Chinese Medicine Supplementing Qi and Activating Blood Circulation Relieves the Progression of Diabetic Cardiomyopathy.

BACKGROUND: Diabetic cardiomyopathy (DCM) is the leading cause of diabetic death as the final occurrence of heart failure and arrhythmia. Traditional Chinese medicine is usually used to treat various diseases including diabetes. OBJECTIVE: This study sought to investigate the effects of Traditional Chinese medicine supplementing Qi and activating blood circulation (SAC) in DCM. METHODS: After the construction of the DCM model by streptozotocin (STZ) injection and high glucose/fat diet feeding, rats were administered intragastrically with SAC. Then, cardiac systolic/diastolic function was evaluated by detecting left ventricular systolic pressure (LVSP), maximal rate of left ventricular pressure rise (+LVdp/dtmax), and fall (-LVdp/dtmax), heart rate (HR), left ventricular ejection fraction (EF), LV fractional shortening (FS) and left ventricular end-diastolic pressure (LVEDP). Masson's and TUNEL staining were used to assess fibrosis and cardiomyocyte apoptosis. RESULTS: DCM rats exhibited impaired cardiac systolic/diastolic function manifested by decreasing LVSP, + LVdp/dtmax, -LVdp/dtmax, HR, EF and FS, and increasing LVEDP. Intriguingly, traditional Chinese medicine SAC alleviated the above-mentioned symptoms, indicating a potential role in improving cardiac function. Masson's staining substantiated that SAC antagonized the increased collagen deposition and interstitial fibrosis area and the elevations in protein expression of fibrosisrelated collagen I and fibronectin in heart tissues of DCM rats. Furthermore, TUNEL staining confirmed that traditional Chinese medicine SAC also attenuated cardiomyocyte apoptosis in DCM rats. Mechanically, DCM rats showed the aberrant activation of the TGF-ß/Smad signaling, which was inhibited after SAC. CONCLUSION: SAC may exert cardiac protective efficacy in DCM rats via the TGF-ß/Smad signaling, indicating a new promising therapeutic approach for DCM.

Ginsenoside RG1-induced mesenchymal stem cells alleviate diabetic cardiomyopathy through secreting exosomal circNOTCH1 to promote macrophage M2 polarization.

Diabetic cardiomyopathy (DCM) is a cardiac complication resulting from long-term uncontrolled diabetes, characterized by myocardial fibrosis and abnormal cardiac function. This study aimed at investigating the potential of ginsenoside RG1 (RG1)-induced mesenchymal stem cells (MSCs) in alleviating DCM. A DCM mouse model was constructed, and the effects of RG1-induced MSCs on myocardial function and fibrosis in diabetic mice were evaluated. RG1-induced MSCs were cocultured with high glucose-treated fibroblasts for subsequent functional and mechanism assays. It was discovered that RG1-induced MSCs secrete exosomes that induce macrophage M2 polarization. Mechanistically, exosomes derived from RG1-induced MSCs transferred circNOTCH1 into macrophages, activating the NOTCH signaling pathway. A competing endogenous RNA (ceRNA) regulatory axis consisting of circNOTCH1, miR-495-3p, and NOTCH1 was found to contribute to DCM alleviation.. This study unveiled that exosomal circNOTCH1 secreted by RG1-induced MSCs can alleviate DCM by activating the NOTCH signaling pathway to induce macrophage M2 polarization. This finding may contribute to the development of new therapeutic approaches for DCM.

Effect of taurine administration on symptoms, severity, or clinical outcome of dilated cardiomyopathy and heart failure in humans: a systematic review.

Background: Taurine, 2-aminoethanesulfonic acid, is an amino acid found in animal products. Taurine is produced for human consumption as a supplement and ingredient in beverages. Supplementation is a safe, inexpensive, and effective treatment for dilated cardiomyopathy (DCM) in domestic mammals, however it is currently unlicensed in Europe and the United States for human medical treatment. Recent genome-wide association studies of DCM have identified the locus of the taurine transporter ( SLC6A6). To assess whether taurine supplementation may be a novel therapeutic option for DCM, we undertook a systematic review. Methods: Four electronic databases (PubMed, Cochrane Central Register, Web of Science, Biomed Central) were searched until 11/03/21. Included studies of human participants reported measured phenotypes or symptoms for cardiomyopathy, heart failure (HF), or altered left ventricle structure or function, administering taurine in any formulation, by any method. Non-English articles were excluded. Meta-analysis was completed in R software (version 3.6.0). The Newcastle-Ottawa Scale quality assessment score (NOQAS) tool was used to assess bias. Results: 285 articles were identified, of which eleven met our criteria for inclusion. Only one paper was deemed "high quality" using the NOQAS tool. Taurine supplementation varied across studies; by dose (500 mg to 6g per day), frequency (once to thrice daily), delivery method (tablet, capsule, drink, powder), and duration (2 to 48 weeks). Patient inclusion was all-cause HF patients with ejection fraction (EF) <50% and no study was specific to DCM. While improvements in diastolic and systolic function, exercise capacity, and haemodynamic parameters were described, only EF and stroke volume were measured in enough studies to complete a meta-analysis; the association was not significant with all-cause HF (P<0.05). No significant safety concerns were reported. Conclusions: A formal clinical trial is needed to address whether taurine supplementation is beneficial to the approximately 1/250 individuals with DCM in the population.

Combination Therapy of Alpha-Lipoic Acid, Gliclazide and Ramipril Protects Against Development of Diabetic Cardiomyopathy via Inhibition of TGF-ß/Smad Pathway.

Background: Diabetic cardiomyopathy (DCM) is a major long-term complication of diabetes mellitus, accounting for over 20% of annual mortality rate of diabetic patients globally. Although several existing anti-diabetic drugs have improved glycemic status in diabetic patients, prevalence of DCM is still high. This study investigates cardiac effect of alpha-lipoic acid (ALA) supplementation of anti-diabetic therapy in experimental DCM. Methods: Following 12 h of overnight fasting, 44 male Sprague Dawley rats were randomly assigned to two groups of healthy control (n = 7) and diabetic (n = 37) groups, and fasting blood glucose was measured. Type 2 diabetes mellitus (T2DM) was induced in diabetic group by intraperitoneal (i.p.) administration of nicotinamide (110 mg/kg) and streptozotocin (55 mg/kg). After confirmation of T2DM on day 3, diabetic rats received monotherapies with ALA (60 mg/kg; n = 7), gliclazide (15 mg/kg; n = 7), ramipril (10 mg/kg; n = 7) or combination of the three drugs (n = 7) for 6 weeks while untreated diabetic rats received distilled water and were used as diabetic control (n = 9). Rats were then sacrificed, and blood, pancreas and heart tissues were harvested for analyses using standard methods. Results: T2DM induction caused pancreatic islet destruction, hyperglycemia, weight loss, high relative heart weight, and development of DCM, which was characterized by myocardial degeneration and vacuolation, cardiac fibrosis, elevated cardiac damage markers (plasma and cardiac creatine kinase-myocardial band, brain natriuretic peptide and cardiac troponin I). Triple combination therapy of ALA, gliclazide and ramipril preserved islet structure, maintained body weight and blood glucose level, and prevented DCM development compared to diabetic control (p < 0.001). In addition, the combination therapy markedly reduced plasma levels of inflammatory markers (IL-1ß, IL-6 and TNF-α), plasma and cardiac tissue malondialdehyde, triglycerides and total cholesterol while significantly increasing cardiac glutathione and superoxide dismutase activity and high-density lipoprotein-cholesterol compared to diabetic control (p < 0.001). Mechanistically, induction of T2DM upregulated cardiac expression of TGF-ß1, phosphorylated Smad2 and Smad3 proteins, which were downregulated following triple combination therapy (p < 0.001). Conclusion: Triple combination therapy of ALA, gliclazide and ramipril prevented DCM development by inhibiting TGF-ß1/Smad pathway. Our findings can be extrapolated to the human heart, which would provide effective additional pharmacological therapy against DCM in T2DM patients.

Loranthus acaciae: Alternative medicine for ß-lactamase producer and methicillin-resistant Staphylococcus aureus.

Recently, we reported high antibacterial efficiency of Loranthus acaciae (LA) against different standard strains of bacteria including Methicillin-Resistant Staphylococcus aureus (MRSA). Therefore, this study aimed to confirm the effectiveness of LA against clinically isolated Staphylococcus aureus (SA) including ß-lactamase producer (Blac) and MRSA. Forty-eight SA isolates collected from various clinical samples were used in this study. Antibiotics susceptibility profile was determined for twenty different antibiotics using automated Microscan Walkaway 96 Plus system as recommended by Clinical and Laboratory Standards Institute (CLSI) guidelines. This system also identified ß-lactamase producers and MRSA. In the meantime, LA ethanolic extract was fractionated using liquid-liquid fraction method to hexane, dichloromethane DCM and methanol 80% fractions. Antimicrobial activities of LA extract and fraction were performed with agar well diffusion method for all SA isolates, MIC and MBC were also recorded. Phytochemical screening for various phyto-constituent classes of LA ethanolic extract was determined. Out of 48 SA isolates, Cefoxitin-positive MRSA represent 31 (64.6%), Blac 17 (35.4%), and 41 (85.4%) were multidrug-resistant SA, which was resistant at least to one antibiotic from three different categories. All isolates were resistant to ampicillin and penicillin. Antimicrobial activities of LA extract and fractions revealed that ethanol extract was active against all isolated SA with inhibition zone ranged from 33 ± 2.00 to 25 ± 3.05 mm. While DCM exhibited the largest inhibition zone range from 37 ± 3.00 to 33 ± 2.00 mm. This study is first of its kind conforming the high antibacterial activity of LA against SA isolated from a different source of infection. The study concluded that LA extract and fractions are active and give positive result for all isolated SA. Therefore, suitable pharmacological formulation of LA extract as a promising antibacterial agent for the treatment of SA infection should be given extreme priority.

Molecular Mechanism of Medicinal Pair Astragali Radix-Angelicae Sinensis Radix Against Diabetic Cardiomyopathy / 中国实验方剂学杂志

Objective:To explore the action mechanism of medicinal pair Astragali Radix-Angelicae Sinensis Radix against diabetic cardiomyopathy （DCM） based on network pharmacology and<italic> in vivo </italic>animal experiment. Method:The active ingredients and targets of Astragali Radix and Angelicae Sinensis Radix were retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP） and Bioinformatics Analysis Tool for Molecular mechANism of Traditional Chinese Medicine （BATMAN-TCM）， and the relevant targets of DCM from the disease database. The common specific targets between the medicinal pair and DCM obtained via comparison were used for constructing the main active ingredients of Astragali Radix-Angelicae Sinensis Radix-DCM-target network， followed by protein-protein interaction （PPI） analysis of compound-DCM common targets and the screening of important modules using Molecular Complex Detection （MCODE） plugin. The gene ontology （GO） and Kyoto encyclopedia of genes and genomes （KEGG） enrichment analysis was carried out based on DAVID for exploring the possible molecular mechanisms， which were then subjected to experimental verification. Result:A total of 126 core targets of Astragali Radix-Angelicae Sinensis Radix for treating DCM were screened out based on network pharmacology. As indicated by KEGG pathway enrichment analysis， the above-mentioned key targets might be related to such pathways as inflammatory response， oxidative stress， insulin resistance， and apoptosis. The findings of <italic>in vivo</italic> animal experiments demonstrated that Astragali Radix-Angelicae Sinensis Radix delayed high glucose-induced cardiomyocyte injury of DCM rats， suggesting that this medicinal pair intervened in the pathological process to a certain extent. Conclusion:Astragali Radix-Angelicae Sinensis Radix alleviates DCM possibly by acting on multiple targets including interleukin-6， vascular endothelial growth factor A， tumor necrosis factor， TP53 gene， and nuclear transcription factor， regulating apoptosis and glucolipid metabolism， and improving oxidative stress and inflammatory response. The research based on network pharmacology and experimental verification has provided new ideas for investigating the pathogenesis of DCM and its clinical treatment.

Fronto-thalamic structural and effective connectivity and delusions in schizophrenia: a combined DTI/DCM study.

BACKGROUND: Schizophrenia (SZ) is a complex disorder characterized by a range of behavioral and cognitive symptoms as well as structural and functional alterations in multiple cortical and subcortical structures. SZ is associated with reduced functional network connectivity involving core regions such as the anterior cingulate cortex (ACC) and the thalamus. However, little is known whether effective coupling, the directed influence of one structure over the other, is altered during rest in the ACC-thalamus network. METHODS: We collected resting-state fMRI and diffusion-weighted MRI data from 18 patients and 20 healthy controls. We analyzed fronto-thalamic effective connectivity using dynamic causal modeling for cross-spectral densities in a network consisting of the ACC and the left and right medio-dorsal thalamic regions. We studied structural connectivity using fractional anisotropy (FA). RESULTS: We found decreased coupling strength from the right thalamus to the ACC and from the right thalamus to the left thalamus, as well as increased inhibitory intrinsic connectivity in the right thalamus in patients relative to controls. ACC-to-left thalamus coupling strength correlated with the Positive and Negative Syndrome Scale (PANSS) total positive syndrome score and with delusion score. Whole-brain structural analysis revealed several tracts with reduced FA in patients, with a maximum decrease in white matter tracts containing fronto-thalamic and cingulo-thalamic fibers. CONCLUSIONS: We found altered effective and structural connectivity within the ACC-thalamus network in SZ. Our results indicate that ACC-thalamus network activity at rest is characterized by reduced thalamus-to-ACC coupling. We suggest that positive symptoms may arise as a consequence of compensatory measures to imbalanced fronto-thalamic coupling.

Generation and Application of the Zebrafish heg1 Mutant as a Cardiovascular Disease Model.

Cardiovascular disease (CVD) is the leading cause of global mortality, which has caused a huge burden on the quality of human life. Therefore, experimental animal models of CVD have become essential tools for analyzing the pathogenesis, developing drug screening, and testing potential therapeutic strategies. In recent decades, zebrafish has entered the field of CVD as an important model organism. HEG1, a heart development protein with EGF like domains 1, plays important roles in the development of vertebrate cardiovascular system. Loss of HEG1 will affect the stabilization of vascular endothelial cell connection and eventually lead to dilated cardiomyopathy (DCM). Here, we generated a heg1-specific knockout zebrafish line using CRISPR/Cas9 technology. Zebrafish heg1 mutant demonstrated severe cardiovascular malformations, including atrial ventricular enlargement, heart rate slowing, venous thrombosis and slow blood flow, which were similar to human heart failure and thrombosis phenotype. In addition, the expression of zebrafish cardiac and vascular markers was abnormal in heg1 mutants. In order to apply zebrafish heg1 mutant in cardiovascular drug screening, four Traditional Chinese Medicine (TCM) herbs and three Chinese herbal monomers were used to treat heg1 mutant. The pericardial area, the distance between sinus venosus and bulbus arteriosus (SV-BA), heart rate, red blood cells (RBCs) accumulation in posterior cardinal vein (PCV), and blood circulation in the tail vein were measured to evaluate the therapeutic effects of those drugs on DCM and thrombosis. Here, a new zebrafish model of DCM and thrombosis was established, which was verified to be suitable for drug screening of cardiovascular diseases. It provided an alternative method for traditional in vitro screening, and produced potential clinical related drugs in a rapid and cost-effective way.

Antioxidant and antiglycation activities of traditional plants and identification of bioactive compounds from extracts of Hordeum vulgare by LC-MS and GC-MS.

Glycation has been involved in Schiff base reaction lead to hyperglycemia at cellular level. The current study aimed to identify the bioactive compounds from selected folkloric plants for their antiglycation and antioxidant potential. Methanol extracts demonstrated the highest activities, therefore, it was further fractionated using n-hexane, dichloromethane, ethyl acetate, and methanol solvents to isolate the nonpolar compounds from the Hordeum vulgare. Moreover, n-hexane and dichloromethane fractions of H. vulgare demonstrated the best antioxidant (61.58% and 62.89%) and antiglycation activities (72.52% and 61.52%) at 2 mg/ml, respectively. Analytical techniques of LC-MS and GC-MS were employed for identification of bioactive compounds; Biochanin A in dichloromethane (DCM) and Vitamin E in n-hexane fractions. There was a strong correlation between antioxidant and antiglycation activities (r = 0.97 and r = 0.96) of DCM & n-hexane fractions of H. vulgare. Findings of this study established the role of Biochanin A and Vit E from H. vulgare as potent antiglycation agents. PRACTICAL APPLICATIONS: The results of this study confirmed the potential role of Black Barley has involved in the inhibition of protein glycation, which can be the potential treatment to reduce the complications of Diabetic Patients. The Black Barley has a rich source of identified compounds Biochanin A and Vitamin E. We can use this plant as a staple food in curing the severity of diabetes. The other practical approach is to use this plant as an ingredient of different food products. The extraction of identified bioactive compounds from the plant will be a good and cheap source of the treatment.

Generative modelling of the thalamo-cortical circuit mechanisms underlying the neurophysiological effects of ketamine.

Cortical recordings of task-induced oscillations following subanaesthetic ketamine administration demonstrate alterations in amplitude, including increases at high-frequencies (gamma) and reductions at low frequencies (theta, alpha). To investigate the population-level interactions underlying these changes, we implemented a thalamo-cortical model (TCM) capable of recapitulating broadband spectral responses. Compared with an existing cortex-only 4-population model, Bayesian Model Selection preferred the TCM. The model was able to accurately and significantly recapitulate ketamine-induced reductions in alpha amplitude and increases in gamma amplitude. Parameter analysis revealed no change in receptor time-constants but significant increases in select synaptic connectivity with ketamine. Significantly increased connections included both AMPA and NMDA mediated connections from layer 2/3 superficial pyramidal cells to inhibitory interneurons and both GABAA and NMDA mediated within-population gain control of layer 5 pyramidal cells. These results support the use of extended generative models for explaining oscillatory data and provide in silico support for ketamine's ability to alter local coupling mediated by NMDA, AMPA and GABA-A.

Effects of hunger, satiety and oral glucose on effective connectivity between hypothalamus and insular cortex.

The hypothalamus and insular cortex play an essential role in the integration of endocrine and homeostatic signals and their impact on food intake. Resting-state functional connectivity alterations of the hypothalamus, posterior insula (PINS) and anterior insula (AINS) are modulated by metabolic states and caloric intake. Nevertheless, a deeper understanding of how these factors affect the strength of connectivity between hypothalamus, PINS and AINS is missing. This study investigated whether effective (directed) connectivity within this network varies as a function of prandial states (hunger vs. satiety) and energy availability (glucose levels and/or hormonal modulation). To address this question, we measured twenty healthy male participants of normal weight twice: once after 36 â€‹h of fasting (except water consumption) and once under satiated conditions. During each session, resting-state functional MRI (rs-fMRI) and hormone concentrations were recorded before and after glucose administration. Spectral dynamic causal modeling (spDCM) was used to assess the effective connectivity between the hypothalamus and anterior and posterior insula. Using Bayesian model selection, we observed that the same model was identified as the most likely model for each rs-fMRI recording. Compared to satiety, the hunger condition enhanced the strength of the forward connections from PINS to AINS and reduced the strength of backward connections from AINS to PINS. Furthermore, the strength of connectivity from PINS to AINS was positively related to plasma cortisol levels in the hunger condition, mainly before glucose administration. However, there was no direct relationship between glucose treatment and effective connectivity. Our findings suggest that prandial states modulate connectivity between PINS and AINS and relate to theories of interoception and homeostatic regulation that invoke hierarchical relations between posterior and anterior insula.

Revealing the multisensory modulation of auditory stimulus in degraded visual object recognition by dynamic causal modeling.

Recent evidence from neurophysiological and functional imaging research has demonstrated that semantically congruent sounds can modulate the identification of a degraded visual object. However, it remains unclear how different integration regions interact with each other when only a visual object was obscured. The present study aimed to elucidate the neural bases of cross-modal functional interactions in degraded visual object recognition. Naturally degraded images and semantically congruent sounds were used in our experiment. Participants were presented with three different modalities of audio-visual stimuli: auditory only (A), degraded visual only (Vd), and simultaneous auditory and degraded visual (AVd). We used conjunction analysis and the classical 'max criterion' to define three audiovisual integration cortical hubs: the visual association cortex, the superior temporal sulcus and the Heschl's gyrus. Dynamic causal modeling (DCM) was then used to infer effective connectivity between these regions. The DCM results revealed that the modulation of an auditory stimulus resulted in increased connectivity from the Heschl's gyrus to the visual association cortex and from the superior temporal sulcus to the visual association cortex. It was shown that the visual association cortex is modulated not only via feedback and top-down connections from higher-order convergence areas but also via lateral feedforward connectivity from the auditory cortex. The present findings give support to interconnected models of cross-modal information integration.

Altered Effective Connectivity of Central Autonomic Network in Response to Negative Facial Expression in Adults With Cannabis Use Disorder.

BACKGROUND: Cannabis use is associated with an increased risk of stress-related adverse cardiovascular events. Because brain regions of the central autonomic network largely overlap with brain regions related to the neural response to emotion and stress, the central autonomic network may mediate the autonomic response to negative emotional stimuli. We aimed to obtain evidence to determine whether neural connectivity of the central autonomic network is altered in individuals with cannabis use disorder (CUD) when they are exposed to negative emotional stimuli. METHODS: Effective (directional) connectivity (EC) analysis using dynamic causal modeling was applied to functional magnetic resonance imaging data acquired from 23 subjects with CUD and 23 control subjects of the Human Connectome Project while they performed an emotional face-matching task with interleaving periods of negative-face (fearful/angry) and neutral-shape stimuli. The EC difference (modulatory change) was measured during the negative-face trials relative to the neutral-shape trials. RESULTS: The CUD group was similar to the control group in nonimaging measures and brain activations but showed greater modulatory changes in left amygdala to hypothalamus EC (positively associated with Perceived Stress Scale score), right amygdala to bilateral fusiform gyri ECs (positively associated with Perceived Stress Scale score), and left ventrolateral prefrontal cortex to bilateral fusiform gyri ECs (negatively associated with Perceived Stress Scale score). CONCLUSIONS: Left amygdala to hypothalamus EC and right amygdala to bilateral fusiform gyri ECs are possibly part of circuits underlying the risk of individuals with CUD to stress-related disorders. Correspondingly, left ventrolateral prefrontal cortex to bilateral fusiform gyri ECs are possibly part of circuits reflecting a protective mechanism.

Role of the supplementary motor area in auditory sensory attenuation.

Self-generated tones elicit smaller brain responses as compared to externally generated tones. This phenomenon known as sensory attenuation has been explained in terms of an internal forward model in which the brain predicts the upcoming events and thereby attenuates the sensory processing. Such prediction processes have been suggested to occur via an efference copy of the motor command that is sent from the motor system to the lower order sensory cortex. However, little is known about how the prediction is implemented in the brain's network organization. Because the supplementary motor area (SMA) is a primary brain structure of the motor system, we attributed the implementation of the prediction to the SMA. To address this question, we examined generative network models for auditory ERPs. ERPs were evoked by either a self-generated or externally generated tone, while subjects were paying attention to their motor action or to the tone. The tone itself was the same throughout all conditions. The network models consisted of three subsets embedding alternative hypotheses of the hierarchical structures: (1) auditory fields of the temporal lobe, (2) adding connections to the SMA, and (3) adding prediction signal to the SMA. The model comparison revealed that all ERP responses were mediated by the network connections across the auditory cortex and the SMA. Importantly, the prediction signal to the SMA was required when the tone was self-generated irrespective of the attention factor, whereas the externally generated tone did not require the prediction. We discussed these results in the context of the predictive coding framework.

Evaluation of Therapeutic Potential of Eugenol-A Natural Derivative of Syzygium aromaticum on Cervical Cancer

Background: The intendment of this study is to determine the pursuance in ­ vitro anticancer activity and cytotoxicity of Syzygium aromaticum against the human cervical cancer cell line (HeLa) compared to the normal cell lines. Apoptogenic properties of DCM extract of Eugenol was determined in this entire study. Materials and Methods: HeLa cell lines were cultured in DMEM medium and incubated with different concentration of DCM ­ Eugenol extract. MTT assay brought out the way to determine the cell viability and quantification was done with the optical absorbance at 570 nm and 620 nm as reference. Apoptotic cells were affirmed by dual staining using acridine orange bromide. Besides, the morphology of the nucleus was also confirmed by dual staining. Eugenol inhibited 50% growth (IC50) of HeLa cell lines at 200 mg/ml of extract concentration. Results: Inhibitory efficacy of eugenol isolated from Syzyzgyium aromaticum showed the cell ­ viability in time and dose dependent manner with consistent morphological changes. Flow cytometer determined the apoptosis confirming the cytotoxicity value for MTT at IC50 with 81.85% cell viability. Dual staining firmly enacts the damaged cells due to AO indicating apoptosis confirmation by dual staining. Morphological analysis also clearly states that nil apoptosis has been seen in control and similarly in eugenol treated when compared to cancerous HeLa cell ­ line. Conclusion: Evaluation of cytotoxicity effect of eugenol isolated from Syzygium aromaticum showed it can be unrivalled dormant source of prodigious changes in HeLa cell line indicating (revealing) that chemotherapeutic agent.

Evaluation of di-calcium malate, used as a novel food ingredient and as a source of calcium in foods for the general population, food supplements, total diet replacement for weight control and food for special medical purposes.

The present scientific opinion deals with the evaluation of the safety of di-calcium malate (DCM) proposed as a novel food ingredient and as a source of calcium for use in foods for the general population, food supplements, total diet replacement for weight control and food for special medical purposes (FSMP), and with the bioavailability of calcium from this source. The structural formula of the proposed complex is based on expert judgement and not supported by any analytical data. On the basis of the available data, the Panel concluded that there was insufficient scientific evidence of a difference between the proposed novel food ingredient named as di-calcium malate (DCM) and calcium malate already authorised as a source of calcium included in Annex II to Directive 2002/46/EC. Accordingly, the Panel was unable to assess the safety of DCM as a novel food ingredient. On the basis of the results provided, the Panel considered that DCM does not completely dissociate into calcium and malic acid. The Panel concluded that when DCM dissociates, calcium would be available following ingestion of DCM and the bioavailability would appear similar to values reported for other sources of calcium already permitted. Furthermore, the Panel concluded that on the basis of the information available it was not possible to calculate the exposure to DCM as a source of calcium to foods for the general population, food supplements, total diet replacement for weight control and FSMP.

Learning Control Over Emotion Networks Through Connectivity-Based Neurofeedback.

Most mental functions are associated with dynamic interactions within functional brain networks. Thus, training individuals to alter functional brain networks might provide novel and powerful means to improve cognitive performance and emotions. Using a novel connectivity-neurofeedback approach based on functional magnetic resonance imaging (fMRI), we show for the first time that participants can learn to change functional brain networks. Specifically, we taught participants control over a key component of the emotion regulation network, in that they learned to increase top-down connectivity from the dorsomedial prefrontal cortex, which is involved in cognitive control, onto the amygdala, which is involved in emotion processing. After training, participants successfully self-regulated the top-down connectivity between these brain areas even without neurofeedback, and this was associated with concomitant increases in subjective valence ratings of emotional stimuli of the participants. Connectivity-based neurofeedback goes beyond previous neurofeedback approaches, which were limited to training localized activity within a brain region. It allows to noninvasively and nonpharmacologically change interconnected functional brain networks directly, thereby resulting in specific behavioral changes. Our results demonstrate that connectivity-based neurofeedback training of emotion regulation networks enhances emotion regulation capabilities. This approach can potentially lead to powerful therapeutic emotion regulation protocols for neuropsychiatric disorders.

Translating state-of-the-art spinal cord MRI techniques to clinical use: A systematic review of clinical studies utilizing DTI, MT, MWF, MRS, and fMRI.

BACKGROUND: A recent meeting of international imaging experts sponsored by the International Spinal Research Trust (ISRT) and the Wings for Life Foundation identified 5 state-of-the-art MRI techniques with potential to transform the field of spinal cord imaging by elucidating elements of the microstructure and function: diffusion tensor imaging (DTI), magnetization transfer (MT), myelin water fraction (MWF), MR spectroscopy (MRS), and functional MRI (fMRI). However, the progress toward clinical translation of these techniques has not been established. METHODS: A systematic review of the English literature was conducted using MEDLINE, MEDLINE-in-Progress, Embase, and Cochrane databases to identify all human studies that investigated utility, in terms of diagnosis, correlation with disability, and prediction of outcomes, of these promising techniques in pathologies affecting the spinal cord. Data regarding study design, subject characteristics, MRI methods, clinical measures of impairment, and analysis techniques were extracted and tabulated to identify trends and commonalities. The studies were assessed for risk of bias, and the overall quality of evidence was assessed for each specific finding using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework. RESULTS: A total of 6597 unique citations were identified in the database search, and after full-text review of 274 articles, a total of 104 relevant studies were identified for final inclusion (97% from the initial database search). Among these, 69 studies utilized DTI and 25 used MT, with both techniques showing an increased number of publications in recent years. The review also identified 1 MWF study, 11 MRS studies, and 8 fMRI studies. Most of the studies were exploratory in nature, lacking a priori hypotheses and showing a high (72%) or moderately high (20%) risk of bias, due to issues with study design, acquisition techniques, and analysis methods. The acquisitions for each technique varied widely across studies, rendering direct comparisons of metrics invalid. The DTI metric fractional anisotropy (FA) had the strongest evidence of utility, with moderate quality evidence for its use as a biomarker showing correlation with disability in several clinical pathologies, and a low level of evidence that it identifies tissue injury (in terms of group differences) compared with healthy controls. However, insufficient evidence exists to determine its utility as a sensitive and specific diagnostic test or as a tool to predict clinical outcomes. Very low quality evidence suggests that other metrics also show group differences compared with controls, including DTI metrics mean diffusivity (MD) and radial diffusivity (RD), the diffusional kurtosis imaging (DKI) metric mean kurtosis (MK), MT metrics MT ratio (MTR) and MT cerebrospinal fluid ratio (MTCSF), and the MRS metric of N-acetylaspartate (NAA) concentration, although these results were somewhat inconsistent. CONCLUSIONS: State-of-the-art spinal cord MRI techniques are emerging with great potential to improve the diagnosis and management of various spinal pathologies, but the current body of evidence has only showed limited clinical utility to date. Among these imaging tools DTI is the most mature, but further work is necessary to standardize and validate its use before it will be adopted in the clinical realm. Large, well-designed studies with a priori hypotheses, standardized acquisition methods, detailed clinical data collection, and robust automated analysis techniques are needed to fully demonstrate the potential of these rapidly evolving techniques.

Impaired prefrontal synaptic gain in people with psychosis and their relatives during the mismatch negativity.

The mismatch negativity (MMN) evoked potential, a preattentive brain response to a discriminable change in auditory stimulation, is significantly reduced in psychosis. Glutamatergic theories of psychosis propose that hypofunction of NMDA receptors (on pyramidal cells and inhibitory interneurons) causes a loss of synaptic gain control. We measured changes in neuronal effective connectivity underlying the MMN using dynamic causal modeling (DCM), where the gain (excitability) of superficial pyramidal cells is explicitly parameterised. EEG data were obtained during a MMN task--for 24 patients with psychosis, 25 of their first-degree unaffected relatives, and 35 controls--and DCM was used to estimate the excitability (modeled as self-inhibition) of (source-specific) superficial pyramidal populations. The MMN sources, based on previous research, included primary and secondary auditory cortices, and the right inferior frontal gyrus. Both patients with psychosis and unaffected relatives (to a lesser degree) showed increased excitability in right inferior frontal gyrus across task conditions, compared to controls. Furthermore, in the same region, both patients and their relatives showed a reversal of the normal response to deviant stimuli; that is, a decrease in excitability in comparison to standard conditions. Our results suggest that psychosis and genetic risk for the illness are associated with both context-dependent (condition-specific) and context-independent abnormalities of the excitability of superficial pyramidal cell populations in the MMN paradigm. These abnormalities could relate to NMDA receptor hypofunction on both pyramidal cells and inhibitory interneurons, and appear to be linked to the genetic aetiology of the illness, thereby constituting potential endophenotypes for psychosis.

Brain effective connectivity during motor-imagery and execution following stroke and rehabilitation.

Brain areas within the motor system interact directly or indirectly during motor-imagery and motor-execution tasks. These interactions and their functionality can change following stroke and recovery. How brain network interactions reorganize and recover their functionality during recovery and treatment following stroke are not well understood. To contribute to answering these questions, we recorded blood oxygenation-level dependent (BOLD) functional magnetic resonance imaging (fMRI) signals from 10 stroke survivors and evaluated dynamical causal modeling (DCM)-based effective connectivity among three motor areas: primary motor cortex (M1), pre-motor cortex (PMC) and supplementary motor area (SMA), during motor-imagery and motor-execution tasks. We compared the connectivity between affected and unaffected hemispheres before and after mental practice and combined mental practice and physical therapy as treatments. The treatment (intervention) period varied in length between 14 to 51 days but all patients received the same dose of 60 h of treatment. Using Bayesian model selection (BMS) approach in the DCM approach, we found that, after intervention, the same network dominated during motor-imagery and motor-execution tasks but modulatory parameters suggested a suppressive influence of SM A on M1 during the motor-imagery task whereas the influence of SM A on M1 was unrestricted during the motor-execution task. We found that the intervention caused a reorganization of the network during both tasks for unaffected as well as for the affected hemisphere. Using Bayesian model averaging (BMA) approach, we found that the intervention improved the regional connectivity among the motor areas during both the tasks. The connectivity between PMC and M1 was stronger in motor-imagery tasks whereas the connectivity from PMC to M1, SM A to M1 dominated in motor-execution tasks. There was significant behavioral improvement (p = 0.001) in sensation and motor movements because of the intervention as reflected by behavioral Fugl-Meyer (FMA) measures, which were significantly correlated (p = 0.05) with a subset of connectivity. These findings suggest that PMC and M1 play a crucial role during motor-imagery as well as during motor-execution task. In addition, M1 causes more exchange of causal information among motor areas during a motor-execution task than during a motor-imagery task due to its interaction with SM A. This study expands our understanding of motor network involved during two different tasks, which are commonly used during rehabilitation following stroke. A clear understanding of the effective connectivity networks leads to a better treatment in helping stroke survivors regain motor ability.