bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Endogenous Lipids and Proteins on the Antioxidant, in vitro Starch Digestibility, and Pasting Properties of Sorghum Flour
Authors: Irondi Emmanuel Anyachukwu , Adewuyi Adekemi Esther , Aroyehun Tolulope Muktar
Published: January 2022

This study evaluated the effect of endogenous lipids and proteins on the antioxidants, starch digestibility, and pasting properties of sorghum (Sorghum bicolor) flour (SF). Endogenous lipids and/or proteins were removed from different portions of SF to obtain defatted (DF), deproteinized (DP), and defatted and deproteinized (DF-DP) flours. Bioactive constituents (total phenolics, tannins, flavonoids, saponins, and anthocyanins), antioxidant activities [2,2-Azinobis (3-ethyl-benzothiazoline-6-sulfonic acid) radical cation (ABTS*+) and 2, 2-Diphenyl-2-picrylhydrazyl radical (DPPH*) scavenging activities, reducing power, and Fe2+ chelating capacity], starch, amylose, starch hydrolysis index (HI), estimated glycemic index (eGI), and pasting properties of treated and control (untreated) flours were determined. The control flour (SF) had significantly higher (p < 0.05) levels of all the bioactive constituents and antioxidant activity tested than the DF, DP, and DF-DP flours, while the DF-DP flour had the least levels of bioactive constituents and antioxidant activity. In contrast, the starch, amylose, HI, and eGI were consistently in the order of DF-DP > DF > DP > control flour (p < 0.05). The control flour had the highest (p < 0.05) peak viscosity, and the least peak time and pasting temperature, while the DF flour had the highest final viscosity. Therefore, endogenous lipids and proteins contribute to the antioxidant, starch digestibility, and pasting properties of sorghum flour.
The Role of MRI Pancreatic Protocol in Assessing Response to Neoadjuvant Therapy for Patients With Borderline Resectable Pancreatic Cancer
Authors: Hussien Nervana , Hussien Rasha S. , Saad Darine Helmy Amin , El Kassas Mohamed , Elkhatib Walid F. , Ezz El Din Mai
Published: January 2022

Background

Borderline Resectable Pancreatic Cancer (BRPC) remains a unique entity that is difficult to categorize due to variance in definitions and the small number of patients. The ultimate goal is to achieve a free resection (R0) after a favorable response to neoadjuvant therapy that is somewhat difficult to assess by current radiological parameters.

Aim

To evaluate the role of Magnetic Resonance Imaging (MRI) pancreatic protocol, including Diffusion-Weighted Imaging (DWI), in patients with BRPC receiving neoadjuvant therapy, and further compare it to RECIST criteria and outcome.

Methods

Histologically confirmed BRPC patients were prospectively included. DWI-MRI was performed pre- and post-therapy. Clinical characteristics with ensuing operability were recorded and correlated to radiological RECIST/apparent diffusion coefficient (ADC) change, preoperative therapy administrated, surgical resection status, and survival.

Results

Out of 30 BRPC cases, only 11 (36.7%) ultimately underwent pancreaticoduodenectomy. Attaining a stationary or stable disease via ADC/RECIST was achieved in the majority of cases (60%/53.3% respectively). Of the 12 patients (40%) who achieved a regression by ADC, 11 underwent surgery with an R0 status. These surgical cases showed variable RECIST responses (PR=5, SD=4, PD=3). Responders by ADC to neoadjuvant therapy were significantly associated to presenting with abdominal pain (p =0.07), a decline in post-therapy CA19-9 (p<0.001), going through surgery (p<0.001), and even achieving better survival (p<0.001 vs. 0.66).

Conclusion

DWI-MRI ADC picked up patients most likely to undergo a successful operative procedure better than traditional RECIST criteria. An algorithm incorporating novel radiological advances with CA19-9 deserves further assessment in future studies.
Machine and Deep Learning Prediction Of Prostate Cancer Aggressiveness Using Multiparametric MRI
Authors: Bertelli Elena , Mercatelli Laura , Marzi Chiara , Pachetti Eva , Baccini Michela , Barucci Andrea , Colantonio Sara , Gherardini Luca , Lattavo Lorenzo , Pascali Maria Antonietta , Agostini Simone , Miele Vittorio
Published: January 2022

Prostate cancer (PCa) is the most frequent male malignancy and the assessment of PCa aggressiveness, for which a biopsy is required, is fundamental for patient management. Currently, multiparametric (mp) MRI is strongly recommended before biopsy. Quantitative assessment of mpMRI might provide the radiologist with an objective and noninvasive tool for supporting the decision-making in clinical practice and decreasing intra- and inter-reader variability. In this view, high dimensional radiomics features and Machine Learning (ML) techniques, along with Deep Learning (DL) methods working on raw images directly, could assist the radiologist in the clinical workflow. The aim of this study was to develop and validate ML/DL frameworks on mpMRI data to characterize PCas according to their aggressiveness. We optimized several ML/DL frameworks on T2w, ADC and T2w+ADC data, using a patient-based nested validation scheme. The dataset was composed of 112 patients (132 peripheral lesions with Prostate Imaging Reporting and Data System (PI-RADS) score ≥ 3) acquired following both PI-RADS 2.0 and 2.1 guidelines. Firstly, ML/DL frameworks trained and validated on PI-RADS 2.0 data were tested on both PI-RADS 2.0 and 2.1 data. Then, we trained, validated and tested ML/DL frameworks on a multi PI-RADS dataset. We reported the performances in terms of Area Under the Receiver Operating curve (AUROC), specificity and sensitivity. The ML/DL frameworks trained on T2w data achieved the overall best performance. Notably, ML and DL frameworks trained and validated on PI-RADS 2.0 data obtained median AUROC values equal to 0.750 and 0.875, respectively, on unseen PI-RADS 2.0 test set. Similarly, ML/DL frameworks trained and validated on multi PI-RADS T2w data showed median AUROC values equal to 0.795 and 0.750, respectively, on unseen multi PI-RADS test set. Conversely, all the ML/DL frameworks trained and validated on PI-RADS 2.0 data, achieved AUROC values no better than the chance level when tested on PI-RADS 2.1 data. Both ML/DL techniques applied on mpMRI seem to be a valid aid in predicting PCa aggressiveness. In particular, ML/DL frameworks fed with T2w images data (objective, fast and non-invasive) show good performances and might support decision-making in patient diagnostic and therapeutic management, reducing intra- and inter-reader variability.
Post-hoc Analysis of Pharmacodynamics and Single-Agent Activity of CD3xCD123 Bispecific Antibody APVO436 in Relapsed/Refractory AML and MDS Resistant to HMA or Venetoclax Plus HMA
Authors: Watts Justin , Lin Tara L. , Mims Alice , Patel Prapti , Lee Cynthia , Shahidzadeh Anoush , Shami Paul , Cull Elizabeth , Cogle Christopher R. , Wang Eunice , Uckun Fatih M.
Published: January 2022

APVO436 is a recombinant bispecific antibody designed to direct host cytotoxic T-cells to CD123-expressing blast cells in patients with hematologic malignancies. APVO436 showed promising tolerability and single-agent activity in relapsed or refractory (R/R) acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The primary purpose of this post-hoc analysis was to evaluate the therapeutic and pharmacodynamic effects of APVO436 in 14 R/R AML/MDS patients who had failed treatment with hypomethylating agents (HMA) or venetoclax plus HMA prior to being enrolled in the APVO436 Phase 1 dose-escalation study that was recently completed. Eight of these 14 patients had R/R AML and had failed treatment with HMA (N=2) or venetoclax plus HMA (N=6). The remaining 6 patients had R/R MDS and had also failed treatment with HMA (N=5) or venetoclax plus HMA (N=1). They were treated with APVO436 at submicrogram dose levels >0.08 mcg/kg that were active in preclinical NOD/SCID mouse xenograft models of AML. APVO436 activated patients’ T-cells as evidenced by reduced numbers of circulating CD123+CD34+ and CD33+CD34+ peripheral blasts. Single-agent activity was observed at dose levels ranging from 0.1 mcg/kg to 0.7 mcg/kg in 4 R/R AML patients (50%), including 3 patients with prolonged stable disease (SD) and one patient with complete remission (CR). Likewise, 3 MDS patients had SD (50%) and 3 additional MDS patients (50%) had a marrow CR at dose levels ranging from 0.1 mcg/kg to 0.8 mcg/kg. The median survival for the combined group of 14 R/R AML/MDS patients was 282 days. This early evidence of single-agent activity of APVO436 in R/R AML/MDS patients who failed HMA with or without venetoclax provides proof of concept supporting its in vivo immunomodulatory and anti-leukemic activity and warrants further investigation of its clinical impact potential.
New Insights Into c.815_824dup Pathogenic Variant of BRCA1 in Inherited Breast Cancer: A Founder Mutation of West African Origin
Authors: Diop Jean Pascal Demba , Sène Andréa Régina Gnilane , Dia Yacouba , Ba Seydi Abdoul , Mbacke Serigne Saliou , Ly Cheikh Ameth Tidiane , Sarr Pierre Diaga , Diouf Doudou , Ka Sidy , Mbengue Babacar , Gueye Serigne Modou Kane , Diop Pape Saloum , Sylla Niang Maguette , Gueye Papa Madieye , Lopez Sall Philomene , Dem Ahmadou , Cisse Aynina , Dieye Alioune , Ndiaye Rokhaya
Published: January 2022

Founder mutations have been reported inBRCA1andBCRA2in different ethnic groups with inherited breast cancer. Testing of targeted mutations in specific populations is important for cancer prevention in mutation carriers. In Sub-Saharan Africa, only a few studies have reported specific founder mutations in inherited breast cancer. The pathogenic variant c.815_824dup ofBRCA1has been reported as the most frequent among African American populations with inherited breast cancer and was supposed to have a West African origin. Recent report from Senegal identified this variant in women with inherited breast cancer at the highest frequency ever reported. The variant was linked to a common haplotype confirming its founder effect in West Africa. In this article, we review the mutation history of c.815_824dup and discuss how it spread out of Africa through the transatlantic slave trade.
Study Protocol of the Exercise Study: Unraveling Limitations for Physical Activity in Children With Chronic Diseases in Order to Target Them With Tailored Interventions—A Randomized Cross Over Trial
Authors: Scheffers Linda E. , Helbing Willem A. , Utens Elisabeth M. W. J. , Dieleman Gwen C. , Dulfer Karolijn , Noske Josefien , van den Broek Eline A. , Walet Sylvia , Olieman Joanne F. , Escher Johanna C. , Pijnenburg Marielle W. , van der Ploeg Ans T. , van den Berg Linda E.
Published: January 2022

Introduction: Physical activity is associated with many physiological and psychological health benefits across the lifespan. Children with a chronic disease often have lower levels of daily physical activity, and a decreased exercise capacity compared to healthy peers. In order to learn more about limitations for physical activity, we investigate children with four different chronic diseases: children with a Fontan circulation, children with Broncho Pulmonary Dysplasia (BPD), Pompe disease and inflammatory bowel disease (IBD). Each of these diseases is likely to interfere with physical activity in a different way. Knowing the specific limitations for physical activity would make it possible to target these, and increase physical activity by a personalized intervention. The aim of this study is to first investigate limitations for physical activity in children with various chronic diseases. Secondly, to measure the effects of a tailored exercise intervention, possibly including a personalized dietary advice and/or psychological counseling, on exercise capacity, endurance, quality of life, fatigue, fear for exercise, safety, muscle strength, physical activity levels, energy balance, and body composition.

Methods and Analysis: This randomized crossover trial will aim to include 72 children, aged 6–18 years, with one of the following diagnosis: a Fontan circulation, BPD, Pompe disease and IBD. Eligible patients will participate in the 12-week tailored exercise intervention and are either randomized to start with a control period or start with the intervention. The tailored 12-week exercise interventions, possibly including a personalized dietary advice and/or psychological counseling, will be designed based on the found limitations for physical activity in each disease group during baseline measurements by the Rotterdam Exercise Team. Effects of the tailored training interventions will be measured on the following endpoints: exercise capacity (measured by cardiopulmonary exercise test), endurance, physical activity levels, muscle strength, quality of life, fatigue, fear for exercise, disease activity, cardiac function (in children with a Fontan circulation), energy balance, and body composition.

Ethics and Dissemination: Conducted according to the Declaration of Helsinki and Good Clinical Practice. Medical-ethical approval was obtained.

Trial Registration Number: NL8181, https://www.trialregister.nl/trial/8181.
Screen Time, Age and Sunshine Duration Rather Than Outdoor Activity Time Are Related to Nutritional Vitamin D Status in Children With ASD
Authors: Shan Ling , Dong Hanyu , Wang Tiantian , Feng Junyan , Jia Feiyong
Published: January 2022

Objective: This study aimed to investigate the possible association among vitamin D, screen time and other factors that might affect the concentration of vitamin D in children with autism spectrum disorder (ASD).

Methods: In total, 306 children with ASD were recruited, and data, including their age, sex, height, weight, screen time, time of outdoor activity, ASD symptoms [including Autism Behavior Checklist (ABC), Childhood Autism Rating Scale (CARS) and Autism Diagnostic Observation Schedule–Second Edition (ADOS-2)] and vitamin D concentrations, were collected. A multiple linear regression model was used to analyze the factors related to the vitamin D concentration.

Results: A multiple linear regression analysis showed that screen time (β = −0.122, P = 0.032), age (β = −0.233, P < 0.001), and blood collection month (reflecting sunshine duration) (β = 0.177, P = 0.004) were statistically significant. The vitamin D concentration in the children with ASD was negatively correlated with screen time and age and positively correlated with sunshine duration.

Conclusion: The vitamin D levels in children with ASD are related to electronic screen time, age and sunshine duration. Since age and season are uncontrollable, identifying the length of screen time in children with ASD could provide a basis for the clinical management of their vitamin D nutritional status.
Interaction of Serum Alkaline Phosphatase and Folic Acid Treatment on Chronic Kidney Disease Progression in Treated Hypertensive Adults
Authors: Zhang Yuanyuan , He Panpan , Wang Guobao , Liang Min , Xie Di , Nie Jing , Liu Chengzhang , Song Yun , Liu Lishun , Wang Binyan , Li Jianping , Zhang Yan , Wang Xiaobin , Huo Yong , Hou Fan Fan , Xu Xiping , Qin Xianhui
Published: January 2022

The relation of alkaline phosphatase (ALP) with chronic kidney disease (CKD) is still uncertain. We aimed to examine the prospective association between serum ALP and CKD progression, and the modifying effect of serum ALP on folic acid in preventing CKD progression in treated hypertensive patients. This is a post-hoc analysis of 12,734 hypertensive adults with relevant measurements and without liver disease at baseline from the renal sub-study of the China Stroke Primary Prevention Trial, where participants were randomly assigned to daily treatments of 10 mg enalapril and 0.8 mg folic acid, or 10 mg enalapril alone. The primary outcome was CKD progression, defined as a decrease in estimated glomerular filtration rate (eGFR) of ≥30% and to a level of <60 ml/min/1.73 m2 if baseline eGFR was ≥60 ml/min/1.73 m2; or a decrease in eGFR of ≥50% if baseline eGFR was <60 ml/min/1.73 m2; or end-stage renal disease. Over a median of 4.4 years, in the enalapril only group, participants with baseline serum ALP≥110IU/L (quartile 4) had a significantly higher risk of CKD progression (3.4% vs 2.3%; adjusted OR,1.61; 95%CI:1.11, 2.32), compared with those with ALP<110IU/L. For those with enalapril and folic acid treatment, compared with the enalapril only treatment, the risk of CKD progression was reduced from 3.4 to 2.1% (adjusted OR, 0.53; 95%CI:0.34, 0.83) among participants with baseline ALP≥110IU/L, whereas there was no significant effect among those with ALP<110IU/L. In hypertensive patients, higher serum ALP was associated with increased risk of CKD progression, and this risk was reduced by 47% with folic acid treatment.
Jatrorrhizine: A Review of Sources, Pharmacology, Pharmacokinetics and Toxicity
Authors: Zhong Furong , Chen Yang , Chen Jia , Liao Hailang , Li Yirou , Ma Yuntong
Published: January 2022

Jatrorrhizine, an isoquinoline alkaloid, is a bioactive metabolite in common medicinal plants, such as Berberis vernae Schneid., Tinospora sagittata (Oliv.) Gagnep. and Coptis chinensis Franch. These plants have been used for centuries in traditional medicine for their wide-ranging pharmacological properties. This review emphasizes the latest and comprehensive information on the sources, pharmacology, pharmacokinetics and toxicity of jatrorrhizine. Studies on this alkaloid were collected from scientific internet databases, including the Web of Science, PubMed, ScienceDirect, Google Scholar, Elsevier, Springer, Wiley Online Library and Europe PMC and CNKI, using a combination of keywords involving “jatrorrhizine”, “sources”, “pharmacology,” “pharmacokinetics,” and “toxicology”. Jatrorrhizine exhibits anti-diabetic, antimicrobial, antiprotozoal, anticancer, anti-obesity and hypolipidemic properties, along with central nervous system activities and other beneficial activity. Studies of jatrorrhizine have laid the foundation for its application to the treatment of various diseases, but some issues still exist. Further investigations might emphasize 1) specific curative mechanisms of jatrorrhizine and clinical utility, 2) application prospect in the treatment of metabolic disorders, 3) comprehensive investigations of the toxicity mechanisms and 4) interactions of jatrorrhizine with other pharmaceuticals and development of derivatives.
Application Potential of Plant-Derived Medicines in Prevention and Treatment of Platinum-Induced Peripheral Neurotoxicity
Authors: Xu Xiaowei , Jia Liqun , Ma Xiaoran , Li Huayao , Sun Changgang
Published: January 2022

As observed with other chemotherapeutic agents, the clinical application of platinum agents is a double-edged sword. Platinum-induced peripheral neuropathy (PIPN) is a common adverse event that negatively affects clinical outcomes and patients’ quality of life. Considering the unavailability of effective established agents for preventing or treating PIPN and the increasing population of cancer survivors, the identification and development of novel, effective interventions are the need of the hour. Plant-derived medicines, recognized as ideal agents, can not only help improve PIPN without affecting chemotherapy efficacy, but may also produce synergy. In this review, we present a brief summary of the mechanisms of platinum agents and PIPN and then focus on exploring the preventive or curative effects and underlying mechanisms of plant-derived medicines, which have been evaluated under platinum-induced neurotoxicity conditions. We identified 11 plant extracts as well as 17 plant secondary metabolites, and four polyherbal preparations. Their effects against PIPN are focused on oxidative stress and mitochondrial dysfunction, glial activation and inflammation response, and ion channel dysfunction. Also, ten clinical trials have assessed the effect of herbal products in patients with PIPN. The understanding of the molecular mechanism is still limited, the quality of clinical trials need to be further improved, and in terms of their efficacy, safety, and cost effectiveness studies have not provided sufficient evidence to establish a standard practice. But plant-derived medicines have been found to be invaluable sources for the development of natural agents with beneficial effects in the prevention and treatment of PIPN.
Discovery of Novel Reductive Elimination Pathway for 10-Hydroxywarfarin
Authors: Pouncey Dakota L. , Barnette Dustyn A. , Sinnott Riley W. , Phillips Sarah J. , Flynn Noah R. , Hendrickson Howard P. , Swamidass S. Joshua , Miller Grover P.
Published: January 2022

Coumadin (R/S-warfarin) anticoagulant therapy is highly efficacious in preventing the formation of blood clots; however, significant inter-individual variations in response risks over or under dosing resulting in adverse bleeding events or ineffective therapy, respectively. Levels of pharmacologically active forms of the drug and metabolites depend on a diversity of metabolic pathways. Cytochromes P450 play a major role in oxidizing R- and S-warfarin to 6-, 7-, 8-, 10-, and 4′-hydroxywarfarin, and warfarin alcohols form through a minor metabolic pathway involving reduction at the C11 position. We hypothesized that due to structural similarities with warfarin, hydroxywarfarins undergo reduction, possibly impacting their pharmacological activity and elimination. We modeled reduction reactions and carried out experimental steady-state reactions with human liver cytosol for conversion of rac-6-, 7-, 8-, 4′-hydroxywarfarin and 10-hydroxywarfarin isomers to the corresponding alcohols. The modeling correctly predicted the more efficient reduction of 10-hydroxywarfarin over warfarin but not the order of the remaining hydroxywarfarins. Experimental studies did not indicate any clear trends in the reduction for rac-hydroxywarfarins or 10-hydroxywarfarin into alcohol 1 and 2. The collective findings indicated the location of the hydroxyl group significantly impacted reduction selectivity among the hydroxywarfarins, as well as the specificity for the resulting metabolites. Based on studies with R- and S-7-hydroxywarfarin, we predicted that all hydroxywarfarin reductions are enantioselective toward R substrates and enantiospecific for S alcohol metabolites. CBR1 and to a lesser extent AKR1C3 reductases are responsible for those reactions. Due to the inefficiency of reactions, only reduction of 10-hydroxywarfarin is likely to be important in clearance of the metabolite. This pathway for 10-hydroxywarfarin may have clinical relevance as well given its anticoagulant activity and capacity to inhibit S-warfarin metabolism.
Therapeutic Opportunities of GPBAR1 in Cholestatic Diseases
Authors: Zhang Fangling , Xiao Xiaolin , Li Yong , Wu Hefei , Deng Xinyu , Jiang Yinxiao , Zhang Wenwen , Wang Jian , Ma Xiao , Zhao Yanling
Published: January 2022

GPBAR1, a transmembrane G protein-coupled receptor for bile acids, is widely expressed in multiple tissues in humans and rodents. In recent years, GPBAR1 has been thought to play an important role in bile homeostasis, metabolism and inflammation. This review specifically focuses on the function of GPBAR1 in cholestatic liver disease and summarizes the various pathways through which GPBAR1 acts in cholestatic models. GPBAR1 mainly regulates cholestasis in a holistic system of liver-gallbladder-gut formation. In the state of cholestasis, the activation of GPBAR1 could regulate liver inflammation, induce cholangiocyte regeneration to maintain the integrity of the biliary tree, control the hydrophobicity of the bile acid pool and promote the secretion of bile HCO3−. All these functions of GPBAR1 might be clear ways to protect against cholestatic diseases and liver injury. However, the characteristic of GPBAR1-mediated proliferation increases the risk of proliferation of cholangiocarcinoma in malignant transformed cholangiocytes. This dichotomous function of GPBAR1 limits its use in cholestasis. During disease treatment, simultaneous activation of GPBAR1 and FXR receptors often results in improved outcomes, and this strategy may become a crucial direction in the development of bile acid-activated receptors in the future.
Effects of Exogenous Hydrogen Sulfide in the Hypothalamic Paraventricular Nucleus on Gastric Function in Rats
Authors: Li Chenyu , Sun Hongzhao , Shi Yuan , Yu Yan , Ji Xiaofeng , Li Enguang , Zhou Xiaofan , Liu Xiaomeng , Xue Xikang , Sun Haiji
Published: January 2022

Background: Hydrogen sulfide (H2S) is a new type of gas neurotransmitter discovered in recent years. It plays an important role in various physiological activities. The hypothalamus paraventricular nucleus (PVN) is an important nucleus that regulates gastric function. This study aimed to clarify the role of H2S in the paraventricular nucleus of the hypothalamus on the gastric function of rats.

Methods: An immunofluorescence histochemistry double-labelling technique was used to determine whether cystathionine-beta-synthase (CBS) and c-Fos neurons are involved in PVN stress. Through microinjection of different concentrations of NaHS, physiological saline (PS), D-2-Amino-5-phosphonovaleric acid (D-AP5), and pyrrolidine dithiocarbamate (PDTC), we observed gastric motility and gastric acid secretion.

Results: c-Fos and CBS co-expressed the most positive neurons after 1 h of restraint and immersion, followed by 3 h, and the least was at 0 h. After injection of different concentrations of NaHS into the PVN, gastric motility and gastric acid secretion in rats were significantly inhibited and promoted, respectively (p < 0.01); however, injection of normal saline, D-AP5, and PDTC did not cause any significant change (p > 0.05). The suppressive effect of NaHS on gastrointestinal motility and the promotional effect of NaHS on gastric acid secretion could be prevented by D-AP5, a specific N-methyl-D-aspartic acid (NMDA) receptor antagonist, and PDTC, an NF-κB inhibitor.

Conclusion: There are neurons co-expressing CBS and c-Fos in the PVN, and the injection of NaHS into the PVN can inhibit gastric motility and promote gastric acid secretion in rats. This effect may be mediated by NMDA receptors and the NF-κB signalling pathway.
Relevance of Peptide Homeostasis in Metabolic Retinal Degenerative Disorders: Curative Potential in Genetically Modified Mice
Authors: Pöstyéni Etelka , Ganczer Alma , Kovács-Valasek Andrea , Gabriel Robert
Published: January 2022

The mammalian retina contains approximately 30 neuropeptides that are synthetized by different neuronal cell populations, glia, and the pigmented epithelium. The presence of these neuropeptides leaves a mark on normal retinal molecular processes and physiology, and they are also crucial in fighting various pathologies (e.g., diabetic retinopathy, ischemia, age-related pathologies, glaucoma) because of their protective abilities. Retinal pathologies of different origin (metabolic, genetic) are extensively investigated by genetically manipulated in vivo mouse models that help us gain a better understanding of the molecular background of these pathomechanisms. These models offer opportunities to manipulate gene expression in different cell types to help reveal their roles in the preservation of retinal health or identify malfunction during diseases. In order to assess the current status of transgenic technologies available, we have conducted a literature survey focused on retinal disorders of metabolic origin, zooming in on the role of retinal neuropeptides in diabetic retinopathy and ischemia. First, we identified those neuropeptides that are most relevant to retinal pathologies in humans and the two clinically most relevant models, mice and rats. Then we continued our analysis with metabolic disorders, examining neuropeptide-related pathways leading to systemic or cellular damage and rescue. Last but not least, we reviewed the available literature on genetically modified mouse strains to understand how the manipulation of a single element of any given pathway (e.g., signal molecules, receptors, intracellular signaling pathways) could lead either to the worsening of disease conditions or, more frequently, to substantial improvements in retinal health. Most attention was given to studies which reported successful intervention against specific disorders. For these experiments, a detailed evaluation will be given and the possible role of converging intracellular pathways will be discussed. Using these converging intracellular pathways, curative effects of peptides could potentially be utilized in fighting metabolic retinal disorders.
Cancer Chemoprevention: A Strategic Approach Using Phytochemicals
Authors: G. Mohan Shankar , Swetha Mundanattu , Keerthana C K , Rayginia Tennyson P , Anto Ruby John
Published: January 2022

Cancer chemoprevention approaches are aimed at preventing, delaying, or suppressing tumor incidence using synthetic or natural bioactive agents. Mechanistically, chemopreventive agents also aid in mitigating cancer development, either by impeding DNA damage or by blocking the division of premalignant cells with DNA damage. Several pre-clinical studies have substantiated the benefits of using various dietary components as chemopreventives in cancer therapy. The incessant rise in the number of cancer cases globally is an issue of major concern. The excessive toxicity and chemoresistance associated with conventional chemotherapies decrease the success rates of the existent chemotherapeutic regimen, which warrants the need for an efficient and safer alternative therapeutic approach. In this scenario, chemopreventive agents have been proven to be successful in protecting the high-risk populations from cancer, which further validates chemoprevention strategy as rational and promising. Clinical studies have shown the effectiveness of this approach in managing cancers of different origins. Phytochemicals, which constitute an appreciable proportion of currently used chemotherapeutic drugs, have been tested for their chemopreventive efficacy. This review primarily aims to highlight the efficacy of phytochemicals, currently being investigated globally as chemopreventives. The clinical relevance of chemoprevention, with special emphasis on the phytochemicals, curcumin, resveratrol, tryptanthrin, kaempferol, gingerol, emodin, quercetin genistein and epigallocatechingallate, which are potential candidates due to their ability to regulate multiple survival pathways without inducing toxicity, forms the crux of this review. The majority of these phytochemicals are polyphenols and flavanoids. We have analyzed how the key molecular targets of these chemopreventives potentially counteract the key drivers of chemoresistance, causing minimum toxicity to the body. An overview of the underlying mechanism of action of these phytochemicals in regulating the key players of cancer progression and tumor suppression is discussed in this review. A summary of the clinical trials on the important phytochemicals that emerge as chemopreventives is also incorporated. We elaborate on the pre-clinical and clinical observations, pharmacokinetics, mechanism of action, and molecular targets of some of these natural products. To summarize, the scope of this review comprises of the current status, limitations, and future directions of cancer chemoprevention, emphasizing the potency of phytochemicals as effective chemopreventives.
Discovery of the Potential Novel Pharmacodynamic Substances From Zhi-Zi-Hou-Po Decoction Based on the Concept of Co-Decoction Reaction and Analysis Strategy
Authors: Feng Xin , Bi Yuelin , Wang Jiaqi , Li Tianyi , Yu Gengyuan , Zhang Tonghua , Xu Haoran , Zhang Chenning , Sun Yikun
Published: January 2022

Background: Zhi-Zi-Hou-Po Decoction (ZZHPD), a classic traditional Chinese medicine (TCM) formula, is clinically used to treat insomnia and depression. The analysis strategy based on the concept of co-decoction of TCM is helpful to analyse the effective substances of TCM formula in depth.

Aim of the study: This manuscript intends to take ZZHPD as a model sample to explore the phenomenon of co-decoction of complex formula in the combination of liquid chromatography-mass spectrometry (LC-MS) technology, data analysis, and molecular docking.

Materials and methods: In the current research, an innovative LC-MS method has been established to study the active ingredients in ZZHPD, and to identify the ingredients absorbed into the blood and brain tissues of mice. And molecular docking was used to study the binding pattern and affinities of known compounds of the brain tissue toward insomnia related proteins.

Results: Based on new processing methods and analysis strategies, 106 chemical components were identified in ZZHPD, including 28 blood components and 18 brain components. Then, by comparing the different compounds in the co-decoction and single decoction, it was surprisingly found that 125 new ingredients were produced during the co-decoction, 2 of which were absorbed into the blood and 1 of which was absorbed into brain tissue. Ultimately, molecular docking studies showed that 18 brain components of ZZHPD had favourable binding conformation and affinity with GABA, serotonin and melatonin receptors. The docking results of GABRA1 with naringenin and hesperidin, HCRTR1 with naringenin-7-O-glucoside, poncirenin and genipin 1-gentiobioside, and luteolin with SLC6A4, GLO1, MAOB and MTNR1A may clarify the mechanism of action of ZZHPD in treating insomnia and depression.

Conclusion: Our study may provide new ideas for further exploring the effective substances in ZZHPD.
A New Biomarker Tool for Risk Stratification in “de novo” Acute Heart Failure (OROME)
Authors: Agra-Bermejo Rosa M. , Cacho-Antonio Carla , Gonzalez-Babarro Eva , Rozados-Luis Adriana , Couselo-Seijas Marinela , Gómez-Otero Inés , Varela-Román Alfonso , López-Canoa José N , Gómez-Rodríguez Isabel , Pata María , Eiras Sonia , González-Juanatey Jose R.
Published: January 2022

Background: Inflammation is one of the mechanisms involved in heart failure (HF) pathophysiology. Thus, the acute phase reactant protein, orosomucoid, was associated with a worse post-discharge prognosis in de novo acute HF (AHF). However, the presence of anti-inflammatory adipokine, omentin, might protect and reduce the severity of the disease. We wanted to evaluate the value of omentin and orosomucoid combination for stratifying the risk of these patients.

Methods and Results: Two independent cohorts of patients admitted for de novo AHF in two centers were included in the study (n = 218). Orosomucoid and omentin circulating levels were determined by ELISA at discharge. Patients were followed-up for 317 (3–575) days. A predictive model was determined for the primary endpoint, death, and/or HF readmission. Differences in survival were evaluated using a Log-rank test. According to cut-off values of orosomucoid and omentin, patients were classified as UpDown (high orosomucoid and low omentin levels), equal (both proteins high or low), and DownUp (low orosomucoid and high omentin levels). The Kaplan Meier determined a worse prognosis for the UpDown group (Long-rank test p = 0.02). The predictive model that includes the combination of orosomucoid and omentin groups (OROME) + NT-proBNP values achieved a higher C-index = 0.84 than the predictive model with NT-proBNP (C-index = 0.80) or OROME (C-index = 0.79) or orosomucoid alone (C-index = 0.80).

Conclusion: The orosomucoid and omentin determination stratifies de novo AHF patients into the high, mild, and low risk of rehospitalization and/or death for HF. Its combination with NT-proBNP improves its predictive value in this group of patients.
Impact and Possible Mechanism(s) of Adipose Tissue-Derived Mesenchymal Stem Cells on T-Cell Proliferation in Patients With Rheumatic Disease
Authors: Kuca-Warnawin Ewa , Olesińska Marzena , Szczȩsny Piotr , Kontny Ewa
Published: January 2022

Objectives: Systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) are chronic wasting, incurable rheumatic diseases of autoimmune background, in which T cells play a critical pathogenic role. Autologous adipose tissue-derived mesenchymal stem cells (ASCs) may represent an alternative therapeutic option for SLE and SSc patients, but the biology of these cells is poorly understood.

Methods: Herein, we evaluated the anti-proliferative impact of ASCs of healthy donors (HD/ASCs, 5 reference cell lines), SLE patients (n = 20), and SSc patients (n = 20) on T lymphocytes. To assess the direct and indirect pathway of ASCs action, peripheral blood mononuclear cells (PBMCs) and purified CD4+ T cells of HD were activated and co-cultured in cell-to-cell contact (C-C) and transwell (T-W) conditions with untreated or cytokine (TNF + IFNΥ, TI)-licensed ASCs, then analyzed by flow cytometry to rate the proliferation response of CD8+ and/or CD4+ T cells. The concentrations of kynurenines, prostaglandin E2 (PGE2), interleukin 10 (IL-10), and transforming growth factor β (TGFβ) were measured from culture supernatants. Specific inhibitors of these factors (1-MT, indomethacin, and cytokine-neutralizing antibody) were used to assess their contribution to anti-proliferative ASCs action.

Results: All tested ASCs significantly decreased the number of proliferating CD4+ and CD8+ T cells, the number of division/proliferating cell (PI), and fold expansion (RI), and similarly upregulated kynurenines and PGE2, but not cytokine levels, in the co-cultures with both types of target cells. However, TI-treated SLE/ASCs and SSc/ASCs exerted a slightly weaker inhibitory effect on CD4+ T-cell replication than their respective HD/ASCs. All ASCs acted mainly via soluble factors. Their anti-proliferative effect was stronger, and kynurenine levels were higher in the T-W condition than the C-C condition. Blocking experiments indicated an involvement of kynurenine pathway in inhibiting the number of proliferating cells, PI, and RI values as well as PGE2 role in decreasing the number of proliferating cells. TGFβ did not contribute to ASCs anti-proliferative capabilities, while IL-10 seems to be involved in such activity of only SLE/ASCs.

Conclusion: The results indicate that SLE/ASCs and SSc/ASCs retain their capability to restrain the expansion of allogeneic CD4+ and CD8+ T cells and act by similar mechanisms as ASCs of healthy donors and thus may have therapeutic value.
Interactions of Environmental Chemicals and Natural Products With ABC and SLC Transporters in the Digestive System of Aquatic Organisms
Authors: Romersi Riccardo F. , Nicklisch Sascha C. T.
Published: January 2022

An organism’s diet is a major route of exposure to both beneficial nutrients and toxic environmental chemicals and natural products. The uptake of dietary xenobiotics in the intestine is prevented by transporters of the Solute Carrier (SLC) and ATP Binding Cassette (ABC) family. Several environmental chemicals and natural toxins have been identified to induce expression of these defense transporters in fish and aquatic invertebrates, indicating that they are substrates and can be eliminated. However, certain environmental chemicals, termed Transporter-Interfering Chemicals or TICs, have recently been shown to bind to and inhibit fish and mammalian P-glycoprotein (ABCB1), thereby sensitizing cells to toxic chemical accumulation. If and to what extent other xenobiotic defense or nutrient uptake transporters can also be inhibited by dietary TICs is still unknown. To date, most chemical-transporter interaction studies in aquatic organisms have focused on ABC-type transporters, while molecular interactions of xenobiotics with SLC-type transporters are poorly understood. In this perspective, we summarize current advances in the identification, localization, and functional analysis of protective MXR transporters and nutrient uptake systems in the digestive system of fish and aquatic invertebrates. We collate the existing literature data on chemically induced transporter gene expression and summarize the molecular interactions of xenobiotics with these transport systems. Our review emphasizes the need for standardized assays in a broader panel of commercially important fish and seafood species to better evaluate the effects of TIC and other xenobiotic interactions with physiological substrates and MXR transporters across the aquatic ecosystem and predict possible transfer to humans through consumption.
Assessing the Role of Uric Acid as a Predictor of Preeclampsia
Authors: Corominas Ana I. , Medina Yollyseth , Balconi Silvia , Casale Roberto , Farina Mariana , Martínez Nora , Damiano Alicia E.
Published: January 2022

We assessed the diagnostic utility of uric acid for the prediction of preeclampsia. An observational prospective approach was carried out during 2014. Preeclamptic women were classified into 4 groups accordingly to the onset of preeclampsia and the presence of intrauterine growth restriction (IUGR). Serum uric acid levels, urea, and creatinine were measured. Receiver operating curves (ROC) of the uric acid levels ratio (UAr) between a dosage before and after the 20th week of gestation were performed. One thousand two hundred and ninety-third pregnant women were enrolled in this study. Eight hundred ten had non-complicated pregnancies, 40 preeclampsia, 33 gestational hypertension, and 20 IUGR without preeclampsia. Uric acid significantly raised after 20 weeks of gestation in women who develop preeclampsia before 34 weeks (Group A) or in those who develop preeclampsia after 37 weeks associated with IUGR (Group C). In women who develop preeclampsia after 34 weeks without IUGR (Groups B and D), uric acid increased after the 30th week of gestation. In all groups, UAr was greater than 1.5. In gestational hypertension, UAr was superior to 1.5 toward the end of gestation, while in IUGR without preeclampsia, the behavior of serum uric acid was similar to non-complicated pregnancies. In all cases, urea and creatinine showed normal values, confirming that patients had no renal compromise. ROC area was 0.918 [95% confidence interval (CI): 0.858–0.979) for the preeclampsia group and 0.955 (95% CI: 0.908–1.000) for Group A. UAr at a cut-off point ≥1.5 had a very low positive predictive value, but a high negative predictive value of 99.5% for preeclampsia and it reached 100% for Group A. Thus, a UAr less than 1.5 may be a helpful parameter with a strong exclusion value and high sensitivity for those women who are not expected to develop preeclampsia. Additionally, this low-cost test would allow for better use of resources in developing countries.
IL-33 and Soluble ST2 Are Associated With Recurrent Spontaneous Abortion in Early Pregnancy
Authors: Zhao Long , Fu Jinhua , Ding Feng , Liu Juan , Li Lin , Song Qi , Fu Yinghui
Published: January 2022

Normal pregnancy is related to the successful transition from type 1 cellular immunity to type 2 cellular immunity. Therefore, this study aimed to investigate whether there is abnormal expression of cytokines in the process of inducing Recurrent spontaneous abortion (RSA). Interleukin (IL)-33 is a new member of the IL-1 family, and ST2, as IL-33’s receptor, induced the production of type 2 cytokines. In this study, blood samples were collected from 19 non-pregnant women of normal childbearing age, 28 normal pregnant women, and 33 women with RSA. The serum concentrations of IL-33 and ST2 were detected by flow cytometry. Our results showed that the serum concentrations of IL-33 and ST2 in the RSA group were significantly higher than those in the healthy control group (IL-33: P < 0.05; ST2: P < 0.0001), and IL-33 and ST2 had a higher level in the process of RSA predictive value. In addition, this study initially found that the serum concentrations of IL-33 and ST2 were not significantly correlated with the number of weeks of pregnancy, and there was a lower correlation between IL-33 and ST2 during RSA. This result may be related to the small number of cases. This study is the first time to correlate the changes in serum concentrations of IL-33 and ST2 with RSA, which may be a novel biomarker for the prediction and treatment of RSA.
The Central Role of Multiple P450 Genes and Their Co-factor CPR in the Development of Permethrin Resistance in the Mosquito Culex quinquefasciatus
Authors: Gong Youhui , Li Ting , Li Qi , Liu Shikai , Liu Nannan
Published: January 2022

Mosquitoes’ increasing resistance to insecticides is becoming a major threat for control efforts worldwide. Multiple P450 genes that are up-regulated in permethrin resistant strains of Culex quinquefasciatus have been linked to the development of resistance. In the current study, we characterized the function of six P450 genes, CYP6P14, CYP6BZ2, CYP9J33, CYP9J34, CYP9J40, and CYP9J45, that are overexpressed in the permethrin resistant Culex mosquitoes and showed their capability in metabolism of permethrin. These six P450 genes can convert 3-phenoxybenzoic alcohol (PBCHO) to a less toxic product, 3-phenoxybenzoic acid (PBCOOH), indicating that these P450s play an important role in permethrin degradation pathways. Although we know multiple P450 genes are over-expressed in permethrin resistant Culex mosquitoes, it remains to be seen whether cytochrome P450-reductase (CPR) gene that are co-overexpressed with P450 genes in permethrin resistant mosquitoes do indeed serve as a resistance mechanism. An in-depth investigation of the expression of CPR gene in resistant mosquitoes was conducted in permethrin resistant mosquitoes. The finding of CPR gene overexpression in permethrin resistant mosquitoes suggested the importance of co-overexpression of multiple P450 genes with their obligatory electron donor CPR in the complex detoxification system, boosting the metabolism of permethrin and hence the development of permethrin resistance in Cx. quinquefasciatus.
Endometriosis in the Mouse: Challenges and Progress Toward a ‘Best Fit’ Murine Model
Authors: Burns Katherine A. , Pearson Amelia M. , Slack Jessica L. , Por Elaine D. , Scribner Alicia N. , Eti Nazmin A. , Burney Richard O.
Published: January 2022

Endometriosis is a prevalent gynecologic condition associated with pelvic pain and infertility characterized by the implantation and growth of endometrial tissue displaced into the pelvis via retrograde menstruation. The mouse is a molecularly well-annotated and cost-efficient species for modeling human disease in the therapeutic discovery pipeline. However, as a non-menstrual species with a closed tubo-ovarian junction, the mouse poses inherent challenges as a preclinical model for endometriosis research. Over the past three decades, numerous murine models of endometriosis have been described with varying degrees of fidelity in recapitulating the essential pathophysiologic features of the human disease. We conducted a search of the peer-reviewed literature to identify publications describing preclinical research using a murine model of endometriosis. Each model was reviewed according to a panel of ideal model parameters founded on the current understanding of endometriosis pathophysiology. Evaluated parameters included method of transplantation, cycle phase and type of tissue transplanted, recipient immune/ovarian status, iterative schedule of transplantation, and option for longitudinal lesion assessment. Though challenges remain, more recent models have incorporated innovative technical approaches such as in vivo fluorescence imaging and novel hormonal preparations to overcome the unique challenges posed by murine anatomy and physiology. These models offer significant advantages in lesion development and readout toward a high-fidelity mouse model for translational research in endometriosis.