Functional Dyspepsia: Current Understanding and Future Perspective.

BACKGROUND: Functional dyspepsia (FD) is a common disorder characterized by chronic or recurrent upper abdominal pain or discomfort without any structural abnormalities in the gastrointestinal tract. FD is categorized into two subgroups based on symptoms: postprandial distress syndrome (PDS) and epigastric pain syndrome. SUMMARY: The pathophysiology of FD involves several mechanisms. Delayed gastric emptying is observed in approximately 30% of FD patients but does not correlate with symptom patterns or severity. Impaired gastric accommodation is important in the pathophysiology, particularly for PDS. Visceral hypersensitivity, characterized by heightened sensitivity to normal activities, contributes to the perception of discomfort or pain in FD. Alterations to the duodenal mucosa, including impaired mucosal barrier function and low-grade inflammation, are also implicated in the pathogenesis of FD. Microbial dysbiosis and psychological factors such as stress can further exacerbate symptoms. Treatment options include dietary modifications, establishing a physician-patient relationship, acid suppressants, prokinetics, neuromodulators, and behavioral therapies. Dietary recommendations include eating smaller, more frequent meals, and avoiding trigger foods. Acid suppressants are used as the first-line treatment. Prokinetics and neuromodulators aim to improve gastric motility and central pain processing, respectively. Behavioral therapies, including cognitive behavioral therapy and hypnotherapy, have shown benefits for refractory FD. Severe and refractory cases may require combination therapies or experimental treatments. KEY MESSAGES: FD is a disorder of gut-brain interaction involving diverse pathophysiological mechanisms. Individualized treatment based on symptoms and responses to interventions is crucial. Further research is needed to improve the understanding of FD and advance the development of effective therapies.

Disturbance of Immune Microenvironment in Androgenetic Alopecia through Spatial Transcriptomics.

Androgenetic alopecia (AGA) is characterized by microinflammation and abnormal immune responses, particularly in the upper segment of hair follicles (HFs). However, the precise patterns of immune dysregulation remain unclear, partly due to limitations in current analysis techniques to preserve tissue architecture. The infundibulum, a major part of the upper segment of HFs, is associated with significant clusters of immune cells. In this study, we investigated immune cells around the infundibulum, referred to as peri-infundibular immune infiltration (PII). We employed spatial transcriptome profiling, a high-throughput analysis technology, to investigate the immunological disruptions within the PII region. Our comprehensive analysis included an evaluation of overall immune infiltrates, gene set enrichment analysis (GSEA), cellular deconvolution, differential expression analysis, over-representation analysis, protein-protein interaction (PPI) networks, and upstream regulator analysis to identify cell types and molecular dysregulation in immune cells. Our results demonstrated significant differences in immune signatures between the PII of AGA patients (PII-A) and the PII of control donors (PII-C). Specifically, PII-A exhibited an enrichment of CD4+ helper T cells, distinct immune response patterns, and a bias toward a T helper (Th) 2 response. Immunohistochemistry revealed disruptions in T cell subpopulations, with more CD4+ T cells displaying an elevated Th2 response and a reduced Th1-cytotoxic response compared to PII-C. These findings reveal the unique immune landscapes of PII-A and PII-C, suggesting potential for the development of innovative treatment approaches.

New Mechanisms to Prevent Heart Failure with Preserved Ejection Fraction Using Glucagon-like Peptide-1 Receptor Agonism (GLP-1 RA) in Metabolic Syndrome and in Type 2 Diabetes: A Review.

This review examines the impact of obesity on the pathophysiology of heart failure with preserved ejection fraction (HFpEF) and focuses on novel mechanisms for HFpEF prevention using a glucagon-like peptide-1 receptor agonism (GLP-1 RA). Obesity can lead to HFpEF through various mechanisms, including low-grade systemic inflammation, adipocyte dysfunction, accumulation of visceral adipose tissue, and increased pericardial/epicardial adipose tissue (contributing to an increase in myocardial fat content and interstitial fibrosis). Glucagon-like peptide 1 (GLP-1) is an incretin hormone that is released from the enteroendocrine L-cells in the gut. GLP-1 reduces blood glucose levels by stimulating insulin synthesis, suppressing islet α-cell function, and promoting the proliferation and differentiation of ß-cells. GLP-1 regulates gastric emptying and appetite, and GLP-1 RA is currently indicated for treating type 2 diabetes (T2D), obesity, and metabolic syndrome (MS). Recent evidence indicates that GLP-1 RA may play a significant role in preventing HFpEF in patients with obesity, MS, or obese T2D. This effect may be due to activating cardioprotective mechanisms (the endogenous counter-regulatory renin angiotensin system and the AMPK/mTOR pathway) and by inhibiting deleterious remodeling mechanisms (the PKA/RhoA/ROCK pathway, aldosterone levels, and microinflammation). However, there is still a need for further research to validate the impact of these mechanisms on humans.

Micro-inflammation related gene signatures are associated with clinical features and immune status of fibromyalgia.

BACKGROUND: Fibromyalgia (FM) is a multifaceted disease. Along with the genetic, environmental and neuro-hormonal factors, inflammation has been assumed to have role in the pathogenesis of FM. The aim of the present study was to explore the differences in clinical features and pathophysiology of FM patients under different inflammatory status. METHODS: The peripheral blood gene expression profile of FM patients in the Gene Expression Omnibus database was downloaded. Differentially expressed inflammatory genes were identified, and two molecular subtypes were constructed according to these genes used unsupervised clustering analysis. The clinical characteristics, immune features and pathways activities were compared further between the two subtypes. Then machine learning was used to perform the feature selection and construct a classification model. RESULTS: The patients with FM were divided into micro-inflammation and non-inflammation subtypes according to 54 differentially expressed inflammatory genes. The micro-inflammation group was characterized by more major depression (p = 0.049), higher BMI (p = 0.021), more active dendritic cells (p = 0.010) and neutrophils. Functional enrichment analysis showed that innate immune response and antibacterial response were significantly enriched in micro-inflammation subtype (p < 0.050). Then 5 hub genes (MMP8, ENPP3, MAP2K3, HGF, YES1) were screened thought three feature selection algorithms, an accurate classifier based on the 5 hub DEIGs and 2 clinical parameters were constructed using support vector machine model. Model scoring indicators such as AUC (0.945), accuracy (0.936), F1 score (0.941), Brier score (0.079) and Hosmer-Lemeshow goodness-of-fit test (χ2 = 4.274, p = 0.832) proved that this SVM-based classifier was highly reliable. CONCLUSION: Micro-inflammation status in FM was significantly associated with the occurrence of depression and activated innate immune response. Our study calls attention to the pathogenesis of different subtypes of FM.

Use of the systemic inflammation response index (SIRI) as a novel prognostic marker for patients on peritoneal dialysis.

BACKGROUND: The systemic inflammatory response index (SIRI), a novel inflammation maker, has proven to be associated with prognostic outcomes in various diseases. However, few studies have been conducted assessing how SIRI may influence outcomes of patients on peritoneal dialysis (PD). Herein, we assessed the predictive value of SIRI on mortality all-cause mortality, including cardiovascular disease (CVD) in PD patients. METHODS: A total of 646 PD patients were enrolled in this study. PD patients received regular PD treatments at the Zhujiang Hospital from 1 January 2011 to 31 December 2018. SIRI values could be computed as follows: neutrophil count × monocyte count/lymphocyte count. Patients were divided into two groups according to the median level of SIRI. Cox regression analysis and Kaplan-Meier methods were applied to analyze the relationship between SIRI and mortality outcomes in PD patients. RESULTS: During the median 31-month follow-up period, 97 (15.0%) PD patients died from all-causes, and 47 (49.0%) died of CVD. Kaplan-Meier analyses revealed that a high SIRI corresponded to the high mortality of all-cause deaths, including CVD (both p < 0.001) in patients on PD. After adjusting for potential confounders, the higher SIRI level was significantly associated with an increased all-cause mortality (HR: 2.007, 95% CI: 1.304-3.088, p = 0.002) and cardiovascular mortality (HR: 2.847, 95% CI: 1.445-5.608, p = 0.002). CONCLUSIONS: SIRI was a promising predictor of mortality in PD patients, with a higher SIRI corresponding to increased risk of mortality.

[Meta-analysis of Bailing Capsules in improvement of microinflammation and nutritional status among maintenance hemodialysis patients].

This Meta-analysis was designed to evaluate the effects of Bailing Capsules on microinflammation and nutritional status of maintenance hemodialysis patients, and to determine its efficacy and safety. The randomized controlled trials concerning the intervention of microinflammation and nutritional status in maintenance hemodialysis patients with Bailing Capsules were searched from Chinese and English databases including CNKI, Wanfang, VIP, PubMed, EMbase, and Cochrane Library. A total of 16 articles were obtained, involving 1 095 cases. As revealed by Meta-analysis,(1)Bailing Capsules lowered the levels of serum high sensitivity C-reactive protein(SMD=-0.92, 95%CI[-1.05,-0.80], P<0.000 01), interleukin-6(SMD=-1.49, 95%CI[-1.96,-1.02], P<0.000 01), and tumor necrosis factor-α(SMD=-1.48, 95%CI[-1.68,-1.28], P<0.000 01) in patients with maintenance hemodialysis, thus alleviating microinflammation.(2)Bailing Capsules elevated the levels of serum hemoglobin(SMD=1.37, 95%CI[1.21, 1.54], P<0.000 01), albumin(SMD=0.78, 95%CI[0.57, 0.98], P<0.000 01), and triglyceride(SMD=0.29, 95%CI[0.07, 0.50], P=0.01) in patients with hemodialysis to improve their nutritional status.(3)Bailing Capsules reduced the incidence of cardiovascular events(RR=0.45, 95%CI[0.34, 0.59], P<0.000 01).(4)A total of six patients presented with mild gastrointestinal discomfort after receiving Bailing Capsules, and no serious adverse reactions were observed. The sequential analysis showed that the sample size of this Meta-analysis had reached the expected value. Meanwhile, the grade of evidence quality suggested that the outcome indicators were mainly low or extremely low in quality. In conclusion, Bailing Capsules might have potential advantages in alleviating microinflammation, improving nutritional status, and reducing the incidence of cardiovascular events. However, in view of the low quality and evidence of the included literature, high-quality clinical trials are needed to further confirm the efficacy and safety of Bailing Capsules.

Circulating extracellular DNA is in association with continuous metabolic syndrome score in healthy adolescents.

Obesity is associated with chronic low-grade inflammation that eventually leads to metabolic complications. Extracellular DNA (ecDNA) is a damage-associated molecular pattern. Extracellular mitochondrial DNA can activate innate immunity. We hypothesized that ecDNA, especially of mitochondrial origin, could be associated with components of the metabolic syndrome in young healthy probands. In a cross-sectional study, healthy adolescents (n = 1,249) provided blood samples. Anthropometric data, blood pressure, and blood counts were assessed. In addition, biochemical analysis of sera or plasma was conducted, including the quantification of advanced oxidation protein products (AOPPs) as a marker of oxidative stress induced by neutrophil or monocyte activation. Plasma ecDNA was isolated and measured by fluorometry. Nuclear and mitochondrial DNA were quantified by real-time PCR. Males had higher total plasma ecDNA [15 (11-21) vs. 11 (8-17) ng/mL; median (interquartile range)], nuclear [1,760 (956-3,273) vs. 1,153 (600-2,292) genome equivalents (GE)/mL], and mitochondrial [37,181 (14,836-90,896) vs. 30,089 (12,587-72,286) GE/mL] DNA. ecDNA correlated positively with the continuous metabolic syndrome score (r = 0.158 for males and r = 0.134 for females). Stronger correlations were found between ecDNA of mitochondrial origin and AOPP (r = 0.202 and 0.186 for males and females, respectively). Multivariate regression analysis revealed associations of nuclear DNA with leukocyte and erythrocyte counts. The results of this study of healthy adolescents show that circulating ecDNA is associated with the risk of metabolic syndrome, not with obesity per se. The association between mitochondrial ecDNA and AOPP requires further attention as it supports a potential role of mitochondria-induced sterile inflammation in the pathogenesis of the metabolic syndrome.

Low serum vitamin D concentration is correlated with anemia, microinflammation, and oxidative stress in patients with peritoneal dialysis.

BACKGROUND: Peritoneal dialysis (PD) is a form of dialysis to replace the function of kidney, that uses the peritoneum as a dialysis membrane to remove metabolites and water retained in the body. Vitamin D deficiency is prevalent in patients treated with PD. This research investigated the correlation between serum 25-hydroxyvitamin D [25(OH)D] concentration and anemia, microinflammation, and oxidative stress in PD patients. METHODS: 62 PD patients and 56 healthy volunteers were recruited in this research. Serum concentrations of 25(OH)D and basic parameters of anemia were detected. The correlation between serum 25(OH)D concentration with anemia, oxidative stress, and microinflammatory state were analyzed. RESULTS: In the PD group, the concentration of 25(OH)D was lower than the healthy control (HC) group (p < 0.001). Hemoglobin, red blood cell count (RBC), and total iron binding capacity (TIBC) in the PD group was significantly lower (all p < 0.001), while high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α) concentrations were significantly higher, than the HC group (all p < 0.001). In the PD group, malondialdehyde (MDA) concentration was higher than in the HC group (p < 0.001), while superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were lower (both p < 0.001). Serum 25(OH)D exhibited positive correlation with hemoglobin (r = 0.4509, p = 0.0002), RBC (r = 0.3712, p = 0.0030), TIBC (r = 0.4700, p = 0.0001), SOD (r = 0.4992, p < 0.0001) and GSH-Px (r = 0.4312, p = 0.0005), and negative correlation with hs-CRP (r = - 0.4040, p = 0.0011), TNF-α (r = - 0.4721, p = 0.0001), IL-6 (r = - 0.5378, p < 0.0001) and MDA (r = - 0.3056, p = 0.0157). CONCLUSION: In conclusion, reduced serum 25(OH)D concentrations in PD patients contribute to anemia, oxidative stress and microinflammatory state.

Understanding Pattern Hair Loss-Hair Biology Impacted by Genes, Androgens, Prostaglandins and Epigenetic Factors.

Pattern hair loss (PHL) is the most frequent cause of hair loss in men and women, accounting for 65% of consultations in a hair referral center. PHL is understood to represent a hereditary, age-dependent progressive thinning of the scalp hair, which follows distinct clinical patterns with notable differences depending on sex and age of onset. Clinical and investigative advances have helped us to understand some of the pathogenic steps, leading to PHL. Besides genetic factors and peculiarities of androgen metabolism, additional pathogenic factors that are suspected include microbiomata, oxidative stress, and microinflammation. While further suspects are likely to be exposed, individual diversity of causal agents, as well as of the sequence of events, or combined factors, must be kept in mind. A large number of therapeutic molecules claimed to be active and patented in this field, and their limited efficacy in offering a definitive cure of PHL confirm the complexity of PHL. The aim of therapy is to retard progression of hair thinning and increase hair coverage of the scalp. As yet, two FDA-approved drugs are available for this purpose, oral finasteride, and topical solution of minoxidil. Variations in posology and formulation allow for an enhancement of patient comfort and treatment efficacy. Antiandrogen treatments in women with normal androgen levels have questionable efficacy while having health risks.

Fibrinogen/Albumin ratio: A more powerful prognostic index for patients with end-stage renal disease.

BACKGROUND: Microinflammation is linked to an increased risk of death due to cardiovascular disease (CVD) in patients with end-stage renal disease (ESRD). Although the fibrinogen/albumin ratio (FAR), a novel inflammatory marker, has been shown to predict mortality in various diseases, limited evidence is available for its role in ESRD. The purpose of this study is to explore the prognostic value of the FAR in ESRD patients on peritoneal dialysis (PD). METHODS: In this retrospective observational study, we enrolled patients with ESRD who underwent PD therapy in our hospital between 1 January 2011 and 31 December 2017. The Kaplan-Meier method and Cox proportional hazards models were used to determine the contact between the FAR level and mortality. RESULTS: A total of 562 patients were enrolled in our research. The median FAR was 0.12, and patients were divided into two groups (low FAR group: FAR < 0.12, n = 250, and high FAR group: FAR ≥ 0.12, n = 312) according to the median FAR. Kaplan-Meier curves showed that the cumulative incidences of both all-cause mortality and CVD mortality were significantly higher in patients with FAR ≥ 0.12 (both P < .001). In multivariable analysis, the high FAR group had an important increased risk of all-cause and CVD mortality (HR: 1.80; 95% CI: 1.03-3.14, P = .038 and HR: 2.31; 95% CI: 1.17-4.59, P = .016, respectively). CONCLUSIONS: Our results suggest that a high baseline FAR value is an independent prognostic factor in ESRD patients on PD.

Factors of microinflammation in non-diabetic chronic kidney disease: a pilot study.

BACKGROUND: The relationships between digestive bacterial translocation, uremic toxins, oxidative stress and microinflammation in a population of chronic kidney disease (CKD) patients without metabolic nor inflammatory disease are unknown. METHODS: Bacterial translocation, uremic toxins, oxidative stress, and inflammation were assessed by measuring plasma levels of 16S ribosomal DNA (16S rDNA), p-cresyl sulfate (PCS), indoxyl sulfate (IS), indole acetic acid (IAA), F2-isoprostanes, hsCRP and receptor I of TNFα (RITNFα) in patients without metabolic nor inflammatory disease. 44 patients with CKD from stage IIIB to V and 14 controls with normal kidney function were included from the nephrology outpatients. 11 patients under hemodialysis (HD) were also included. Correlations between each factor and microinflammation markers were studied. RESULTS: 16S rDNA levels were not increased in CKD patients compared to controls but were decreased in HD compared to non-HD stage V patients (4.7 (3.9-5.3) vs 8.6 (5.9-9.7) copies/µl, p = 0.002). IS, PCS and IAA levels increased in HD compared to controls (106.3 (73.3-130.4) vs 3.17 (2.4-5.1) µmol/l, p < 0.0001 for IS; 174.2 (125-227.5) vs 23.7 (13.9-52.6) µmol/l, p = 0.006 for PCS; and 3.7 (2.6-4.6) vs 1.3 (1.0-1.9) µmol/l, p = 0.0002 for IAA). Urea increased in non-HD stage V patients compared to controls (27.6 (22.7-30.9) vs 5.4 (4.8-6.4) mmol/l, p < 0.0001) and was similar in HD and in non-HD stage V (19.3 (14.0-24.0) vs 27.6 (22.7-30.9) mmol/l, p = 0.7). RITNFα levels increased in HD patients compared to controls (12.6 (9.6-13.3) vs 1.1 (1.0-1.4) ng/ml, p < 0.0001); hsCRP levels increased in non-HD stage V patients compared to controls (2.9 (1.4-8.5) vs 0.8 (0.5-1.7) mg/l, p = 0.01) and remained stable in HD patients (2.9 (1.4-8.5) vs 5.1 (0.9-11.5) mg/l, p = 1). F2-isoprostanes did not differ in CKD patients compared to controls. Among uremic toxins, IS and urea were correlated to RITNFα (r = 0.8, p < 0.0001 for both). PCS, IS and urea were higher in patients with hsCRP≧5 mg/l (p = 0.01, 0.04 and 0.001 respectively). 16S rDNA, F2-isoprostanes were not correlated to microinflammation markers in our study. CONCLUSIONS: In CKD patients without any associated metabolic nor inflammatory disease, only PCS, IS, and urea were correlated with microinflammation. Bacterial translocation was decreased in patients under HD and was not correlated to microinflammation.

Gender difference in radiotherapy-induced carotid stenosis.

Radiotherapy (RT) is often the first choice of treatment for cancer of the larynx. Studies have shown that the incidence of carotid stenosis (CS) after radiotherapy of laryngeal cancer is increasing, and that gender difference in radiotherapy-induced side effects exist. Thus, we examined the gender difference in the incidence of CS and the impact of microinflammatory factors after radiotherapy. We reported this study on patients who received radiotherapy as part of the treatment for laryngeal cancer in the Jilin Province in China. One hundred sixty-four males and 152 females were treated with radiotherapy between 2006 and 2016. The carotid diameter was determined by measuring carotid intima-media thickness in the common, external and internal carotid artery. Microinflammatory conditions were assessed by measuring the level of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Other studied risk factors included age, treatment modalities, radiation dose and energy, the height of the radiation field, and the follow-up time. CS was detected in 161 (50.9%) of the 316 patients. Carotid stenosis was mainly clinically unsuspected, two patients had anamnesis of unconsciousness. Importantly, fewer women (36.1%) had CS than men (64.6%) (p=0.004). Furthermore, male patients showed higher serum levels of hs-CRP, IL-6, and TNF-α. Taken together, our study suggested that women underoing radiotherapy of laryngeal cancer are less likely to have CS than men. Therefore, routine assessment after irradiation of laryngeal cancer seems necessary for clinical detection of asymptomatic CS, particularly in male patients.

Correlation among soluble receptors for advanced glycation end-products, soluble vascular adhesion protein-1/semicarbazide-sensitive amine oxidase (sVAP-1) and cardiometabolic risk markers in apparently healthy adolescents: a cross-sectional study.

In non-diabetics, low levels of soluble receptor for advanced glycations end products (sRAGE) associate with an increased risk of development of diabetes, cardiovascular afflictions, or death. The majority of studies in non-diabetics report an inverse relationship between measures of obesity, cardiometabolic risk factors and sRAGE and/or endogenous secretory RAGE (esRAGE) levels. To elucidate whether this inconsistency is related to the metabolically healthy obese phenotype, or a different impact of the risk factors in presence and absence of obesity, we analyzed data from 2206 apparently healthy adolescents (51 % girls) aged 15-to-19 years. The association of sRAGE levels with soluble vascular adhesion protein-1/semicarbazide sensitive amine oxidase (sVAP-1/SSAO) was also investigated. Centrally obese, including metabolically healthy, adolescents present significantly lower sRAGE and esRAGE, but not sVAP-1, levels in comparison with their lean counterparts. An increasing number of cardiometabolic risk factors did not associate with significant changes in sRAGE, esRAGE or sVAP-1 levels either in lean or in obese subjects. In multivariate analyses, WHtR, hsCRP, markers of glucose homeostasis, renal function, adiponectin, and sVAP-1 associated significantly with sRAGE and esRAGE. SVAP-1 correlated significantly with glycemia, adiponectin, hsCRP, and sRAGE. Thus, in adolescents, a decline in sRAGE and esRAGE precedes the development of metabolic syndrome. When combined, standard and non-standard cardiometabolic risk factors explain only minor proportion in a variability of sRAGE and esRAGE (8 %-11 %); or sVAP-1 (12 %-20 %). Elucidation of pathogenetic mechanisms underlying early decline in sRAGE and esRAGE levels in obese adolescents and their clinical impact with regard to future cardiometabolic health requires further studies.

Impact of the Banff 2013 classification on the diagnosis of suspicious versus conclusive late antibody-mediated rejection in allografts without acute dysfunction.

BACKGROUND: The Banff classification is used worldwide to characterize pathological findings in renal allograft biopsies. During the 11th Banff meeting, relevant changes were introduced in the diagnostic criteria for Category 2 antibody-mediated rejection (ABMR). Here, we assess the effect of these changes on the diagnosis of late chronic ABMR. METHODS: Seventy-three indication renal graft biopsies (chronic dysfunction, proteinuria and/or the presence of de novo donor-specific antibodies) from 68 kidney transplant recipients initially classified following the Banff 2009 criteria were reviewed and reclassified as per the new Banff 2013 criteria. RESULTS: The diagnostic category changed in 18% of the study biopsies with Banff 2013. The reclassification mainly involved Category 2 cases, from which 23.5% of the biopsies from older patients with worse graft function were overlooked by Banff 2009. ABMR was ruled out in 13% of cases under the Banff 2009 criteria. A significant number of the study samples were conclusively diagnosed as ABMR (40% as per Banff 2009 and 74% as per Banff 2013; P = 0.006), because of the inclusion of microvascular inflammation and the acceptance of some ultrastructural diagnostic criteria. However, when following the criteria of the new classification, samples with histological signs of chronic ABMR, in which human leucocyte antigen donor-specific antibodies are not detected or ultrastructural studies are not performed, may be inadequately characterized. CONCLUSIONS: The Banff 2013 classification helps in making a diagnosis of late ABMR, identifying cases, decreasing the percentage of suspected ABMR and making more conclusive diagnoses.

Macrophages Are Involved in Gut Bacterial Translocation and Reversed by Lactobacillus in Experimental Uremia.

BACKGROUND: Uremia causes gut microbiome dysbiosis, which is characterized by a reduction in beneficial bacteria. Intestinal bacterial translocation (BT) contributes to microinflammation in uremia, which is associated with adverse outcomes. Whether macrophages are involved in BT remains unclear. AIMS: We investigated the involvement of macrophages in BT and microinflammation in uremic rats and whether Lactobacillus LB can influence macrophage activity. METHODS: Male Sprague-Dawley rats were randomly divided into three groups: sham, uremia, and uremia + probiotic. Macrophages and GFP-labeled tracer bacteria in intestinal and extraintestinal tissues were observed by fluorescence microscopy. The macrophage ultrastructure was examined by transmission electron microscopy. Immunochemistry was used to analyze the expression of cluster of differentiation 11a (CD11a), inducible nitric oxide synthase (iNOS), and intercellular adhesion molecule-1 (ICAM-1). RT-PCR and Western blot were employed to assess the mRNA and protein expression of early growth response gene 1 (EGR1) and toll-like receptor 4 (TLR4). RESULTS: In uremic rats, the colocalization of GFP-labeled tracer bacteria and macrophages was visible in intestinal and extraintestinal tissues. Compared with the sham group, the uremic macrophages showed fewer cytoplasmic protrusions and pseudopodia. Administration of Lactobacillus LB restored the protrusions and pseudopodia. Compared with the sham group, the uremia group exhibited macrophages with higher staining intensities for CD11a, iNOS, and ICAM-1, and higher mRNA and protein expression of TLR4 and EGR1. CONCLUSIONS: Intestinal macrophages in the uremic rats are polarized toward a proinflammatory phenotype, resulting in microinflammation. Macrophages with impaired phagocytic function are associated with BT. Lactobacillus LB reduces BT by enhancing macrophage phagocytosis.

Sphingosine-1-phosphate mediates AKT/ERK maintenance of dental pulp homoeostasis.

AIM: To investigate the cell status of dental pulp cells (DPCs) in a sphingosine-1-phosphate (S1P)-induced microinflammation environment and the possible mechanisms of cell homoeostasis maintenance by S1P. METHODOLOGY: Sphingosine-1-phosphate receptor (S1PR) expression was examined in DPCs within a local S1P-induced microinflammation model established using 1 µmol L(-1) S1P. U0126 [extracellular signal-regulated kinase (ERK) inhibitor], LY294002 (AKT inhibitor) and Y27632 (ROCK inhibitor) were used to inhibit corresponding signalling pathways of DPCs. CCK8 and cell cycle analysis tested cell proliferation. Immunofluorescence staining JC-1 detected changes of mitochondrial membrane potential (ΔΨm). Tests for apoptosis and the apoptosis-related proteins Bax and Bcl-2 were assessed by flow cytometry and western blot analysis, respectively. Expressions of ERK and AKT were evaluated by western blot analysis. The results were analysed using the Student's t-test and the significance level set at P < 0.05. RESULTS: Expressions of S1PR1, S1PR2 and S1PR3 in DPCs differed amongst individuals. DPCs maintained self-homoeostasis in response to S1P-induced microinflammation via S1PRs. During this repair process, ERK, AKT and ROCK had a short-term complementary interaction at 60 min, but then AKT and ERK gradually played decisive roles after 24 h in proliferation enhancement and apoptosis inhibition, respectively (P > 0.05). CONCLUSIONS: The AKT-ERK balance may determine whether DPC homoeostasis in S1P-induced microinflammation is maintained by synergistic regulation of cell growth and apoptosis.

Chrysin, an anti-inflammatory molecule, abrogates renal dysfunction in type 2 diabetic rats.

Diabetic nepropathy (DN) is considered as the leading cause of end-stage renal disease (ESRD) worldwide, but the current available treatments are limited. Recent experimental evidences support the role of chronic microinflammation in the development of DN. Therefore, the tumor necrosis factor-alpha (TNF-α) pathway has emerged as a new therapeutic target for the treatment of DN. We investigated the nephroprotective effects of chrysin (5, 7-dihydroxyflavone) in a high fat diet/streptozotocin (HFD/STZ)-induced type 2 diabetic Wistar albino rat model. Chrysin is a potent anti-inflammatory compound that is abundantly found in plant extracts, honey and bee propolis. The treatment with chrysin for 16weeks post induction of diabetes significantly abrogated renal dysfunction and oxidative stress. Chrysin treatment considerably reduced renal TNF-α expression and inhibited the nuclear transcription factor-kappa B (NF-кB) activation. Furthermore, chrysin treatment improved renal pathology and suppressed transforming growth factor-beta (TGF-ß), fibronectin and collagen-IV protein expressions in renal tissues. Chrysin also significantly reduced the serum levels of pro-inflammatory cytokines, interleukin-1beta (IL-1ß) and IL-6. Moreover, there were no appreciable differences in fasting blood glucose and serum insulin levels between the chrysin treated groups compared to the HFD/STZ-treated group. Hence, our results suggest that chrysin prevents the development of DN in HFD/STZ-induced type 2 diabetic rats through anti-inflammatory effects in the kidney by specifically targeting the TNF-α pathway.

Probiotic Bifidobacterium animalis subsp. lactis Bi-07 alleviates bacterial translocation and ameliorates microinflammation in experimental uraemia.

AIM: Uraemia is characterized by intestinal bacterial translocation, which contributes to the development of microinflammation. Probiotics enhance the intestinal barrier and overall health of the host. The present study investigated whether the probiotic Bifidobacterium animalis subsp. lactis Bi-07 alleviates bacterial translocation and ameliorates microinflammation in experimental uraemia. METHODS: Sixty Sprague-Dawley rats were divided into three groups of 20 rats each: the sham group, which underwent only laparotomy; the uraemia group, which underwent 5/6 nephrectomy; and the uraemia + probiotic group, which underwent 5/6 nephrectomy and daily intragastric administration of B. animalis subsp. lactis Bi-07 for 4 weeks. Bacterial translocation was evaluated by polymerase chain reaction amplification of the green fluorescent protein (GFP) gene from oral GFP-labelled Escherichia coli in the peripheral blood, mesenteric lymph nodes, liver, and spleen. Intestinal permeability, plasma inflammatory biomarker levels, and endotoxin levels were measured. Jejunum, ileum, and colon specimens were removed for histological examination. RESULTS: Uraemic rats exhibited a significantly higher incidence of bacterial translocation (70%) than did sham rats (10%). Probiotic treatment resulted in a decrease in bacterial translocation (20%). Intestinal permeability, inflammatory biomarker levels, and endotoxin levels in uraemic rats were significantly higher than those in the sham group. After treatment with the probiotic, inflammatory biomarker levels significantly decreased. Uraemic rats demonstrated superficial mucosal erosion and inflammatory cell infiltration in the small intestine, and administration of the probiotic alleviated these lesions. CONCLUSION: The probiotic B. animalis subsp. lactis Bi-07 alleviate bacterial translocation and ameliorate microinflammation through the recovery of intestinal mucosal integrity.

Niaodukang mixture inhibits micro-inflammation in CKD rats by enhancing MiR-146a levels in enterogenous exosomes.

ETHNOPHARMACOLOGICAL RELEVANCE: The Niaodukang mixture (NDK) is a preparation known for its ability to lower serum creatine levels in individuals with chronic kidney disease (CKD) and is commonly administered at medical facilities like the Zhongshan Hospital of Traditional Chinese Medicine. The initial use of NDK was mainly to treat CKD. Our hospital frequently utilizes NDK, which consists of Rheum officinaleBaill., Salvia miltiorrhiza Bunge., Astragalus aaronii (Eig) Zohary., Carthamus tinctorius L., and Sanguisorba officinalis L., for treating patients with CKD-MBD. It has the effects of eliminating dampness and turbidity and dredging kidney collaterals. However, The impact and process of NDK in chronic kidney disease remain unknown. AIM OF THE STUDY: To determine whether microRNA-146a (miR-146a) is associated with CKD micro-inflammationand whether NDK protects against CKD micro-inflammation by modulating the miR-146a/nuclear factor kappa-B (NF-κB) signaling pathway. MATERIALS AND METHODS: (1) An adenine-induced rat model of chronic kidney disease was created through the use of materials and methods. The levels of miR-146a in exosomes from plasma and ileum were determined by RT-PCR. (2) Human cloned colon adenocarcinoma (Caco-2)cellswere stimulated with lipopolysaccharide (LPS)and transfected with miR-146a mimic and inhibitor. Following that, the Western blot and RT-PCR techniques were used to measure the protein and mRNA quantities of Toll-like receptor 4 (TLR4), NF-κB, and TNF receptor-associated factor 6 (TRAF6). (3) Enzyme-linked immunosorbent assay (ELISA) was used to identify serum levels of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α). (4) Plasma exosomes were extracted, and the exosomes in intestinal tissues were extracted via ultrahigh-speed centrifugation.Negative staining electron microscopy was used to analyze the morphology of exosomes and the ultrastructure of intestinal tissue and exosomes. The particle size of the exosomes was measured using nanoparticle tracking analysis. RESULTS: The pathological characteristics of CKD rats included those associated with systemic micro-inflammation, which may be associated with the release of exosomes in intestinal tissue. NDK suppressed the inflammatory response in Caco-2 cells and decreased the levels of IL-1ß, IL-6, and TNF-α in rats with CKD. The expression of miR-146a, which regulates inflammation, differed between plasma-derived and enterogenous exosomes in CKD rats, which may be due to stimulation of ileal exosome release into the blood. NDK effectively reduced the levels of TRAF6, NF-κB, and TLR4 in the ileum tissue of CKD rats. CONCLUSION: NDK can effectively improve micro-inflammation in CKD ratsby enhancing the release of enterogenous exosomes, thereby enhancing the release of exosome-associated miR-146a and inhibiting micro-inflammation.