identified between two cytokines-C-C motif chemokine 19 (OR = 1.0005, p = 0.0478) and Fms-related tyrosine kinase 3 ligand (OR = 1.0005, p = 0.0210)-and AD incidence. Conversely, transforming growth factor-alpha (OR = 0.8630, p = 0.0298), CD40L receptor (OR = 0.7737, p = 1.1265E-09) and Interleukin-12 subunit beta (OR = 0.8987, p = 0.0333) showed inverse associations with ALS, MS and PD, respectively. The consistency observed in various MR analyses, alongside sensitivity analysis, underscored the absence of horizontal pleiotropy, thus supporting our causal findings. This study reveals, for the first time, a genetically anchored causal nexus between levels of circulating inflammatory cytokines and the risk of neurodegenerative diseases.

Bidirectional two-sample Mendelian randomization analysis unveils causal association between inflammatory cytokines and the risk of diabetic nephropathy.

OBJECTIVE: Previous observational studies have indicated associations between various inflammatory cytokines and diabetic nephropathy (DN) caused by type 2 diabetes mellitus (T2DM). However, the causality remains unclear. We aimed to further evaluate the causal association between 91 inflammatory cytokines and DN using bidirectional two-sample Mendelian randomization (MR) analysis. METHOD: Summary statistics for DN were obtained from a publicly available genome-wide association study (GWAS) analysis. Data pertaining to inflammatory cytokines were derived from a GWAS protein quantitative trait locus (pQTL) study. The primary analytical approach employed the inverse variance weighted (IVW) method, complemented by MR-Egger regression, weighted mode (WM), and weighted median (WME) methods to evaluate the causal association between inflammatory cytokines and DN. Sensitivity analyses were conducted to validate the robustness of the findings. RESULT: Among individuals of European ancestry, the IVW method results revealed a positive causal association between the gene expression of tumor necrosis factor ligand superfamily member 14 (TNFSF14), and TNF-related activation-induced cytokine (TRANCE) with DN. Conversely, a negative causal association was observed between the gene expression of interleukin-1-alpha (IL-1α), and transforming growth factor-alpha (TGF-α) with DN. Among individuals of East Asian ancestry, the IVW method results indicated a negative causal association between the gene expression of glial cell line-derived neurotrophic factor (GDNF) and DN. Notably, these findings persisted without evidence of horizontal pleiotropy or heterogeneity, ensuring their robustness and reliability. CONCLUSION: The MR analysis underscores a causal association between inflammatory cytokines and DN, providing an important reference and evidence for the study of DN.

Lactobacillus rhamnosus GG and Bifidobacterium animalis subsp. lactis BB-12 promote infected wound healing via regulation of the wound microenvironment.

Infected wounds can result in complex clinical complications and delayed healing, presenting a significant global public health challenge. This study explored the effects of topical application of two probiotics, Lactobacillus rhamnosus GG (LGG) and Bifidobacterium animalis subsp. lactis BB-12, on the microenvironment of infected wounds and their impact on wound healing. LGG and BB-12 were applied separately and topically on the Staphylococcus aureus (S. aureus)-infected skin wounds of the rat model on a daily basis. Both probiotics significantly accelerated wound healing, demonstrated by enhanced granulation tissue formation and increased collagen deposition, with BB-12 showing superior efficacy. LGG and BB-12 both effectively inhibited neutrophil infiltration and decreased the expression of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6). Notably, BB-12 markedly reduced IL-6 levels, while LGG significantly lowered TNF-α, transforming growth factor-ß (TGF-ß) and vascular endothelial growth factor (VEGF). Additionally, both probiotics promoted macrophage polarization towards the anti-inflammatory M2 phenotype. Microbiota analysis revealed that LGG and BB-12 significantly decreased the abundance of pathogenic bacteria (e.g. Staphylococcus and Proteus) and increased the proportion of beneficial bacteria (e.g. Corynebacterium). Particularly, BB-12 was more effective in reducing Staphylococcus abundance, whereas LGG excelled in promoting Corynebacterium growth. These findings suggest the ability of LGG and BB-12 to modulate the wound microenvironment, enhance wound healing and provide valuable insights for the management of infected wounds.

Associations between single nucleotide polymorphisms of cytokines and hepatitis B virus-related liver cirrhosis: A case-control study.

BACKGROUND AND AIMS: Various inflammatory and immune cytokines play key roles in the progression of hepatitis B virus (HBV)-related liver cirrhosis (LC). This study explored the relationship between single nucleotide polymorphisms (SNPs) in cytokines with the combined effect of polymorphisms and gender-polymorphisms interaction and LC risk. METHODS: In this study, a case-control design was used, samples were selected from 45 patients with hepatitis B-related cirrhosis and 45 age-gender-matched chronic HBV-infected patients without cirrhosis attending the tumor hospital of Wuwei Academy of Medical Sciences. Fifteen SNPs were examined using a real-time polymerase chain reaction allelic discrimination system. Logistic regression was utilized to assess cytokine-associated SNPs and the association between SNPs and LC progression in HBV-infected patients. RESULTS: The multivariate-adjusted logistic model revealed that the GG/AG dominant model (OR, 16.38; 95% CI, 1.13-236.70) and G allele (OR, 5.93; 95% CI, 0.98-36.01) of rs1800896 were associated with an increased risk of cirrhosis in CHB patients. Instead, rs2227306 CT presented a reduced cirrhosis risk (OR, 0.22; 95% CI, 0.04-1.38). Rs2055979 AA/AC was negatively associated with the risk of cirrhosis, potentially reversed in males (p = 0.021). Rs1799964 CC/CT was positively related to the risk of cirrhosis but reduced the risk of cirrhosis in males (OR, 0.13; 95% CI, 0.022-0.808; p = 0.028). Both rs1799964 TT and rs1799724 CT/TT genotype showed a synergistic effect in reducing the risk of cirrhosis with rs1800896 AA (OR, 0.08; 95% CI, 0.01-1.43 and OR, 0.12; 95% CI, 0.01-2.21). CONCLUSION: Polymorphisms rs1800896 and rs2227306 are potentially associated with the risk of cirrhosis. For the first time, the study highlights that the rs2055979 AA/AC and rs1799964 CC/CT polymorphism interact with gender and its potential reversal of cirrhosis risk in males. Furthermore, rs1800896 AA showed a synergistic effect with rs1799964 TT and rs1799724 CT/TT to prevent the progression of HBV infection to cirrhosis.

Unraveling the impact of lysosomal dysfunction on myeloproliferative neoplasm.

BACKGROUND: Lysosomal dysfunction (LD) impacts cytokine regulation, inflammation, and immune responses, influencing the development and progression of cancer. Inflammation is implicated in the pathogenesis of myeloproliferative neoplasm (MPN). With a hypothesis that LD significantly contributes to MPN carcinogenesis by inducing abnormal inflammation, our objective was to elucidate the pathophysiological mechanisms of MPN arising from an LD background. METHODS: Genotyping of the LD background was performed in a cohort of MPN patients (n = 190) and healthy controls (n = 461). Logistic regression modeling, utilizing genotype data, was employed to estimate the correlation between LD and MPN. Whole transcriptome sequencing (WTS) (LD carriers = 8, non-carriers = 6) and single-cell RNA sequencing data (LD carriers = 2, non-carriers = 2, healthy controls = 2) were generated and analyzed. RESULTS: A higher variant frequency of LD was observed in MPN compared to healthy controls (healthy, 4.9%; MPN, 7.8%), with the highest frequency seen in polycythemia vera (PV) (odds ratio = 2.33, p = 0.03). WTS revealed that LD carriers exhibited upregulated inflammatory cytokine ligand-receptor genes, pathways, and network modules in MPNs compared to non-carriers. At the single-cell level, there was monocyte expansion and elevation of cytokine ligand-receptor interactions, inflammatory transcription factors, and network modules centered on monocytes. Notably, Oncostatin-M (OSM) consistently emerged as a candidate molecule involved in the pathogenesis of LD-related PV. CONCLUSIONS: In summary, an LD background is prevalent in MPN patients and leads to increased cytokine dysregulation and inflammation. OSM, as one of the potential molecules, plays a crucial role in PV pathogenesis by impairing lysosomal function.

Effects of Azithromycin on Blood Inflammatory Gene Expression and Cytokine Production in Sarcoidosis.

INTRODUCTION: In sarcoidosis granulomas, monocyte-derived macrophages are activated by pro-inflammatory cytokines including TNF and IL-6. Current drug treatment for sarcoidosis aims to suppress inflammation but disabling side effects can ensue. The macrolide azithromycin may be anti-inflammatory. We aimed to determine whether treatment with azithromycin affects blood inflammatory gene expression and monocyte functions in sarcoidosis. METHODS: Blood samples were collected from patients with chronic pulmonary sarcoidosis enrolled in a single arm, open label clinical trial who received oral azithromycin 250 mg once daily for 3 months. Whole blood inflammatory gene expression with or without LPS stimulation was measured using a 770-mRNA panel. Phenotypic analysis and cytokine production were conducted by flow cytometry and ELISA after 24h stimulation with growth factors and TLR ligands. mTOR activity was assessed by measuring phosphorylated S6RP. RESULTS: Differential gene expression analysis indicated a state of heightened myeloid cell activation in sarcoidosis. Compared with controls, sarcoidosis patients showed increased LPS responses for several cytokines and chemokines. Treatment with azithromycin had minimal effect on blood gene expression overall, but supervised clustering analysis identified several chemokine genes that were upregulated. At the protein level, azithromycin treatment increased LPS-stimulated TNF and unstimulated IL-8 production. No other cytokines showed significant changes following azithromycin. Blood neutrophil counts fell during azithromycin treatment whereas mononuclear cells remained stable. Azithromycin had no detectable effects on mTOR activity or activation markers. CONCLUSION: Blood myeloid cells are activated in sarcoidosis, but azithromycin therapy did not suppress inflammatory gene expression or cytokine production in blood. TRIAL REGISTRATION: EudraCT 2019-000580-24 (17 May 2019).