Causality of genetically determined blood metabolites on irritable bowel syndrome: A Mendelian randomization study.

BACKGROUND: Irritable bowel syndrome (IBS) is one of the most common functional bowel disorders and dysmetabolism plays an important role in the pathogenesis of disease. Nevertheless, there remains a lack of information regarding the causal relationship between circulating metabolites and IBS. A two-sample Mendelian randomization (MR) analysis was conducted in order to evaluate the causal relationship between genetically proxied 486 blood metabolites and IBS. METHODS: A two-sample MR analysis was implemented to assess the causality of blood metabolites on IBS. The study utilized a genome-wide association study (GWAS) to examine 486 metabolites as the exposure variable while employing a GWAS study with 486,601 individuals of European descent as the outcome variable. The inverse-variance weighted (IVW) method was used to estimate the causal relationship of metabolites on IBS, while several methods were performed to eliminate the pleiotropy and heterogeneity. Another GWAS data was used for replication and meta-analysis. In addition, reverse MR and linkage disequilibrium score regression (LDSC) were employed for additional assessment. Multivariable MR analysis was conducted in order to evaluate the direct impact of metabolites on IBS. RESULTS: Three known and two unknown metabolites were identified as being associated with the development of IBS. Higher levels of butyryl carnitine (OR(95%CI):1.10(1.02-1.18),p = 0.009) and tetradecanedioate (OR(95%CI):1.13(1.04-1.23),p = 0.003)increased susceptibility of IBS and higher levels of stearate(18:0)(OR(95%CI):0.72(0.58-0.89),p = 0.003) decreased susceptibility of IBS. CONCLUSION: The metabolites implicated in the pathogenesis of IBS possess potential as biomarkers and hold promise for elucidating the underlying biological mechanisms of this condition.

Rhizoma Alismatis Decoction improved mitochondrial dysfunction to alleviate SASP by enhancing autophagy flux and apoptosis in hyperlipidemia acute pancreatitis.

BACKGROUND: Acute pancreatitis (AP) is an inflammatory disorder of the exocrine pancreas, especially hyperlipidemia acute pancreatitis (HLAP) is the third leading cause of acute pancreatitis which is more severe with a greater incidence of persistent multiorgan failure. HLAP inflicts injury upon the organelles within the acinar cell, particularly mitochondria, the endolysosomal-autophagy system, and is accompanied by senescence-associated secretory phenotype (SASP). RAD, only two consists of Rhizoma Alismatis and Atractylodes macrocephala Rhizoma, which is best known for its ability to anti-inflammatory and lipid-lowering. Nevertheless, the mechanism by which RAD alleviates HLAP remains obscure, necessitating further investigation. PURPOSE: The study aimed to assess the effects of the RAD on HLAP and to elucidate the underlying mechanism in vivo and in vitro, offering a potential medicine for clinical treatment for HLAP. STUDY DESIGN AND METHODS: C57BL/6 mice with hyperlipidemia acute pancreatitis were induced by HFD and CER, then administrated with RAD. AR42J were stimulated by cerulein or conditioned medium and then cultured with RAD. Serums were analyzed to evaluate potential pancreas and liver damage. Furthermore, tissue samples were obtained for histological, and protein investigations by H&E, Oil red staining, and Western blot. In addition, western blot and immunofluorescent staining were utilized to estimate the effect of RAD on mitochondrial function, autophagy flux, and SASP. RESULTS: In vivo, RAD considerably alleviated systemic inflammation while attenuating TC, TG, AMY, LPS, inflammatory cytokines, histopathology changes, oxidative damage, mitochondrial fission, and autophagy markers in HLAP mice. Impaired autophagy flux and mitochondrial dysfunction resulted in a significant enhancement of NLRP3 and IL-1ß in the pancreas. RAD could reverse these changes. In vitro, RAD significantly restored mitochondrial membrane potential and oxidative phosphorylation levels. RAD decreased Beclin-1 and LC3-II expression and increased LAMP-1 and Parkin-Pink expression, which showed that RAD significantly ameliorated HLAP-induced damage to the mitochondria function by suppressing mitochondrial oxidative damage and enhancing autophagy flux and mitophagy to remove the damaged mitochondria. In addition, we found that RAD could up-regulate the expression of BAX, and Bad and down-regulate the expression of p16, and p21, indicating that RAD could promote damaged cell apoptosis and alleviate SASP. CONCLUSIONS: This study revealed that RAD ameliorates mitochondrial function to alleviate SASP through enhancing autophagy flux, mitophagy, and apoptosis which provided a molecular basis for the advancement and development of protection strategies against HLAP.

The Overlap Subgroup of Functional Dyspepsia Exhibits More Severely Impaired Gastric and Autonomic Functions.

GOALS: A combination of multiple tests was introduced to noninvasively investigate the differences in pathophysiologies among functional dyspepsia (FD) subgroups, including postprandial distress syndrome (PDS), epigastric pain syndrome (EPS), and overlap. BACKGROUND: It has not been extensively evaluated whether different pathophysiologies are involved in FD subgroups. STUDY: This multicenter study included 364 FD patients fulfilling Rome IV criteria and 47 healthy controls. A combined noninvasive gastric and autonomic function test was performed: The electrogastrogram and electrocardiogram were recorded simultaneously in the fasting state and after a drink test. Symptoms after drinking were recorded using visual analog scale. RESULTS: (1) Compared with HC, FD patients showed a decreased maximum tolerable volume (MTV) ( P <0.01) and percentage of normal gastric slow waves [normal gastric slow waves (%NSW)] ( P <0.01), and increased postdrinking symptoms, anxiety ( P <0.01), and depression ( P <0.01). The drink reduced %NSW in both FD patients and HC; however, the effect was more potent in patients. (2) The PDS and overlap groups displayed a reduced MTV ( P <0.05). The overlap group exhibited a higher symptom score at 30 minutes after drinking, and higher anxiety and depression scores, and a higher sympathovagal ratio than the EPS ( P <0.05 for all) and PDS ( P <0.01 for all). (3) In the PDS subgroup, the MTV, postprandial sympathovagal ratio, and depression were associated with the overall dyspepsia symptom scale (DSS, P =0.034, 0.021, 0.043, respectively). No significant associations were found in the other 2 subgroups. CONCLUSIONS: The combination of multiple tests can detect pathophysiological abnormities in FD patients. Overall, patients with overlap symptoms display more severe pathophysiologies.

Soli-enabled noncontact heart rate detection for sleep and meditation tracking.

Heart rate (HR) is a crucial physiological signal that can be used to monitor health and fitness. Traditional methods for measuring HR require wearable devices, which can be inconvenient or uncomfortable, especially during sleep and meditation. Noncontact HR detection methods employing microwave radar can be a promising alternative. However, the existing approaches in the literature usually use high-gain antennas and require the sensor to face the user's chest or back, making them difficult to integrate into a portable device and unsuitable for sleep and meditation tracking applications. This study presents a novel approach for noncontact HR detection using a miniaturized Soli radar chip embedded in a portable device (Google Nest Hub). The chip has a [Formula: see text] dimension and can be easily integrated into various devices. The proposed approach utilizes advanced signal processing and machine learning techniques to extract HRs from radar signals. The approach is validated on a sleep dataset (62 users, 498 h) and a meditation dataset (114 users, 1131 min). The approach achieves a mean absolute error (MAE) of 1.69 bpm and a mean absolute percentage error (MAPE) of [Formula: see text] on the sleep dataset. On the meditation dataset, the approach achieves an MAE of 1.05 bpm and a MAPE of [Formula: see text]. The recall rates for the two datasets are [Formula: see text] and [Formula: see text], respectively. This study represents the first application of the noncontact HR detection technology to sleep and meditation tracking, offering a promising alternative to wearable devices for HR monitoring during sleep and meditation.

C-reactive protein/albumin ratio and IL-6 are associated with disease activity in patients with ulcerative colitis.

BACKGROUND: Cytokines are key mediators of the inflammation in ulcerative colitis (UC); there are inconsistent data on cytokines profile in patients with UC. C-reactive protein/albumin ratio (CRP/ALB) has also been found as an inflammatory indicator. However, the role of CRP/ALB in UC remains unclear. We aimed to evaluate the CRP/ALB ratio and cytokines profile in patients with UC. We further explore the association between CRP/ALB and inflammatory markers, such as erythrocyte sedimentation rate (ESR), fecal calprotectin (FC) and cytokines. METHODS: One hundred thirty UC patients and 65 controls were included in the study. Clinical and laboratory findings were retrospectively reviewed; differences in variables between two groups were examined using the Mann-Whitney U-test. The association between CRP/ALB, cytokines, and clinical parameters was determined by Spearman's correlation test. RESULTS: CRP/ALB levels were significantly elevated in active UC patients. The optimal cutoff level of the CRP/ALB was 0.083. The patients with active UC had a median interleukin-6 (IL-6) level of 7.715 pg/ml (interquartile ranges, IQR 3.475-14.63), which was significantly higher than those in remission (2.95 pg/ml, IQR 2.17-5.44) (p < 0.001). Positive correlations between CRP/ALB and inflammatory markers were also observed. CONCLUSIONS: Our results suggest that CRP/ALB and IL-6 could be potential biomarkers for assessment of clinical activity in Chinese patients with UC.

Associations between red blood cell count and metabolic dysfunction-associated fatty liver disease(MAFLD).

BACKGROUND: Some studies found that red blood cell count (RBC) was an unrecognized risk factor for non-alcoholic fatty liver disease (NAFLD). While the epidemiological data underpinning the evidence is very limited. As there are some differences between the latest criteria of metabolic dysfunction-associated fatty liver disease (MAFLD) and NAFLD, itis necessary to evaluate the relationship between RBC and MAFLD. METHODS: We performed a cross-sectional analysis of the National Health and Nutritional Examination Survey (NHANES)2017-2018 cohort, including 4477 participants. Hepatic steatosis was determined when the value of controlled attenuation parameter (CAP) obtained by Fibroscan was ≥274 dB/m. Multivariate logistic regression analysis was used to estimate the association between RBC and MAFLD. We estimated the adjusted odds ratio (OR) of RBC for MAFLD, and the nonlinear relationship between RBC and MAFLD was further described using smooth curve fittings and threshold-effect analysis. RESULTS: We found that MAFLD risk was significantly higher according to RBC quartiles. The adjusted odds ratio (OR) and 95% confidence intervals (CIs)for the highest RBC quartile were 1.5(1.0, 2.3) for male and 1.1 (0.8, 1.6) for female, respectively. As for male, a non-linear relationship was discovered between RBCs and MAFLD, with a RBC threshold of 4.2. The effect sizes and confidence intervals on the right side of the inflection point were 1.5 (1.0, 2.0) (P for nonlinearity = 0.027). The sensitivity analysis showed a similar result. CONCLUSION: We demonstrated that that elevated RBC level is associated with the higher risk of MAFLD in male. The positive relationship was not significant in females after full adjustment. Our finding provided novel evidence indicating that RBCs might be a potential biomarker for MAFLD.

Evaluation of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio as potential markers for ulcerative colitis: a retrospective study.

PURPOSE: Ulcerative colitis (UC) is a chronic idiopathic inflammatory disorder affecting the large intestine. Inflammatory biomarkers in UC are nonspecific, simple and cheap biomarker is needed. Our study aimed to explore the possible relationship of platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) with the disease activity in UC. Furthermore, the correlation of PLR or NLR with other clinical indicators was evaluated. METHODS: We retrospectively reviewed the clinical data of UC patients presented to the Affiliated Hospital of Nanjing TCM University. A total of 306 UC patients were included in the study. Clinical characteristics, NLR, PLR, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fecal calprotectin (FC) and other data were collected. RESULTS: PLR and NLR were elevated in active UC patients than those in remission. The receiver-operating characteristic (ROC) analysis revealed the optimal cutoff of NLR for active UC was 2.19, with sensitivity and specificity of 78.8 and 65%, respectively. For PLR, the best cut-off value was 147.96, with sensitivity and specificity of 58.3 and 75%, respectively. Both NLR and PLR were positively correlated with CRP, ESR and FC. CONCLUSIONS: PLR and NLR were elevated in patients with active UC as compared with patients in remission. NLR and PLR could be used in patients with UC as noninvasive markers of disease activity.

The design and synthesis of redox-responsive oridonin polymeric prodrug micelle formulation for effective gastric cancer therapy.

Advanced gastric cancer (GC) is a significant threat to human health. Oridonin (ORI), isolated from the Chinese herb Rabdosia rubescens, has demonstrated great potential in GC therapy. However, the application of ORI in the clinic was greatly hindered by its poor solubility, low bioavailability, and rapid plasma clearance. Herein, a simple and novel redox-sensitive ORI polymeric prodrug formulation was synthesized by covalently attaching ORI to poly(ethylene glycol)-block-poly(l-lysine) via a disulfide linker, which can self-assemble into micelles (P-ss-ORI) in aqueous solutions and produce low critical micelle concentrations (about 10 mg L-1), characterized by small size (about 80 nm), negative surface charge (about -12 mV), and high drug loading efficiency (18.7%). The in vitro drug release study showed that P-ss-ORI can rapidly and completely release ORI in a glutathione (GSH)-rich environment and under low pH conditions. Moreover, in vitro and in vivo investigations confirmed that P-ss-ORI could remarkably extend the blood circulation time of ORI, enrich in tumor tissue, be effectively endocytosed by GC cancer cells, and quickly and completely release the drug under high intracellular GSH concentrations and low pH conditions, all these characteristics ultimately inhibit the growth of GC. This redox and pH dual-responsive P-ss-ORI formulation provides a useful strategy for GC treatment.

Protective effect of baicalin on the regulation of Treg/Th17 balance, gut microbiota and short-chain fatty acids in rats with ulcerative colitis.

Baicalin is reported as an effective drug for ulcerative colitis (UC). However, its effect on gut microbiota and short-chain fatty acids (SCFAs) remains unknown. In this study, we investigated the role of baicalin on Th17/Treg balance, gut microbiota community, and SCFAs levels in trinitrobenzene sulphonic acid (TNBS)-induced UC rat model. We found the DAI scores were significantly increased in the TNBS-treated rats, while reduced in the baicalin-treated group in a dose-dependent manner, accompanied with the alleviation of mucosal injury, the reduction of ZO-1, Occludin, and MUC2 expression. At the meanwhile, baicalin repressed the increased levels of reactive oxygen species (ROS) and MDA, while deceased the GSH and SOD levels in colon tissue of rats treated with TNBS. On the other hand, administration of baicalin attenuated the TNBS-induced upregulations of Th17/Treg ratio, indicating a strong amelioration in the colorectal inflammation. More importantly, pyrosequencing of the V4 regions of 16S rRNA genes in rat feces revealed a deviation of the gut microbiota in response to baicalin treatment. In particular, the decreased Firmicutes-to-Bacteroidetes ratios and endotoxin-bearing Proteobacteria levels indicated that baicalin reversed TNBS-induced gut dysbiosis OTUs. In addition, we further investigated the fecal levels of major SCFAs in rats and found that baicalin significantly resorted the fecal butyrate levels in rats treated with TNBS. The increased butyrate levels were in consistent with the higher abundance of butyrate-producing species such as Butyricimonas spp., Roseburia spp., Subdoligranulum spp., and Eubacteriu spp. in baicalin-treated group. In conclusion, our findings suggest that baicalin possibly protected rats against ulcerative colitis by regulation of Th17/Treg balance, and modulation of both gut microbiota and SCFAs. Baicalin may be used as a prebiotic agent to treat ulcerative colitis-associated inflammation and gut dysbiosis.

Effect of Gubi prescription on caveolin-1 expression and phosphoinositide 3 kinase/protein kinase B and Fas signal pathways in rats with knee osteoarthritis.

OBJECTIVE: To investigate the effects of Gubi prescription on the expression of caveolin-1, and the phosphoinositide 3 kinase/protein kinase B (PI3K/Akt) and Fas signal pathways in rats with knee osteoarthritis (KOA). METHODS: Forty KOA model rats were established using a modification of Hulth's method. Rats were divided into five groups by the random number method: model, positive drug (Vicolli group), and high-, medium-, and low-dose Gubi prescription groups (n = 8/group). In the sham surgery group (n = 8), only anterior and posterior cruciate ligaments of rats were exposed during surgery. A normal group (n = 8) consisted of rats with no treatment. Rats were intragastrically administered corresponding drugs once every day for eight consecutive weeks. Then, rat synovial membranes were extracted and histomorphological changes were recorded. mRNA expression was measured by q-PCR. Serum superoxide dismutase (SOD), malondialdehyde (MDA), nitric oxide (NO), and interleukin 1ß (IL-1ß) levels were measured. Western blotting determined the effects of Gubi prescription on protein expressions of caveolin-1, Bax, Bcl-2, Fas, and caspase-3 in chondrocytes from KOA rats. The knee cartilage of rats was excised and cultured under aseptic conditions. After coincubation of chondrocytes with Gubi prescription-containing serum, IL-1ß, and siRNA, Western blotting was used to determine the protein expressions of caveolin-1, Bax, Bcl-2, Fas, and caspase-3. RESULTS: The morphological score of the articular synovium in the model group was significantly higher than in the normal group (P < 0.01). The morphological score in the high- and medium-dose Gubi prescription groups was lower than in the model group (P < 0.05). Chondrocytes from the decoction-containing serum group had a lower expression of Bax (P < 0.05), and higher expressions of Bcl-2 (P < 0.05) and caspase-3 (P < 0.05) compared with the model group. Chondrocytes in the decoction-containing serum group had higher expressions of Bax and Bcl-2 (P < 0.01) and lower expressions of caveolin-1 and Fas (P < 0.05) compared with the model group. Compared with the model group, Bax and caspase-3 expressions were reduced in the chondrocytes of all three Gubi prescription groups (P < 0.05) whereas Bcl-2 expression was increased (P < 0.05). Compared with the model group, the expressions of caveolin-1 and Fas (P < 0.05) were reduced in groups that received high- and medium-doses of Gubi prescription. Gubi prescription increased the serum level of SOD and significantly reduced those of MDA, NO and IL-1ß (P < 0.05). CONCLUSION: Gubi prescription suppressed the chondrocyte-related PI3K/Akt and Fas signal pathways and inhibited the overexpression of caveolin-1 in rat chondrocytes.

[Effects and efficacy observation of acupuncture on serum 5-HT in patients with diarrhea-predominant irritable bowel syndrome].

OBJECTIVE: To evaluate the clinical efficacy of acupuncture for treatment of diarrhea-predominant irritable bowel syndrome and discuss its action mechanism. METHODS: Fifty-seven cases were randomly divided into two groups. The acupuncture group (29 cases) was treated with acupuncture at Taichong (LR 3), Zusanli (ST 36) and Sanyinjiao (SP 6) etc., once a day and 5 times per week. The medication group (28 cases) was treated with oral administration of pinaverium (50 mg each time, 3 times a day) and live combined bifidobacterium and lactobacillus tablet (4 tablets each time, 3 times a day). Four weeks were taken as a treatment course in both groups. Before and after treatment ELISA method was applied to measure the level of serum 5-HT of the patients in two groups. The scores of clinical symptoms were observed before treatment, after one and four weeks of treatment and 3 months after treatment, respectively. RESULTS: The level of serum 5-HT was significantly reduced in the acupuncture group and medication group (P < 0.01, P < 0.05), which had no statistical difference between two groups (P > 0.05). Compared with the medication group, the scores of clinical symptoms were obviously improved in the acupuncture group after one and four weeks of treatment and 3 months after treatment (P < 0.01, P < 0.05). The total effective rate was 89.66% (26/29) in the acupuncture group, which was superior to 67.85% (19/28) in the medication group (P < 0.05). CONCLUSION: The efficacy of acupuncture is superior to that of medicine in the treatment of diarrhea-predominant irritable bowel syndrome. The acupuncture treatment could reduce the visceral sensitivity, improve the intestinal motility and regulate the imbalance of brain-intestine interactive function.

Clinical evaluation of Soothing Gan and invigorating Pi acupuncture treatment on diarrhea-predominant irritable bowel syndrome.

OBJECTIVE: To explore the effect of Soothing Gan and invigorating Pi (SGIP) acupuncture treatment on the clinical symptoms and quality of life (QOL) in patients with diarrhea-predominant irritable bowel syndrome (IBS-D). METHODS: With a single-blinded randomized control study adopted, 63 patients who met the inclusion criteria were assigned by a random number table to two groups, 31 in the treatment group and 32 in the drug control group. The treatment group received SGIP acupuncture therapy; while the control group was treated orally with pinaverium bromide. The treatment duration of both groups was 28 days. The clinical efficacy was evaluated and compared by scoring patient's symptom and QOL. RESULTS: A significant difference was found by variance analysis in efficacies between the two groups (P<0.01), shown as the quicker initiation of effect (P<0.05) and the more evident clinical improvement in symptoms along the increase in treatment duration, as well as the more significant elevation of QOL in the acupuncture treatment group (P<0.01). SGIP displayed its superiority especially in improving dysphoria, conflict behavior, dietary restrictions, and social responses. CONCLUSION: SGIP acupuncture treatment could effectively alleviate the degree and frequency of symptoms' attack in IBS-D patients, such as abdominal pain, diarrhea, abdominal distension, etc., markedly relieve the tenesmic sensation, with the efficacy better than that of pinaverium bromide, showing a preponderance in improving patient's QOL.

Covariance-based approaches to aeroacoustic noise source analysis.

In this paper, several covariance-based approaches are proposed for aeroacoustic noise source analysis under the assumptions of a single dominant source and all observers contaminated solely by uncorrelated noise. The Cramér-Rao Bounds (CRB) of the unbiased source power estimates are also derived. The proposed methods are evaluated using both simulated data as well as data acquired from an airfoil trailing edge noise experiment in an open-jet aeroacoustic facility. The numerical examples show that the covariance-based algorithms significantly outperform an existing least-squares approach and provide accurate power estimates even under low signal-to-noise ratio (SNR) conditions. Furthermore, the mean-squared-errors (MSEs) of the so-obtained estimates are close to the corresponding CRB especially for a large number of data samples. The experimental results show that the power estimates of the proposed approaches are consistent with one another as long as the core analysis assumptions are obeyed.

ASEO: a method for the simultaneous estimation of single-trial event-related potentials and ongoing brain activities.

Cognitive functions are often studied by recording electric potentials from the brain over repeated presentations of a sensory stimulus or repeated performance of a motor action. Each repetition is called a trial. Recent work has demonstrated that contrary to the traditional view, the event-related potential (ERP) can vary from trial to trial and the background ongoing activity often contains rich information about the cognitive state of the brain. Based on such a variable signal plus ongoing activity model, an iterative parameter estimation method is proposed in which both the single-trial parameters of the ERP and the autoregressive representation of the ongoing activity are obtained simultaneously. This technique, referred to as the analysis of single-trial ERP and ongoing activities method, is first tested on simulation examples, and then applied to the local field potential recordings from monkeys performing a visuomotor task.

Multistatic adaptive microwave imaging for early breast cancer detection.

We propose a new multistatic adaptive microwave imaging (MAMI) method for early breast cancer detection. MAMI is a two-stage robust Capon beamforming (RCB) based image formation algorithm. MAMI exhibits higher resolution, lower sidelobes, and better noise and interference rejection capabilities than the existing approaches. The effectiveness of using MAMI for breast cancer detection is demonstrated via a simulated 3-D breast model and several numerical examples.