The Combination of Zhuli Decoction and N-butylphthalide Inhibits Cell Apoptosis Induced by CO Poisoning through the PI3K/AKT/GSK-3ß Signaling Pathway.

Carbon monoxide poisoning (COP) represents a significant global health burden, characterized by its morbidity and high mortality rates. The pathogenesis of COP-induced brain injury is complex, and effective treatment modalities are currently lacking. In this study, we employed network pharmacology to identify therapeutic targets and associated signaling pathways of Zhuli Decoction (ZLD) for COP. Subsequently, we conducted both in vitro and in vivo experiments to validate the therapeutic efficacy of ZLD in combination with N-butylphthalide (NBP) for acute COP-induced injury. Our network pharmacology analysis revealed that the primary components of ZLD exerted therapeutic effects through the modulation of multiple targets and pathways. The in vitro and in vivo experiments demonstrated that the combination of NBP and ZLD effectively inhibited apoptosis and up-regulated the activities of P-PI3K (Tyr458), P-AKT (Ser473), P-GSK-3ß (Ser9), and Bcl-2, thus leading to the protection of neuronal cells and improvement in cognitive function in rats following COP, which was better than the effects observed with NBP or ZLD alone. The rescue experiment further showed that LY294002, a PI3K inhibitor, significantly attenuated the therapeutic efficacy of NBP + ZLD. The neuroprotection effects of NBP and ZLD against COP-induced brain injury are closely linked to the activation of the PI3K/AKT/GSK-3ß signaling pathway.

Basiliximab Treatment for Patients With Steroid-Refractory Acute Graft-Versus-Host Disease Following Matched Sibling Donor Hematopoietic Stem Cell Transplantation.

Basiliximab is an important treatment for steroid-refractory acute graft-versus-host disease (SR-aGVHD). We performed this retrospective study to evaluate the efficacy and safety of basiliximab treatment in SR-aGVHD patients following matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) (n = 63). Overall response rate (ORR) was 63.5% and 54% at any time and at day 28 after basiliximab treatment. Grade III-IV aGVHD before basiliximab treatment predicted a poor ORR after basiliximab treatment. The rates of virus, bacteria, and fungi infections were 54%, 23.8%, and 3.1%, respectively. With a median follow-up of 730 (range, 67-3,042) days, the 1-year probability of overall survival and disease-free survival after basiliximab treatment were 58.6% (95% confidence interval [CI] = 47.6%-72.2%) and 55.4% (95% CI = 44.3%-69.2%), respectively. The 3-year cumulative incidence of relapse and non-relapse mortality after basiliximab treatment were 18.9% (95% CI = 8.3%-29.5%) and 33.8% (95% CI = 21.8%-45.7%), respectively. Comorbidities burden before allo-HSCT, severity of aGVHD and liver aGVHD before basiliximab treatment showed negative influences on survival. Thus, basiliximab was safe and effective treatment for SR-aGVHD following MSD-HSCT.

A Novel Tetramethylpyrazine Chalcone Hybrid- HCTMPPK, as a Potential Anti-Lung Cancer Agent by Downregulating MELK.

Purpose: Lung adenocarcinoma currently ranks the leading causes of cancer-related mortality worldwide. Many anti-inflammation herbs, like tetramethylpyrazine, have shown their anti-tumor potentials. Here, we evaluated the role of a novel chalcone derivative of tetramethylpyrazine ((E) -1- (E) -1- (2-hydroxy-5-chlorophenyl) -3- (3,5,6-trimethylpyrazin-2-yl) -2-propen-1, HCTMPPK) in lung adenocarcinoma. Methods: The effects of HCTMPPK on cell proliferation, apoptosis, and invasion were investigated by in-vitro assays, including CCK-8, colony formation assay, flow cytometry, transwell assay, and wound-healing assay. The therapeutic potential of HCTMPPK in vivo was evaluated in xenograft mice. To figure out the target molecules of HCTMPPK, a network pharmacology approach and molecular docking studies were employed, and subsequent experiments were conducted to confirm these candidate molecules. Results: HCTMPPK effectively suppressed the proliferative activity and migration, as well as enhanced the apoptosis of A549 cells in a concentration-dependent manner. Consistent with this, tumor growth was inhibited by HCTMPPK significantly in vivo. Regarding the mechanisms, HCTMPPK down-regulated Bcl-2 and MMP-9 and up-regulating Bax and cleaved-caspase-3. Subsequently, we identified 601 overlapping DEGs from LUAD patients in TCGA and GEO database. Then, 15 hub genes were identified by PPI network and CytoHubba. Finally, MELK was verified to be the HCTMPPK targeted site, through the molecular docking studies and validation experiments. Conclusion: Overall, our study indicates HCTMPPK as a potential MELK inhibitor and may be a promising candidate for the therapy of lung cancer.

Label-Free Identification of AML1-ETO Positive Acute Myeloid Leukemia Using Single-Cell Raman Spectroscopy.

Acute myeloid leukemia (AML) is a malignant hematological tumor disease. Chromosomal abnormality is an independent prognostic factor in AML. AML with t(8:21) (q22; q22)/AML1-ETO (AE) is an independent disease group. In this research, a new method based on Raman spectroscopy is reported for label-free single-cell identification and analysis of AE fusion genes in clinical AML patients. Raman spectroscopy reflects the intrinsic vibration information of molecules in a label-free and non-destructive manner, and the fingerprint Raman spectrum of cells characterizes intracellular molecular types and relative concentration information, so as to realize the identification and molecular metabolism analysis of different kinds of cells. We collected the Raman spectra of bone marrow cells from clinically diagnosed AML M2 patients with and without the AE fusion gene. Through comparison of the average spectra and identification analysis based on multivariate statistical methods such as principal component analysis and linear discriminant analysis, the distinction between AE positive and negative sample cells in M2 AML patients was successfully achieved, and the single-cell identification accuracy was more than 90%. At the same time, the Raman spectra of the two types of cells were analyzed by the multivariate curve resolution alternating least squares decomposition method. It was found that the presence of the AE fusion gene may lead to the metabolic changes of lipid and nucleic acid in AML cells, which was consistent with the results of genomic and metabolomic multi-omics studies. The above results indicate that single-cell Raman spectroscopy has the potential for early identification of AE-positive AML.

Use of antiviral drugs and incidence of Parkinson's disease in Taiwan.

Patients infected with herpes zoster might be at risk for Parkinson's disease (PD). However, antiviral drugs may impede viral deoxyribonucleic acid (DNA) synthesis. This study aimed to determine whether the currently observed association between herpes zoster and PD is consistent with previous findings, and whether antiviral drug use is associated with PD. This retrospective cohort study used the Longitudinal Generation Tracking Database. We included patients aged 40 years and above and applied propensity score matching at 1:1 ratio for study comparability. PD risk was evaluated using Cox proportional hazards regression methods. A total of 234,730 people were analyzed. The adjusted hazard ratio (aHR) for PD in patients with herpes zoster was 1.05. Furthermore, the overall incidence of PD was lower in those treated with antiviral drugs than in the untreated ones (3.17 vs. 3.76 per 1,000 person-years); the aHR was 0.84. After stratifying for sex or age, a similar result was observed. In conclusion, herpes zoster may increase the risk of PD, particularly among females, but receiving antiviral treatment reduces the risk by 16%. Therefore, using antiviral drugs may help prevent PD. However, additional research is required to determine the underlying mechanism(s).

Dynamic effective connectivity in the cerebellar dorsal dentate nucleus and the cerebrum, cognitive impairment, and clinical correlates in patients with schizophrenia.

BACKGROUND: Schizophrenia (SZ) is characterized by disconnected cerebral networks. Recent studies have shown that functional connectivity between the cerebellar dorsal dentate nucleus (dDN) and cerebrum is correlated with psychotic symptoms, and processing speed in SZ patients. Dynamic effective connectivity (dEC) is a reliable indicator of brain functional status. However, the dEC between the dDN and cerebrum in patients with SZ remains largely unknown. METHODS: Resting-state functional MRI data, symptom severity, and cognitive performance were collected from 74 SZ patients and 53 healthy controls (HC). Granger causality analysis and sliding time window methods were used to calculate dDN-based dEC maps for all subjects, and k-means clustering was performed to obtain several dEC states. Finally, between-group differences in dynamic effective connectivity variability (dECV) and clinical correlations were obtained using two-sample t-tests and correlation analysis. RESULTS: We detected four dEC states from the cerebrum to the right dDN (IN states) and three dEC states from the right dDN to the cerebrum (OUT states), with SZ group having fewer transitions in the OUT states. SZ group had increased dECV from the right dDN to the right middle frontal gyrus (MFG) and left lingual gyrus (LG). Correlations were found between the dECV from the right dDN to the right MFG and symptom severity and between the dECV from the right dDN to the left LG and working memory performance. CONCLUSIONS: This study reveals a dynamic causal relationship between cerebellar dDN and the cerebrum in SZ and provides new evidence for the involvement of cerebellar neural circuits in neurocognitive functions in SZ.

The Effect of Inhibiting the Wingless/Integrated (WNT) Signaling Pathway on the Early Embryonic Disc Cell Culture in Chickens.

The utilization of chicken embryonic-derived pluripotent stem cell (PSC) lines is crucial in various fields, including growth and development, vaccine and protein production, and germplasm resource protection. However, the research foundation for chicken PSCs is relatively weak, and there are still challenges in establishing a stable and efficient PSC culture system. Therefore, this study aims to investigate the effects of the FGF2/ERK and WNT/ß-catenin signaling pathways, as well as different feeder layers, on the derivation and maintenance of chicken embryonic-derived PSCs. The results of this study demonstrate that the use of STO cells as feeder layers, along with the addition of FGF2, IWR-1, and XAV-939 (FIX), allows for the efficient derivation of chicken PSC-like cells. Under the FIX culture conditions, chicken PSCs express key pluripotency genes, such as POUV, SOX2, and NANOG, as well as specific proteins SSEA-1, C-KIT, and SOX2, indicating their pluripotent nature. Additionally, the embryoid body experiment confirms that these PSC-like cells can differentiate into cells of three germ layers in vitro, highlighting their potential for multilineage differentiation. Furthermore, this study reveals that chicken Eyal-Giladi and Kochav stage X blastodermal cells express genes related to the primed state of PSCs, and the FIX culture system established in this research maintains the expression of these genes in vitro. These findings contribute significantly to the understanding and optimization of chicken PSC culture conditions and provide a foundation for further exploration of the biomedical research and biotechnological applications of chicken PSCs.

Lost in Rotation: How TiO2 and ZnO Nanoparticles Disrupt Coordinated Epithelial Cell Rotation.

Coordinated cell movement is a cardinal feature in tissue organization that highlights the importance of cells working together as a collective unit. Disruptions to this synchronization can have far-reaching pathological consequences, ranging from developmental disorders to tissue repair impairment. Herein, it is shown that metal oxide nanoparticles (NPs), even at low and non-toxic doses (1 and 10 µg mL-1), can perturb the coordinated epithelial cell rotation (CECR) in micropatterned human epithelial cell clusters via distinct nanoparticle-specific mechanisms. Zinc oxide (ZnO) NPs are found to induce significant levels of intracellular reactive oxygen species (ROS) to promote mitogenic activity. Generation of a new localized force field through changes in the cytoskeleton organization and an increase in cell density leads to the arrest of CECR. Conversely, epithelial cell clusters exposed to titanium dioxide (TiO2) NPs maintain their CECR directionality but display suppressed rotational speed in an autophagy-dependent manner. Thus, these findings reveal that nanoparticles can actively hijack the nano-adaptive responses of epithelial cells to disrupt the fundamental mechanics of cooperation and communication in a collective setting.

Textured Perovskite/Silicon Tandem Solar Cells Achieving Over 30% Efficiency Promoted by 4-Fluorobenzylamine Hydroiodide.

Monolithic textured perovskite/silicon tandem solar cells (TSCs) are expected to achieve maximum light capture at the lowest cost, potentially exhibiting the best power conversion efficiency. However, it is challenging to fabricate high-quality perovskite films and preferred crystal orientation on commercially textured silicon substrates with micrometer-size pyramids. Here, we introduced a bulky organic molecule (4-fluorobenzylamine hydroiodide (F-PMAI)) as a perovskite additive. It is found that F-PMAI can retard the crystallization process of perovskite film through hydrogen bond interaction between F- and FA+ and reduce (111) facet surface energy due to enhanced adsorption energy of F-PMAI on the (111) facet. Besides, the bulky molecular is extruded to the bottom and top of perovskite film after crystal growth, which can passivate interface defects through strong interaction between F-PMA+ and undercoordinated Pb2+/I-. As a result, the additive facilitates the formation of large perovskite grains and (111) preferred orientation with a reduced trap-state density, thereby promoting charge carrier transportation, and enhancing device performance and stability. The perovskite/silicon TSCs achieved a champion efficiency of 30.05% based on a silicon thin film tunneling junction. In addition, the devices exhibit excellent long-term thermal and light stability without encapsulation. This work provides an effective strategy for achieving efficient and stable TSCs.

The alterations of oral, airway and intestine microbiota in chronic obstructive pulmonary disease: a systematic review and meta-analysis.

Background: Increasing evidence indicates the microbial ecology of chronic obstructive pulmonary disease (COPD) is intricately associated with the disease's status and severity, and distinct microbial ecological variations exist between COPD and healthy control (HC). This systematic review and meta-analysis aimed to summarize microbial diversity indices and taxa relative abundance of oral, airway, and intestine microbiota of different stages of COPD and HC to make comparisons. Methods: A comprehensive systematic literature search was conducted in PubMed, Embase, the Web of Science, and the Cochrane Library databases to identify relevant English articles on the oral, airway, and intestine microbiota in COPD published between 2003 and 8 May 2023. Information on microbial diversity indices and taxa relative abundance of oral, airway, and intestine microbiota was collected for comparison between different stages of COPD and HC. Results: A total of 20 studies were included in this review, involving a total of 337 HC participants, 511 COPD patients, and 154 AECOPD patients. We observed that no significant differences in alpha diversity between the participant groups, but beta diversity was significantly different in half of the included studies. Compared to HC, Prevotella, Streptococcus, Actinomyces, and Veillonella of oral microbiota in SCOPD were reduced at the genus level. Most studies supported that Haemophilus, Lactobacillus, and Pseudomonas were increased, but Veillonella, Prevotella, Actinomyces, Porphyromonas, and Atopobium were decreased at the genus level in the airway microbiota of SCOPD. However, the abundance of Haemophilus, Lactobacillus and Pseudomonas genera exhibited an increase, whereas Actinomyces and Porphyromonas showed a decrease in the airway microbiota of AECOPD compared to HC. And Lachnospira of intestine microbiota in SCOPD was reduced at the genus level. Conclusion: The majority of published research findings supported that COPD exhibited decreased alpha diversity compared to HC. However, our meta-analysis does not confirm it. In order to further investigate the characteristics and mechanisms of microbiome in the oral-airway- intestine axis of COPD patients, larger-scale and more rigorous studies are needed. Systematic review registration: PROSPERO (https://www.crd.york.ac.uk/prospero/), identifier CRD42023418726.

COVID-19 was associated with the complications after allogeneic hematopoietic stem cell transplantation.

We aimed to identify the severity and duration of COVID-19 infection on complications after allo-HSCT. Enrolled 179 hospitalized patients with COVID-19 were categorized into long-term infection (> 18 days, n = 90) or short-term infection group (≤ 18 days, n = 89) according to the median duration of COVID-19. The severity of COVID-19 was categorized as asymptomatic infection, mild, moderate, severe, and critical illness according to guidelines of National Institutes of Health. Particularly, severe illness and critical illness were classified as serious infection. Asymptomatic infection, mild illness and moderate illness were classified as non-serious infection. The 150-day probabilities of poor graft function (PGF), cytomegalovirus (CMV) pneumonia and non-relapse mortality (NRM) were significantly higher in long-term infection group. The 150-day probabilities of CMV pneumonia and NRM after COVID-19 were higher in serious infection group. The 150-day probabilities of overall survival (OS) was significantly lower in long-term and serious infection group. In multivariable analysis, the severity of COVID-19 was associated with NRM and OS, and the duration of COVID-19 was associated with PGF. In summary, our data reported that the severity and duration of COVID-19 were associated with several complications and contribute to poor outcomes after allo-HSCT.

Exploring the association between cardiovascular health and bowel health.

Chronic constipation, diarrhea, and fecal incontinence have high incidence, potential disability, and socioeconomic impact, imposing a heavy burden on the quality of life. We aim to explore the association between cardiovascular health (CVH) and bowel health from National Health and Nutrition Survey 2005-2010. CVH is assessed using Life's Essential 8 (LE8). Chronic constipation, chronic diarrhea, and fecal incontinence are assessed based on Bristol Stool Form Scale classification, bowel movements, and bowel leakage. Better health behaviors (odds ratio [OR]: 0.71, 95% confidence interval [CI] 0.53-0.94, p = 0.02) and worse health factors (OR: 1.45, CI 1.03-2.04, p = 0.04) were associated with less chronic constipation. Less chronic diarrhea is correlated with better CVH (OR: 0.53, 95% CI 0.35-0.79, p = 0.003) and health factors (OR: 0.61, CI 0.46-0.81, p = 0.001). Meanwhile, the proportion of chronic diarrhea significantly decreases when the health behaviors score exceeds 59.42. Lower fecal incontinence was associated with better health behaviors (OR: 0.63, CI 0.44-0.90, p = 0.01) CVH. Better CVH and health behaviors are both linked to lower all-cause mortality in participants with chronic constipation and chronic diarrhea. A higher health behaviors score is also associated with less all-cause mortality in patients with fecal incontinence. Maintaining CVH at the population level contributes to intestinal health, achieving the dual management of both while saving on healthcare costs. However, further prospective research is needed to confirm these associations.

HMGB2 is a biomarker associated with poor prognosis promoting radioresistance in glioma by targeting base excision repair pathway.

BACKGROUND: High mobility group box 2 (HMGB2) is considered as a biomarker of poor prognosis in various cancers.This study aims to investigate the effect and mechanism of HMGB2 in gliomas. METHODS: With the glioma related on-line and our local hospital databases, the expression differences of HMGB2,Kaplan-Meier survival analysis and COX regression analysis were performed.The correlation analysis between the clinicopathological features and imaging parameters with the HMGB2 expression had been done. Then GSEA and PPI networks were carried out to find out the most significant pathway. The pathway inhibitor was applied to verify HMGB2's participation. CCK8,EDU assays,γ-H2AX immunofluorescence staining and colony formation assay were conducted to observe effects on glioma cells. RESULTS: Available datasets showed that HMGB2 was highly expressed in glioma and patients with high expression of HMGB2 had poorer prognosis and molecular characteristics. Protein level evidence of western blot and immunohistochemistry from our center supported the conclusions above. Analysis on imaging features suggested that HMGB2 expression level had an inverse association with ADCmean but positively with the thickness of enhancing margin. Results from GSEA and PPI network analysis exhibited that HMGB2 was involved in base excision repair (BER) signaling pathway. Experimental evidence demonstrated that the overexpression of HMGB2 promoted the proliferation of glioma cells and enhanced the radio-resistance. CONCLUSIONS: HMGB2 could promote glioma development and enhance the radioresistance of glioma cells, potentially related to the BER pathway, suggesting it may serve as an underlying biomarker for patients with glioma.

Concomitant Central and Peripheral Nervous System Involvement Associated With Mycoplasma pneumoniae Infection in Pediatric Patients: Two Case Reports and Literature Review.

BACKGROUND: Mycoplasma pneumoniae (M. pneumoniae) is a common pathogen for community-acquired pneumonia and is also implicated in a broad array of extra-pulmonary manifestations. M. pneumoniae infection is rarely associated with concurrent central nervous system (CNS) and peripheral nervous system (PNS) involvement in children. METHODS: We report 2 patients who presented with acute encephalitis and polyradiculitis due to M. pneumoniae infection and review the literature to discuss the pathogenesis and treatment of concomitant CNS and PNS involvement associated with M. pneumoniae infection. RESULTS: We report two 6-year-old boys with M. pneumoniae antecedent infection who presented initially with impaired consciousness followed by limb weakness, limb pain and urinary retention, and responded well to immunotherapy. CONCLUSIONS: We described 2 patients who presented symptomatic combined CNS and PNS involvement with persistent urinary retention associated with M. pneumoniae infection. We found autoimmunity plays an important role and recommend that antibiotics and immunomodulators should be administered with concurrent CNS and PNS involvement associated with M. pneumoniae.

GPS2 ameliorates cigarette smoking-induced pulmonary vascular remodeling by modulating the ras-Raf-ERK axis.

BACKGROUND: Mitogen-activated protein kinase (MAPK)signaling-mediated smoking-associated pulmonary vascular remodeling (PVR) plays an important role in the pathogenesis of group 3 pulmonary hypertension (PH). And G protein pathway suppressor 2 (GPS2) could suppress G-protein signaling such as Ras and MAPK, but its role in cigarette smoking -induced PVR (CS-PVR) is unclear. METHODS: An in vivo model of smoke-exposed rats was constructed to assess the role of GPS2 in smoking-induced PH and PVR. In vitro, the effects of GPS2 overexpression and silencing on the function of human pulmonary arterial smooth cells (HPASMCs) and the underlying mechanisms were explored. RESULTS: GPS2 expression was downregulated in rat pulmonary arteries (PAs) and HPASMCs after CS exposure. More importantly, CS-exposed rats with GPS2 overexpression had lower right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), and wall thickness (WT%) than those without. And enhanced proliferation and migration of HPASMCs induced by cigarette smoking extract (CSE) can be evidently inhibited by overexpressed GPS2. Besides, GPS2siRNA significantly enhanced the proliferation, and migration of HPASMCs as well as activated Ras and Raf/ERK signaling, while these effects were inhibited by zoledronic acid (ZOL). In addition, GPS2 promoter methylation level in rat PAs and HPASMCs was increased after CS exposure, and 5-aza-2-deoxycytidine (5-aza) inhibited CSE-induced GPS2 hypermethylation and downregulation in vitro. CONCLUSIONS: GPS2 overexpression could improve the CS-PVR, suggesting that GPS2 might serve as a novel therapeutic target for PH-COPD in the future.