bluuebunny/crossref_metadata_2025 huggingface dataset:
[68Ga]Ga-PSMA PET/MRI, histological PSMA expression and preliminary experience with [177Lu]Lu-PSMA therapy in relapsing high-grade glioma
Authors: Truckenmueller Peter , Graef Josefine , Scheel Michael , Vajkoczy Peter , Capper David , Kaul David , Furth Christian , Amthauer Holger , Brenner Winfried , Onken Julia Sophie
Published: September 2022

Purpose

High-grade gliomas (HGG) are still associated with a dismal prognosis. Prostate specific membrane antigen (PSMA) is discussed as a theranostic target for PSMA-directed radioligand therapy ([177Lu]Lu-PSMA RLT). Here, we report on the correlation of [68Ga]Ga-PSMA uptake with histological PSMA expression and on our preliminary experience with [177Lu]Lu-PSMA RLT in relapsing HGG.

Methods

Patients with relapsing HGG underwent [68Ga]Ga-PSMA PET/MRI to evaluate eligibility for an individualized treatment approach with [177Lu]Lu-PSMA. Standard uptake values (SUV) for tumor and liver and respective tumor-to-background ratios (compared to the liver) (TBR) on [68Ga]Ga-PSMA PET/MRI were assessed. Eligibility criteria for [177Lu]Lu-PSMA therapy were exhaustion of all standard treatment options available and TBRmax>1.0. In 11 samples, immunohistochemical PSMA expression was determined, quantified using the H-score and correlated with uptake on [68Ga]Ga-PSMA PET/MRI.

Results

We included 20 patients with a median age of 53 years (IQR 42-57). The median SUV on [68Ga]Ga-PSMA PET/MRI was 4.5 (3.7-6.2) for SUVmax and 1.4 (1.1-1.7) for SUVmean. The respective TBR was maximum 0.6 (0.4-0.8) and mean 0.3 (0.2-0.4). High TBRmax correlated with increased endothelial PSMA expression [H-score of 65 (62.5-77.5)]. Three patients (15%) presented a TBRmax>1.0 and qualified for [177Lu]Lu-PSMA RLT. No treatment related toxicity was observed.

Conclusion

Only a minority of patients with relapsing HGG qualified for [177Lu]Lu-PSMA RLT. Our data demonstrates that PSMA expression in the neo-vasculature corresponds to PSMA uptake on [68Ga]Ga-PSMA PET/MRI and might be used as a screening tool for patient selection. Future prospective studies need to focus the debate on TBRmax thresholds as inclusion criteria for PSMA RLT.
Pediatric kidney transplant recipients with and without underlying structural kidney disease have a comparable risk of hospitalization associated with urinary tract infections
Authors: Spiwak Elizabeth , Nailescu Corina , Schwaderer Andrew
Published: September 2022

Introduction

Urinary tract infections (UTIs) are a common and potentially serious kidney transplant complication. Pediatric kidney transplants are potentially at increased risk for UTIs when structural kidney disease is the underlying end-stage kidney disease (ESKD) etiology. The objective of this manuscript is to determine if children with structural kidney disorders are more prone to UTIs post kidney transplant.

Materials and methods

Hospitalizations for pediatric kidney transplant recipients were retrospectively reviewed over a 4-year period for UTIs in the diagnostic codes. The patient’s age, sex, graft age, underlying diagnosis for cause of ESKD, symptoms at presentation, urinalysis results, and urine culture results were recorded. UTI rates, febrile UTI rates, and UTI rates in the 1st year post-transplant were compared between children with ESKD due to structural vs. non-structural kidney disease.

Results

Overall, 62 of 145 pediatric patients with kidney transplants accounted for 182 hospitalizations for kidney transplant complications over the 4-year study period. UTIs were components of 34% of the hospitalizations. Overall, UTI rates, febrile UTI rates, and UTI rates for the 1st year post kidney transplant were comparable for children with vs. without structural ESKD etiologies.

Conclusion

Urinary tract infections are frequent components of hospitalizations for pediatric kidney transplant recipients. Children with and without structural kidney disease as an ESKD etiology have similar UTI rates indicating that UTI susceptibility is primarily due to the transplant process and/or medication regimens. UTIs represent a potentially modifiable risk factor for pediatric kidney transplant complications.
An iris puncture technique for restoration of the anterior chamber in vitrectomy for pediatric vitreoretinopathies
Authors: Chen Chunli , Hu Feng , Tian Tian , Cheng Yizhe , Fei Ping , Zhao Peiquan
Published: September 2022

Purpose

To present a novel usage of iris puncture-assisted lensectomy with anterior vitrectomy or vitrectomy in pediatric patients with the absence of anterior chamber caused by various advanced vitreoretinopathies complicated with capsule-endothelial, iris-endothelial adhesion, and secondary glaucoma.

Design

Prospective study.

Materials and methods

Forty-one patients were enrolled in this consecutive, prospective study. The iris puncture was performed in all patients using a 20G Vitrectomy Microsurgical Knife, followed by the lensectomy with anterior vitrectomy or vitrectomy. Demographic information, the number of iris puncture times, surgical procedure, intraoperative and postoperative complications, therapy, and prognosis were collected. Patients were followed up for at least 6 months.

Results

A total of 18 female patients and 23 male patients were included, with a mean age of 9.5 ± 7.5 months. The formation of anterior chamber formation was achieved in 28 (68.3%) eyes, with only 1 initial episode of iris puncture, 11 (26.8%) patients required 2 episodes, and 3 episodes of iris puncture, with additional external drainage of subretinal fluid, were needed in the remaining 2 (4.9%) patients. Except for iris incarceration, which occurred in 7 (17%) eyes during operation, there was no iridodialysis or subretinal fluid overflow during operation. At the last visit (mean: 12.16 ± 5.38 months of follow-up), all eyes had a reconstructed anterior chamber with normal depth. No synechiae between the iris and the cornea occurred after surgery. The mean postoperative intraocular pressure was 6.23 ± 1.64 mmHg. A hazy cornea vanished in 31 out of 41 (75.6%) eyes, relieved in 8 out of 41 eyes (19.5%), and 2 out of 41 eyes (4.88%) did not change. In the 25 eyes accepting vitrectomy and lensectomy, 20 out of 25 (80%) achieved different degrees of reattachment.

Conclusion

The innovative iris puncture technique is effective, simple, and safe management for the anterior chamber disappearance caused by various advanced pediatric vitreoretinopathies, which helped to lower the intraocular pressure and offers a chance for lensectomy with anterior vitrectomy or vitrectomy.
Efficacy and tolerance of enteral nutrition in children with biliary atresia awaiting liver transplantation
Authors: Privat Elodie , Aumar Madeleine , Ley Delphine , Tran Léa Chantal , Coopman Stéphanie , Guimber Dominique , Turck Dominique , Gottrand Frédéric
Published: September 2022

Objectives

Malnutrition is common in children with biliary atresia (BA) awaiting liver transplantation (LT). Few studies have evaluated the effectiveness of enteral nutrition (EN) in these patients. The objective of this work was to assess the efficacy and tolerance of EN in children with BA awaiting LT.

Methods

A total of 31 patients with BA followed between 1995 and 2018 were retrospectively included. Anthropometric indicators (weight, length, and head circumference) and adverse effects of EN were noted at the start (T0) and the end (T1) of EN. The z-scores for anthropometric indicators were compared between T0 and T1.

Results

The median age at T0 was 7 months (interquartile range [IQR] 5–9), and the median duration of EN was 9 months (IQR 3–17). The z-scores for anthropometric variables improved from T0 to T1: –1.6 (IQR –2.5 to –1.0) to –0.5 (IQR –1.8 to 0.3) for median weight for age; –1.3 (IQR –2.4 to 0) to –0.4 (IQR –2.0 to 0.7) for length for age; –0.9 (IQR –2.3 to –0.3) to –0.3 (IQR –1.2 to 0.1) for weight for length; and –1.2 (IQR –2.1 to –0.6) to –0.2 (IQR –1.6 to 0.4) for body mass index (p < 0.05 for all comparisons). Nearly all (94%) of the patients had a weight-for-length z-score > –2 at the end of EN; 23% had adverse effects and 10% had complications leading to the cessation of EN.

Conclusion

EN is effective and well tolerated in infants with BA awaiting LT.
Investigation of the pharmacological effect and mechanism of mountain-cultivated ginseng and garden ginseng in cardiovascular diseases based on network pharmacology and zebrafish experiments
Authors: Yu Ting , Zhang Yan-Xin , Liu Xin-Juan , Chen Dan-Qing , Wang Dan-Dan , Zhu Guo-Qin , Gao Qi
Published: September 2022

Ginseng (Panax ginseng C.A. Mey) is a kind of perennial herb of the Panax genus in the Araliaceae family. The secondary metabolites of mountain-cultivated ginseng (MCG) and garden ginseng (GG) vary greatly due to their different growth environments. To date, the differences in their pharmacological effects on cardiovascular diseases (CVDs) and their clinical applications remain unclear. To distinguish between the components of MCG and GG, ultra-high-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF/MS) was performed. Next, the relationship between the expression of metabolites and the categories of the sample were analyzed using supervised partial least squares discriminant analysis and orthogonal partial least squares discriminant analysis. A network-based pharmacology approach was developed and applied to determine the underlying mechanism of different metabolites in CVD. In the present study, the role of MCG and GG in angiogenesis and their protective effects on damaged blood vessels in a vascular injury model of zebrafish were investigated. Using UPLC-Q-TOF/MS, 11 different metabolites between MCG and GG were identified. In addition, 149 common target genes associated with the metabolites and CVD were obtained; these targets were related to tumor protein P53, proto-oncogene tyrosine-protein kinase Src, human ubiquitin-52 amino acid fusion protein, ubiquitin-40S ribosomal protein S27a, polyubiquitin B, signal transducer and activator of transcription 3, isocitrate dehydrogenase 1, vascular endothelial growth factor A, glycose synthase kinase-3B, and coagulation factor II and were associated with the regulation of the phosphoinositide 3-kinase-Akt signaling pathway, the tumor necrosis factor signaling pathway, and the hypoxia-inducible factor-1 (HIF-1) signaling pathway, which play important roles in the curative effect in CVD treatment. Both types of ginseng can promote the growth of the subintestinal vessel plexus and protect injured intersegmental vessels through the HIF-1α/vascular endothelial growth factor signaling pathway in a dose-dependent manner. In addition, MCG has a stronger impact than GG. This is the first time metabolomics and network pharmacology methods were combined to study the difference between MCG and GG on CVDs, which provides a significant theoretical basis for the clinical treatment of CVD with two kinds of ginseng.
Role of resveratrol in inhibiting pathological cardiac remodeling
Authors: Fan Shaowei , Hu Yuanhui , You Yaping , Xue Wenjing , Chai Ruoning , Zhang Xuesong , Shou Xintian , Shi Jingjing
Published: September 2022

Cardiovascular disease is a group of diseases with high mortality in clinic, including hypertension, coronary heart disease, cardiomyopathy, heart valve disease, heart failure, to name a few. In the development of cardiovascular diseases, pathological cardiac remodeling is the most common cardiac pathological change, which often becomes a domino to accelerate the deterioration of the disease. Therefore, inhibiting pathological cardiac remodeling may delay the occurrence and development of cardiovascular diseases and provide patients with greater long-term benefits. Resveratrol is a non-flavonoid polyphenol compound. It mainly exists in grapes, berries, peanuts and red wine, and has cardiovascular protective effects, such as anti-oxidation, inhibiting inflammatory reaction, antithrombotic, dilating blood vessels, inhibiting apoptosis and delaying atherosclerosis. At present, the research of resveratrol has made rich progress. This review aims to summarize the possible mechanism of resveratrol against pathological cardiac remodeling, in order to provide some help for the in-depth exploration of the mechanism of inhibiting pathological cardiac remodeling and the development and research of drug targets.
SHP2 inhibition improves celastrol-induced growth suppression of colorectal cancer
Authors: Zhang Linxi , Hu Xuefei , Meng Qingying , Li Ye , Shen Hao , Fu Yating , Zhang Fan , Chen Jiahui , Zhang Wei , Chang Wenjun , Pan Yamin
Published: September 2022

This study aimed to explore novel targets for celastrol sensitization in colorectal cancer (CRC) based on differentially regulated signals in response to high- or low-dose celastrol. Targeting signals were investigated using Western blotting or phosphorylated receptor tyrosine kinase (RTK) arrays. Corresponding inhibitors for the signals were individually combined with low-dose celastrol for the assessment of combined anti-CRC effects, based on proliferation, apoptosis, colony assays, and xenograft models. The potential mechanism for the combination of celastrol and SHP2 inhibition was further examined. Low-dose celastrol (<1 µM) did not effectively suppress AKT and ERK signals in CRC cells compared to high-dose celastrol (>1 µM). However, when combined with an AKT or ERK inhibitor, low-dose celastrol could cooperatively suppress CRC proliferation. Furthermore, failed AKT or ERK inhibition by low-dose celastrol may be due to reactivated RTK-SHP2 signaling with negative feedback. The combination of celastrol and the SHP2 inhibitor resulted in greatly reduced AKT and ERK signals, as well as greater inhibition of CRC growth than celastrol alone. Moreover, the mechanism underlying combination suppression was also involved in the activation of immune cell infiltration (mainly for CD8+ cells) in CRC tissues. Failure to inhibit RTK-SHP2-AKT/ERK signaling contributed to the lack of CRC growth suppression by low-dose celastrol. However, the combination of celastrol and the SHP2 inhibitor resulted in synergistic inhibition of CRC growth and provided a promising therapeutic target.
Inhibition of fucosylation by 2-fluorofucose attenuated acetaminophen-induced liver injury via its anti-inflammation and anti-oxidative stress effects
Authors: Liu Zhaoguo , Tu Mengjue , Shi Jianan , Zhou Hong , Meng Guoliang , Gu Jianguo , Wang Yuqin
Published: September 2022

Fucosylation is a common glycan terminal modification, which has been reported to be inhibited by 2-fluorofucose (2FF) both in vivo and in vitro. The present study aimed to investigate the effect of 2FF on acetaminophen (APAP)-induced acute liver injury, and further clarified the possible mechanisms. In the present study, inhibition of fucosylation by 2FF relieved APAP-induced acute liver injury in vivo. Pretreatment with 2FF remarkably suppressed APAP-induced oxidative stress and mitochondria damage. 2FF markedly enhanced the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and simultaneously promoted the expression of downstream proteins including HO-1 and NQO1. Furthermore, pretreatment with 2FF significantly suppressed the expression of inflammation-associated proteins, such as COX2 and iNOS. The data from lectin blot assay revealed that the alteration of α1,6-fucosylation was involved in APAP-induced acute liver injury. The second part of this study further confirmed that the enhancements to antioxidant capacity of 2FF pretreatment and α1,6-fucose deficiency were related to Nrf2/keap1 and NF-κB signaling pathways in HepG2 cells. Taken together, the current study suggested that 2FF might have a potential therapeutic effect for APAP-induced acute liver injury.
Development of a physiomimetic model of acute respiratory distress syndrome by using ECM hydrogels and organ-on-a-chip devices
Authors: Marhuenda Esther , Villarino Alvaro , Narciso Maria , Elowsson Linda , Almendros Isaac , Westergren-Thorsson Gunilla , Farré Ramon , Gavara Núria , Otero Jorge
Published: September 2022

Acute Respiratory Distress Syndrome is one of the more common fatal complications in COVID-19, characterized by a highly aberrant inflammatory response. Pre-clinical models to study the effect of cell therapy and anti-inflammatory treatments have not comprehensively reproduced the disease due to its high complexity. This work presents a novel physiomimetic in vitro model for Acute Respiratory Distress Syndrome using lung extracellular matrix-derived hydrogels and organ-on-a-chip devices. Monolayres of primary alveolar epithelial cells were cultured on top of decellullarized lung hydrogels containing primary lung mesenchymal stromal cells. Then, cyclic stretch was applied to mimic breathing, and an inflammatory response was induced by using a bacteriotoxin hit. Having simulated the inflamed breathing lung environment, we assessed the effect of an anti-inflammatory drug (i.e., dexamethasone) by studying the secretion of the most relevant inflammatory cytokines. To better identify key players in our model, the impact of the individual factors (cyclic stretch, decellularized lung hydrogel scaffold, and the presence of mesenchymal stromal cells) was studied separately. Results showed that developed model presented a more reduced inflammatory response than traditional models, which is in line with what is expected from the response commonly observed in patients. Further, from the individual analysis of the different stimuli, it was observed that the use of extracellular matrix hydrogels obtained from decellularized lungs had the most significant impact on the change of the inflammatory response. The developed model then opens the door for further in vitro studies with a better-adjusted response to the inflammatory hit and more robust results in the test of different drugs or cell therapy.
Xiao-Yao-San protects against anti-tuberculosis drug-induced liver injury by regulating Grsf1 in the mitochondrial oxidative stress pathway
Authors: Bai Zijun , Tao Weiwei , Zhou Yiqun , Cao Yi , Yu Shun , Shi Zheng
Published: September 2022

Background: Xiao-Yao-San (XYS) is a traditional Chinese prescription that regulates gastrointestinal function, improves mental and psychological abnormalities, and enhances liver function. However, the underlying mechanism of XYS for relieving anti-tuberculosis (AT) drug-induced liver injury is not clear.

Objective: The current study examined whether XYS alleviated the symptoms of AT drug-induced liver injury in mice via the mitochondrial oxidative stress pathway.

Methods: BALB/c male mice were randomly divided into four groups of 12 animals, including a control group, a model group, a 0.32 g/kg XYS group, and a 0.64 g/kg XYS group. The effect of XYS on the degree of liver injury was observed using haematoxylin and eosin staining (HE) and oil red O staining of pathological sections, biochemical parameters, and reactive oxygen species (ROS) levels. The protein expression of mitochondrial synthesis-related proteins and ferroptosis-related proteins was examined using Western blotting.

Results: XYS improved the pathological changes in liver tissue and reduced the level of oxidative stress in liver-injured mice. XYS increased the expression of mitochondrial synthesis-related proteins and reversed the expression of ferroptosis-related proteins. Knockdown of G-rich RNA sequence binding factor 1 (Grsf1) expression with Grsf1 shRNA blocked the protective effects of XYS in liver injury.

Conclusion: Our findings suggest that XYS alleviates AT drug-induced liver injury by mediating Grsf1 in the mitochondrial oxidative stress pathway.
Gastroprotective mechanism of modified lvdou gancao decoction on ethanol-induced gastric lesions in mice: Involvement of Nrf-2/HO-1/NF-κB signaling pathway
Authors: Xie Lei , Luo Minyi , Li Junlin , Huang Wenguan , Tian Guangjun , Chen Xiuyun , Ai Ying , Zhang Yan , He Haolan , Jinyang He
Published: September 2022

Modified Lvdou Gancao decoction (MLG), a traditional Chinese medicine formula, has been put into clinical use to treat the diseases of the digestive system for a long run, showing great faculty in gastric protection and anti-inflammatory, whereas its protective mechanisms have not been determined. The current study puts the focus on the protective effect and its possible mechanisms of MLG on ethanol-induced gastric lesions in mice. In addition to various gastric lesion parameters and histopathology analysis, the activities of a list of relevant indicators in gastric mucosa were explored including ALDH, ADH, MDA, T-SOD, GSH-Px, and MPO, and the mechanisms were clarified using RT-qPCR, ELISA Western Blot and immunofluorescence staining. The results showed that MLG treatment induced significant increment of ADH, ALDH, T-SOD, GSH-Px, NO, PGE2 and SS activities in gastric tissues, while MPO, MDA, TNF-α and IL-1β levels were on the decline, both in a dose-dependent manner. In contrast to the model group, the mRNA expression of Nrf-2 and HO-1 in the MLG treated groups showed an upward trend while the NF-κB, TNFα, IL-1β and COX2 in the MLG treated groups had a downward trend simultaneously. Furthermore, the protein levels of p65, p-p65, IκBα, p-IκBα, iNOS, COX2 and p38 were inhibited, while Nrf2, HO-1, SOD1, SOD2 and eNOS were ramped up in MLG treatment groups. Immunofluorescence intensities of Nrf2 and HO-1 in the MLG treated groups were considerably enhanced, with p65 and IκBα diminished simultaneously, exhibiting similar trends to that of qPCR and western blot. To sum up, MLG could significantly ameliorate ethanol-induced gastric mucosal lesions in mice, which might be put down to the activation of alcohol metabolizing enzymes, attenuation of the oxidative damage and inflammatory response to maintain the gastric mucosa. The gastroprotective effect of MLG might be achieved through the diminution of damage factors and the enhancement of defensive factors involving NF-κB/Nrf2/HO-1 signaling pathway. We further confirmed that MLG has strong potential in preventing and treating ethanol-induced gastric lesions.
Cloning and characterization of a novel functional organic anion transporting polypeptide 3A1 isoform highly expressed in the human brain and testis
Authors: Bakos Éva , Német Orsolya , Kucsma Nóra , Tőkési Natália , Stieger Bruno , Rushing Elisabeth , Tőkés Anna-Mária , Kele Péter , Tusnády Gábor E. , Özvegy-Laczka Csilla
Published: September 2022

Organic anion transporting polypeptide 3A1 (OATP3A1, encoded by the SLCO3A1 gene) is a prostaglandin, oligopeptide, and steroid/thyroid hormone transporter with wide tissue distribution, expressed, e.g., in the human brain and testis. Although the physiological importance of OATP3A1 has not yet been clarified, based on its expression pattern, substrate recognition, and evolutionary conservation, OATP3A1 is a potential pharmacological target. Previously, two isoforms of OATP3A1, termed as V1 and V2, have been characterized. Here, we describe the cloning and functional characterization of a third isoform, OATP3A1_V3. The mRNA of isoform V3 is formed by alternative splicing and results in an OATP3A1 protein with an altered C-terminus compared to isoforms V1 and V2. Based on quantitative PCR, we demonstrate the widespread expression of SLCO3A1_V3 mRNA in human organs, with the highest expression in the brain and testis. By generation of an isoform V3-specific antibody and immunostaining, we show that the encoded protein is expressed in the human choroid plexus, neurons, and both germ and Sertoli cells of the testis. Moreover, we demonstrate that in contrast to isoform V1, OATP3A1_V3 localizes to the apical membrane of polarized MDCKII cells. Using HEK-293 cells engineered to overexpress OATP3A1_V3, we verify the protein’s functionality and identify dehydroepiandrosterone sulfate as a novel OATP3A1 substrate. Based on their distinct expression patterns but overlapping functions, OATP3A1 isoforms may contribute to transcellular (neuro)steroid transport in the central nervous system.
DL-3-n-butylphthalide for acute ischemic stroke: An updated systematic review and meta-analysis of randomized controlled trials
Authors: Wang Huan , Ye Kaili , Li Dan , Liu Yuxin , Wang Deren
Published: September 2022

Background:DL -3-n-butylphthalide (NBP) is widely used as a neuroprotective drug in stroke patients in China. A systematic review in 2010 suggested NBP to be safe and effective at promoting neurological recovery, but could not conclude whether it decreased risk of long-term death or disability. Since numerous randomized controlled trials (RCTs) have been conducted on NBP since 2010, we performed an updated systematic review and meta-analysis of safety and efficacy data.

Method:We searched electronic databases and reference lists to identify RCTs that compared patients who received NBP or not (including placebo). Methodological quality of RCTs was assessed using the Revised Cochrane Risk of Bias Tool 2.0, and data were meta-analyzed using Review Manager 5.4 software.

Results:Fifty-seven RCTs involving 8,747 participants were included. Twenty trials examined NBP as a capsule, 29 as an injection, and 8 as sequential injection-capsule therapy. Meta-analyses showed that NBP treatment was associated with a reduction in composite outcome of death and dependency (risk ratio 0.59, 95% CI 0.42 to 0.83; 260 participants; 2 studies), death (risk ratio 0.32, 95% CI 0.13 to 0.75; 2,287 participants; 10 studies), modified Rankin Scale score (mean difference -0.80, 95% CI -0.88 to -0.72; 568 participants; 4 studies), and an increase in Barthel Index, which assesses the ability to engage in basic activities of daily living (mean difference 11.08, 95% CI 9.10 to 13.05; 2,968 participants; 22 studies). Meta-analyses found that NBP significantly reduced neurological deficit based on National Institute of Health Stroke Scale (mean difference -3.39, 95% CI -3.76 to -3.03; 7.283 participants; 46 studies) and Chinese Stroke Scale (mean difference -4.16, 95% CI -7.60 to -0.73; 543 participants; 4 studies). Of the adverse events reported in 31 trials, elevated transaminase (incidence, 1.39-17.53%), rash (0-1.96%) and gastrointestinal discomfort (1.09-6.15%) were most frequent and no serious adverse events were reported.

Conclusion:This update review confirms that NBP can help acute ischemic stroke patients regain the ability to perform activities of daily living, reduce their neurological deficit and short-term death rates. However, the available evidence on whether NBP reduces risk of long-term death or dependence after ischemic stroke remains insufficient.
Phosphatidylethanolamine-binding protein 4 deficiency exacerbates carbon tetrachloride-induced liver fibrosis by regulating the NF-κB signaling pathway
Authors: Luo Qianqian , Ling Yuanyi , Li Yufei , Qu Xiaoqin , Shi Qiaoqing , Zheng Shuangyan , Li Yanhong , Huang Yonghong , Zhou Xiaoyan
Published: September 2022

Liver fibrosis is a pathological process which can progress to hepatocirrhosis, even hepatocellular carcinoma. Phosphatidylethanolamine-binding protein 4 (PEBP4) is a secreted protein involved in regulating many molecular pathways, whereas its roles in diseases including hepatic fibrosis remain undefined. The nuclear factor-κappa B (NF-κB) signaling pathway has been found to be involved in the development of liver fibrosis. In this study, we generated a hepatocyte-conditional knockout (CKO) mouse model of PEBP4, and explored the potential functions of PEBP4 on liver fibrosis and the NF-κB signaling pathway in a mouse model of carbon tetrachloride (CCl4)-induced liver fibrosis. We demonstrated that PEBP4 CKO aggravated CCl4-triggered liver fibrosis, as evidenced by altered histopathology, an increase in the activities of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and hydroxyproline (HYP) levels, and more collagen deposition, as well as by enhanced expression of fibrotic markers including α-smooth muscle actin (α-SMA), collagen I and collagen III. Mechanistically, PEBP4 deficiency activated the NF-κB signaling pathway, as indicated by increased phosphorylation of NF-κB p65 and inhibitor protein κB inhibitor-α (IκB-α), and nuclear NF-κB p65 expression in the fibrotic liver. Notably, the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) partially blocked the activation of the NF-κB pathway, and reversed the pro-fibrotic effect of PEBP4 deletion in CCl4-treated mice. Together, these results suggest that PEBP4 deficiency results in aggravation of liver fibrosis and activation of the NF-κB signaling pathway, supporting a novel concept that PEBP4 is a crucial player in hepatic fibrosis, but also might be a negative regulator of the NF-κB signaling in liver fibrosis.
Intestinal anti-inflammatory and visceral analgesic effects of a Serpylli herba extract in an experimental model of irritable bowel syndrome in rats
Authors: Ruiz-Malagón Antonio Jesús , Rodríguez-Sanchez María José , Rodríguez-Sojo María Jesús , Vezza Teresa , Pischel Ivo , Algieri Francesca , Rodríguez-Cabezas María Elena , Rodríguez-Nogales Alba , Gálvez Julio
Published: September 2022

Ethnopharmacological relevance:Serpylli herba extract (SHE), composed of the aerial parts of wild thyme (Thymus serpyllum L.) (Lamiaceae family), is traditionally used in Europe and North Africa to treat diarrhea, gastric ulcers, intestinal parasites and upper respiratory tract infections. Recently, SHE has generated a great interest for irritable bowel syndrome (IBS) management, probably due to its intestinal anti-inflammatory properties shown in experimental colitis and the fact that its active components could preserve the intestinal barrier integrity, which is altered in patients with IBS.

Aim of study: We aimed to test the effects of a SHE in a rat experimental model resembling human IBS.

Materials and methods: IBS was provoked by deoxycholic acid (DCA). Rats were then treated with SHE (100 mg/kg) or gabapentin (70 mg/kg) and different inflammatory and gut barrier integrity markers were evaluated. Moreover, several gut hypersensitivity and hyperalgesia determinations were performed.

Results: SHE improved referred pain and visceral hypersensitivity. Additionally, SHE enhanced immune status by downregulating of the expression of the pro-inflammatory mediators Il-1β, Il-6, Ifn-γ, Tlr-4, and the inducible enzyme Cox-2, thus inducing visceral analgesia, and promoting the restore of the gut barrier function by upregulating the mucins Muc-2 and Muc-3. These anti-inflammatory effects could be related to its action on mast cells since it significantly inhibited the β-Hexosaminidase production in RBL-2H3 cells. Lastly, SHE also seems to modulate the serotonin pathway by restoring the altered expression of the 5-HT receptors Htr-3 and Htr-4.

Conclusion: SHE could be considered a potential new treatment for IBS, since it ameliorates hypersensitivity, visceral hyperalgesia, and inflammation. These beneficial effects may be due to the inhibition of mast cells degranulation and serotonin pathway.
Protective effects of mitochondrial fission inhibition on ox-LDL induced VSMC foaming via metabolic reprogramming
Authors: Fang Yijin , Zhu Yu , Wu Yue , Liu Liangming , Wang Huadong
Published: September 2022

Atherosclerosis (AS) is one of the most common diseases in middle-age and elderly population. Lipid metabolism disorder induced foaming of vascular smooth muscle cell (VSMC) is an important pathological process of AS. Mitochondria plays an important role in lipids metabolism. While it is not known whether regulating mitochondrial function can protect ox-LDL induced VSMC foaming via metabolic reprogramming. With ox-LDL induced mouse model of VSMC injury, the injury effect of ox-LDL and the protective effect of mdivi-1, the mitochondrial fission inhibitor on mitochondrial morphology and function of VSMC, and the formation of lipid droplet were observed. With metabonomics and proteomics techniques, the main lipid metabolites and regulation proteins were identified. The results showed that Ox-LDL induced a significant mitochondrial fission and fragmentation of VSMC, and mitochondrial function disorder along with lipid deposition and foaming. Mdivi-1 significantly antagonized the damage effect of ox-LDL on mitochondrial morphology and function of VSMC, and blocked the lipid deposition. Metabonomics analysis found 848 different metabolites between ox-LDL and mdivi-1 treatment group, in which the lipid metabolites were the main, and heptadecanoic acid, palmitoleic acid and myristic acid were the critical metabolites changed most. Proteomics results showed that there were 125 differential expressed proteins between ox-LDL and mdivi-1 treatment, acetyl -CoA carboxylase1 and fatty acid synthase were the main differential expressed proteins. This study suggest that Mitochondrial fission plays an important role in VSMC lipid deposition and foaming. Inhibition of mitochondrial fission may effectively fight against ox-LDL induced lipid deposition and foaming of VSMC via improving mitochondrial function and metabolic reprogramming. This finding provides a new insight for prevention and treatment of AS.
Nanoformulation improves antitumor efficacy of MAOI immune checkpoint blockade therapy without causing aggression-related side effects
Authors: Brown James , Li Zhe , Wang Xi , Kim Yu Jeong , Wang Yu-Chen , Zuo Yanning , Hong Weizhe , Wang Pin , Li Bo , Yang Lili
Published: September 2022

MAOIs, a well-established class of antidepressant that operate through the inhibition of monoamine oxidase to increase available serotonin, have recently been identified as a surprisingly effective candidate for the circumvention of tumor-induced immune suppression due to their abilities to enhance antitumor T cell activity through autocrine serotonin signaling and depolarize alternatively activated tumor-associated macrophages through a reduction in reactive oxygen species production. However, this impressive class of antidepressants-turned-cancer-drugs can induce aggressive behavioral side effects when administered in immunotherapeutic doses. In this study, we investigated the possibility of avoiding these neurological side effects while simultaneously improving antitumor activity by establishing crosslinked multilamellar liposomal vesicles (cMLVs) containing the MAOI phenelzine (PLZ). Our results showed that cMLV-PLZ treatment increases antitumor efficacy in a B16-OVA mouse melanoma model compared to treatment with free phenelzine. We also found that nanoformulation resulted in the complete elimination of MAOI-related aggression. These findings suggest a promising direction for the future of MAOIs repurposed for cancer immunotherapies.
Metabolic reprogramming: A novel therapeutic target in diabetic kidney disease
Authors: Wang Mengdi , Pang Yanyu , Guo Yifan , Tian Lei , Liu Yufei , Shen Cun , Liu Mengchao , Meng Yuan , Cai Zhen , Wang Yuefen , Zhao Wenjing
Published: September 2022

Diabetic kidney disease (DKD) is one of the most common microvascular complications of diabetes mellitus. However, the pathological mechanisms contributing to DKD are multifactorial and poorly understood. Diabetes is characterized by metabolic disorders that can bring about a series of changes in energy metabolism. As the most energy-consuming organs secondary only to the heart, the kidneys must maintain energy homeostasis. Aberrations in energy metabolism can lead to cellular dysfunction or even death. Metabolic reprogramming, a shift from mitochondrial oxidative phosphorylation to glycolysis and its side branches, is thought to play a critical role in the development and progression of DKD. This review focuses on the current knowledge about metabolic reprogramming and the role it plays in DKD development. The underlying etiologies, pathological damages in the involved cells, and potential molecular regulators of metabolic alterations are also discussed. Understanding the role of metabolic reprogramming in DKD may provide novel therapeutic approaches to delay its progression to end-stage renal disease.
The burden of carbapenem-resistant Enterobacterales infection in a large Thai tertiary care hospital
Authors: Tangsawad Watcharaphon , Kositamongkol Chayanis , Chongtrakool Piriyaporn , Phisalprapa Pochamana , Jitmuang Anupop
Published: September 2022

Background: Carbapenem-resistant Enterobacterales (CRE) are resistant to several other classes of antimicrobials, reducing treatment options and increasing mortality. We studied the clinical characteristics and burden of hospitalized adult patients with CRE infections in a setting where treatment options are limited.

Methods: A retrospective cohort study included adult inpatients between January 2015–December 2019 at Siriraj Hospital in Bangkok, Thailand. Clinical and microbiological data were reviewed.

Results: Of 420 patients with CRE infections, the mean age was 65.00 ± 18.89 years, 192 (45.72%) were male, and 112 (26.90%) were critically ill. Three hundred and eighty (90.48%) had Klebsiella pneumoniae, and 40 (9.52%) had Escherichia coli infections. The mean APACHE II score was 14.27 ± 6.36. Nearly half had previous hospitalizations (48.81%), 41.2% received antimicrobials, and 88.1% had undergone medical procedures before the onset of infection. The median time of onset of CRE infection was 16 days after admission. Common sites of infection were bacteremia (53.90%) and pneumonia (45.47%). Most CRE-infected patients had septic shock (63.10%) and Gram-negative co-infections (62.85%). Colistin (29.95%) and non-colistin (12.91%) monotherapies, and colistin-based (44.78%) and non-colistin-based (12.36%) combination therapies were the best available antimicrobial therapies (BAAT). The median length of hospitalization was 31 days, and the median hospitalization cost was US$10,435. The in-hospital mortality rate was 68.33%. Septic shock [adjusted odds ratio (aOR) 10.73, 5.65–20.42, p <0 .001], coinfection (aOR 2.43, 1.32–4.47, p = 0.004), mechanical ventilation (aOR 2.33, 1.24–4.36, p = 0.009), and a high SOFA score at onset (aOR 1.18, 1.07–1.30, p <0 .001) were associated with mortality.

Conclusion: CRE infection increases mortality, hospital stays, and healthcare costs. A colistin-based regimen was the BAAT in this study. Therefore, newer antimicrobial agents are urgently needed.
Efficacy and safety of zhibitai in the treatment of hyperlipidemia: A systematic review and meta-analysis
Authors: Wang Chunyang , Pang Wentai , Du Xuechen , Zhai Jiani , Zhong Mengyuan , Zhuang Ming , An Jiali , Cao Lujia , Zhang Li , Zheng Wenke , Zhang Junhua
Published: September 2022

Objective: To evaluate the efficacy and safety of Zhibitai (ZBT) in the treatment of patients with hyperlipidemia (HLP).

Methods: A search of 8 electronic databases was conducted to find randomized controlled trials (RCTs), to evaluate the efficacy and safety of ZBT for the treatment of HLP. The risk of bias in randomized controlled trials was assessed by using the Cochrane Collaboration Risk of Bias tool for randomized controlled trials 2.0 (RoB 2.0). The primary outcomes were the levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). The total effective rate served as the secondary outcome. The incidence of adverse events was considered the safety outcome. Review Manager 5.4 was used to conduct meta-analyses. Data were pooled by random-effects or fixed-effects model to obtain the mean difference (MD), risk ratio (RR), odds ratio (OR), and 95% confidence interval (CI).

Results: There were 28 eligible RCTs with a total of 2,952 participants. Overall, we verified that ZBT plus conventional therapy (CT) was superior to CT for the treatment of HLP [TC: MD = −0.50, 95% CI (−0.80, −0.19); TG: MD = −0.38, 95% CI (−0.49, −0.27); LDL-C: MD = −0.50, 95% CI (−0.69, −0.31); HDL-C: MD = 0.17, 95% CI (0.11, 0.24); total effective rate: OR = 4.26, 95% CI (2.28, 7.95)]. There were no significant differences in the primary outcomes between ZBT alone vs. CT (p > 0.05). For safety, the ZBT group (with CT or alone) outperformed the CT group [ZBT alone: RR = 0.51, 95% CI (0.32, 0.81); ZBT plus CT: RR = 0.51, 95% CI (0.30, 0.89)]. For each outcome, the subgroups and the sensitivity analysis matched the overall results.

Conclusion: ZBT may be safe and beneficial to HLP patients, especially for serum lipid management. ZBT can be used along with CT for the treatment of HLP. However, it is necessary to conduct more rigorous RCTs to confirm these findings.

Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/], identifier [CRD42022316251].
Model yeast as a versatile tool to examine the antioxidant and anti-ageing potential of flavonoids, extracted from medicinal plants
Authors: Zahoor Hira , Watchaputi Kwanrutai , Hata Janejira , Pabuprapap Wachirachai , Suksamrarn Apichart , Chua Lee Suan , Soontorngun Nitnipa
Published: September 2022

The demand for the production of herbal extracts for cosmetics, food, and health supplements, known as plant-based medicine, is rising globally. Incorporating herbal extracts could help to create higher value products due to the functional properties of bioactive compounds. Because the phytochemical composition could vary depending on the processing methods, a simple bioassay of herbal bioactive compounds is an important screening method for the purposes of functional characterization and quality assurance. As a simplified eukaryotic model, yeast serves as a versatile tool to examine functional property of bioactive compounds and to gain better understanding of fundamental cellular processes, because they share similarities with the processes in humans. In fact, aging is a well-conserved phenomenon between yeast and humans, making yeast a powerful genetic tool to examine functional properties of key compounds obtained from plant extracts. This study aimed to apply a well-established model yeast, Saccharomyces cerevisiae, to examine the antioxidant and anti-aging potential of flavonoids, extracted from medicinal plants, and to gain insight into yeast cell adaptation to oxidative stress. Some natural quercetin analogs, including morin, kaempferol, aromadendrin, and steppogenin, protected yeast cells against oxidative stress induced by acetic acid, as shown by decreased cell sensitivity. There was also a reduction in intracellular reactive oxygen species following acetic acid treatment. Using the chronological aging assay, quercetin, morin, and steppogenin could extend the lifespan of wild-type S. cerevisiae by 15%–25%. Consistent with the fact that oxidative stress is a key factor to aging, acetic acid resistance was associated with increased gene expression of TOR1, which encodes a key growth signaling kinase, and MSN2 and MSN4, which encode stress-responsive transcription factors. The addition of the antioxidant morin could counteract this increased expression, suggesting a possible modulatory role in cell signaling and the stress response of yeast. Therefore, yeast represents a versatile model organism and rapid screening tool to discover potentially rejuvenescent molecules with anti-aging and anti-oxidant potential from natural resources and to advance knowledge in the molecular study of stress and aging.
Aconiti lateralis radix praeparata total alkaloids exert anti-RA effects by regulating NF-κB and JAK/STAT signaling pathways and promoting apoptosis
Authors: Wu Yeke , Liu Yi , Zhang Lele , Wen Lan , Xie Yunfei
Published: September 2022

Aconiti Lateralis Radix Praeparata (“Fuzi” in Chinese) is one of the traditional herbs widely used to intervene rheumatoid arthritis (RA), while Fuzi total alkaloids (FTAs) are the main bioactive components. However, the treatment targets and specific mechanisms of FTAs against RA have not been fully elucidated. The purpose of the present study was to confirm the anti-rheumatism effects of FTAs and reveal its potential molecular mechanisms. In TNF-α-induced MH7A cells model, we found that FTAs showed inhibitory effects on proliferation. While, FTAs significantly decreased the expression levels of IL-1β, IL-6, MMP-1, MMP-3, PGE2, TGF-β, and VEGF. FTAs also enhanced the progress of apoptosis and arrested the cell cycle at G0/G1 phase to prevent excessive cell proliferation. In addition, FTAs inhibited the hyperactivity of NF-κB and JAK/STAT signaling pathways, and regulated the cascade reaction of mitochondrial apoptosis signaling pathway. The results suggested that FTAs exerted anti-inflammatory effects by inhibiting NF-κB and JAK/STAT signaling pathways, promoted apoptosis by stimulating mitochondrial apoptosis signaling pathway, and inhibited cell proliferation by modulating cell cycle progression.
Toxicological evaluation of water-extract sericin from silkworm (Bombyx mori) in pregnant rats and their fetus during pregnancy
Authors: Li Jinyue , Wen Pingjing , Qin Guangqiu , Zhang Jiehong , Zhao Peng , Ye Yixin
Published: September 2022

Sericin is a natural protein produced by the silkworm Bombyx mori, which has a wide range of biological activities and has a broad application prospect in multiple areas. However, systemic toxicity and safety assessment of sericin is still rare. This study was aimed to evaluate the toxic effects of water-extract sericin from cocoons of Bombyx mori in pregnant rats and their fetuses during pregnancy. Eighty pregnant rats were randomly divided into three treatment groups, one negative and one positive control group. The treatment groups were administered water-extract sericin solutions at doses of 1,000, 500, and 250 mg/kg, while the negative and positive control groups were administered pure water and 300 mg/kg aspirin, respectively. Rats were exposed daily by oral gavage from the seventh day of gestation for 10 consecutive days and sacrificed on the 20th day of gestation. The results showed that water-extract sericin did not induce any treatment-related changes on pregnant rats (clinical signs, body weights, food consumption, ovarian and uterine weights) and fetuses (body weights, body lengths, tail lengths, visceral, and skeletal development). The no-observed-adverse-effect-level (NOAEL) of sericin was determined to be 1,000 mg/kg body weight in rats. These results indicated that water-extract sericin is of low teratogenic potential under the experimental conditions of this study.
CYP2D6 gene polymorphism and apatinib affect the metabolic profile of fluvoxamine
Authors: Ye Zhize , Chen Bingbing , Gao Nanyong , Kong Qihui , Hu Xiaoqin , Lu Zhongqiu , Qian Jianchang , Hu Guoxin , Cai Jianping , Wu Bin
Published: September 2022

This study aimed 1) to investigate the influence of CYP2D6 variants on the catalyzing of fluvoxamine, and 2) to study the interaction between fluvoxamine and apatinib. An enzymatic reaction system was setup and the kinetic profile of CYP2D6 in metabolizing fluvoxamine was determined. In vivo, drug-drug interaction was investigated using Sprague–Dawley (SD) rats. Fluvoxamine was given gavage with or without apatinib. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to determine the concentrations of fluvoxamine and desmethyl-fluvoxamine. The results demonstrated that the relative clearance rates of CYP2D6.A5V, V104A, D337G, F164L, V342M, R440C and R497C increased significantly compared with CYP2D6.1, ranging from 153.626% ± 6.718% to 394.310% ± 33.268%. The activities of other variants reduced to different extent, or even lost function, but there was no statistical difference. The IC50 of apatinib against fluvoxamine disposition was determined, which is 0.190 μM in RLM and 6.419 μM in HLM, respectively. In vivo, apatinib can enhance the plasma exposure of fluvoxamine remarkably characterized by increased AUC, Tmax and Cmax. Meanwhile, the produce of desmethyl fluvoxamine was dramatically inhibited, both AUC and Cmax decreased significantly. Mechanistically, apatinib inhibit the generation of fluvoxamine metabolite with a mixed manner both in RLM and HLM. Furthermore, there were differences in the potency of apatinib in suppressing fluvoxamine metabolism among CYP2D6.1, 2 and 10. In conclusion, CYP2D6 gene polymorphisms and drug-drug interaction can remarkably affect the plasma exposure of fluvoxamine. The present study provides basis data for guiding individual application of fluvoxamine.