Chang-Kang-Fang alleviates diarrhea predominant irritable bowel syndrome (IBS-D) through inhibiting TLR4/NF-κB/NLRP3 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Chang-Kang-Fang (CKF), originated from traditional Chinese medicine (TCM) formulas, has been utilized to treat diarrhea predominant irritable bowel syndrome (IBS-D) based on clinical experience. However, the underlying mechanism of CKF for treating IBS-D remains unclear and need further clarification. AIM OF THE STUDY: The objective of this present investigation was to validate the efficacy of CKF on IBS-D model rats and to uncover its potential mechanism for the treatment of IBS-D. MATERIALS AND METHODS: We first established the IBS-D rat model through neonatal maternal separation (NMS) in combination with restraint stress (RS) and the administration of senna decoction via gavage. To confirm the therapeutic effect of CKF on treating IBS-D, abdominal withdrawal reflex (AWR) scores, the quantity of fecal pellets, and the fecal water content (FWC) were measured to evaluate the influence of CKF on visceral hypersensitivity and the severity of diarrhea symptom after the intragastric administration of CKF for 14 days. Subsequently, enzyme linked immunosorbent assay (ELISA) was applied to assess the effect of CKF on neuropeptides substance P (SP) and 5-hydroxytryptamine (5-HT), as well as inflammatory cytokines in serum and in intestinal tissues. Further, colonic pathological changes, the amount of colonic mast cells, and the expression level of occludin in rat colon tissues, were investigated by hematoxylin-eosin (HE) staining, toluidine blue staining, and immunohistochemistry, respectively. To explore the underlying mechanisms, alterations in colonic RNA transcriptomics for the normal, model, and CKF treatment groups were assessed using RNA sequencing (RNA-Seq). Subsequently, quantitative real-time polymerase chain reaction (qRT-PCR), Western blot (WB), and immunofluorescence (IF) assays were applied to validate the effect of CKF on predicted pathways in vivo and in vitro. In addition, to elucidate the potential active compounds in CKF, 11 representative components found in CKF were selected, and their anti-inflammation potentials were evaluated using LPS-treated RAW264.7 cell models. RESULTS: CKF treatment significantly reduced the number of fecal pellets, attenuated visceral hypersensitivity, and decreased 5-HT and SP concentrations in serum and colon tissues, along with a reduction in colonic mast cell counts, correlating with improved symptoms in IBS-D rats. Meanwhile, CKF treatment reduced the colonic inflammatory cell infiltration, lowered the levels of IL-6, TNF-α, and IL-1ß in serum and colon tissues, and increased the occludin protein expression in colon tissues to improve inflammatory response and colonic barrier function. RNA-Seq, in conjugation with our previous network pharmacology analysis, indicated that CKF might mitigate the symptoms of IBS-D rats by inhibiting the Toll like receptor 4/Nuclear factor kappa-B/NLR family pyrin domain-containing protein 3 (TLR4/NF-κB/NLRP3) pathway, which was confirmed by WB, IF, and qRT-PCR experiments in vivo and in vitro. Furthermore, coptisine, berberine, hyperoside, epicatechin, and gallic acid present in CKF emerged as potential active components for treating IBS-D, as they demonstrated in vitro anti-inflammatory effects. CONCLUSION: Our findings demonstrate that CKF effectively improves the symptoms of IBS-D rats, potentially through the inhibition of the TLR4/NF-κB/NLRP3 pathway. Moreover, this study unveils the potential bioactive components in CKF that could be applied in the treatment of IBS-D.

Deciphering chemical and metabolite profiling of Chang-Kang-Fang by UPLC-Q-TOF-MS/MS and its potential active components identification.

Chang-Kang-Fang (CKF) formula, a Traditional Chinese Medicine (TCM) prescription, has been widely used for the treatment of irritable bowel syndrome (IBS). However, its potential material basis and underlying mechanism remain elusive. Therefore, this study employed an integrated approach that combined ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) with network pharmacology to systematically characterize the phytochemical components and metabolites of CKF, as well as elucidating its underlying mechanism. Through this comprehensive analysis, a total of 150 components were identified or tentatively characterized within the CKF formula. Notably, six N-acetyldopamine oligomers from CicadaePeriostracum and eight resin glycosides from Cuscutae Semen were characterized in this formula for the first time. Meanwhile, 149 xenobiotics (58 prototypes and 91 metabolites) were detected in plasma, urine, feces, brain, and intestinal contents, and the in vivo metabolic pathways of resin glycosides were elaborated for the first time. Furthermore, network pharmacology and molecular docking analyses revealed that alkaloids, flavonoids, chromones, monoterpenes, N-acetyldopamine dimers, p-hydroxycinnamic acid, and Cus-3/isomer might be responsible for the beneficial effects of CKF in treating IBS, and CASP8, MARK14, PIK3C, PIK3R1, TLR4, and TNF may be its potential targets. These discoveries offer a comprehensive understanding of the potential material basis and clarify the underlying mechanism of the CKF formula in treating IBS, facilitating the broader application of CKF in the field of medicine.

[Carbohydrate-based quality consistency evaluation of Saposhnikoviae Radix].

This study aims to evaluate the quality consistency of Saposhnikoviae Radix based on carbohydrates, and explore the potential of carbohydrates as the internal quality control indicators of Saposhnikoviae Radix. The total polysaccharides were quantified by UV-Vis spectrophotometry and the molecular weight range of the polysaccharides was determined by high performance gel-permeation chromatography-evaporative light scattering detection(HPGPC-ELSD). The monosaccharides in polysaccharides and the free monosaccharides were quantified by high performance liquid chromatography-UV detection(HPLC-UV), and the oligosaccharides and fructose were quantified by high performance liquid chromatography-evaporative light scattering detection(HPLC-ELSD). The carbohydrate-based quality of Saposhnikoviae Radix was compared among 45 batches of commercial samples and 13 batches of self-collected samples. The results showed that the molecular weight distribution, monosaccharide composition, oligosaccharide, and free monosaccharide composition were similar in the 58 batches of samples. The average content of total polysaccharides, oligosaccharides, and total free monosaccharides in commercial samples were 39.66, 148.79, and 68.62 mg·g~(-1), respectively. The content showed significant differences among batches, with the highest differences of 3.51, 1.75, and 2.58 times, respectively. The RSD of the relative ratios of monosaccharides in the polysaccharides in commercial samples reached 28%-45%. The average content of total polysaccharides, oligosaccharides, and total free monosaccharides in self-collected samples were 68.07, 145.76, and 42.04 mg·g~(-1), respectively, with the inter-region differences of 2.88, 1.88, and 1.07 times, respectively. The RSD of the relative ratios of monosaccharides in polysaccharides in self-collected samples ranged from 8.2% to 59%. The total polysaccharides and total free monosaccharides in self-collected samples were 1.72 times higher and 1.63 times lower, respectively, than those in commercial samples. The content of oligosaccharides was similar between self-collected samples and commercial samples. To sum up, carbohydrates are one of the material bases for the internal quality consistency of Saposhnikoviae Radix. The qualitative characteristics of polysaccharides and the quantitative characteristics of polysaccharides and oligosaccharides are related to the origin of medicinal materials. Moreover, the quantitative characteristics of polysaccharides and free monosaccharides may be related to the storage conditions. Carbohydrates are potential indicators for the quality control of Saposhnikoviae Radix and deserve attention.

Co-existing polysaccharides affect the systemic exposure of major bioactive ingredients in Chang-Kang-Fang, a multi-herb prescription for treatment of irritable bowel syndrome.

ETHNOPHARMACOLOGICAL RELEVANCE: Chang-Kang-Fang (CKF) is a traditional Chinese herbal formula used for treatment of irritable bowel syndrome (IBS) in China. Decoction is the administration form of CKF in clinical practice. Previously, CKF has been confirmed with activities of releasing pain and reversing disorders of intestinal propulsion. And alkaloids, monoglycosides, chromones were found as the main bioactive components potentially contributing to the efficacy of CKF. Polysaccharide was also a major constituent in CKF. But if and how polysaccharides influence the systemic exposure of bioactive components in CKF is unknown. AIM OF THE STUDY: In this study, we aimed to demonstrate the contribution of the co-existed polysaccharides on the systemic exposure of the major bioactive components from CKF in normal and IBS model rats. MATERIALS AND METHODS: An UPLC-TQ-MS with multiple reaction monitoring (MRM) scan method was developed and validated for quantifying six major small molecular bioactive ingredients of CKF in the plasma samples, including magnoflorine (MAG), berberine (BBR), albiflorin (ALB), paeoniflorin (PAE), 5-O-methylvisamminol (5-OM) and prim-O-glucosylcimifugin (POG). The rats received CKF decoction (CKF) and CKF small molecule portion (knockout of polysaccharides, CKFSM), respectively. IBS model rats were induced by daily bondage and gavage of Sennae Folium decoction (derived from the leaf of Cassia angustifolia Vahl). The effects of the co-existing polysaccharides on the pharmacokinetic parameters of six small molecular bioactive components in normal and IBS model rats were systematically evaluated. The potential gut microbiota involved mechanisms of the effects was validated by broad-spectrum antibiotic (ABX) treatment. RESULTS: The selectivity, precision, accuracy, recovery and matrix effect of the established quantification method were all within acceptable limits of biological sample. In normal rats, the co-existing polysaccharides significantly reduced the AUC(0-t) of MAG and PAE compared with CKFSM group. The Cmax and AUC(0-t) of other four compound were not influenced by co-existing polysaccharides. However, in IBS model rats, compared with CKFSM group, the Cmax and AUC(0-t) of the six ingredients significantly increased in CKF group. For CKF + ABX group, the Cmax of six ingredients decreased significantly when compared with CKF group, and the AUC(0-t) of MAG, BBR, ALB, PAE also reduced with significant differences. CONCLUSIONS: A reliable and sensitive UPLC-TQ-MS method was successfully developed and validated for evaluating influence of co-existing polysaccharides on pharmacokinetic behavior of six major small molecules components in CKF. The co-existing polysaccharides enhanced the systemic exposure of six bioactive small molecules in CKF under IBS pathological state potentially via gut microbiota involvement.

Fatigue Detection of Pilots' Brain Through Brains Cognitive Map and Multilayer Latent Incremental Learning Model.

This work proposes a nonparametric prior induced deep sum-logarithmic-multinomial mixture (DSLMM) model to detect pilots' cognitive states through the developed brain power map. DSLMM uses multinormal distribution to infer the latent variable of each neuron in the first layer of the network. These latent variables obeyed a sum-logarithmic distribution that is backpropagated to its observation vector and the number of neurons in the next layer. Multinormal distribution is used to segment the extended observation vector to form a matrix associated with the width of the next layer. This work also proposes an adaptive topic-layer stochastic gradient Riemann (ATL-SGR) Markov chain Monte Carlo (MCMC) inference method to learn its global parameters without heuristic assumptions. The experimental results indicate that DSLMM can extract more probability distribution contained in the brain power map layer by layer, and achieve higher pilot cognition detection accuracy.

Integrating multiple-chromatographic approaches to evaluate chemical consistency of Chang-Kang-Fang preparations from mixed-herb decoction and combined single-herb decoction.

Chang-Kang-Fang formula (CKF), a multi-herbs traditional Chinese medicine (TCM) prescription for treating irritable bowel syndrome (IBS), has been clinically applied in the traditional form of mixed-herb decoction (MHD), or in the modern form of combined single-herb decoction (cSHD, so called dispensing granule decoction) in the near decades, but the chemical consistency between the MHD and cSHD is still unknown. Herein, a new strategy by integrating multiple-chromatographic approaches to characterize both polysaccharides and small molecules was developed to compare the chemical consistency between MHD and cSHD. Sixteen small molecules were simultaneously qualified and quantified by UPLC-QTOF-MS/MS, the molecular weight distribution of polysaccharides was characterized by HPGPC-ELSD, while the monosaccharide composition and total saccharides content were determined by HPLC-PDA and UV-VIS, respectively. It was found that the molecular weight range and monosaccharide composition of polysaccharides, as well as the composition of small molecules, were identical between MHD and cSHD. However, the contents of berberine, epiberberine, coptisine, palmatine, albiflorin and paeoniflorin in MHD were significantly lower than those in cSHD, whereas the content of polysaccharides in MHD was higher than that in cSHD, indicating that there is a significant difference in the quality between MHD and cSHD, in particular for the relative contents of major small molecules and polysaccharides. Whether or not these quality variations affect the efficacy and safety of CKF deserves further investigation.

Rotated Sphere Haar Wavelet and Deep Contractive Auto-Encoder Network With Fuzzy Gaussian SVM for Pilot's Pupil Center Detection.

How to track the attention of the pilot is a huge challenge. We are able to capture the pupil status of the pilot and analyze their anomalies and judge the attention of the pilot. This paper proposes a new approach to solve this problem through the integration of spherical Haar wavelet transform and deep learning methods. First, considering the application limitations of Haar wavelet and other wavelets in spherical signal decomposition and reconstruction, a feature learning method based on the spherical Haar wavelet is proposed. In order to obtain the salient features of the spherical signal, a rotating spherical Haar wavelet is also proposed, which has a consistent scale in the same direction between the reconstructed image and the original image. Second, in order to find a better characteristic representation of the spherical signal, a higher contractive autoencoder (HCAE) is designed for the potential representation of the spherical Haar wavelet coefficients, which has two penalty items, respectively, from Jacobian and two order items from Taylor expansion of the point x for the contract learning of sample space. Third, in order to improve the classification performance, this paper proposes a fuzzy Gaussian support vector machine (FGSVM) as the top classification tool of the deep learning model, which can punish some Gaussian noise from the output of the deep HCAE network (DHCAEN). Finally, a DHCAEN-FGSVM classifier is proposed to identify the location of the pupil center. The experimental results of the public data set and actual data show that our model is an effective method for spherical signal detection.

Systematic metabolite profiling of N-acetyldopamine oligomers from Cicadae Periostracum in rats by ultra-high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry.

Cicadae Periostracum (CP), the cast-off shell of Cryptotympana atrata, is specified in Chinese Pharmacopoeia for relieving fever and eliminating ulcer. N-acetyldopamine oligomers are the major characteristic bioactive components with antioxidant and anti-inflammatory activities that may be responsible for the efficacy of CP. However, the exposed components and metabolites of N-acetyldopamine oligomers of CP (NOCP) in vivo are still unknown. In present study, the metabolic profile of total NOCP and N-acetyldopamine dimer B in rats were systematically investigated by ultra-high liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UPLC-QTOF-MS/MS). In biosamples of NOCP group, 34 prototypes and 15 metabolites were identified or tentatively characterized, including 5 metabolites in plasma, 3 prototype and 9 metabolites in urine, 2 metabolites in bile, 34 prototypes and 8 metabolites in feces, respectively. In dimer B group, the prototype and 8 metabolites were identified, including 2 metabolites in plasma, 4 metabolites in urine, 1 metabolite in bile and 5 metabolites in feces, respectively. Oxidation, and hydrogenation were supposed to be the major phase I reactions, while methylation, sulfation, and glucuronidation were the main phase II reactions of NOCP and dimer B. M10 and M13 might undergo enterohepatic circulation in rats. It is concluded that NOCP and dimer B were mainly absorbed in the form of metabolites, and metabolites are probably the major bioactive forms of NOCP and dimer B. The outcomes of this study provided helpful information for extensively elucidating biological and pharmacological mechanisms of NOCP.

Leisure-time physical activity and milk intake synergistically reduce the risk of pathoglycemia: A cross-sectional study in adults in Beijing, China.

BACKGROUND AND OBJECTIVES: To evaluate the synergistic and individual associations of leisure-time physical activity (LTPA) intensity and the frequency of milk intake in adulthood with newly diagnosed pathoglycemia. Pathoglycemia comprised impaired fasting glucose (IFG) and type 2 diabetes mellitus (T2DM). METHODS AND STUDY DESIGN: This cross-sectional study of 3977 adults was conducted in Mentougou District, Beijing, China. After excluding ineligible individuals or those with missing data, 2977 participants were included in the final analysis. Data on LTPA, milk intake, and other demographic characteristics were obtained through previously designed questionnaires. Newly diagnosed pathoglycemia was determined based on fasting plasma glucose (FPG) concentration. RESULTS: Among all participants, 21.4% had newly diagnosed pathoglycemia, 9.9% engaged in moderate to vigorous leisure-time physical activity (MVLTPA), and 63.7% drank milk more than once weekly. Relative to those who engaged in low-intensity LTPA and drank milk less than once weekly, those who engaged in MVLTPA (OR: 0.584, 95%CI: 0.410-0.810) and drank milk more than once weekly (OR: 0.734, 95% CI: 0.614-0.878) had a lower risk of pathoglycemia; this association was greater when both variables interacted (OR: 0.446, 95% CI: 0.287-0.669). CONCLUSIONS: MVLTPA and enough frequency of milk intake synergistically decreased the risk of pathoglycemia. A future interventional study including both factors should be performed.

Quality consistency evaluation on four origins of Cicadae Periostracum by ultra-performance liquid chromatography coupled with quadrupole/time-of-flight mass spectrometry analysis.

Cicadae Periostracum, which is derived from the slough of Cicadidae insects, is a commonly used crude drug in traditional Chinese medicine (TCM). As specified in Chinese Pharmacopoeia, Cryptotympana atrata (CA) is the only official species of this crude drug. However, the slough of other three species, i.e., Auritibicen flammatus (AF), Cryptotympana mandrina (CM) and Platypleura kaempferi (PK), have been also used as the origins of Cicadae Periostracum in Chinese herbal market, although whether the quality of these four origins is consistent or not is still unknown. In present study, ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS/MS) was employed to qualitatively and quantitatively compare the chemical profiles of the four origins. Totally, 34 N-acetyldopamine polymers were identified from the four origins, including 4 N-acetyldopamine dimers, 11 N-acetyldopamine trimers, 10 N-acetyldopamine tetramers, and 9 N-acetyldopamine pentamers. AF, CM and PK had similar chemical profiles with that of CA. The contents and compositional ratio of the four types of polymers in CA, AF and CM were consistent with each other, but significantly lower or different in PK. All these results suggested that AF and CM might be considered as the potential resources of Cicadae Periostracum concerning their consistent holistic quality, whereas whether PK could be used as potential origin of Cicadae Periostracum or not need further evaluation for their different compositional ratios and contents of the four types of N-acetyldopamine polymers. This is the first study on chemical profiling and comparison of N-acetyldopamine polymers in four origins of Cicadae Periostracum, which is beneficial for potential resources utilization and quality standard improvement of Cicadae Periostracum.

Associations of physical activity and egg intake with hypertension among Chinese middle-aged and older population.

To explore the independent and interaction associations of physical activity (PA) and egg intake with hypertension. A cross-sectional study of 2189 individuals (aged ≥50 years) selected using multi-stage stratified random sampling was conducted in Mentougou of Beijing, China. Data of PA and egg intake were obtained from questionnaire survey, and blood pressure from physical examination. Individuals were divided into four groups by the level of PA: low, medium, high level 1 and high level 2; and were also divided into three groups by daily amount of egg intake: <1 egg/day, 1 egg/day and >1 egg/day. Self-reported hypertension was defined if individual had a self-reported diagnosis of hypertension or use of antihypertensive medication; examined abnormal blood pressure was defined if individual didn't belong to self-reported hypertension and mean blood pressure was above 130/80 mmHg measured during this examination. After adjusting demographic characteristics, health behavior, BMI, and family history of CVD, compared with medium level PA group, high level 2 group was associated with higher self-reported rate (OR: 1.5, 95% CI: 1.18-2.01) and examined abnormal rate (OR: 1.8, 95% CI: 1.21-2.20). The self-reported rate and examined abnormal rate in <1 egg/day group were both higher than 1 egg/day group (OR: 1.4, 95% CI: 1.06-1.91; OR: 1.4, 95% CI: 1.08-1.92). Compared with medium level PA and 1 egg/day group, high level 2 and >1 egg/day group with higher examined abnormal rate (OR: 2.3, 95% CI: 1.28-4.01), high level 2 and <1 egg/day group with higher self-reported rate and examined abnormal rate (OR: 2.5, 95% CI: 1.10-3.82; OR: 2.9, 95% CI: 1.54-4.96). In conclusion, excessive high level PA and inadequate egg intake were associated with hypertension, respectively, and the association further increased when both existed at the same time. Besides, moderate PA combined with reasonable egg intake was associated with the low examination rate of hypertension.

Soy product consumption and type 2 diabetes among adults in Beijing, China.

BACKGROUND AND OBJECTIVES: To examine the association between the frequency of soy products consumption and type 2 diabetes or impaired fasting glucose. METHODS AND STUDY DESIGN: A cross-sectional study of 3,314 subjects aged 18-79 years was conducted in Beijing, China in 2016. Consumption of soy products was assessed by a validated food-frequency questionnaire and examined with type 2 diabetes or impaired fasting glucose risk using multiple logistic regression. RESULTS: 509 of the 3,314 participants (15.4%) included in the current analyses had diabetes, and among them 453 were diabetes uncontrolled. The prevalence of impaired fasting glucose was 11.9%. After adjustment for demographic variables, smoke, alcohol, physical activity and BMI, soy products consumption was inversely associated with type 2 diabetes risk and impaired fasting glucose. ORs and 95% CI for diabetes uncontrolled across soy products consumption frequencies (monthly, weekly, daily) were 1 (reference), 0.819 (0.627-1.070), 0.605 (0.387, 0.944) respectively (ptrend=0.033). ORs (95% CI) for impaired fasting glucose across soy products consumption frequencies were 1 (reference), 0.873 (0.661-1.152), 0.616 (0.385, 0.985) respectively (ptrend=0.046). CONCLUSIONS: Consuming soy products daily may decrease the risk of diabetes and impaired fasting glucose.

Photonic ADC: overcoming the bottleneck of electronic jitter.

Accurate conversion of wideband multi-GHz analog signals into the digital domain has long been a target of analog-to-digital converter (ADC) developers, driven by applications in radar systems, software radio, medical imaging, and communication systems. Aperture jitter has been a major bottleneck on the way towards higher speeds and better accuracy. Photonic ADCs, which perform sampling using ultra-stable optical pulse trains generated by mode-locked lasers, have been investigated for many years as a promising approach to overcome the jitter problem and bring ADC performance to new levels. This work demonstrates that the photonic approach can deliver on its promise by digitizing a 41 GHz signal with 7.0 effective bits using a photonic ADC built from discrete components. This accuracy corresponds to a timing jitter of 15 fs - a 4-5 times improvement over the performance of the best electronic ADCs which exist today. On the way towards an integrated photonic ADC, a silicon photonic chip with core photonic components was fabricated and used to digitize a 10 GHz signal with 3.5 effective bits. In these experiments, two wavelength channels were implemented, providing the overall sampling rate of 2.1 GSa/s. To show that photonic ADCs with larger channel counts are possible, a dual 20-channel silicon filter bank has been demonstrated.

[Study on the chemical constituents of Rumex patientia].

OBJECTIVE: To study the chemical constituents of roots of Rumex patientia. METHODS: The compounds were separated and purified by silica column chromatopraphy, Sephadex LH-20 and identified by several spectroscopic methods. RESULTS: Seven constituents were identified as nepodin (1), nepodin-8-O-beta-D-glucopyranoside (2), chrysophanol-8-O-beta-D-glucopyranoside (3), emodin-6-O-beta-D-glucopyranoside (4), emodin-8-O-beta-D-glucopyranoside (5), 1, 3, 5-trihydroxy-7-methylanthraquinone (6), physcion-8-O-beta-D-glucopyranoside (7), respectively. CONCLUSION: Compound 1 is isolated from this plant for the first time and compound 6 is isolated from Rumex L. for the first time.

Effect of carrier lifetime on forward-biased silicon Mach-Zehnder modulators.

We present a systematic study of Mach-Zehnder silicon optical modulators based on carrier-injection. Detailed comparisons between modeling and measurement results are made with good agreement obtained for both DC and AC characteristics. A figure of merit, static VpiL, as low as 0.24Vmm is achieved. The effect of carrier lifetime variation with doping concentration is explored and found to be important for the modulator characteristics.