Immune Activation Inflammation Research Articles

Comprehensive analysis of Pan-Immune Inflammation and all-cause mortality in rheumatoid arthritis: a database-driven approach, 1999-2018

BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease marked by systemic inflammation and immune dysregulation, leading to a higher risk of all-cause mortality. The Pan-Immune Inflammation Value (PIV), a novel biomarker capturing immune-inflammatory activity, has shown prognostic value in various diseases. However, its role in predicting outcomes in RA patients remains largely unexplored.ObjectivesThis study aimed to evaluate the association between PIV and all-cause mortality in RA patients, investigate nonlinear relationships, and identify threshold effects.MethodsData from the 1999–2018 National Health and Nutrition Examination Survey (NHANES) were used, including 1,882 RA patients. PIV was calculated as (neutrophil count×platelet count×monocyte count)/lymphocyte count and categorized into quartiles (Q1–Q4). Multivariable Cox proportional hazards models were applied to assess the relationship between PIV and mortality, with results expressed as hazard ratios (HRs) and 95% confidence intervals (CIs). Restricted cubic splines (RCS) explored nonlinear trends, and segmented Cox regression identified threshold effects. Kaplan-Meier survival curves and subgroup analyses validated the findings and assessed potential modifiers.ResultsElevated PIV levels were strongly associated with increased all-cause mortality. Compared to Q1, adjusted HRs for Q2, Q3, and Q4 were 1.60 (95% CI: 1.01–2.53, P = 0.047), 1.70 (95% CI: 1.10–2.63, P = 0.016), and 2.12 (95% CI: 1.33–3.37, P = 0.002), respectively (P for trend < 0.001). RCS analysis revealed a nonlinear relationship with a threshold at PIV = 302. Below this threshold, increasing PIV was associated with higher mortality risk (HR = 1.67, 95% CI: 1.07–2.61, P = 0.024). Conversely, above the threshold, further increases in PIV were linked to reduced mortality risk (HR = 0.98, 95% CI: 0.97–0.99, P = 0.026). Kaplan-Meier survival curves showed a clear decline in survival probability with increasing PIV quartiles (P < 0.001). Subgroup analyses confirmed consistent findings, with a notable interaction observed in diabetic patients (P for interaction = 0.002).ConclusionsPIV is a significant and independent predictor of all-cause mortality in RA patients, characterized by a nonlinear association and a distinct threshold effect. These findings highlight the potential of PIV as a pragmatic biomarker for stratifying mortality risk and informing personalized treatment strategies in RA.

Inflammatory disease progression shapes nanoparticle biomolecular corona-mediated immune activation profiles

Polymeric nanoparticles (NPs) are promising tools used for immunomodulation and drug delivery in various disease contexts. The interaction between NP surfaces and plasma-resident biomolecules results in the formation of a biomolecular corona, which varies patient-to-patient and as a function of disease state. This study investigates how the progression of acute systemic inflammatory disease influences NP corona compositions and the corresponding effects on innate immune cell interactions, phenotypes, and cytokine responses. NP coronas alter cell associations in a disease-dependent manner, induce differential co-stimulatory and co-inhibitory molecule expression, and influence cytokine release. Integrated multi-omics analysis of proteomics, lipidomics, metabolomics, and cytokine datasets highlight a set of differentially enriched TLR4 ligands that correlate with dynamic NP corona-mediated immune activation. Pharmacological inhibition and genetic knockout studies validate that NP coronas mediate this response through TLR4/MyD88/NF-κB signaling. Our findings illuminate the personalized nature of corona formation under a dynamic inflammatory condition and its impact on NP-mediated immune activation profiles and inflammation, suggesting that disease progression-related alterations in plasma composition can manifest in the corona to cause unintended toxicity and altered therapeutic efficacy.

A post-injury immune challenge with lipopolysaccharide following adult traumatic brain injury alters neuroinflammation and the gut microbiome acutely, but has little effect on chronic outcomes.

Patients with a traumatic brain injury (TBI) are susceptible to hospital-acquired infections, presenting a significant challenge to an already-compromised immune system. The consequences and mechanisms by which this dual insult worsens outcomes are poorly understood. This study aimed to explore how a systemic immune stimulus (lipopolysaccharide, LPS) influences outcomes following experimental TBI in young adult mice. Male and female C57Bl/6 J mice underwent controlled cortical impact or sham surgery, followed by 1 mg/kg i.p. LPS or saline-vehicle at 4 days post-TBI, before behavioral assessment and tissue collection at 6 h, 24 h, 7 days or 6 months. LPS induced acute sickness behaviors including weight loss, transient hypoactivity, and increased anxiety-like behavior. Early systemic immune activation by LPS was confirmed by increased spleen weight and serum cytokines. In brain tissue, gene expression analysis revealed a time course of inflammatory immune activation in TBI or LPS-treated mice (e.g., IL-1β, IL-6, CCL2, TNFα), which was exacerbated in TBI + LPS mice. This group also presented with fecal microbiome dysbiosis at 24 h post-LPS, with reduced bacterial diversity and changes in the relative abundance of key bacterial genera associated with sub-acute neurobehavioral and immune changes. Chronically, TBI induced hyperactivity and cognitive deficits, brain atrophy, and increased seizure susceptibility, similarly in vehicle and LPS-treated groups. Together, findings suggest that an immune challenge with LPS early after TBI, akin to a hospital-acquired infection, alters the acute neuroinflammatory response to injury, but has no lasting effects. Future studies could consider more clinically-relevant models of infection to build upon these findings.

Impact of Low Inclusion Rate of Olive Cake in Dairy Cow Rations on Uterine Health and Fertility Indices During Early Lactation.

Olive cake was incorporated at a low inclusion rate (3.7%) into the rations of dairy cows through partial substitution of maize, and its effects on milk production, general health, and fertility traits were investigated. Multiparous purebred Holstein dairy cows (n = 148) were divided into two groups: a treated group (n = 86) and a control group (n = 62). The control ration (group C) was modified by replacing 1 kg of maize with an equal quantity of olive cake (group T). The experiment lasted from 60 days prepartum to 150 days postpartum. Electronic aids were utilized to quantify daily milk yield and detect estrus expression, while clinical and uterine examinations were performed weekly. Blood samples, uterine epithelial cells, and endometrial tissue samples were collected from a subgroup of healthy animals in both groups at specific time points. Blood samples were examined to determine the β-hydroxybutyric acid (BHBA), acute phase proteins (haptoglobin [Hpt] and serum amyloid A [SAA]), progesterone, and pregnancy-associated glycoproteins concentrations. Uterine epithelial cells were assessed for polymorphonuclear neutrophil (PMN) counts, and the expression of nine genes encoding inflammatory cytokines and immune system activation was analyzed in uterine biopsy tissue. No significant differences (p > 0.05) were observed between groups in milk yield, general morbidity, clinical endometritis, or conception rates. However, animals in group T came to estrus approximately 6 days earlier (p = 0.013) than those in group C; progesterone concentrations on day 7 of the subsequent cycle tended (p = 0.07) to be higher in group T. On day 21, BHBA concentrations were higher in group C than in group T (p < 0.05). Throughout the experiment, Hpt levels in group T were consistently lower (p < 0.001), while SAA was lower on day 7 compared to group C. From days 21 to 42 postpartum, there was a significant reduction in PMN numbers (group C p = 0.02; group T p < 0.0001), with a tendency for a greater reduction rate in group T (p = 0.08). Among the genes studied, a significant difference was revealed in the expression of the ILA1 gene, with strong correlations of gene expression in group C and weak to moderate correlations in group T. In conclusion, under the conditions of this experiment, the inclusion of olive cake into dairy cows' rations did not affect milk production but improved certain health and fertility parameters, making olive cake a suitable alternative feedstuff for high-producing animals.

MiR-223 and Chromogranin A Affect Inflammatory Immune Cell Activation in Liver Metastasis of Neuroendocrine Neoplasms.

Neuroendocrine neoplasms (NENs) are a diverse group originating from endocrine cells/their precursors in pancreas, small intestine, or lung. The key serum marker is chromogranin A (CgA). While commonly elevated in patients with NEN, its prognostic value is still under discussion. Secretion/posttranslational proteolytic cleavage of CgA results in multiple bioactive fragments, which are essential regulators of the cardiovascular and immune system. miR-223, regulator of Nrlp3 inflammasome and neutrophil activation, was recently found to have decreased in patients with NEN. We performed flow cytometry of circulating neutrophils in a patient cohort (n = 10) with NEN, microdissection and histology of tumor tissue. Subsequently, in vitro transfections using the well-established human pancreatic NEN cell line (BON), and co-culture experiments with primary macrophages and neutrophils were performed. Serum miR-223 in patients correlated with the expression of the neutrophil activation marker CD15 in circulating cells. Neutrophilic CD62L/CD63 showed good discrimination compared to healthy controls. Immune cell-derived miR-155, miR-193 and miR-223 colocalize with neutrophil in the extra-tumoral tissue alongside Nlrp3-associated caspase-1 activation. miR-223 knockdown in BON decreased the CgA intracellularly, increased in cellular granularity and caspase-1 activation. Plasmin inhibitor a2-aP reverted those effects. Western Blot showed fragmented CgA following miR-223 knockdown, which altered the inflammatory potential of neutrophils. Our data hence provide initial insights into an immunoregulatory mechanism via miR-223 and CgA in NEN cells, as regulation of miR-223 in NEN may affect tumor-associated inflammation.

Key role of macrophages in the progression of hepatic fibrosis.

Liver fibrosis is a pathological change characterized by excessive deposition of extracellular matrix caused by chronic liver injury, and the mechanisms underlying its development are associated with endothelial cell injury, inflammatory immune cell activation, and HSC activation. Furthermore, hepatic macrophages exhibit remarkable heterogeneity and hold central functions in the evolution of liver fibrosis, with different subgroups exerting dual effects of promotion and regression. Currently, targeted macrophage therapy for reversing hepatic fibrosis has been extensively studied and has shown promising prospects. In this review, we will discuss the dual role of macrophages in liver fibrosis and provide new insights into reversing liver fibrosis based on macrophages.

A time-dependent interactive effect of nitrite and ammonia on inflammatory and immune response in the head kidney of silver carp (Hypophthalmichthys molitrix)

Nitrite and ammonia stress frequently have harmful effects on aquatic animals. However, the effect of ammonia combined with nitrite on immunity is unclear. Aimed to determine their interactive effect on head kidney, silver carp were exposed to ammonia (15 mg/L), nitrite (10 mg/L), or ammonia+nitrite (15 mg/L + 10 mg/L), and control conditions for 48 h. The results showed that exposure to nitrite and ammonia caused loss of cytoplasm and vacuolar degeneration of cells in head kidney. Following exposure to nitrite and ammonia, tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β) levels decreased significantly, while immunoglobulin M (IgM) and complement 3 (C3) levels increased significantly (P < 0.05). Additionally, TNF-α and C3 were significantly affected synergistically by 24 h of exposure to ammonia+nitrite, while significantly antagonistic effect on IL-1β and C3 was observed after 48 h of exposure. After 48 h of exposure, differently expressed genes (DEGs) induced by ammonia, nitrite, and their combination were mainly assigned to molecular function and biological process, and complement and coagulation cascade pathway was enriched with the highest number of immunity-associated DEGs. Integrated biomarker response (IBR) in nitrite group was higher than that in ammonia group, and the combination of ammonia and nitrite increased and decreased the IBR induced by ammonia and nitrite after 24 and 48 h of exposure, respectively. In conclusion, the toxicities of ammonia and nitrite toward head kidney displayed inflammatory suppression and immune activation, and their had synergistic and antagonistic effects on head kidney at 24 h and 48 h, respectively.

Transcriptomic Profile of the Male Rat Hypothalamus and Nucleus Accumbens After Paroxetine Treatment and Withdrawal: Possible Causes of Sexual Dysfunction.

Paroxetine, a selective serotonin reuptake inhibitor (SSRI), may induce sexual dysfunction during treatment and upon discontinuation. The mechanisms involved have been poorly explored so far. We have analyzed, by RNA sequencing, the whole transcriptomic profile in the hypothalamus and nucleus accumbens (NAc) (two brain regions involved in sexual behavior) of male rats daily treated for 2weeks with paroxetine (T0) and at 1month of withdrawal (T1). Data here reported show seven differentially expressed genes (DEGs) at T0 and 1 at T1 in the hypothalamus and 245 at T0 and 6 at T1 in the NAc. In addition, Gene-Set Enrichment, Gene Ontology, and Reactome analyses confirm that inflammatory signature and immune system activation were present at T0 in both brain areas. Considering that inflammation is generally associated with depression and that no paradigms inducing the pathology were here applied, these SSRI pro-depressive effects should be considered in patients without a clear indication of depression. Moreover, DEGs related to neurotransmitters with a role in sexual behavior and the reward system, such as dopamine (e.g., sialyltransferase 8B-ST8SIA3), glutamate (e.g., glutamate receptor ionotropic delta-2-GRID2) and GABA (e.g., glutamate decarboxylase type 2-GAD2) or associated with neurexin and neuroligin pathways and brain-derived neurotrophic factor (BDNF) signaling, were reported to be dysregulated in the NAc, further confirming dysfunction in this brain area. Interestingly, the analysis of DEGs altered at T1 in the NAc confirms the persistence of some of these side effects providing further information for post-SSRI sexual dysfunction (PSSD) etiopathogenesis.

Analysis of the Mechanism Underlying Radiotherapy Resistance Caused by Oligodendroglia Cells in Glioblastoma by Applying the Single-cell RNA Sequencing Technology.

Glioblastoma (GBM) is an aggressive malignancy. The inherent resistance of GBM to radiotherapy poses great challenges for clinical treatment. The primary objective of this study is to explore the molecular mechanisms of radiotherapy resistance in GBM and identify the key influencing factors that contribute to this phenomenon. The single-cell RNA sequencing (scRNA-seq) data of GBM were downloaded from the Gene Expression Omnibus (GEO) database. Cells were clustered using the Seurat R package, and the clusters were annotated using the CellMarker database. Pseudotime analysis was conducted using Monocle2. Marker scores were calculated based on the RNA-seq data of GBM from the UCSC database, and the enrichment of Hallmark gene sets was measured with the AUCell package. Furthermore, the most frequently mutated genes were identified using the simple nucleotide variation data from The Cancer Genome Atlas (TCGA) applying the maftools package. This study identified two oligodendrocyte subsets (ODC3 and ODC4) as radiotherapy-resistant groups in GBM. Enrichment and Pseudotime analysis revealed that the inflammatory response and immune activation pathways were enriched in ODC3, while the cell division and interferon response pathways were enriched in ODC4. The enrichment scores of hallmark gene sets further confirmed that ODC3 and ODC4 subpopulations developed radiotherapy resistance via distinct molecular mechanisms. Analysis of gene mutation frequencies showed that TP53 exhibited the most significant change in mutation frequency, indicating that it was an important risk factor involved in radiotherapy resistance in GBM. We identified two ODC subpopulations that exhibited resistance to radiotherapy, providing a new perspective and potential targets for personalized treatment strategies for GBM.

Microbiota and Recurrent Pregnancy Loss (RPL); More than a Simple Connection.

Recurrent Pregnancy Loss (RPL) affects 1-2% of women, and its triggering factors are unclear. Several studies have shown that the vaginal, endometrial, and gut microbiota may play a role in RPL. A decrease in the quantity of Lactobacillus crispatus in local microbiota has been associated with an increase in local (vaginal and endometrial) inflammatory response and immune cell activation that leads to pregnancy loss. The inflammatory response may be triggered by gram-negative bacteria, lipopolysaccharides (LPS), viral infections, mycosis, or atypia (tumor growth). Bacterial structures and metabolites produced by microbiota could be involved in immune cell modulation and may be responsible for immune cell activation and molecular mimicry. Gut microbiota metabolic products may increase the amount of circulating pro-inflammatory lymphocytes, which, in turn, will migrate into vaginal or endometrial tissues. Local pro-inflammatory Th1 and Th17 subpopulations and a decrease in local Treg and tolerogenic NK cells are accountable for the increase in pregnancy loss. Local microbiota may modulate the local inflammatory response, increasing pregnancy success. Analyzing local and gut microbiota may be necessary to characterize some RPL patients. Although oral supplementation of probiotics has not been shown to modify vaginal or endometrial microbiota, the metabolites produced by it may benefit patients. Lactobacillus crispatus transplantation into the vagina may enhance the required immune tolerogenic response to achieve a normal pregnancy. The effect of hormone stimulation and progesterone to maintain early pregnancy on microbiota has not been adequately studied, and more research is needed in this area. Well-designed clinical trials are required to ascertain the benefit of microbiota modulation in RPL.

Differentiating Stages of Bipolar and Unipolar Depression-The Possible Role of sICAM-1 and sVCAM-1.

Increased immune-inflammatory activation has been repeatedly linked to etiopathogenesis and the progression of both major depressive disorder (MDD) and bipolar depression (BD). We explore the role of soluble intercellular cell adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) in diagnostic differentiation and disorder progression in patients with MDD and BD. Serum levels of sICAM-1 and sVCAM-1 were measured in 137 patients (MDD = 93 and BD = 44) and compared with 73 healthy controls. The severity of psychopathology was assessed using the Hamilton Depression Rating Scale and Clinical Global Impression Scale. After adjustment for multiple confounders, we noticed significant downregulation of sVCAM-1 and upregulation of sICAM-1 levels in both patient groups. Decreased sVCAM-1 levels were detected in patients with acute episodes of BD when compared to MDD. Immune mediators were related to indicators of progression in both mood disorders. They also followed different post-treatment normalization patterns in MDD and BD and in relation to the stage of each disorder. Adhesion molecules could potentially be useful in discriminating between patients with MDD and BD and determining the possible progression of the disorders. Future nosological methods should include time-dependent pathoplasticity and biological correlates, at least for affective disorders.

Association of the systemic immune-inflammation index with all-cause and cardiovascular mortality in individuals with rheumatoid arthritis

The systemic immune-inflammation index (SII), a metric reflecting systemic inflammatory response and immune activation, remains underexplored concerning its correlation with mortality among rheumatoid arthritis (RA) patients. This study aimed to delineate the association between SII and both all-cause and cardiovascular mortality within the cohort of American adults diagnosed with RA, utilizing data from the National Health and Nutrition Examination Survey (NHANES) spanning 1999 to 2018. The investigation extracted data from NHANES cycles between 1999 and 2018, identifying RA patients through questionnaire responses. The SII was computed based on complete blood counts, employing the formula: (platelets × neutrophils) / lymphocytes. The optimal SII cutoff value for significant survival outcomes was determined using maximally selected rank statistics. Multivariable Cox proportional hazards models assessed the relationship between SII levels and mortality (all-cause and cardiovascular) among RA patients, with subgroup analyses examining potential modifications by clinical confounders. Additionally, restricted cubic spline (RCS) analyses were conducted to explore the linearity of the SII-mortality association. The study encompassed 2070 American adults with RA, among whom 287 exhibited a higher SII (≥ 919.75) and 1783 a lower SII (< 919.75). Over a median follow-up duration of 108 months, 602 participants died. After adjustments for demographic, socioeconomic, and lifestyle variables, a higher SII was associated with a 1.48-fold increased risk of all-cause mortality (hazard ratio [HR] = 1.48, 95% confidence interval [CI] 1.21–1.81, P < 0.001) and a 1.51-fold increased risk of cardiovascular mortality (HR = 1.51, 95% CI 1.04–2.18, P = 0.030) compared to a lower SII. Kaplan–Meier analyses corroborated significantly reduced survival rates within the higher SII cohort for both all-cause and cardiovascular mortality (Pall-cause mortality < 0.0001 and Pcardiovascular mortality = 0.0004). RCS analyses confirmed a positive nonlinear relationship between SII and mortality rates. In conclusion, the SII offers a straightforward indicator of the equilibrium between detrimental innate inflammation and beneficial adaptive immunity. Our investigation, utilizing a comprehensive and nationally representative sample, reveals that elevated SII levels independently forecast a greater risk of mortality from all causes, as well as cardiovascular-specific mortality, in individuals suffering from RA. These insights underscore the clinical relevance of the SII as an affordable and readily accessible biomarker. Its incorporation into regular clinical practice could significantly enhance the precision of risk assessment and forecasting for patients with RA, facilitating more tailored and effective management strategies. Specifically, patients with high SII levels could be identified for more stringent cardiovascular risk management, including closer monitoring, lifestyle interventions, and aggressive pharmacological treatments to mitigate their increased risk of mortality.

Complete blood count-based inflammation indexes and symptom severity in people with schizophrenia spectrum disorders: An analysis based on structural equation modelling

IntroductionSchizophrenia spectrum disorders (SSDs) are associated with immune-inflammatory activation. Recently, complete blood count (CBC)-based inflammation indexes such as the neutrophil-to-lymphocyte ratio (NLR), the monocyte-to-lymphocyte ratio (MLR), and the platelet-to-lymphocyte ratio (PLR) have emerged as reproducible and cost-effective inflammation markers in mental disorders. In this study, we aimed at investigating the relationship of NLR, MLR, and PLR with symptom severity in people with SSDs, testing interactions with relevant clinical variables. MethodsWe included inpatients with SSDs aged 18–65 consecutively hospitalized from May 2020 to March 2024. Socio-demographic and clinical data were recorded. CBC-based ratios were estimated from routinely collected blood samples. Structural equation modelling (SEM) was performed to test relationships involving symptom severity constructs and CBC-based ratios, accounting for substance use disorder, antipsychotic treatment, and obesity. ResultsTwo hundred sixty-six participants met inclusion criteria. The SEM analysis uncovered a significant relationship of MLR with positive (coeff.: 0.19, p=0.048) and negative (coeff.: 0.27, p=0.004) symptoms, also showing a significant link of substance use disorder and antipsychotic treatment with symptom severity as well as of antipsychotic treatment with obesity. ConclusionsNotwithstanding the cross-sectional design and the somewhat limited sample representativeness, this study showed a significant relationship between the MLR – but not the NLR or the PLR – and the severity of both positive and negative symptoms, testing at the same time the interactions with other clinical variables. Considering the insufficiency and inconsistency of data in this field, further research is needed to validate our findings and elucidate the underlying mechanisms driving the observed relationships between the MLR and SSD symptoms.

Multi-cohort analysis reveals immune subtypes and predictive biomarkers in tuberculosis

Tuberculosis (TB) remains a significant global health threat, necessitating effective strategies for diagnosis, prognosis, and treatment. This study employs a multi-cohort analysis approach to unravel the immune microenvironment of TB and delineate distinct subtypes within pulmonary TB (PTB) patients. Leveraging functional gene expression signatures (Fges), we identified three PTB subtypes (C1, C2, and C3) characterized by differential immune-inflammatory activity. These subtypes exhibited unique molecular features, functional disparities, and cell infiltration patterns, suggesting varying disease trajectories and treatment responses. A neural network model was developed to predict PTB progression based on a set of biomarker genes, achieving promising accuracy. Notably, despite both genders being affected by PTB, females exhibited a relatively higher risk of deterioration. Additionally, single-cell analysis provided insights into enhanced major histocompatibility complex (MHC) signaling in the rapid clearance of early pathogens in the C3 subgroup. This comprehensive approach offers valuable insights into PTB pathogenesis, facilitating personalized treatment strategies and precision medicine interventions.

Propionate and butyrate counteract renal damage and progression to chronic kidney disease.

Short-chain fatty acids (SCFAs), mainly acetate, propionate and butyrate, are produced by gut microbiota through fermentation of complex carbohydrates that cannot be digested by the human host. They affect gut health and can contribute at the distal level to the pathophysiology of several diseases, including renal pathologies. SCFA levels were measured in chronic kidney disease (CKD) patients (n=54) at different stages of the disease, and associations with renal function and inflammation parameters were examined. The impact of propionate and butyrate in pathways triggered in tubular cells under inflammatory conditions was analysed using genome-wide expression assays. Finally, a pre-clinical mouse model of folic acid-induced transition from acute kidney injury to CKD was used to analyse the preventive and therapeutic potential of these microbial metabolites in the development of CKD. Faecal levels of propionate and butyrate in CKD patients gradually reduce as the disease progresses, and do so in close association with established clinical parameters for serum creatinine, blood urea nitrogen and the estimated glomerular filtration rate. Propionate and butyrate jointly downregulated the expression of 103 genes related to inflammatory processes and immune system activation triggered by tumour necrosis factor-α in tubular cells. In vivo, the administration of propionate and butyrate, either before or soon after injury, respectively, prevented and slowed the progression of damage. This was indicated by a decrease in renal injury markers, the expression of pro-inflammatory and pro-fibrotic markers, and recovery of renal function over the long term. Propionate and butyrate levels are associated with a progressive loss of renal function in CKD patients. Early administration of these SCFAs prevents disease advancement in a pre-clinical model of acute renal damage, demonstrating their therapeutic potential independently of the gut microbiota.

Methionine-choline deficient diet deteriorates DSS-induced murine colitis through disturbance of gut microbes and infiltration of macrophages.

Ulcerative colitis (UC) is associated with changed dietary habits and mainly linked with the gut microbiota dysbiosis, necroptosis of epithelial cells, and mucosal ulcerations. Liver dysfunction and abnormal level of liver metabolism indices were identified in UC patients, suggesting a close interaction between gut and liver disorders. Methionine-choline deficient diet (MCD) has been shown to induce persistent alterations of gut microbiota and metabolome during hepatitis. In this study we further explored the disease phenotypes in UC patients and investigated whether MCD functioned as a trigger for UC susceptibility. After assessing 88 serum specimens from UC patients, we found significant liver dysfunction and dyslipidemia including abnormal ALT, AST, TG, TC, LDL-c and HDL-c. Liver dysfunction and dyslipidemia were confirmed in DSS-induced colitis mice. We fed mice with MCD for 14 days to cause mild liver damage, and then treated with DSS for 7 days. We found that MCD intake significantly exacerbated the pathogenesis of mucosal inflammation in DSS-induced acute, progressive, and chronic colitis, referring to promotion of mucosal ulcers, colon shortening, diarrhea, inflammatory immune cell infiltration, cytokines release, and abnormal activation of inflammatory macrophages in colon and liver specimens. Intraperitoneal injection of clodronate liposomes to globally delete macrophages dramatically compromised the pathogenesis of MCD-triggering colitis. In addition, MCD intake markedly changed the production pattern of short-chain fatty acids (SCFAs) in murine stools, colons, and livers. We demonstrated that MCD-induced colitis pathogenesis largely depended on the gut microbes and the disease phenotypes could be transmissible through fecal microbiota transplantation (FMT). In conclusion, this study supports the concept that intake of MCD predisposes to experimental colitis and enhances its pathogenesis via modulating gut microbes and macrophages in mice.

Transcriptional Changes in Radiation-Induced Lung Injury: A Comparative Analysis of Two Radiation Doses for Preclinical Research.

In a recent stereotactic body radiation therapy animal model, radiation pneumonitis and radiation pulmonary fibrosis were observed at around 2 and 6 weeks, respectively. However, the molecular signature of this model remains unclear. This study aimed to examine the molecular characteristics at these two stages using RNA-seq analysis. Transcriptomic profiling revealed distinct transcriptional patterns for each stage. Inflammatory response and immune cell activation were involved in both stages. Cell cycle processes and response to type II interferons were observed during the inflammation stage. Extracellular matrix organization and immunoglobulin production were noted during the fibrosis stage. To investigate the impact of a 10 Gy difference on fibrosis progression, doses of 45, 55, and 65 Gy were tested. A dose of 65 Gy was selected and compared with 75 Gy. The 65 Gy dose induced inflammation and fibrosis as well as the 75 Gy dose, but with reduced lung damage, fewer inflammatory cells, and decreased collagen deposition, particularly during the inflammation stage. Transcriptomic analysis revealed significant overlap, but differences were observed and clarified in Gene Ontology and KEGG pathway analysis, potentially influenced by changes in interferon-gamma-mediated lipid metabolism. This suggests the suitability of 65 Gy for future preclinical basic and pharmaceutical research connected with radiation-induced lung injury.

Assessment of Clinical Analgesic Levels and Serum Biomarkers in Patients with Rheumatoid Arthritis: A Randomized Controlled Trial Comparing the Efficacy of Diclofenac and Methotrexate Combined Therapy with Extracorporeal Shockwave Therapy.

Rheumatoid arthritis (RA) is one of the most common forms of arthritis. Extracorporeal shockwave therapy (ESWT) has been identified as a viable alternative therapeutic approach in light of the present protracted clinical course of pharmacological treatment, and changes in levels of marker proteins in the blood samples of RA patients can be utilized to assess treatment outcomes. A randomized controlled trial was conducted involving forty patients diagnosed with rheumatoid arthritis (RA) who were assigned randomly to two groups. The first group received a combination of diclofenac and methotrexate (MTX) consisting of 25 mg of diclofenac administered thrice daily and 15 mg of MTX administered once weekly. Individual follow-up assessments were carried out after 7 and 14 days. Meanwhile, patients in the second group underwent two sessions of Extracorporeal Shockwave Therapy (ESWT), with a 7-day interval between sessions. Evaluations were conducted on day 7 and day 14. Patients who displayed pain control and stability were advised to continue the treatment, whereas those who had inflammation and discomfort were administered specific medications, and their progress was closely monitored until day 28. Blood samples were collected from both groups prior to treatment, after the first treatment, and after the second treatment. Four marker proteins (NRP-1, CELF-6, COX-2, and RGS-1) and two inflammatory cytokines (IL-6 and IL-17) were measured using western blot and RT-PCR techniques. A statistical analysis was conducted on the levels of specific proteins and inflammatory factors before and after treatment to evaluate its impact. Both groups exhibited statistically significant differences in the serum level of target biomarkers before and after the intervention. However, the ESWT group demonstrated a more noticeable effect, while the diclofenac + MTX group exhibited a delayed anti-inflammatory effect compared to ESWT. Both treatments significantly improved joint function, relieved pain, and reduced inflammation in patients. However, ESWT demonstrated a more prominent clinical analgesic effect compared to the combination treatment of diclofenac and MTX. Furthermore, ESWT produced a more immediate and noteworthy anti-inflammatory impact by regulating NRP-1 expression, a trophic factor receptor that facilitates vascular endothelial cell migration and tissue repair through angiogenesis, and regulating RGS-1 to limit inflammatory signal transmission and immune cell activation.

Clinical Significance of Pregnancy Zone Protein Expression in Patients With Locally Advanced Gastric Cancer After Curative Resection.

Pregnancy zone protein (PZP), encoded by PZP, belongs to the α-2-macroglobulin superfamily, and plays an important role in inflammatory responses and immune cell activation in cancer. However, the relationship between gastric cancer (GC) and PZP is poorly studied. This study investigated the clinical significance of PZP expression in GC tissues of patients with locally advanced GC after curative resection. Using quantitative polymerase chain reaction, we measured PZP expression in GC tissues and adjacent normal gastric mucosa of 253 patients with pStage II/III GC who underwent curative resection. We compared the expression levels of PZP in GC tissues and adjacent normal gastric mucosa and examined the relationship of PZP expression in GC tissues with clinicopathological factors and overall survival (OS). PZP expression was significantly associated with histology, venous invasion, and pathological stage. The high PZP expression group had significantly worse OS than did the low expression group (5-year survival 48.6% vs. 68.5%, p=0.0003). Furthermore, in multivariate analysis, high PZP expression was an independent factor for poor OS (hazard ratio=1.984, 95% confidence interval=1.307-3.012, p=0.0013). In post-curative resection patients with locally advanced GC, PZP expression in GC tissue may be a useful prognostic marker.

Emerging Insights into Molecular Mechanisms of Inflammation in Myelodysplastic Syndromes.

Inflammation impacts human hematopoiesis across physiologic and pathologic conditions, as signals derived from the bone marrow microenvironment, such as pro-inflammatory cytokines and chemokines, have been shown to alter hematopoietic stem cell (HSCs) homeostasis. Dysregulated inflammation can skew HSC fate-related decisions, leading to aberrant hematopoiesis and potentially contributing to the pathogenesis of hematological disorders such as myelodysplastic syndromes (MDS). Recently, emerging studies have used single-cell sequencing and muti-omic approaches to investigate HSC cellular heterogeneity and gene expression in normal hematopoiesis as well as in myeloid malignancies. This review summarizes recent reports mechanistically dissecting the role of inflammatory signaling and innate immune response activation due to MDS progression. Furthermore, we highlight the growing importance of using multi-omic techniques, such as single-cell profiling and deconvolution methods, to unravel MDSs' heterogeneity. These approaches have provided valuable insights into the patterns of clonal evolution that drive MDS progression and have elucidated the impact of inflammation on the composition of the bone marrow immune microenvironment in MDS.