Screening of rosmarinic acid from Salvia miltiorrhizae acting on the novel target TRPC1 based on the 'homology modelling-virtual screening-molecular docking-affinity assay-activity evaluation' method.

CONTEXT: Salvia miltiorrhizae Bunge (Lamiaceae) is a traditional Chinese medicine (TCM) for the treatment of 'thoracic obstruction'. Transient receptor potential canonical channel 1 (TRPC1) is a important target for myocardial injury treatment. OBJECTIVE: This work screens the active component acting on TRPC1 from Salvia miltiorrhizae. MATERIALS AND METHODS: TCM Systems Pharmacology Database and Analysis Platform (TCMSP) was used to retrieve Salvia miltiorrhiza compounds for preliminary screening by referring to Lipinski's rule of five. Then, the compound group was comprehensively scored by AutoDock Vina based on TRPC1 protein. Surface plasmon resonance (SPR) was used to determine the affinity of the optimal compound to TRPC1 protein. Western blot assay was carried out to observe the effect of the optimal compound on TRPC1 protein expression in HL-1 cells, and Fura-2/AM detection was carried out to observe the effect of the optimal compound on calcium influx in HEK293 cells. RESULTS: Twenty compounds with relatively good characteristic parameters were determined from 202 compounds of Salvia miltiorrhiza. Rosmarinic acid (RosA) was obtained based on the molecular docking scoring function. RosA had a high binding affinity to TRPC1 protein (KD value = 1.27 µM). RosA (50 µM) could reduce the protein levels (417.1%) of TRPC1 after oxygen-glucose deprivation/reperfusion (OGD/R) in HL-1 cells and it could inhibit TRPC1-mediated Ca2+ influx injury (0.07 ΔRatio340/380) in HEK293 cells. DISCUSSION AND CONCLUSIONS: We obtained the potential active component RosA acting on TRPC1 from Salvia miltiorrhizae, and we speculate that RosA may be a promising clinical candidate for myocardial injury therapy.

Differential Maturation of Auditory Cortex Activity in Young Children with Autism and Typical Development.

Maturation of auditory cortex neural encoding processes was assessed in children with typical development (TD) and autism. Children 6-9 years old were enrolled at Time 1 (T1), with follow-up data obtained ~ 18 months later at Time 2 (T2), and ~ 36 months later at Time 3 (T3). Findings suggested an initial period of rapid auditory cortex maturation in autism, earlier than TD (prior to and surrounding the T1 exam), followed by a period of faster maturation in TD than autism (T1-T3). As a result of group maturation differences, post-stimulus group differences were observed at T1 but not T3. In contrast, stronger pre-stimulus activity in autism than TD was found at all time points, indicating this brain measure is stable across time.

Insights to the 3D internal morphology and metal oxidation states of single atmospheric aerosol particles by synchrotron-based methodology.

The morphology and metal oxidation states of atmospheric aerosols are pertinent to their formation processes and ensuing interactions with surrounding gases, vapors and other environments upon deposition, such as human respiratory tract, soil and water. Although much progress has been made in recent years through single-particle techniques, considerably less is known with respect to the three-dimensional (3D) internal morphology of single atmospheric aerosol particles due to the limited penetration depth of electron microscopy. In this study, for the first time, a novel synchrotron-based transmission X-ray microscopy (TXM) methodology has been developed to visualize the 3D internal chemical mixing state and structure of single particles. The results show that the TXM is more applicable to the imaging of solid particles containing high-density elements, e.g., iron (Fe), aluminum (Al), silicone (Si), carbon (C) and sulfur (S), and/or solid particles of sizes larger than about 100 nm. In addition, the TXM is capable to reveal the fine 3D topographic features of single particles. The derived 3D internal and external information would be difficult to discern in the 2D images from electron microscopy. The TXM 3D images illustrate that aerosol particles exhibit complex internal mixing state and structure, e.g., homogeneously-, heterogeneously-mixed, multiple inclusions, fibrous, porous, and core-shell configuration. When coupled with the synchrotron-based X-ray fluorescence spectrometry (XRF) and absorption near-edge spectroscopy (XANES) of an X-ray nanoprobe in the energy range of 4-15 keV, the 3D morphology of single particles is further supplemented with the spatial distribution and oxidation sates of selected elements, including Fe, vanadium (V), manganese (Mn), chromium (Cr) and arsenic (As). The presented cross-platform, synchrotron-based methodology shows promise in complementing existing single-particle techniques and providing new insights to the heterogeneity of single-particle micro-physicochemical states relevant to the aerosol chemistry, optical properties, and their environmental and health impacts.

State-Level Social Vulnerability Index and Healthcare Access in Patients With Atherosclerotic Cardiovascular Disease (from the BRFSS Survey).

We analyzed the association between social vulnerability index (SVI) and healthcare access among patients with atherosclerotic cardiovascular disease (ASCVD). Using cross-sectional data from the Behavioral Risk Factor Surveillance System 2016 to 2019, we identified measures related to healthcare access in individuals with ASCVD, which included healthcare coverage, presence of primary care clinician, duration since last routine checkup, delay in access to healthcare, inability to see doctor because of cost, and cost-related medication nonadherence. We analyzed the association of state-level SVI (higher SVI denotes higher social vulnerability) and healthcare access using multivariable-adjusted logistic regression models. The study population comprised 203,347 individuals aged 18 years or older who reported a history of ASCVD. In a multivariable-adjusted analysis, prevalence odds ratios (95% confidence interval) for participants residing in states in the third tertile of SVI compared with those in the first tertile (used as reference) were as follows: absence of healthcare coverage = 1.03 (0.85 to 1.24), absence of primary care clinician = 1.33 (1.12 to 1.58), >1 year since last routine checkup = 1.09 (0.96 to 1.23), delay in access to healthcare = 1.39 (1.18, 1.63), inability to see a doctor because of cost = 1.21 (1.06 to 1.40), and cost-related medication nonadherence = 1.10 (0.83 to 1.47). In conclusion, SVI is associated with healthcare access in those with pre-existing ASCVD. Due to the ability of SVI to simultaneously and holistically capture many of the factors of social determinants of health, SVI can be a useful measure for identifying high-risk populations.

Abnormal auditory mismatch fields in adults with autism spectrum disorder.

The auditory mismatch field (MMF) is a pre-attentive processing component, reflecting neural discrimination and inhibitory processing. Abnormal MMFs have been reported in children with autism spectrum disorder (ASD) along with an association with abnormal language comprehension; however, relatively little is known about MMF abnormalities to contrasting vowel stimuli in adults with ASD. To better understand the neurophysiological mechanisms underlying auditory language discrimination of vowel stimuli in individuals with ASD, magnetoencephalography was used to measure MMFs during an auditory oddball paradigm with vowel stimuli (/a/ and /u/) in adults with ASD. MMFs arising from left and right superior temporal gyrus are reported from nine high-functioning right handed males with ASD (22.22 ± 5.74yrs) and sixteen typically developing (TD) right handed males (27.25 ± 6.63yrs). The MMF was delayed in adults with ASD (188.90 ± 5.8 ms) as compared to the TD participants (173.08 ± 4.31 ms, p < 0.05). Replicating previous findings in children, the earlier M100 component to single stimulus tokens was also delayed in adults with ASD (108.59 ± 4.1 ms) compared to the TD participants (94.60 ± 3.0 ms, p < 0.05). However, there was no correlation between delayed M100 latency and MMF latency. Furthermore, whereas TD participants showed a leftward lateralization of MMF amplitude, participants with ASD showed an opposite (rightward) lateralization. Findings suggest that adults with ASD have hemispherically- and temporally- abnormal auditory discrimination processing in addition to and distinct from abnormal neurophysiological mechanisms in earlier cortical responses.

Delayed Auditory Evoked Responses in Autism Spectrum Disorder across the Life Span.

The M50 and M100 auditory evoked responses reflect early auditory processes in the primary/secondary auditory cortex. Although previous M50 and M100 studies have been conducted on individuals with autism spectrum disorder (ASD) and indicate disruption of encoding simple sensory information, analogous investigations of the neural correlates of auditory processing through development from children into adults are very limited. Magnetoencephalography was used to record signals arising from the left and right superior temporal gyrus during auditory presentation of tones to children/adolescents and adults with ASD as well as typically developing (TD) controls. One hundred and thirty-two participants (aged 6-42 years) were included into the final analyses (children/adolescents: TD, n = 36, 9.21 ± 1.6 years; ASD, n = 58, 10.07 ± 2.38 years; adults: TD, n = 19, 26.97 ± 1.29 years; ASD, n = 19, 23.80 ± 6.26 years). There were main effects of group on M50 and M100 latency (p < 0.001) over hemisphere and frequency. Delayed M50 and M100 latencies were found in participants with ASD compared to the TD group, and earlier M50 and M100 latencies were associated with increased age. Furthermore, there was a statistically significant association between language ability and both M50 and M100 latencies. Importantly, differences in M50 and M100 latencies between TD and ASD cohorts, often reported in children, persisted into adulthood, with no evidence supporting latency convergence.

By our bootstraps: Comparing methods for measuring auditory 40 Hz steady-state neural activity.

Although the 40 Hz auditory steady-state response (ASSR) is of clinical interest, the construct validity of EEG and MEG measures of 40 Hz ASSR cortical microcircuits is unclear. This study evaluated several MEG and EEG metrics by leveraging findings of (a) an association between the 40 Hz ASSR and age in the left but not right hemisphere, and (b) right- > left-hemisphere differences in the strength of the 40 Hz ASSR. The contention is that, if an analysis method does not demonstrate a left 40 Hz ASSR and age relationship or hemisphere differences, then the obtained measures likely have low validity. Fifty-three adults were presented 500 Hz stimuli modulated at 40 Hz while MEG and EEG were collected. ASSR activity was examined as a function of phase similarity (intertrial coherence) and percent change from baseline (total power). A variety of head models (spherical and realistic) and a variety of dipole source modeling strategies (dipole source localization and dipoles fixed to Heschl's gyri) were compared. Several sensor analysis strategies were also tested. EEG sensor measures failed to detect left 40 Hz ASSR and age associations or hemisphere differences. A comparison of MEG and EEG head-source models showed similarity in the 40 Hz ASSR measures and in estimating age and left 40 Hz ASSR associations, indicating good construct validity across models. Given a goal of measuring the 40 Hz ASSR cortical microcircuits, a source-modeling approach was shown to be superior in measuring this construct versus methods that rely on EEG sensor measures.

Energy utilization of induced pluripotent stem cell-derived cardiomyocyte in Fabry disease.

BACKGROUND: Fabry disease (FD) is a lysosomal storage disease in which glycosphingolipids (GB3) accumulate in organs of the human body, leading to idiopathic hypertrophic cardiomyopathy and target organ damage. Its pathophysiology is still poorly understood. OBJECTIVES: We aimed to generate patient-specific induced pluripotent stem cells (iPSC) from FD patients presenting cardiomyopathy to determine whether the model could recapitulate key features of the disease phenotype and to investigate the energy metabolism in Fabry disease. METHODS: Peripheral blood mononuclear cells from a 30-year-old Chinese man with a diagnosis of Fabry disease, GLA gene (IVS4+919G>A) mutation were reprogrammed into iPSCs and differentiated into iPSC-CMs and energy metabolism was analyzed in iPSC-CMs. RESULTS: The FD-iPSC-CMs recapitulated numerous aspects of the FD phenotype including reduced GLA activity, cellular hypertrophy, GB3 accumulation and impaired contractility. Decreased energy metabolism with energy utilization shift to glycolysis was observed, but the decreased energy metabolism was not modified by enzyme rescue replacement (ERT) in FD-iPSCs-CMs. CONCLUSION: This model provided a promising in vitro model for the investigation of the underlying disease mechanism and development of novel therapeutic strategies for FD. This potential remedy for enhancing the energetic network and utility efficiency warrants further study to identify novel therapies for the disease.

Antihyperglycemic and antioxidant activities of twig extract from Cinnamomum osmophloeum.

This is the first report concerning the α-glucosidase, α-amylase and protein tyrosine phosphatase 1B (PTP1B) inhibitory activities of cinnamon twig extracts. Comparing the antihyperglycemic activity of renewable plant parts, indigenous cinnamon (Cinnamomum osmophloeum; tǔ ròu guì) twig extracts (CoTE) showed better α-glucosidase and α-amylase activities than leaf, 2-cm branch and 5-cm branch extracts. Chemotype of C. osmophloeum has no influence on the antihyperglycemic activities and proanthocyanidin contents of CoTE. Among four soluble fractions obtained from CoTE by following bioactivity-guided fractionation procedure, the n-butanol soluble fraction (BSF) with abundant proanthocyanidins and condensed tannins, exhibited the best antihyperglycemic and PTP1B inhibitory activities. In addition, the BSF displayed the excellent DPPH free-radical scavenging and ferrous ion-chelating activities. The antihyperglycemic and antioxidant activities of all four soluble fractions from CoTE showed high correlation coefficient with their proanthocyanidin and condensed tannin contents. Furthermore, CoTE had no toxicity on 3T3-L1 preadiocytes. Results obtained demonstrated that CoTE has excellent antihyperglycemic, antioxidant and PTP1B inhibitory activities, and thus has great potential as a source for natural health products.

Resting-state alpha in autism spectrum disorder and alpha associations with thalamic volume.

Alpha circuits (8-12 Hz), necessary for basic and complex brain processes, are abnormal in autism spectrum disorder (ASD). The present study obtained estimates of resting-state (RS) alpha activity in children with ASD and examined associations between alpha activity, age, and clinical symptoms. Given that the thalamus modulates cortical RS alpha rhythms, associations between thalamic structure and alpha activity were examined. RS magnetoencephalography was obtained from 47 typically-developing children (TDC) and 41 children with ASD. RS alpha activity was measured using distributed source localization. Left and right thalamic volume measurements were also obtained. In both groups, the strongest alpha activity was observed in Calcarine Sulcus regions. In Calcarine regions, only TDC showed the expected association between age and alpha peak frequency. ASD had more alpha activity than TDC in regions bordering the Central Sulcus as well as parietal association cortices. In ASD, whereas greater left Central Sulcus relative alpha activity was associated with higher Social Responsiveness Scale (SRS) scores, greater Calcarine region relative alpha activity was associated with lower SRS scores. Although thalamic volume group differences were not observed, relationships between thalamic volume and Calcarine alpha power were unique to TDC. The present study also identified a failure to shift peak alpha frequency as a function of age in primary alpha-generating areas in children with ASD. Findings suggested that increased RS alpha activity in primary motor and somatosensory as well as parietal multimodal areas-with increased alpha thought to reflect greater inhibition-might impair the ability to identify or interpret social cues. Finally, to our knowledge, this is the first study to report associations between thalamic volume and alpha power, an association observed only in TDC. The lack of thalamic and alpha associations in ASD suggests thalamic contributions to RS alpha abnormalities in ASD.

Interaction between hydrogen sulfide and nitric oxide on cardiac protection in rats with metabolic syndrome / 中国医学科学院学报

<p><b>OBJECTIVE</b>To investigate the interaction between hydrogen sulfide (H2S)/cystathionine gamma-lyase (CSE) system and nitric oxide (NO)/nitric oxide synthase (NOS) system on cardiac protection in metabolic syndrome (MS) rats.</p><p><b>METHODS</b>Forty one male Sprague-Dawley rats were randomly divided into 6 groups: control group, MS group, H2S donor group, CSE inhibitor group, NOS inhibitor group, and NO donor group. The MS rat model was established by a high-fat diet of 16 weeks. Rats in control and MS groups were subjected to normal saline and the other four groups were respectively subjected to sodium hydrosulfide (NaHS, 56 μmol/kg), D,L-propargylglycine (PPG, 37.5 mg/kg), Nψ-nitro-L-arginine methyl ester (L-NAME, 18 mg/kg), L-Arginine (500 mg/kg) every day. Four weeks later, the obesity indices, blood sugar of oral glucose tolerance test in each time point (0,30,60, and 120 minutes) and blood lipids (cholesterol, triglyceride, high density lipoprotein, low density lipoprotein) were measured. The computer-based electrophysiological recorder system was used to measure the changes of the left ventricular systolic pressure (LVSP), the left ventricular end diastolic pressure (LVEDP), the maximal rate of pressure increase in the contraction phase (+dP/dtmax), and the maximal rate of pressure decrease in the diastole phase (-dP/dtmax). H2S and NO concentration in plasma and myocardium, as well as CSE, constitutive NOS (cNOS), and inducible NOS (iNOS) activities in myocardium were measured with colorimetric method. Reverse transcription-polymerase chain reaction was used to assess the gene expression of CSE and endothelial NOS (eNOS) mRNAs.</p><p><b>RESULTS</b>Compared with control group, the obesity indices, blood sugar at each time point, and blood lipids significantly increased in MS group (P<0.05). H2S and NO concentration in plasma and myocardium, CSE and cNOS activities in myocardium, the expressions of CSE mRNA and eNOS mRNA, and the myocardial function significantly decreased in MS group (P<0.05). Compared with MS group, NO concentration in plasma and myocardium, cNOS and iNOS activities in myocardium, and the expression of eNOS mRNA significantly increased in CSE inhibitor group (P<0.05). However, activities of cNOS and iNOS in myocardium and the expression of eNOS mRNA were significantly decreased in H2S donor group (P<0.01), while the myocardial function significantly increased (P<0.05). H2S concentration in plasma and myocardium, and the expression of CSE mRNA significantly increased in NOS inhibitor group (P<0.05). However, in NO donor group, the CSE activity in myocardium and the expression of CSE mRNA significantly decreased (P<0.05). And the myocardial function was improved significantly (P<0.05).</p><p><b>CONCLUSIONS</b>Both the H2S/CSE and NO/NOS systems appear to have a mutual down-regulation effect on myocardium in MS rats. Meanwhile, exogenous H2S and NO supplement is cardioprotective in rat model of MS.</p>

Neuromagnetic oscillations to emotional faces and prosody.

Higher association cortices as well as unisensory areas can support multisensory integration [D. Senkowski et al. (2008) Trends Neurosci., 31, 401-409]. The present study investigated whether audiovisual integration of emotional information emerges early at unisensory or later at higher association cortices. Emotional stimuli were presented in three blocks: audiovisual (AV), auditory (A) and visual (V). Eighteen participants performed a delayed emotional recognition task (happy, angry or neutral prosody and/or facial expression) while whole-brain magnetoencephalography (MEG) data were obtained. Time-frequency evoked and total power analyses were performed on the sensor data, and source localization of the frequencies of interest performed via a synthetic aperture magnetometry beamformer. To examine crossmodal integration between bimodal and unimodal conditions, two contrasts were specified: AV > A and AV > V. In the AV > A contrast, early effects were observed on both the temporal and the occipital evoked responses. However, at the source level, early alpha suppression was limited to the occipital sources without changes in temporal cortices. In the AV > V contrast, sensor and source findings revealed increased alpha suppression only in temporal cortices, with no changes in visual cortex. Thus, no crossmodal effect in unisensory areas emerged. Instead, increased frontal alpha activity in both the AV > A and AV > V contrasts supports the view that affective information from face and prosody converges at higher association cortices.

Early sensory encoding of affective prosody: neuromagnetic tomography of emotional category changes.

In verbal communication, prosodic codes may be phylogenetically older than lexical ones. Little is known, however, about early, automatic encoding of emotional prosody. This study investigated the neuromagnetic analogue of mismatch negativity (MMN) as an index of early stimulus processing of emotional prosody using whole-head magnetoencephalography (MEG). We applied two different paradigms to study MMN; in addition to the traditional oddball paradigm, the so-called optimum design was adapted to emotion detection. In a sequence of randomly changing disyllabic pseudo-words produced by one male speaker in neutral intonation, a traditional oddball design with emotional deviants (10% happy and angry each) and an optimum design with emotional (17% happy and sad each) and nonemotional gender deviants (17% female) elicited the mismatch responses. The emotional category changes demonstrated early responses (<200 ms) at both auditory cortices with larger amplitudes at the right hemisphere. Responses to the nonemotional change from male to female voices emerged later ( approximately 300 ms). Source analysis pointed at bilateral auditory cortex sources without robust contribution from other such as frontal sources. Conceivably, both auditory cortices encode categorical representations of emotional prosodic. Processing of cognitive feature extraction and automatic emotion appraisal may overlap at this level enabling rapid attentional shifts to important social cues.