A novel STAT3 inhibitor negatively modulates platelet activation and aggregation.

The signal transducer and activator of transcription 3 (STAT3) plays a critical role in platelet functions. This study sought to understand the effects of the STAT3 inhibitor SC99 on platelet activation and aggregation. Immunoblotting assays were applied to measure the effects of SC99 on the STAT3 signaling pathway. A ChronoLog aggregometer was used to evaluate platelet aggregation. A flow cytometer was used to evaluate P-selectin expression in the presence of SC99. AlamarBlue and Annexin-V staining were used to evaluate platelet viability and apoptosis, respectively. A fluorescence microscope was applied to analyze platelet spreading. SC99 inhibited the phosphorylation of JAK2 and STAT3 in human platelets but had no effects on the phosphorylation of AKT, p65 or Src, all of which are involved in platelet activation. Further studies revealed that SC99 inhibited human platelet aggregation induced by collagen and thrombin in a dose-dependent manner. SC99 inhibited thrombin-induced P-selectin expression and fibrinogen binding to single platelets. Moreover, SC99 inhibited platelet spreading on fibrinogen and clot retraction mediated by outside-in signaling. SC99 inhibited platelet aggregation in mice but it did not significantly prolong the bleeding time. Taken together, the present study revealed that SC99 inhibited platelet activation and aggregation as a STAT3 inhibitor. This agent can be developed as a promising treatment for thrombotic disorders.

The association of CYP1A1 genetic polymorphisms and additional gene-gene interaction with ischemic stroke in the eastern Han of China.

The aim of this study was to investigate the association between CYP1A1 gene polymorphism and ischaemic stroke (IS) risk, and the impact of gene-gene interaction on IS risk based on a Chinese Han case-control study. A total of 1162 subjects (612 men and 550 women), with a mean age of 63.1 ± 12.5 years old, were selected, including 580 IS patients and 582 normal controls. Logistic regression was performed to investigate association between single-nucleotide polymorphisms (SNP) and IS risk, and generalized multifactor dimensionality reduction (GMDR) was used to analyze the gene-gene interaction. Logistic regression analysis showed that the frequency for rs4646903 minor alleles was lower in cases than that in normal controls, and C allele of rs4646903 was 20.7 % in ischemic stroke cases and 27.1 % in controls subjects (p < 0.001). Logistic analysis showed the significant association between genotypes of variants in rs4646903 and decreased ischemic stroke risk. GMDR analysis indicated that there was a significant two-locus model (p = 0.0107) involving rs4646903 and rs1048943, indicating a potential gene-gene interaction between rs4646903 and rs1048943. Overall, the two- locus models had a cross-validation consistency of 9 of 10, and had the testing accuracy of 60.72 %. Subjects with TC or CC of rs4646903 and AG or GG of rs1048943 genotype have lowest ischemic stroke risk, compared to subjects with TT of rs4646903 and AA of rs1048943 genotype, and OR (95 % CI) was 0.63 (0.42-0.89). rs4646903 minor alleles and interaction between rs4646903 and rs1048943 were associated with decreased IS risk.

Speckle noise removal applied to ultrasound image of carotid artery based on total least squares model.

An ultrasonic image speckle noise removal method by using total least squares model is proposed and applied onto images of cardiovascular structures such as the carotid artery. On the basis of the least squares principle, the related principle of minimum square method is applied to cardiac ultrasound image speckle noise removal process to establish the model of total least squares, orthogonal projection transformation processing is utilized for the output of the model, and the denoising processing for the cardiac ultrasound image speckle noise is realized. Experimental results show that the improved algorithm can greatly improve the resolution of the image, and meet the needs of clinical medical diagnosis and treatment of the cardiovascular system for the head and neck. Furthermore, the success in imaging of carotid arteries has strong implications in neurological complications such as stroke.

An investigation on the changes of serum CCK-8, substance P, and 5-HT in patients with post-stroke insomnia.

BACKGROUND: At present, the pathogenesis of post-stroke insomnia (PSI) is still inconclusive. OBJECTIVE: To explore the changes and significance of serum cholecystokinin-8 (CCK-8), substance P (SP), and 5-hydroxytryptamine (5-HT) in patients with PSI. METHODS: Ninety-one patients with stroke were selected as the research subjects, and according to the score of the Athens Insomnia Scale (AIS), they were divided into the insomnia group and the non-insomnia group. The serum levels of CCK-8, SP, and 5-HT in the two groups were compared to explore their relationships with PSI. RESULTS: Among the 91 patients, 56 were in the insomnia group and 35 were in the non-insomnia group, and the incidence of insomnia was 61.5%. There was no significant difference in the serum levels of CCK-8, SP, and 5-HT between the two groups (P= 0.696, 0.980, and 0.809, respectively). One-way analysis of variance showed that there was no significant correlation between the serum levels of CCK-8, SP, 5-HT, and the AIS score (P= 0.7393, 0.9581, and 0.5952, respectively). CONCLUSION: The incidence of PSI was relatively high, but it could not be proved that CCK-8, SP, and 5-HT were involved in the pathogenesis of PSI. There might exist other neurotransmitters involved in the pathophysiological process of PSI, which should be further explored.

Examining the Role of GLU/GABA to GLN Metabolic Cycle in the Pathogenesis of Post-Stroke Depressive Disorder and Insomnia.

Objective: This study aims to elucidate the potential links between the GLU/GABA to GLN metabolic cycle disruptions and the onset of depressive and insomnia disorders following a stroke. We particularly focus on understanding if these disorders share a common underlying pathogenic mechanism. Methods: We examined 63 patients with post-stroke insomnia, 62 patients with post-stroke depression, and 18 healthy individuals. The study involved assessing insomnia using the Acute Insomnia Scale (AIS) and depression using the Hamilton Depression Rating Scale. We measured serum concentrations of GLN, GLU, and GABA and analyzed their correlations with AIS and HAMD scores. Results: Our results indicate no significant difference in the serum levels of GLN, GLU, and GABA between the post-stroke insomnia and depression groups. However, these levels were notably lower in both patient groups compared to the healthy control group. A negative correlation between AIS scores and GABA levels was observed in the post-stroke insomnia group, suggesting a potential link between GABAergic disturbances and insomnia. Conversely, no significant correlation was found between Hamilton Depression Rating Scale scores and the levels of GABA, GLU, or GLN in the post-stroke depression group. Conclusion: The study highlights that abnormalities in the GLU/GABA to GLN metabolic cycle, particularly the levels of GLN, GABA, and GAD, might be intricately linked to the pathogenesis of post-stroke insomnia and depression. Our findings suggest that GABAergic imbalances could be indicative of post-stroke insomnia, serving as potential biological markers for differential diagnosis in clinical settings. Further research is warranted to explore these relationships in greater depth, potentially leading to new diagnostic and therapeutic approaches for post-stroke neuropsychiatric disorders.

Global analysis of population stratification using a smart panel of 27 continental ancestry-informative SNPs.

Over the last decade, several panels of ancestry-informative markers have been proposed for the analysis of population genetic structure. The differentiation efficiency depends on the discriminatory ability of the included markers and the reference population coverage. We previously developed a small set of 27 autosomal single nucleotide polymorphisms (SNPs) for analyzing African, European, and East Asian ancestries. In the current study, we gathered a high-coverage reference database of 110 populations (10,350 individuals) from across the globe. The discrimination power of the panel was re-evaluated using four continental ancestry groups (as well as Indigenous Americans). We observed that all the 27 SNPs demonstrated stratified population specificity leading to a striking ancestral discrimination. Five markers (rs728404, rs7170869, rs2470102, rs1448485, and rs4789193) showed differences (δ > 0.3) in the frequency profiles between East Asian and Indigenous American populations. Ancestry components of all involved populations were accurately accessed compared with those from previous genome-wide analyses, thereafter achieved broadly population separation. Thus, our ancestral inference panel of a small number of highly informative SNPs in combination with a large-scale reference database provides a high-resolution in estimating ancestry compositions and distinguishing individual origins. We propose extensive usage in biomedical studies and forensics.

Identification of vaginal fluid, saliva, and feces using microbial signatures in a Han Chinese population.

In recent years, forensic scientists have focused on the discrimination of body fluids using microbial signatures. In this study, we performed PCR-based detection of microbial signatures of vaginal fluid, saliva, and feces in a Han Chinese population. We investigated the 16S rRNA genes of Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus jensenii, Lactobacillus iners, and Atopobium vaginae in vaginal fluid, the 16S rRNA and the glucosyltransferase enzyme genes of Streptococcus salivarius and Streptococcus mutans in saliva, and the 16S rRNA genes of Enterococcus species, the RNA polymerase ß-subunit gene of Bacteroides uniformis and Bacteroides vulgatus, and the α-1-6 mannanase gene of Bacteroides thetaiotaomicron in feces. As a result, the detection proportions of L. crispatus, L. gasseri, L. jensenii, L. iners, and A. vaginae were 15/16, 5/16, 8/16, 14/16, and 3/16 in 16 vaginal fluid donors, respectively. L. crispatus and L. jensenii were specifically detected in vaginal fluid; L. gasseri, L. iners, and A. vaginae were also detected in non-vaginal fluid. S. salivarius and S. mutans were not specifically detected in saliva. The detection proportions of Enterococcus species, B. uniformis, B. vulgatus, and B. thetaiotaomicron in 16 feces samples were 16/16, 12/16, 15/16, and 11/16, respectively. B. uniformis and B. thetaiotaomicron were specifically detected in feces. In addition, DNA samples prepared for the identification of body fluid can also be used for individual identification by short tandem repeat typing. The mean detection sensitivities of L. crispatus and L. jensenii were 0.362 and 0.249 pg/uL, respectively. In conclusion, L. crispatus, L. jensenii, B. uniformis, and B. thetaiotaomicron can be used as effective markers for forensic identification of vaginal fluid and feces.

Dantrolene enhances the protective effect of hypothermia on cerebral cortex neurons.

Therapeutic hypothermia is the most promising non-pharmacological neuroprotective strategy against ischemic injury. However, shivering is the most common adverse reaction. Many studies have shown that dantrolene is neuroprotective in in vitro and in vivo ischemic injury models. In addition to its neuroprotective effect, dantrolene neutralizes the adverse reaction of hypothermia. Dantrolene may be an effective adjunctive therapy to enhance the neuroprotection of hypothermia in treating ischemic stroke. Cortical neurons isolated from rat fetuses were exposed to 90 minutes of oxygen-glucose deprivation followed by reoxygenation. Neurons were treated with 40 µM dantrolene, hypothermia (at 33°C), or the combination of both for 12 hours. Results revealed that the combination of dantrolene and hypothermia increased neuronal survival and the mitochondrial membrane potential, and reduced intracellular active oxygen cytoplasmic histone-associated DNA fragmentation, and apoptosis. Furthermore, improvements in cell morphology were observed. The combined treatment enhanced these responses compared with either treatment alone. These findings indicate that dantrolene may be used as an effective adjunctive therapy to enhance the neuroprotective effects of hypothermia in ischemic stroke.