bluuebunny/crossref_metadata_2025 huggingface dataset:
Low-molecular-weight heparin therapy reduces 28-day mortality in patients with sepsis-3 by improving inflammation and coagulopathy
Authors: Zhang Ze , Yan Taotao , Ren Danfeng , Zhou Jingwen , Liu Liangru , Li Juan , Fu Shan , Ni Tianzhi , Xu Weicheng , Yang Yuan , Chen Tianyan , He Yingli , Zhao Yingren , Liu Jinfeng
Published: June 2023

Background and aim

Sepsis is a syndromic response to infection and is associated with high mortality, thus imposing a significant global burden of disease. Although low-molecular-weight heparin (LMWH) has been recommended to prevent venous thromboembolism, its anticoagulant and anti-inflammatory effects in sepsis remain controversial. Owing to the modification of the Sepsis-3 definition and diagnostic criteria, further evaluation of the efficacy and benefit population of LMWH is required.

Methods

We performed a retrospective cohort study to assess whether LMWH improved the inflammation, coagulopathy, and clinical outcomes against Sepsis-3 and to identify the target patients. All patients diagnosed with sepsis at the First Affiliated Hospital of Xi'an Jiaotong University (the largest general hospital in northwest China) from January 2016 to December 2020 were recruited and re-evaluated using Sepsis-3 criteria.

Results

After 1:1 propensity score matching, 88 pairs of patients were categorized into the treatment and control groups based on subcutaneous LMWH administration. Compared with the control group, a significantly lower 28-day mortality was observed in the LMWH group (26.1 vs. 42.0%, p = 0.026) with a comparable incidence of major bleeding events (6.8 vs. 8.0%, p = 0.773). Cox regression analysis showed that LMWH administration was the independent protective factor for septic patients (aHR, 0.48; 95% CI, 0.29–0.81; p = 0.006). Correspondingly, the LMWH treatment group showed a significant improvement in inflammation and coagulopathy. Further subgroup analysis showed that LMWH therapy was associated with favorable outcomes in patients younger than 60 years and diagnosed with sepsis-induced coagulopathy (SIC), ISTH overt DIC, non-septic shock, or non-diabetics and in patients included in the moderate-risk group (APACHE II score 20–35 or SOFA score 8–12).

Conclusion

Our study results showed that LMWH improves 28-day mortality by improving inflammatory response and coagulopathy in patients meeting Sepsis-3 criteria. The SIC and ISTH overt DIC scoring systems can better identify septic patients who are likely to benefit more from LMWH administration.
New anti-diabetic drug Morus alba L. (Sangzhi) alkaloids (SZ-A) improves diabetic nephropathy through ameliorating inflammation and fibrosis in diabetic rats
Authors: Li Caina , Liu Quan , Ji Wenming , Fu Yaxin , Cao Hui , Huan Yi , Lei Lei , Gao Xuefeng , Chen Leilei , Feng Cunyu , Zhang Lin , Li Pingping , Liu Yuling , Liu Shuainan , Shen Zhufang
Published: June 2023

Background

Morus alba L. (Sangzhi) alkaloid (SZ-A) is a new antidiabetic drug approved by the China National Medical Products Administration in 2020. Diabetic nephropathy (DN) is a common diabetic complication and an important cause of morbidity and mortality in patients with diabetes. The effects of SZ-A on DN remain unknown.

Purpose

This study evaluated the effects of SZ-A on DN in Zucker diabetic fatty (ZDF) rats and explored the underlying mechanisms based on nitrosative stress, inflammation, and fibrosis.

Methods

Diabetic ZDF rats were orally administered 100 and 200 mg/kg of SZ-A once daily for 9 weeks. The glucose metabolism and kidney function were assayed. The pathological injury and fibrosis of the kidneys were separately evaluated using hematoxylin and eosin staining and Masson’s staining. The oxidative and nitrosative stress and inflammation were assayed by determining the levels of related indices in the blood and kidneys and quantifying the related gene and protein expression. The expression of transforming growth factor β1 (TGFβ1) gene and protein were assayed by quantitative real-time PCR and immunohistochemistry, respectively. The renal transcriptomics was analyzed using RNA sequencing.

Results

Repeated treatment with SZ-A significantly improved glucose metabolism, dose-dependently decreased the levels of blood urea nitrogen, urinary albumin, and β2-microglobulin, and evidently relieved the renal injury in diabetic ZDF rats. As for the mechanisms, SZ-A remarkably ameliorated systemic nitrosative stress through lowering the levels of blood inducible nitric oxide synthase and nitric oxide, and significantly relieved systemic and renal inflammation by reducing the levels of blood interleukin-1β and monocyte chemoattractant protein-1 (MCP-1) and decreasing the levels of renal C-reactive protein content and expression of tumor necrosis factor-α in the kidneys. SZ-A also improved renal fibrosis by lowering the expression of TGFβ1 in the kidneys. Additionally, SZ-A significantly lowered the expression of stimulator of chondrogenesis 1 in the kidneys.

Conclusion

Repeated treatments with SZ-A significantly ameliorates DN by regulating systemic nitrosative stress, renal inflammation, and renal fibrosis partially through inhibition of the cytokine-NO and TGF-β1 signaling in ZDF rats, providing evidence for the additional application of SZ-A in clinical use for the treatment of DN.
Unmet needs and future perspectives in hydroxychloroquine retinopathy
Authors: Yusuf Imran H. , Charbel Issa Peter , Ahn Seong Joon
Published: June 2023

Retinopathy is a well-recognized toxic effect of hydroxychloroquine treatment. As hydroxychloroquine retinopathy is potentially a vision-threatening condition, early detection is imperative to minimize vision loss due to drug toxicity. However, early detection of hydroxychloroquine retinopathy is still challenging even with modern retinal imaging techniques. No treatment has been established for this condition, except for drug cessation to minimize further damage. In this perspective article, we aimed to summarize the knowledge gaps and unmet needs in current clinical practice and research in hydroxychloroquine retinopathy. The information presented in this article may help guide the future directions of screening practices and research in hydroxychloroquine retinopathy.
Altered fecal microbiome and metabolome profiles in rat models of short bowel syndrome
Authors: Huang Yuhua , Jiao Jian , Yao Danhua , Guo Feilong , Li Yousheng
Published: June 2023

Introduction

Short bowel syndrome (SBS) is featured by impaired nutrients and fluids absorption due to massive small intestine resection. Gut dysbiosis has been implicated in SBS, this study aimed to characterize the metagenomic and metabolomic profiles of SBS and identify potential therapeutic targets.

Methods

Fecal samples from SBS and Sham rats (n = 8 per group) were collected for high-throughput metagenomic sequencing. Fecal metabolomics was measured by untargeted liquid chromatography-mass spectrometry.

Results

We found that the species-level α-diversity significantly decreased in SBS rats, accompanied by altered microbiome compositions. The beneficial anaerobes from Firmicutes and Bacteroidetes were depleted while microorganisms from Lactobacillus, Escherichia, Enterococcus, and Streptococcus were enriched in faces from SBS rats. LEfSe analysis identified 17 microbial species and 38 KEGG modules that were remarkably distinct between SBS and Sham rats. In total, 1,577 metabolites with known chemical identity were detected from all samples, among them, 276 metabolites were down-regulated and 224 metabolites were up-regulated in SBS group. The typical signatures of SBS fecal metabolome comprised reduced short-chain fatty acids and products of amino acid metabolism (indole derivatives and p-cresol), as well as altered bile acid spectrum. We revealed 215 robust associations between representative differentially abundant microbial species and metabolites, the species with the same changing trend tended to have a similar correlation with some certain metabolites.

Conclusion

The fecal microbiome and metabolome significantly altered in SBS. Our findings may lay the foundation for developing new strategies to facilitate intestinal adaptation in SBS patients.
Proteomic response of A549 lung cancer cell line to protein-polysaccharide complex Venetin-1 isolated from earthworm coelomic fluid
Authors: Czaplewska Paulina , Bogucka Aleksandra , Macur Katarzyna , Rybicka Magda , Rychłowski Michał , Fiołka Marta J.
Published: June 2023

Earthworms’ celomic fluid has long attracted scientists’ interest due to their toxic properties. It has been shown that the elimination of coelomic fluid cytotoxicity to normal human cells was crucial for the generation of the non-toxic Venetin-1 protein-polysaccharide complex, which exhibits selective activity against Candida albicans cells as well as A549 non-small cell lung cancer cells. To find the molecular mechanisms behind the anti-cancer properties of the preparation, this research investigated the proteome response of A549 cells to the presence of Venetin-1. The sequential window acquisition of all theoretical mass spectra (SWATH-MS) methodology was used for the analysis, which allows for a relative quantitative analysis to be carried out without radiolabelling. The results showed that the formulation did not induce significant proteome responses in normal BEAS-2B cells. In the case of the tumour line, 31 proteins were up regulated, and 18 proteins down regulated. Proteins with increased expression in neoplastic cells are mainly associated with the mitochondrion, membrane transport and the endoplasmic reticulum. In the case of altered proteins, Venetin-1 interferes with proteins that stabilise the structures, i.e., keratin, glycolysis/gluconeogenesis and metabolic processes.
Fusion InPipe, an integrative pipeline for gene fusion detection from RNA-seq data in acute pediatric leukemia
Authors: Vicente-Garcés Clara , Maynou Joan , Fernández Guerau , Esperanza-Cebollada Elena , Torrebadell Montserrat , Català Albert , Rives Susana , Camós Mireia , Vega-García Nerea
Published: June 2023

RNA sequencing (RNA-seq) is a reliable tool for detecting gene fusions in acute leukemia. Multiple bioinformatics pipelines have been developed to analyze RNA-seq data, but an agreed gold standard has not been established. This study aimed to compare the applicability of 5 fusion calling pipelines (Arriba, deFuse, CICERO, FusionCatcher, and STAR-Fusion), as well as to define and develop an integrative bioinformatics pipeline (Fusion InPipe) to detect clinically relevant gene fusions in acute pediatric leukemia. We analyzed RNA-seq data by each pipeline individually and by Fusion InPipe. Each algorithm individually called most of the fusions with similar sensitivity and precision. However, not all rearrangements were called, suggesting that choosing a single pipeline might cause missing important fusions. To improve this, we integrated the results of the five algorithms in just one pipeline, Fusion InPipe, comparing the output from the agreement of 5/5, 4/5, and 3/5 algorithms. The maximum sensitivity was achieved with the agreement of 3/5 algorithms, with a global sensitivity of 95%, achieving a 100% in patients’ data. Furthermore, we showed the necessity of filtering steps to reduce the false positive detection rate. Here, we demonstrate that Fusion InPipe is an excellent tool for fusion detection in pediatric acute leukemia with the best performance when selecting those fusions called by at least 3/5 pipelines.
Establishment and validation of a prognostic signature for pancreatic ductal adenocarcinoma based on lactate metabolism-related genes
Authors: Huang Xin , Zhao Chongyu , Han Yuanxia , Li Shengping
Published: June 2023

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancy with poor prognosis. To improve patient outcomes, it is necessary to gain a better understanding of the oncogenesis and progression of this disease. Metabolic reprogramming, particularly the regulation of lactate metabolism, is known to have a significant impact on tumor microenvironment and could provide valuable insights for the management of PDAC patients. In this study, we aimed to investigate the prognostic potential of lactate metabolism-related genes (LMRGs).

Methods: Transcriptomic data of patients with PDAC along with the clinical outcomes were retrieved from The Cancer Genome Atlas database, and the expression data in normal pancreas from Genotype-Tissue Expression dataset were adopted as the normal control. By using Cox and LASSO regression models, we identified key genes that are differentially expressed in cancerous tissues and related to prognosis. To determine the prognostic value of LMRGs in PDAC, we evaluated their clinical significance and model performance using both the area under the receiver operator characteristic curve (AUC) and calibration curves. In addition, we evaluated the drug sensitivity prediction and immune infiltration by using oncoPredict algorithm, single sample gene set enrichment analysis and Tumor Immune Estimation Resource.

Results: A total of 123 LMRGs were identified through differential gene screening analysis, among which 7 LMRGs were identified to comprise a LMRGs signature that independently predict overall survival of these PDAC patient. The AUC values for the LMRGs signature were 0.786, 0.820, 0.837, and 0.816 for predicting 1-, 2-, 3- and 5-year overall survival respectively. Furthermore, this prognostic signature was used to stratify patients into high-risk and low-risk groups, with the former having worse clinical outcomes. This observation was further validated through analysis of the International Cancer Genome Consortium database. In addition, lower sensitivity to gemcitabine and infiltration of immune effector cells were observed in the cancer tissue of patients in the high-risk group.

Conclusion: In conclusion, our data suggests that a genomic signature comprised of these LMRGs may be a novel predictor of overall clinical outcomes and present therapeutic potential for PDAC patients.
Differences in fall-related characteristics across cognitive disorders
Authors: Minta Karolina , Colombo Giorgio , Taylor William R. , Schinazi Victor R.
Published: June 2023

Approximately 40–60% of falls in the elderly lead to injuries, resulting in disability and loss of independence. Despite the higher prevalence of falls and morbidity rates in cognitively impaired individuals, most fall risk assessments fail to account for mental status. In addition, successful fall prevention programmes in cognitively normal adults have generally failed in patients with cognitive impairment. Identifying the role of pathological aging on fall characteristics can improve the sensitivity and specificity of fall prevention approaches. This literature review provides a thorough investigation into fall prevalence and fall risk factors, the accuracy of fall risk assessments, and the efficacy of fall prevention strategies in individuals with diverse cognitive profiles. We show that fall-related characteristics differ between cognitive disorders and fall risk assessment tools as well as fall prevention strategies should critically consider each patient’s cognitive status to facilitate the identification of fallers at an earlier stage and support clinical decision-making.
Topical and systemic GLP-1R agonist administration both rescue retinal ganglion cells in hypertensive glaucoma
Authors: Lawrence Emily C. N. , Guo Michelle , Schwartz Turner D. , Wu Jie , Lu Jingwen , Nikonov Sergei , Sterling Jacob K. , Cui Qi N.
Published: June 2023

Glaucomatous neurodegeneration, a blinding disease affecting millions worldwide, has a need for the exploration of new and effective therapies. Previously, the glucagon-like peptide-1 receptor (GLP-1R) agonist NLY01 was shown to reduce microglia/macrophage activation, rescuing retinal ganglion cells after IOP elevation in an animal model of glaucoma. GLP-1R agonist use is also associated with a reduced risk for glaucoma in patients with diabetes. In this study, we demonstrate that several commercially available GLP-1R agonists, administered either systemically or topically, hold protective potential in a mouse model of hypertensive glaucoma. Further, the resulting neuroprotection likely occurs through the same pathways previously shown for NLY01. This work contributes to a growing body of evidence suggesting that GLP-1R agonists represent a viable therapeutic option for glaucoma.
Sodium-mediated plateau potentials in an identified decisional neuron contribute to feeding-related motor pattern genesis in Aplysia
Authors: Bédécarrats Alexis , Simmers John , Nargeot Romuald
Published: June 2023

Motivated behaviors such as feeding depend on the functional properties of decision neurons to provide the flexibility required for behavioral adaptation. Here, we analyzed the ionic basis of the endogenous membrane properties of an identified decision neuron (B63) that drive radula biting cycles underlying food-seeking behavior in Aplysia. Each spontaneous bite cycle arises from the irregular triggering of a plateau-like potential and resultant bursting by rhythmic subthreshold oscillations in B63’s membrane potential. In isolated buccal ganglion preparations, and after synaptic isolation, the expression of B63’s plateau potentials persisted after removal of extracellular calcium, but was completely suppressed in a tetrodotoxin (TTX)- containing bath solution, thereby indicating the contribution of a transmembrane Na+ influx. Potassium outward efflux through tetraethylammonium (TEA)- and calcium-sensitive channels was found to contribute to each plateau’s active termination. This intrinsic plateauing capability, in contrast to B63’s membrane potential oscillation, was blocked by the calcium-activated non-specific cationic current (ICAN) blocker flufenamic acid (FFA). Conversely, the SERCA blocker cyclopianozic acid (CPA), which abolished the neuron’s oscillation, did not prevent the expression of experimentally evoked plateau potentials. These results therefore indicate that the dynamic properties of the decision neuron B63 rely on two distinct mechanisms involving different sub-populations of ionic conductances.
Optogenetic manipulation of inhibitory interneurons can be used to validate a model of spatiotemporal sequence learning
Authors: Rozells Jackson , Gavornik Jeffrey P.
Published: June 2023

The brain uses temporal information to link discrete events into memory structures supporting recognition, prediction, and a wide variety of complex behaviors. It is still an open question how experience-dependent synaptic plasticity creates memories including temporal and ordinal information. Various models have been proposed to explain how this could work, but these are often difficult to validate in a living brain. A recent model developed to explain sequence learning in the visual cortex encodes intervals in recurrent excitatory synapses and uses a learned offset between excitation and inhibition to generate precisely timed “messenger” cells that signal the end of an instance of time. This mechanism suggests that the recall of stored temporal intervals should be particularly sensitive to the activity of inhibitory interneurons that can be easily targeted in vivo with standard optogenetic tools. In this work we examined how simulated optogenetic manipulations of inhibitory cells modifies temporal learning and recall based on these mechanisms. We show that disinhibition and excess inhibition during learning or testing cause characteristic errors in recalled timing that could be used to validate the model in vivo using either physiological or behavioral measurements.
Predictive effect of the decline in CD4+ T cell levels in blood on infection in patients with severe hemorrhagic stroke and mechanism
Authors: Wang Yating , Guo Junshuang , Yang Fan , Dong Ruirui , Song Dandan , Huang Peipei , Wen Lijun , Xiang Guoliang , Wang Shuiyu , Teng Junfang , Miao Wang
Published: June 2023

Objective

The purpose of this research was to evaluate the influence of immunity on infection in patients with severe hemorrhagic stroke and explore the mechanism underlying this connection.

Methods

Clinical data obtained from 126 patients with severe hemorrhagic stroke were retrospectively analyzed, and the factors affecting infection were screened by multivariable logistic regression models. Nomograms, calibration curves, the Hosmer–Lemeshow goodness-of-fit test, and decision curve analysis were used to examine the effectiveness of the models in evaluating infection. The mechanism underlying the reduction in CD4+ T-cell levels in blood was explored by analysis of lymphocyte subsets and cytokines in cerebrospinal fluid (CSF) and blood.

Results

The results showed that CD4+ T-cell levels of <300/μL was an independent risk factor for early infection. The models for multivariable logistic regression involving the CD4+ T-cell levels and other influencing factors had good applicability and effectiveness in evaluating early infection. CD4+ T-cell levels decreased in blood but increased in CSF. Similarly, interleukin (IL)-6 and IL-8 levels in CSF had a significant increase, generating a substantial concentration gradient between the CSF and the blood.

Conclusion

Reduced blood CD4+ T-cell counts among patients who had severe hemorrhagic stroke increased the risk of early infection. CSF IL-6 and IL-8 may be involved in inducing the migration of CD4+ T cells into the CSF and decreasing blood CD4+ T-cell levels.
Inflammation in stroke: initial CRP levels can predict poor outcomes in endovascularly treated stroke patients
Authors: Finck Tom , Sperl Philipp , Hernandez-Petzsche Moritz , Boeckh-Behrens Tobias , Maegerlein Christian , Wunderlich Silke , Zimmer Claus , Kirschke Jan , Berndt Maria
Published: June 2023

Background and purpose

Inflammation has been linked to poor prognoses in cardio- and cerebrovascular conditions. As it is known to increase after ischemia, C-reactive protein (CRP) may serve as a surrogate for systemic inflammation and thus be a hallmark of increased tissue vulnerability. The question arises whether CRP in the acute phase of ischemic stroke, prior to mechanical thrombectomy (MT), might help predict outcomes.

Materials and methods

A single-center collective of patients with large-vessel occlusion, who were treated via MT, was analyzed in this observational case–control study. Univariate and multivariate models were designed to test the prognostic value of inflammatory markers (CRP and leukocytosis) in predicting clinical outcomes (modified Rankin score >2) and all-cause mortality 90 days after MT.

Results

A total of 676 ischemic stroke patients treated with MT were included. Of these, 313 (46.3%) showed elevated CRP levels (≥5 mg/l) on admission. Poor clinical outcome and mortality at 90 days occurred in 113 (16.7%) and 335 (49.6%) patients and significantly more frequently when initial CRP levels were elevated [213 (64.5%) vs. 122 (42.1%), p < 0.0001, and 79 (25.2%) vs. 34 (9.4%), p < 0.0001, respectively]. CRP levels were highly predictive for impaired outcomes, especially in patients with atrial fibrillation, in both univariate and multivariate models. Interestingly, patients with initially elevated CRP levels also showed more pronounced increases in CRP post-MT.

Conclusion

Poor outcome and death occur significantly more often in stroke patients with elevated CRP levels before MT. Our findings suggest that stroke patients with atrial fibrillation and elevated inflammatory markers are of particular risk for poor outcomes.
Real world evidence of improved attention and cognition during physical therapy paired with neuromodulation: a brain vital signs study
Authors: Kirby Eric D. , Jones Christina B. , Fickling Shaun D. , Pawlowski Gabriela , Brodie Sonia M. , Boyd Lara A. , Venter Jan , Moser Nicholas , Kalsi-Ryan Sukhvinder , Medvedev George , D’Arcy Ryan C. N.
Published: June 2023

Background

Non-invasive neuromodulation using translingual neurostimulation (TLNS) has been shown to advance rehabilitation outcomes, particularly when paired with physical therapy (PT). Together with motor gains, patient-reported observations of incidental improvements in cognitive function have been noted. Both studies in healthy individuals and case reports in clinical populations have linked TLNS to improvements in attention-related cognitive processes. We investigated if the use of combined TLNS/PT would translate to changes in objective neurophysiological cognitive measures in a real-world clinical sample of patients from two separate rehabilitation clinics.

Methods

Brain vital signs were derived from event-related potentials (ERPs), specifically auditory sensation (N100), basic attention (P300), and cognitive processing (N400). Additional analyses explored the attention-related N200 response given prior evidence of attention effects from TLNS/PT. The real-world patient sample included a diverse clinical group spanning from mild-to-moderate traumatic brain injury (TBI), stroke, Multiple Sclerosis (MS), Parkinson’s Disease (PD), and other neurological conditions. Patient data were also acquired from a standard clinical measure of cognition for comparison.

Results

Results showed significant N100 variation between baseline and endpoint following TLNS/PT treatment, with further examination showing condition-specific significant improvements in attention processing (i.e., N100 and N200). Additionally, CogBAT composite scores increased significantly from baseline to endpoint.

Discussion

The current study highlighted real-world neuromodulation improvements in neurophysiological correlates of attention. Overall, the real-world findings support the concept of neuromodulation-related improvements extending beyond physical therapy to include potential attention benefits for cognitive rehabilitation.
The herbicides glyphosate and glufosinate and the cyanotoxin β-N-methylamino-l-alanine induce long-term motor disorders following postnatal exposure: the importance of prior asymptomatic maternal inflammatory sensitization
Authors: Oummadi Asma , Menuet Arnaud , Méresse Sarah , Laugeray Anthony , Guillemin Gilles , Mortaud Stéphane
Published: June 2023

Background

Prenatal maternal immune activation (MIA) and/or perinatal exposure to various xenobiotics have been identified as risk factors for neurological disorders, including neurodegenerative diseases. Epidemiological data suggest an association between early multi-exposures to various insults and neuropathologies. The “multiple-hit hypothesis” assumes that prenatal inflammation makes the brain more susceptible to subsequent exposure to several kinds of neurotoxins. To explore this hypothesis and its pathological consequences, a behavioral longitudinal procedure was performed after prenatal sensitization and postnatal exposure to low doses of pollutants.

Methods

Maternal exposure to an acute immune challenge (first hit) was induced by an asymptomatic lipopolysaccharide (LPS) dose (0.008 mg/kg) in mice. This sensitization was followed by exposing the offspring to environmental chemicals (second hit) postnatally, by the oral route. The chemicals used were low doses of the cyanotoxin β-N-methylamino-l-alanine (BMAA; 50 mg/kg), the herbicide glufosinate ammonium (GLA; 0.2 mg/kg) or the pesticide glyphosate (GLY; 5 mg/kg). After assessing maternal parameters, a longitudinal behavioral assessment was carried out on the offspring in order to evaluate motor and emotional abilities in adolescence and adulthood.

Results

We showed that the low LPS immune challenge was an asymptomatic MIA. Even though a significant increase in systemic pro-inflammatory cytokines was detected in the dams, no maternal behavioral defects were observed. In addition, as shown by rotarod assays and open field tests, this prenatal LPS administration alone did not show any behavioral disruption in offspring. Interestingly, our data showed that offspring subjected to both MIA and post-natal BMAA or GLA exposure displayed motor and anxiety behavioral impairments during adolescence and adulthood. However, this synergistic effect was not observed in the GLY-exposed offspring.

Conclusion

These data demonstrated that prenatal and asymptomatic immune sensitization represents a priming effect to subsequent exposure to low doses of pollutants. These double hits act in synergy to induce motor neuron disease-related phenotypes in offspring. Thus, our data strongly emphasize that multiple exposures for developmental neurotoxicity regulatory assessment must be considered. This work paves the way for future studies aiming at deciphering cellular pathways involved in these sensitization processes.
Determination of steady-state transcriptome modifications associated with repeated homotypic stress in the rat rostral posterior hypothalamic region
Authors: Campeau Serge , McNulty Connor , Stanley Jacob T. , Gerber Anthony N. , Sasse Sarah K. , Dowell Robin D.
Published: June 2023

Chronic stress is epidemiologically correlated with physical and psychiatric disorders. Whereas many animal models of chronic stress induce symptoms of psychopathology, repeated homotypic stressors to moderate intensity stimuli typically reduce stress-related responses with fewer, if any, pathological symptoms. Recent results indicate that the rostral posterior hypothalamic (rPH) region is a significant component of the brain circuitry underlying response reductions (habituation) associated with repeated homotypic stress. To test whether posterior hypothalamic transcriptional regulation associates with the neuroendocrine modifications induced by repeated homotypic stress, RNA-seq was performed in the rPH dissected from adult male rats that experienced either no stress, 1, 3, or 7 stressful loud noise exposures. Plasma samples displayed reliable increases of corticosterone in all stressed groups, with the smallest increase in the group exposed to 7 loud noises, indicating significant habituation compared to the other stressed groups. While few or no differentially expressed genes were detected 24-h after one or three loud noise exposures, relatively large numbers of transcripts were differentially expressed between the group exposed to 7 loud noises when compared to the control or 3-stress groups, respectively, which correlated with the corticosterone response habituation observed. Gene ontology analyses indicated multiple significant functional terms related to neuron differentiation, neural membrane potential, pre- and post-synaptic elements, chemical synaptic transmission, vesicles, axon guidance and projection, glutamatergic and GABAergic neurotransmission. Some of the differentially expressed genes (Myt1l, Zmat4, Dlx6, Csrnp3) encode transcription factors that were independently predicted by transcription factor enrichment analysis to target other differentially regulated genes in this study. A similar experiment employingin situhybridization histochemical analysis in additional animals validated the direction of change of the 5 transcripts investigated (Camk4, Gabrb2, Gad1, Grin2a and Slc32a) with a high level of temporal and regional specificity for the rPH. In aggregate, the results suggest that distinct patterns of gene regulation are obtained in response to a repeated homotypic stress regimen; they also point to a significant reorganization of the rPH region that may critically contribute to the phenotypic modifications associated with repeated homotypic stress habituation.
Prenatal alcohol exposure dysregulates spinal and circulating immune cell circular RNA expression in adult female rats with chronic sciatic neuropathy
Authors: Noor Shahani , Pritha Ariana N. , Pasmay Andrea A. , Sanchez Jacob E. , Sanchez Joshua J. , Fernandez-Oropeza Annette K. , Sun Melody S. , Dell’Orco Michela , Davies Suzy , Savage Daniel D. , Mellios Nikolaos , Milligan Erin D.
Published: June 2023

Alcohol consumption during pregnancy is associated with Fetal Alcohol Spectrum Disorders (FASD) that results in a continuum of central nervous system (CNS) deficits. Emerging evidence from both preclinical and clinical studies indicate that the biological vulnerability to chronic CNS disease in FASD populations is driven by aberrant neuroimmune actions. Our prior studies suggest that, following minor nerve injury, prenatal alcohol exposure (PAE) is a risk factor for developing adult-onset chronic pathological touch sensitivity or allodynia. Allodynia in PAE rats occurs concurrently with heightened proinflammatory peripheral and spinal glial-immune activation. However, minor nerve-injured control rats remain non-allodynic, and corresponding proinflammatory factors are unaltered. A comprehensive molecular understanding of the mechanism(s) that underlie PAE-induced proinflammatory bias during adulthood remains elusive. Non-coding circular RNAs (circRNAs) are emerging as novel modulators of gene expression. Here, we hypothesized that PAE induces dysregulation of circRNAs that are linked to immune function under basal and nerve-injured conditions during adulthood. Utilizing a microarray platform, we carried out the first systematic profiling of circRNAs in adult PAE rats, prior to and after minor nerve injury. The results demonstrate a unique circRNA profile in adult PAE rats without injury; 18 circRNAs in blood and 32 spinal circRNAs were differentially regulated. Following minor nerve injury, more than 100 differentially regulated spinal circRNAs were observed in allodynic PAE rats. Bioinformatic analysis identified that the parental genes of these circRNAs are linked to the NF-κB complex, a central transcription factor for pain-relevant proinflammatory cytokines. Quantitative real-time PCR was employed to measure levels of selected circRNAs and linear mRNA isoforms. We have validated that circVopp1 was significantly downregulated in blood leukocytes in PAE rats, concurrent with downregulation of Vopp1 mRNA levels. Spinal circVopp1 levels were upregulated in PAE rats, regardless of nerve injury. Additionally, PAE downregulated levels of circItch and circRps6ka3, which are linked to immune regulation. These results demonstrate that PAE exerts long-lasting dysregulation of circRNA expression in blood leukocytes and the spinal cord. Moreover, the spinal circRNA expression profile following peripheral nerve injury is differentially modulated by PAE, potentially contributing to PAE-induced neuroimmune dysregulation.
Association of bevacizumab and stroke in ovarian cancer: a systematic review and meta-analysis
Authors: Song Li , Liu Yan , Chen Zhixin , Li Zeyan , Zhu Shiqin , Zhao Yingjie , Li Huihui
Published: June 2023

Background

The prognosis for patients with ovarian cancer is bleak. Clinical trials have shown the efficacy of bevacizumab in ovarian cancer treatment. However, life-threatening strokes may limit the usage of bevacizumab and require specific follow-up strategies. This study aims to systematically evaluate the risk of stroke of bevacizumab treatment in ovarian cancer.

Methods

We retrieved all relevant articles published up to December 4th, 2022, from Embase, PubMed, Web of Science, and the Cochrane Library. The risk of stroke in patients with ovarian cancer treated with bevacizumab combined with chemotherapy was analyzed. Meta-analysis was performed using the Stata 17 software and R 4.2.1 program.

Results

Six randomized controlled trials (RCTs) of bevacizumab combined with chemotherapy or chemotherapy for ovarian cancer and six single-experimental-arm trials were included in this study. The meta-analysis showed a pooled risk ratio (RR) of 2.14 [95% confidence interval (CI): 0.88–7.99] for patients with ovarian cancer treated with bevacizumab combined with chemotherapy. Subgroup analyses showed that the incidence of stroke-related adverse events in the carboplatin + paclitaxel + bevacizumab group was 0.01% (95% CI: 0.00–0.01, p < 0.01). The incidence of stroke-related adverse events was 0.01% (95% CI: 0.00–0.01, p < 0.01) in patients aged ≥60. The incidence of stroke caused by cerebral ischemia and cerebral hemorrhage was 0.01% (95% CI: 0.01–0.02, p = 0.27) and 0.01% (95% CI: 0.00–0.01, p < 0.01), respectively.

Conclusions

This meta-analysis indicates that chemotherapy combined with bevacizumab may not increase the incidence of stroke in patients with ovarian cancer. However, stroke-related adverse events may be higher in older patients. Cerebral hemorrhage might cause the incidence of stroke more than cerebral ischemia.

Systematic review registration

PROSPERO (CRD42022381003).
Exploring plant polyphenols as anti-allergic functional products to manage the growing incidence of food allergy
Authors: Wu Tianxiang , Li Zhenxing , Wu Yanyan , Yang Xianqing , Li Laihao , Chen Shengjun , Qi Bo , Wang Yueqi , Li Chunsheng , Zhao Yongqiang
Published: June 2023

The active substances derived from plants have received increasing attention owing to their wide range of pharmacological applications, including anti-tumor, anti-allergic, anti-viral, and anti-oxidative activities. The allergy epidemic is a growing global public health problem that threatens human health and safety. Polyphenols from plants have significant anti-allergic effects and are an important source of anti-allergic drug research and development. Here, we describe recent advances in the anti-allergic efficacy of plant polyphenols, including their comprehensive effects on cellular or animal models. The current issues and directions for future development in this field are discussed to provide a theoretical basis for the development and utilization of these active substances as anti-allergic products.
Release of an encrypted, highly potent ACE-inhibitory peptide by enzymatic hydrolysis of moth bean (Vigna aconitifolia) protein
Authors: Goyal Nancy , Hajare Sachin N. , Gautam Satyendra
Published: June 2023

Aim

Dietary approaches for the regulation of blood pressure are the need of the hour. Hence, identifying the foods possessing such activity is gaining importance. With this aim, moth bean (Vigna aconitifolia), an underutilized pulse, was explored for the presence of antihypertensive activity in terms of angiotensin converting enzyme (ACE)-inhibition bioactivity.

Methods

Defatted moth bean protein concentrate was hydrolyzed by using different proteases including Alcalase, papain, and trypsin, to identify the enzyme producing highly potent ACE inhibitory peptides. The hydrolysate showing the highest ACE inhibitory activity was further fractionated using an ultrafiltration membrane (10, 3 and 1 kDa) based on ACE inhibitory activity. The active fraction was further subjected to the ion-exchange chromatography followed by RP-HPLC and LC-MS/MS analysis for the enrichment and identification of ACE inhibitory peptides. Finally, based on the bioinformatic analysis, few peptides were synthesized and evaluated for ACE inhibitory activity, followed by docking study and molecular dynamic simulation of a peptide with the highest ACE inhibitory activity.

Results and discussion

Out of the three proteases, Alcalase-derived hydrolysate showed the highest (~59%) ACE inhibition activity. Molecular weight-based fractionation revealed that <1 kDa fraction possessed the highest ACE inhibitory activity. Activity guided separation of 1 kDa fraction using ion-exchange chromatography, RP-HPLC and LC-MS/MS showed the presence of about 45 peptides. Based on the bioinformatic analysis, 15 peptides were synthesized and evaluated for ACE inhibitory activity. Among these, a novel octapeptide FPPPKVIQ showed the highest ACE inhibitory activity (93.4%) with an IC50 of 0.24 μM. This peptide retained about 59% activity post gastrointestinal digestion simulation. A Dixon plot as well as docking studies revealed the uncompetitive inhibitory nature of this peptide with a Ki value of 0.81 μM. Molecular dynamic simulation studies till 100 ns ensured the stability of the ACE-peptide complex.

Conclusion

Thus, present study identified a novel potent ACE inhibitory peptide from moth bean that can be incorporated in a functional dietary formulation for regulation of hypertension.
The paradox of obesity with normal weight; a cross-sectional study
Authors: Lahav Yair , Kfir Aviv , Gepner Yftach
Published: June 2023

Objective

To evaluate the prevalence of excessive adiposity among normal-weight individuals, and their cardiometabolic risk.

Methods

This cross-sectional study included 3,001 participants (ages 20–95, 52% men, BMI 28.0 ± 5.5 kg/m2) who completed an anthropometric evaluation, dual x-ray absorptiometry (DXA) scan to measure body composition, and cardiometabolic blood markers. Excess adiposity was defined as ≥25% for men and ≥ 35% for women.

Results

Of the entire study participants, 967 were in normal BMI (18.5–24.9 kg/m2) with a wide body fat distribution (4–49%). Of them, 26% of men and 38% of women were classified with excess adiposity. As compared to normal-weight lean participants, normal-weight obese men and women had higher triglycerides (76.5 ± 37.3 vs. 101.2 ± 50.3 mg/dL, p = 0.004 and 84 ± 44.2 vs. 101.4 ± 91.1 mg/dL, p = 0.030; respectively) and elevated low-density lipoprotein cholesterol (103.3 ± 31.7 vs. 119.6 ± 45.5 mg/dL, p = 0.011) and total cholesterol (171.5 ± 40.3 vs. 190.2 ± 39 mg/dL, p = 0.007) for men only. Among NWO, abdominal circumference was prevalent in 60% of the females with NWO (≥88 cm), but only in 4% of males (≥102 cm).

Conclusion

Higher adiposity, even within normal weight, increases cardiometabolic risk, and abdominal waist circumference misclassified obesity in normal-weight individuals. This study highlights the need for a body composition evaluation to determine cardiometabolic risk for adults with normal body weight.
The mediatory effect of inflammatory markers on the association between a body shape index and body roundness index with cardiometabolic risk factor in overweight and obese women: a cross-sectional study
Authors: Mirzababaei Atieh , Abaj Faezeh , Khosravinia Darya , Ghorbani Moloud , Valisoltani Neda , Clark Cain C. T. , Radmehr Mina , Mirzaei Khadijeh
Published: June 2023

Background

Obesity affects body composition and anthropometric measurements. A Body Shape Index (ABSI) and Body Roundness Index (BRI) are reportedly associated with an increased risk of cardiovascular disease. However, the relationship between ABSI, BRI, cardiometabolic factors, and inflammatory elements is not well-elucidated. Therefore, this study sought to examine the mediatory effect of inflammatory markers on the association between ABSI and BRI with cardiometabolic risk factors in overweight and obese women.

Methods

This cross-sectional study was performed on 394 obese and overweight women. The typical food intake of individuals was assessed using a 147-item semi-quantitative Food Frequency Questionnaire (FFQ). Body composition was measured by bioelectrical impedance analysis (BIA). Biochemical parameters, such as inflammatory markers and anthropometric components, were also assessed. For each participant, all measurements were carried out on the same day.

Result

There was a significant positive association between ABSI and AC and CRI.I in subjects with higher ABSI scores before and after adjustment (P < 0.05). In addition, there was a significant positive association between BRI and FBS, TC, TG, AIP, AC, CRI.I, CRI.II, and TyG in participants with higher BRI scores before and after adjustment (P < 0.05). We found that hs-CRP, PAI-1, MCP-1, TGF-β, and Galectin-3 were mediators of these relationships (P < 0.05).

Conclusion

Inflammation can play an important role in the relationship between body shape indices and cardiometabolic risk factors among overweight and obese women.
Ultra-processed food consumption and increased risk of metabolic syndrome: a systematic review and meta-analysis of observational studies
Authors: Shu Long , Zhang Xiaoyan , Zhou Jianying , Zhu Qin , Si Caijuan
Published: June 2023

Background

Although higher consumption of ultra-processed food (UPF) has been linked to a higher risk of metabolic syndrome (MetS), the results remain controversial. Herein, we performed a systematic review and meta-analysis of observational studies to clarify the relationship between UPF consumption defined by the NOVA framework and risk of MetS.

Methods

An extensive literature search on PubMed, ISI Web of Science, EBSCO and China National Knowledge Infrastructure (CNKI) databases was conducted to search for the relevant articles published priori to January 2023, and newly published articles between January 2023 and March 2023 were re-searched. Random-effects or fixed-effects models were adopted to calculate the pooled relative risks (RRs) and 95% confidence intervals (CIs). The between-study heterogeneity was explored using the Cochran's Q test and I-square (I2). Publication bias was investigated using the visual inspection of asymmetry in funnel plots and Begg's and Egger's tests.

Results

Nine studies (six cross-sectional and three prospective cohort studies) totaling 23,500 participants with 6,192 MetS cases were included in the final analysis. The pooled effect size for the highest vs. lowest categories of UPF consumption indicated a positive association with the risk of MetS (RR: 1.25, 95%CI: 1.09–1.42, P < 0.0001). Subgroup analyses revealed a positive association between consumption of UPF and MetS risk in cross-sectional studies (RR: 1.47, 95%CI: 1.16–1.87, P = 0.002), and no significant association in cohort studies (RR: 1.10, 95%CI: 0.96–1.27, P = 0.104), respectively. In addition, a more significant association between UPF consumption and increased risk of MetS was found in the subgroups of study quality <7 (RR: 2.22; 95%CI: 1.28–3.84, P = 0.004) than study quality ≥7 (RR: 1.20; 95%CI: 1.06–1.36, P = 0.005). Similarly, when we performed analyses separately by sample size, there was a significant association between UPF consumption and MetS risk in sample size ≥5,000 (RR: 1.19; 95%CI: 1.11–1.27, P < 0.0001), and in sample size <5,000 (RR: 1.43; 95%CI: 1.08–1.90, P = 0.013), respectively.

Conclusions

Our findings suggest that higher consumption of UPF is significantly associated with an increased risk of MetS. Further longitudinal studies are needed to confirm the effect of UPF consumption on MetS.
Combined with prognostic nutritional index and IgM for predicting the clinical outcomes of gastric cancer patients who received surgery
Authors: Du Zhongze , Sun Hao , Zhao Ruihu , Deng Guiming , Pan Hongming , Zuo Yanjiao , Huang Rong , Xue Yingwei , Song Hongjiang
Published: June 2023

Objective

Although the survival rate of patients who undergo surgery for gastric cancer has greatly improved, still many patients have a poor prognosis. This retrospective study aimed to investigate the predictive ability of the PNI-IgM score, a combined prognostic nutritional index (PNI), and immunoglobulin M (IgM), on the prognosis of patients undergoing surgery for gastric cancer.

Methods

340 patients with gastric cancer who underwent surgery from January 2016 to December 2017 were selected. The PNI-IgM score ranged from 1 to 3: score of 1, low PNI (< 48.45) and low IgM (< 0.87); score of 2, low PNI and high IgM, or high PNI and low IgM; score of 3, high PNI and high IgM. We compared the differences in disease-free survival (DFS) and overall survival (OS) among the three groups, while univariate and multivariate analyses calculated prognostic factors for DFS and OS. In addition, the nomograms were constructed based on the results of multivariate analysis to estimate the 1-, 3- and 5-year survival probability.

Results

There were 67 cases in the PNI-IgM score 1 group, 160 cases in the PNI-IgM score 2 group, and 113 cases in the PNI-IgM score 3 group. The median survival times of DFS in the PNI-IgM score group 1, the PNI-IgM score group 2, and the PNI-IgM score group 3 were 62.20 months, not reached, and not reached, and 67.57 months vs. not reached vs. not reached in three groups for OS. Patients in the PNI-IgM score group 1 had a lower DFS than the PNI-IgM score group 2 (HR = 0.648, 95% CI: 0.418-1.006, P = 0.053) and the PNI-IgM score group 3 (HR = 0.337, 95% CI: 0.194-0.585, P < 0.001). In stratified analysis, PNI-IgM score 1 had a worse prognosis in the age < 60 years group and CA724 < 2.11 U/m group.

Conclusion

PNI-IgM score is a novel combination of nutritional and immunological markers that can be used as a sensitive biological marker for patients with gastric cancer who undergo surgery. The lower the PNI-IgM score, the worse the prognosis.