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Growing evidence suggests that neuroinflammation is a critical driver of the development, worsening, and cell death observed in acute ischemic stroke (AIS). While prior research has demonstrated that tirofiban enhances functional recovery in AIS patients by suppressing platelet aggregation, its impact and underlying mechanisms in AIS-related neuroinflammation remain elusive. The current study established an AIS mouse model employing photochemical techniques and assessed neurological function and brain infarct size using the modified neurological severity scale (mNSS) and 2,3,5-Triphenyltetrazolium chloride (TTC) staining, respectively. Tirofiban significantly reduced the volume of cerebral infarction in AIS mice, accompanied by an enhancement in their neurological functions. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays along with experiments assessing oxidative stress showed that tirofiban mitigated oxidative damage and apoptosis in the ischemic penumbra post-AIS. Additionally, DNA microarray analysis revealed alterations in gene expression patterns in the ischemic penumbra after tirofiban treatment. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed that most gene-level downregulated signaling pathways were closely related to the inflammatory response. Moreover, the protein microarray analysis revealed that tirofiban diminished the expression levels of inflammatory cytokines, such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha, in the ischemic penumbra. Additionally, immunofluorescence staining showed that tirofiban regulated inflammatory responses by altering the state and phenotype of microglia. In conclusion, this study suggests that tirofiban reduces inflammatory response by regulating microglial state and phenotype and lowering the levels of inflammatory factors, providing neuroprotection in acute ischemic stroke., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 IBRO. Published by Elsevier Inc. All rights reserved.)

In a previously published clinical trial, we demonstrated that tirofiban was effective and safe in acute ischemic stroke (AIS) patients who did not undergo early recanalization treatments. We aimed to evaluate neuroimaging characteristics and their clinical significance to guide tirofiban treatment. In this post hoc analysis, location of infarcts (anterior circulation stroke [ACS] vs. posterior circulation stroke [PCS]), degree of cerebral artery stenosis (≤69% vs. ≥70% or occlusion), total infarct volume, and ASPECTS were used to predict the treatment effects of tirofiban, defined as the proportions of excellent and favorable functional outcome (modified Rankin Scale [mRS] score of 0-1, 0-2) at 90 days. ACS patients were more likely to achieve excellent (OR 2.08; 95% CI 1.25-3.45; p = 0.004) and favorable functional outcome (OR 2.28; 95% CI 1.24-4.22; p = 0.008) when treated with tirofiban. However, there was no significant difference in PCS patients between tirofiban and the control group. For patients with severe stenosis (≥70% or occlusion), tirofiban treatment improved the proportion of good outcomes (OR 2.84; 95% CI 1.44-5.60; p = 0.002 for mRS 0-1; OR 2.42; 95% CI 1.22-4.77; p = 0.011 for mRS 0-2). Meanwhile, we found that tirofiban improved outcome in patients with ASPECTS 8-10 and was independent of total infarct volume. These findings support the hypothesis that patients with ACS and severe stenosis may be recommended for tirofiban treatment, which can be predicted independent of total infarct volume., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The GATA family of genes plays various roles in crucial biological processes, such as development, cell differentiation, and disease progression. However, the roles of GATA in insects have not been thoroughly explored. In this study, a genome-wide characterization of the GATA gene family in the silkworm, Bombyx mori, was conducted, revealing lineage-specific expression profiles. Notably, GATA6 is ubiquitously expressed across various developmental stages and tissues, with predominant expression in the midgut, ovaries, and Malpighian tubules. Overexpression of GATA6 inhibits cell growth and promotes apoptosis, whereas, in contrast, knockdown of PARP mitigates the apoptotic effects driven by GATA6 overexpression. Co-immunoprecipitation (co-IP) has demonstrated that GATA6 can interact with Poly (ADP-ribose) polymerase (PARP), suggesting that GATA6 may induce cell apoptosis by activating the enzyme's activity. These findings reveal a dynamic and regulatory relationship between GATA6 and PARP, suggesting a potential role for GATA6 as a key regulator in apoptosis through its interaction with PARP. This research deepens the understanding of the diverse roles of the GATA family in insects, shedding light on new avenues for studies in sericulture and pest management., Competing Interests: Declaration of competing interest The authors declare that they have no conflicts of financial interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Apolipoprotein E (APOE) ε2 and APOE ε4 are the most distinct alleles among the three APOE alleles, both structurally and functionally. However, differences in cognition, brain function, and brain structure between the two alleles have not been comprehensively reported in the literature, especially in non-demented elderly individuals., Methods: A neuropsychological test battery was used to evaluate the differences in cognitive performance in five cognitive domains. Independent component analysis (ICA) and voxel-based morphometry (VBM) were used separately to analyze resting-state functional magnetic resonance imaging (rs-fMRI) data and the structure MRI data between the two groups. Finally, correlations between differential brain regions and neuropsychological tests were calculated., Results: APOE ε2 carriers had better cognitive performance in general cognitive, memory, attention, and executive function than APOE ε4 carriers (all p < 0.05). In ICA analyses of rs-fMRI data, the difference in the resting-state functional connectivity (rsFC) between two groups is shown in 7 brain networks. In addition, VBM analyses of the T1-weighted image revealed that APOE ε2 carriers had a larger thalamus and right postcentral gyrus volume and a smaller bilateral putamen volume than APOE ε4 carriers. Finally, differences in brain function and structure may be might be the reason that APOE ε2 carriers are better than APOE ε4 carriers in cognitive performance., Conclusion: These findings suggest that there are significant differences in brain function and structure between APOE ε2 carriers and APOE ε4 carriers, and these significant differences are closely related to their cognitive performance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wang, Pang, Zhou, Qi, Shi, Han, Man, Wang and Sun.)

Background and Purpose: Chuanzhitongluo (CZTL), a traditional Chinese medicine mixture, is used in the recovery period of acute ischemic stroke (AIS), and effectively improves the prognosis of AIS patients. This study aims to evaluate whether CZTL regulates microglia polarization and inflammatory response to reduce brain damage in the acute phase of AIS., Methods: A mouse model of AIS was prepared by the photochemical method. Cerebral infarct volume was detected by 2,3,5-Triphenyltetrazolium chloride (TTC) staining. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was used to assess neuronal apoptosis. Gene expression profile change was explored by Gene chip. Inflammatory factors were analyzed by Protein microarray. The Immunofluorescence double-labeling assay was executed to elucidate the effects of CD16 + / Iba-1 + and CD206 + / Iba-1 + in the peripheral area of cerebral ischemia., Results: Results revealed that CZTL treatment alleviated the neurological impairment, reduced cerebral infarct volume, and inhibited neuronal apoptosis. CZTL altered gene expression profiles, which indicate that CZTL may be involved in regulating neuroinflammation. CZTL restrained inflammatory responses by down-regulated pro-inflammatory cytokines expression and enhanced anti-inflammatory cytokines level. Further experiments demonstrated that CZTL inhibited the activation of NLRP3 inflammasome, which decreasing the inflammatory response. In addition, CZTL promoted the transformation of microglia from M1 to M2 phenotype., Conclusions: These results indicate that CZTL alleviates neuroinflammation and brain damage after AIS in mice, which may be mediated by modulating microglia polarization., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: There is evidence that the T allele of rs405509 located in the apolipoprotein E ( APOE ) promotor region is a risk factor for Alzheimer's disease (AD). However, the effect of the T/T allele on brain function in non-demented aging is still unclear., Methods: We analyzed the effects of the rs405509 T/T allele on cognitive performances using multiple neuropsychological tests and local brain function using resting-state functional magnetic resonance imaging (rs-fMRI)., Results: Significant differences were found between T/T carriers and G allele carriers on general cognitive status, memory, and attention ( p < 0.05). Rs-fMRI analyses demonstrated decreased amplitude of low frequency fluctuation (ALFF) in the right middle frontal gyrus, decreased percent amplitude of fluctuation (PerAF) in the right middle frontal gyrus, increased regional homogeneity (ReHo) in the right cerebellar tonsil and decreased ReHo in the right putamen, and decreased degree centrality (DC) in the left middle frontal gyrus ( p < 0.05, corrected). Furthermore, significant correlations were found between cognitive performance and these neuroimaging changes ( p < 0.05)., Conclusion: These findings suggest that T/T allele may serve as an independent risk factor that can influence brain function in different regions in non-demented aging., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wu, Zhao, Gu, Han, Wang, Man, Zhao, Liu and Sun.)

Background: As a pattern recognition receptor, Toll-like receptor 7 (TLR7) widely presented in the endosomal membrane of various cells. However, the precise role and mechanism of TLR7 in septic cardiomyopathy remain unknown. This study aims to determine the role of TLR7 in cardiac dysfunction during sepsis and explore the mechanism of TLR7 in septic cardiomyopathy., Methods: We generated a mouse model of septic cardiomyopathy by challenging with lipopolysaccharide (LPS). TLR7-knockout (TLR7 -/- ), wild-type (WT) mice, cardiac-specific TLR7-transgenic (cTG-TLR7) overexpression, and littermates WT (LWT) mice were subjected to septic model. Additionally, to verify the role and mechanism of TLR7 in vitro, we transfected neonatal rat ventricular myocytes (NRVMs) with Ad-TLR7 and TLR7 siRNA before LPS administration. The effects of TLR7 were assessed by Ca 2+ imaging, western blotting, immunostaining, and quantitative real-time polymerase chain reaction (qPCR)., Results: We found that TLR7 knockout markedly exacerbated sepsis-induced systolic dysfunction. Moreover, cardiomyocytes isolated from TLR7 -/- mice displayed weaker Ca 2+ handling than that in WT mice in response to LPS. Conversely, TLR7 overexpression alleviated LPS-induced systolic dysfunction, and loxoribine (TLR7-specific agonist) improved LPS-induced cardiac dysfunction. Mechanistically, these optimized effects were associated with enhanced the adenosine (cAMP)-protein kinase A (PKA) pathway, which upregulated phosphorylate-phospholamban (p-PLN) (Ser16) and promoted sarco/endoplasmic reticulum Ca 2+ ATPase (Serca) and Ryanodine Receptor 2 (RyR2) expression in the sarcoplasmic reticulum (SR), and ultimately restored Ca 2+ handling in response to sepsis. While improved Ca 2+ handling was abrogated after H89 (a specific PKA inhibitor) pretreatment in cardiomyocytes isolated from cTG-TLR7 mice. Consistently, TLR7 overexpression improved LPS-induced Ca 2+ -handling decrement in NRVMs. Nevertheless, TLR7 knockdown showed a deteriorative phenotype., Conclusions: Our data demonstrated that activation of TLR7 protected against sepsis-induced cardiac dysfunction through promoting cAMP-PKA-PLN pathway, and we revealed that TLR7 might be a novel therapeutic target to block the septic cardiomyopathy and support systolic function during sepsis., (© 2020 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Hirschsprung's disease (HD) is an intestinal malformation caused by the innate absence of ganglion cells in the neural plexus of the colorectal wall, and is most common in male infants. It is rare in adult, and is usually left-sided. Herein we reported based on the CARE guidelines a case of a 47-year-old adult female suffering from "right-sided" HD complicated by refractory hypertension and cough. The patient with a history of cesarean section and with digestive unfitness (abdominal pain, distention, and constipation) only since 20 years old had recurrence of HD after initial surgery due to the incomplete removal of the HD-affected bowel based on a diagnosis of "chronic ileus", leading to the relapse of the digestive symptoms and the emergence of some intractable circulatory and respiratory complications which could be hardly controlled by conservative treatment. During the long interval before coming to our department for help, she had been re-hospitalized for several times with various misdiagnoses and supplied merely with symptomatic treatment which could only achieve temporary symptomatic relief. At her admission to our department, the imaging examinations strongly indicated recurrent HD which was further supported by pathological examinations, and right hemi-colectomy was performed to remove the remnant aganglionic intestinal segment. Intraoperative and postoperative pathology supported the completeness of the definitive resection. Post-operation, the patient's bowel motility significantly improved, and interestingly, the complications disappeared. For adult patients with long-term constipation combined with cough and hypertension, rare diseases like HD which requires definite surgery and which could be "right-sided" should not be overlooked. It is vital to diagnose and cure HD patients in childhood. Through the comparison of the two surgeries, it is noteworthy that for diagnosed HD, sufficient removal of the non-functional intestine confirmed by intraoperative pathology is essential., Competing Interests: Conflict-of-interest statement: All the authors have no conflict-of-interest to disclose.

The significant influence of tumor stroma on malignant cells has been extensively investigated in this era of targeted therapy. The tumor microenvironment, as a dynamic system, is orchestrated by various cells including tumor vascular composing cells, inflammatory cells and fibroblasts. As a major and important component in tumor stroma, increasing evidence has shown that spindle-shaped cancer-associated fibroblasts (CAFs) are a significant modifier of cancer evolution, and promote tumorigenesis, tumor invasion and metastasis by stimulating angiogenesis, malignant cell survival, epithelial-mesenchymal transition (EMT) and proliferation via direct cell-to-cell contact or secretion of soluble factors in most digestive solid tumors. CAFs are thought to be activated, characterized by the expression of α-smooth muscle actin, fibroblast activated protein, fibroblast specific protein, vimentin, fibronectin, etc. They are hypothesized to originate from normal or aged fibroblasts, bone marrow-derived mesenchymal cells, or vascular endothelial cells. EMT may also be an important process generating CAFs, and most probably, CAFs may originate from multiple cells. A close link exists between EMT, tumor stem cells, and chemo-resistance of tumor cells, which is largely orchestrated by CAFs. CAFs significantly induce immunosuppression, and may be a prognostic marker in various malignancies. Targeted therapy toward CAFs has displayed promising anticancer efficacy, which further reinforces the necessity to explore the relationship between CAFs and their hosts.

Aim: To investigate the necessity and correctness of acid suppression pre- and post-gastrectomy among gastric carcinoma (GC) patients., Methods: From June 2011 to April 2013, 99 patients who were diagnosed with GC or adenocarcinoma of the gastroesophageal junction (type II or III) and needed surgical management were enrolled. They all underwent gastrectomy by the same operators [35 undergoing total gastrectomy (TG) plus Roux-en-Y reconstruction, 34 distal gastrectomy (DG) plus Billroth I reconstruction, and 30 proximal gastrectomy (PG) plus gastroesophagostomy]. We collected and analyzed their gastrointestinal juice and tissues from the pre-operational day to the 5(th) day post-operation, and 6 mo post-surgery. Gastric pH was detected with a precise acidity meter. Gastric juice contents including potassium, sodium and bicarbonate ions, urea nitrogen, direct and indirect bilirubin, and bile acid were detected using Automatic Biochemical Analyzer. Data regarding tumor size, histological type, tumor penetration and tumor-node-metastasis (TNM) stage were obtained from the pathological records. Reflux symptoms pre- and 6 mo post-gastrectomy were evaluated by reflux disease questionnaire (RDQ) and gastroesophageal reflux disease questionnaire (GERD-Q). SPSS 16.0 was applied to analyze the data., Results: Before surgery, gastric pH was higher than the threshold of hypoacidity (4.25 ± 1.45 vs 3.5, P = 0.000), and significantly affected by age, tumor size and differentiation grade, and potassium and bicarbonate ions; advanced malignancies were accompanied with higher pH compared with early ones (4.49 ± 1.31 vs 3.66 ± 1.61, P = 0.008). After operation, gastric pH in all groups was of weak-acidity and significantly higher than that pre-gastrectomy; on days 3-5, comparisons of gastric pH were similar between the 3 groups. Six months later, gastric pH was comparable to that on days 3-5; older patients were accompanied with higher total bilirubin level, indicating more serious reflux (r = 0.238, P = 0.018); the TG and PG groups had higher RDQ (TG vs DG: 15.80 ± 5.06 vs 12.26 ± 2.14, P = 0.000; PG vs DG: 15.37 ± 3.49 vs 12.26 ± 2.14, P = 0.000) and GERD-Q scores (TG vs DG: 10.54 ± 3.16 vs 9.15 ± 2.27, P = 0.039; PG vs DG: 11.00 ± 2.07 vs 9.15 ± 2.27, P = 0.001) compared with the DG group; all gastric juice contents except potassium ion significantly rose; reflux symptom was significantly associated with patient's body mass index, direct and indirect bilirubin, and total bile acid, while pH played no role., Conclusion: Acidity is not an important factor causing unfitness among GC patients. There is no need to further alkalify gastrointestinal juice both pre- and post-gastrectomy.