bluuebunny/crossref_metadata_2025 huggingface dataset:
Polyadenylated RNA and RNA-Binding Proteins Exhibit Unique Response to Hyperosmotic Stress
Authors: Zaepfel Benjamin L. , Rothstein Jeffrey D.
Published: December 2021

Stress granule formation is a complex and rapidly evolving process that significantly disrupts cellular metabolism in response to a variety of cellular stressors. Recently, it has become evident that different chemical stressors lead to the formation of compositionally distinct stress granules. However, it is unclear which proteins are required for the formation of stress granules under different conditions. In addition, the effect of various stressors on polyadenylated RNA metabolism remains enigmatic. Here, we demonstrate that G3BP1/2, which are common stress granule components, are not required for the formation of stress granules specifically during osmotic stress induced by sorbitol and related polyols. Furthermore, sorbitol-induced osmotic stress leads to significant depletion of nuclear polyadenylated RNA, a process that we demonstrate is dependent on active mRNA export, as well as cytoplasmic and subnuclear shifts in the presence of many nuclear RNA-binding proteins. We assessed the function of multiple shifted RBPs and found that hnRNP U, but not TDP-43 or hnRNP I, exhibit reduced function following this cytoplasmic shift. Finally, we observe that multiple stress pathways lead to a significant reduction in transcription, providing a possible explanation for our inability to observe loss of TDP-43 or hnRNP I function. Overall, we identify unique outcomes following osmotic stress that provide important insight into the regulation of RNA-binding protein localization and function.
A Link Between Methylglyoxal and Heart Failure During HIV-1 Infection
Authors: Dash Prasanta K. , Alomar Fadhel A. , Cox Jesse L. , McMillan JoEllyn , Hackfort Bryan T. , Makarov Edward , Morsey Brenda , Fox Howard S. , Gendelman Howard E. , Gorantla Santhi , Bidasee Keshore R.
Published: December 2021

Early-onset heart failure (HF) continues to be a major cause of morbidity and mortality in people living with human immunodeficiency virus type one (HIV-1) infection (PLWH), yet the molecular causes for this remain poorly understood. Herein NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ humanized mice (Hu-mice), plasma from PLWH, and autopsied cardiac tissues from deceased HIV seropositive individuals were used to assess if there is a link between the glycolysis byproduct methylglyoxal (MG) and HF in the setting of HIV-1 infection. At five weeks post HIV infection, Hu-mice developed grade III-IV diastolic dysfunction (DD) with an associated two-fold increase in plasma MG. At sixteen-seventeen weeks post infection, cardiac ejection fraction and fractional shortening also declined by 26 and 35%, and plasma MG increased to four-fold higher than uninfected controls. Histopathological and biochemical analyses of cardiac tissues from Hu-mice 17 weeks post-infection affirmed MG increase with a concomitant decrease in expression of the MG-degrading enzyme glyoxalase-1 (Glo1). The endothelial cell marker CD31 was found to be lower, and coronary microvascular leakage and myocardial fibrosis were prominent. Increasing expression of Glo1 in Hu-mice five weeks post-infection using a single dose of an engineered AAV2/9 (1.7 × 1012 virion particles/kg), attenuated the increases in plasma and cardiac MG levels. Increasing Glo1 also blunted microvascular leakage, fibrosis, and HF seen at sixteen weeks post-infection, without changes in plasma viral loads. In plasma from virally suppressed PLWH, MG was also 3.7-fold higher. In autopsied cardiac tissues from seropositive, HIV individuals with low viral log, MG was 4.2-fold higher and Glo1 was 50% lower compared to uninfected controls. These data show for the first time a causal link between accumulation of MG and HF in the setting of HIV infection.
Acetylcarnitine Is Associated With Cardiovascular Disease Risk in Type 2 Diabetes Mellitus
Authors: Zhao Shuo , Liu Ming-Li , Huang Bing , Zhao Fu-Rong , Li Ying , Cui Xue-Ting , Lin Rong
Published: December 2021

Objective

This study aimed to identify the association between specific short-chain acylcarnitines and cardiovascular disease (CVD) in type 2 diabetes mellitus (T2DM).

Method

We retrieved 1,032 consecutive patients with T2DM who meet the inclusion and exclusion criteria from the same tertiary care center and extracted clinical information from electronic medical records from May 2015 to August 2016. A total of 356 T2DM patients with CVD and 676 T2DM patients without CVD were recruited. Venous blood samples were collected by finger puncture after 8 h fasting and stored as dried blood spots. Restricted cubic spline (RCS) analysis nested in binary logistic regression was used to identify possible cutoff points and obtain the odds ratios (ORs) and 95% confidence intervals (CIs) of short-chain acylcarnitines for CVD risk in T2DM. The Ryan–Holm step-down Bonferroni procedure was performed to adjust p-values. Stepwise forward selection was performed to estimate the effects of acylcarnitines on CVD risk.

Result

The levels of C2, C4, and C6 were elevated and C5-OH was decreased in T2DM patients with CVD. Notably, only elevated C2 was still associated with increased CVD inT2DM after adjusting for potential confounders in the multivariable model (OR = 1.558, 95%CI = 1.124–2.159, p = 0.008). Furthermore, the association was independent of previous adjusted demographic and clinical factors after stepwise forward selection (OR = 1.562, 95%CI = 1.132–2.154, p = 0.007).

Conclusions

Elevated C2 was associated with increased CVD risk in T2DM.
Microbial Necromass in Soils—Linking Microbes to Soil Processes and Carbon Turnover
Authors: Kästner M. , Miltner A. , Thiele-Bruhn S. , Liang C.
Published: December 2021

The organic matter of living plants is the precursor material of the organic matter stored in terrestrial soil ecosystems. Although a great deal of knowledge exists on the carbon turnover processes of plant material, some of the processes of soil organic matter (SOM) formation, in particular from microbial necromass, are still not fully understood. Recent research showed that a larger part of the original plant matter is converted into microbial biomass, while the remaining part in the soil is modified by extracellular enzymes of microbes. At the end of its life, microbial biomass contributes to the microbial molecular imprint of SOM as necromass with specific properties. Next to appropriate environmental conditions, heterotrophic microorganisms require energy-containing substrates with C, H, O, N, S, P, and many other elements for growth, which are provided by the plant material and the nutrients contained in SOM. As easily degradable substrates are often scarce resources in soil, we can hypothesize that microbes optimize their carbon and energy use. Presumably, microorganisms are able to mobilize biomass building blocks (mono and oligomers of fatty acids, amino acids, amino sugars, nucleotides) with the appropriate stoichiometry from microbial necromass in SOM. This is in contrast to mobilizing only nutrients and consuming energy for new synthesis from primary metabolites of the tricarboxylic acid cycle after complete degradation of the substrates. Microbial necromass is thus an important resource in SOM, and microbial mining of building blocks could be a life strategy contributing to priming effects and providing the resources for new microbial growth cycles. Due to the energy needs of microorganisms, we can conclude that the formation of SOM through microbial biomass depends on energy flux. However, specific details and the variability of microbial growth, carbon use and decay cycles in the soil are not yet fully understood and linked to other fields of soil science. Here, we summarize the current knowledge on microbial energy gain, carbon use, growth, decay, and necromass formation for relevant soil processes, e. g. the microbial carbon pump, C storage, and stabilization. We highlight the factors controlling microbial necromass contribution to SOM and the implications for soil carbon use efficiency (CUE) and we identify research needs for process-based SOM turnover modelling and for understanding the variability of these processes in various soil types under different climates.
The Architecture of Cooperation Among Non-kin: Coalitions to Move Up in Nature’s Housing Market
Authors: Laidre Mark E.
Published: December 2021

The evolution of cooperation among non-kin poses a major theoretical puzzle: why should natural selection favor individuals who help unrelated conspecifics at a cost to themselves? The relevance of architecture to this question has rarely been considered. Here I report cooperation among non-kin in social hermit crabs (Coenobita compressus), where unrelated conspecifics work together to evict larger individuals from a housing market of architecturally remodeled shells. I present (1) the first detailed description of natural coalitions in the wild and (2) a theoretical framework, which examines the evolutionary benefits to each coalition member and predicts when forming a coalition will be successful. In the wild, important ecological and social constraints exist, which are built into the model. Based on these constraints, I show that coalitions can be a successful strategy if several key criteria hold: the coalition is necessary, effective, stable dyadically, and stable polyadically. Notably, the “splitting the spoils” problem—which often undermines non-kin cooperation—is eliminated via architecture: a small individual (C) who helps a medium individual (B) to evict a large individual (A) will ultimately benefit, since C will get B’s left behind shell after B moves into A’s shell. Coalitions, however, can break down due to added layers of social complexity involving third-party “free riders” and “cheaters,” which strategically butt in the architectural queue and thereby steal incentives from the smaller coalition member. Overall, therefore, substantial scope exists for both cooperation and conflict within nature’s housing market of architecture. Experiments are now needed to directly test the impact on coalitions of architecture, from the interior of homes up to whole housing markets.
Difficulties of Prenatal Genetic Counseling for a Subsequent Child in a Family With Multiple Genetic Variations
Authors: Huang Ting-Xuan , Ma Gwo-Chin , Chen Ming , Li Wen-Fang , Shaw Steven W.
Published: December 2021

Many parents with a disabled child caused by a genetic condition appreciate the option of prenatal genetic diagnosis to understand the chance of recurrence in a future pregnancy. Genome-wide tests, such as chromosomal microarray analysis and whole-exome sequencing, have been increasingly used for prenatal diagnosis, but prenatal counseling can be challenging due to the complexity of genomic data. This situation is further complicated by incidental findings of additional genetic variations in subsequent pregnancies. Here, we report the prenatal identification of a baby with a MECP2 missense variant and 15q11.2 microduplication in a family that has had a child with developmental and epileptic encephalopathy caused by a de novo KCNQ2 variant. An extended segregation analysis including extended relatives, in addition to the parents, was carried out to provide further information for genetic counseling. This case illustrates the challenges of prenatal counseling and highlights the need to understand the clinical and ethical implications of genome-wide tests.
Chromatin and Nuclear Dynamics in the Maintenance of Replication Fork Integrity
Authors: Wootton Jack , Soutoglou Evi
Published: December 2021

Replication of the eukaryotic genome is a highly regulated process and stringent control is required to maintain genome integrity. In this review, we will discuss the many aspects of the chromatin and nuclear environment that play key roles in the regulation of both unperturbed and stressed replication. Firstly, the higher order organisation of the genome into A and B compartments, topologically associated domains (TADs) and sub-nuclear compartments has major implications in the control of replication timing. In addition, the local chromatin environment defined by non-canonical histone variants, histone post-translational modifications (PTMs) and enrichment of factors such as heterochromatin protein 1 (HP1) plays multiple roles in normal S phase progression and during the repair of replicative damage. Lastly, we will cover how the spatial organisation of stalled replication forks facilitates the resolution of replication stress.
The Effect of Ketogenic Diet on Inflammatory Arthritis and Cardiovascular Health in Rheumatic Conditions: A Mini Review
Authors: Ciaffi Jacopo , Mitselman Dmitri , Mancarella Luana , Brusi Veronica , Lisi Lucia , Ruscitti Piero , Cipriani Paola , Meliconi Riccardo , Giacomelli Roberto , Borghi Claudio , Ursini Francesco
Published: December 2021

The principle of ketogenic diet (KD) is restriction of carbohydrates to a maximum of 5–10% of the total daily caloric intake, aiming at shifting body metabolism toward ketone bodies. Different studies suggested promising results of KD to help patients to lose weight, to reduce insulin requirements in diabetes, to supplement cancer protocols, to treat neurological conditions and to optimize control of metabolic and cardiovascular diseases. However, literature about the anti-inflammatory properties of KD in rheumatic diseases is still limited. The beneficial effects of weight loss in patients with inflammatory arthritis can be explained by biomechanical and biochemical factors. Obesity is associated with macrophage activation and production of pro-inflammatory cytokines including TNF-α, IL-1b, and IL-6. The clinical effect of KD may be primarily attributed to improvement of insulin sensitivity. Insulin resistance is associated with an increase of TNF-α, IL-1α, IL-1β, IL-6, and leptin. Moreover, reduction of body's adipose tissue and weight loss account for part of the anti-inflammatory effects and for the impact of KD on cardiovascular health. In rheumatoid arthritis, fasting was shown to be effective in reducing disease symptoms, possibly through the production of β-hydroxybutyrate (BHB), the main ketone body. BHB may exert inhibitory effects also on IL-17 and intermittent fasting improved the clinical manifestations of psoriatic arthritis. In ankylosing spondylitis, current literature doesn't allow to draw conclusion about the effects of KD. Future prospective studies will be needed to elucidate the potential beneficial effects of KD on specific domains and clinical outcomes in patients with inflammatory arthritis.
Effect of Stretching of Spastic Elbow Under Intelligent Control in Chronic Stroke Survivors—A Pilot Study
Authors: Rao Sanjana , Huang Meizhen , Chung Sun Gun , Zhang Li-Qun
Published: December 2021

Objective:To assess the short-term effects of strenuous dynamic stretching of the elbow joint using an intelligent stretching device in chronic spastic stroke survivors.

Methods:The intelligent stretching device was utilized to provide a single session of intensive stretching to the spastic elbow joint in the sagittal plane (i.e., elbow flexion and extension). The stretching was provided to the extreme range, safely, with control of the stretching velocity and torque to increase the joint range of motion (ROM) and reduce spasticity and joint stiffness. Eight chronic stroke survivors (age: 52.6 ± 8.2 years, post-stroke duration: 9.5 ± 3.6 years) completed a single 40-min stretching intervention session. Elbow passive and active ROM, strength, passive stiffness (quantifying the non-reflex component of spasticity), and instrumented tendon reflex test of the biceps tendon (quantifying the reflex component of the spasticity) were measured before and after stretching.

Results:After stretching, there was a significant increase in passive ROM of elbow flexion (p= 0.021,r= 0.59) and extension (p= 0.026,r= 0.59). Also, elbow active ROM and the spastic elbow flexors showed a trend of increase in their strength.

Conclusion:The intelligent stretching had a short-term positive influence on the passive movement ROM. Hence, intelligent stretching can potentially be used to repeatedly and regularly stretch spastic elbow joints, which subsequently helps to reduce upper limb impairments post-stroke.
Efficacy of Safinamide and Gender Differences During Routine Clinical Practice
Authors: Pellecchia Maria T. , Picillo Marina , Russillo Maria C. , De Pandis Maria F. , Bonizzoni Erminio , Marjanovic Ivan , Cattaneo Carlo
Published: December 2021

Background: There is increasing evidence of gender differences in the epidemiology and clinical manifestation of both motor and non-motor symptoms of Parkinson's disease (PD). Nevertheless, few data are available on gender differences in the response to antiparkinsonian drugs. Safinamide is a multimodal drug with positive effects on motor and non-motor fluctuations that might improve patients' care and quality of life.

Objective: To analyze gender differences on clinical effects of safinamide in PD patients treated in real-life conditions during the SYNAPSES trial.

Methods: SYNAPSES was a multinational, multicenter, observational study. At baseline, patients with PD diagnosis received safinamide as an add-on to levodopa and were followed up for 12 months, with visits performed every 4 months. A new statistical analysis was performed to describe the efficacy of safinamide in men and women on motor complications, motor symptoms, and adverse events.

Results: Six hundred and sixteen (38%) out of 1,610 patients enrolled in the SYNAPSES study were women and 994 (62%) men. Safinamide improved motor symptoms and motor complications (fluctuations and dyskinesia) in both genders, with a good safety profile and without requiring any change in the concomitant dopaminergic therapy. Clinically significant improvements, according to the criteria developed by Shulman et al., were seen in 46% of male and female patients for the UPDRS motor score and 43.5% of men vs. 39.1% of women for the UPDRS total score.

Conclusions: Safinamide was effective in improving motor fluctuations and dyskinesia and proved to be safe in both male and female patients with PD. Further prospective studies, specifically addressing potential gender differences in response to PD therapies, are needed to develop tailored management strategies.
Fas Apoptosis Inhibitory Molecule Blocks and Dissolves Pathological Amyloid-β Species
Authors: Kaku Hiroaki , Ludlow Alexander V. , Gutknecht Michael F. , Rothstein Thomas L.
Published: December 2021

A number of neurodegenerative diseases are associated with the accumulation of misfolded proteins, including Alzheimer’s disease (AD). In AD, misfolded proteins such as tau and amyloid-β (Aβ) form pathological insoluble deposits. It is hypothesized that molecules capable of dissolving such protein aggregates might reverse disease progression and improve the lives of afflicted AD patients. Here we report new functions of the highly conserved mammalian protein, Fas Apoptosis Inhibitory Molecule (FAIM). We found that FAIM-deficient Neuro 2A cells accumulate Aβ oligomers/fibrils. We further found that recombinant human FAIM prevents the generation of pathologic Aβ oligomers and fibrils in a cell-free system, suggesting that FAIM functions without any additional cellular components. More importantly, recombinant human FAIM disaggregates and solubilizes established Aβ fibrils. Our results identify a previously unknown, completely novel candidate for understanding and treating irremediable, irreversible, and unrelenting neurodegenerative diseases.
Neuroinflammation in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia and the Interest of Induced Pluripotent Stem Cells to Study Immune Cells Interactions With Neurons
Authors: Liu Elise , Karpf Léa , Bohl Delphine
Published: December 2021

Inflammation is a shared hallmark between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). For long, studies were conducted on tissues of post-mortem patients and neuroinflammation was thought to be only bystander result of the disease with the immune system reacting to dying neurons. In the last two decades, thanks to improving technologies, the identification of causal genes and the development of new tools and models, the involvement of inflammation has emerged as a potential driver of the diseases and evolved as a new area of intense research. In this review, we present the current knowledge about neuroinflammation in ALS, ALS-FTD, and FTD patients and animal models and we discuss reasons of failures linked to therapeutic trials with immunomodulator drugs. Then we present the induced pluripotent stem cell (iPSC) technology and its interest as a new tool to have a better immunopathological comprehension of both diseases in a human context. The iPSC technology giving the unique opportunity to study cells across differentiation and maturation times, brings the hope to shed light on the different mechanisms linking neurodegeneration and activation of the immune system. Protocols available to differentiate iPSC into different immune cell types are presented. Finally, we discuss the interest in studying monocultures of iPS-derived immune cells, co-cultures with neurons and 3D cultures with different cell types, as more integrated cellular approaches. The hope is that the future work with human iPS-derived cells helps not only to identify disease-specific defects in the different cell types but also to decipher the synergistic effects between neurons and immune cells. These new cellular tools could help to find new therapeutic approaches for all patients with ALS, ALS-FTD, and FTD.
Sensitivity of Physiological Measures of Acute Driver Stress: A Meta-Analytic Review
Authors: Kerautret Laora , Dabic Stephanie , Navarro Jordan
Published: December 2021

Background: The link between driving performance impairment and driver stress is well-established. Identifying and understanding driver stress is therefore of major interest in terms of safety. Although many studies have examined various physiological measures to identify driver stress, none of these has as yet been definitively confirmed as offering definitive all-round validity in practice.

Aims: Based on the data available in the literature, our main goal was to provide a quantitative assessment of the sensitivity of the physiological measures used to identify driver stress. The secondary goal was to assess the influence of individual factors (i.e., characteristics of the driver) and ambient factors (i.e., characteristics of the context) on driver stress. Age and gender were investigated as individual factors. Ambient factors were considered through the experimental apparatus (real-road vs. driving simulator), automation driving (manual driving vs. fully autonomous driving) and stressor exposure duration (short vs. long-term).

Method: Nine meta-analyses were conducted to quantify the changes in each physiological measure during high-stress vs. low-stress driving. Meta-regressions and subgroup analyses were performed to assess the moderating effect of individual and ambient factors on driver stress.

Results: Changes in stress responses suggest that several measures are sensitive to levels of driver stress, including heart rate, R-R intervals (RRI) and pupil diameter. No influence of individual and ambient factors was observed for heart rate.

Applications and Perspective: These results provide an initial guide to researchers and practitioners when selecting physiological measures for quantifying driver stress. Based on the results, it is recommended that future research and practice use (i) multiple physiological measures, (ii) a triangulation-based methodology (combination of measurement modalities), and (iii) a multifactorial approach (analysis of the interaction of stressors and moderators).
Message Sidedness in Health Claims: Roles of Mood State, Product Involvement, and Self-Rated Health Status
Authors: Lin Hung-Chou , Wang Shih-Tse
Published: December 2021

Most of the previous studies with respect to message sidedness mainly focus on the effect of message sidedness in advertising on behavior of consumers and it is unknown how consumers respond to different message sidedness when a one-sided or two-sided message in claims shown on the package of a healthy food product. This study explores the underlying mechanisms how consumers respond to different message sidedness in claims. The results indicate that two-sided messages in claims are more persuasive than one-sided messages because they pass the “sufficiency threshold.” In addition, the results of this article show that mood state, product involvement, and self-rated health of individuals moderate the relationship between message sidedness in claims and product evaluation.
Association Between Pre-diagnostic Dietary Supplements Intake and Ovarian Cancer Survival: Findings From a Prospective Cohort Study in Chinese Women
Authors: Gu Jia-Hui , Gong Ting-Ting , Wu Qi-Jun , Liu Fang-Hua , Wen Zhao-Yan , Gao Chang , Wei Yi-Fan , Yang Zhuo
Published: December 2021

Background: As a result of a limited number of studies and inconsistent findings, there remains uncertainty in whether pre-diagnostic dietary supplements intake affects survival after ovarian cancer (OC) diagnosis.

Methods: The association between pre-diagnostic dietary supplements intake and all-cause OC mortality was examined in the OC follow-up study, which included a hospital-based cohort (n = 703) of Chinese women diagnosed with OC between 2015 and 2020. Pre-diagnostic dietary supplements information was collected using self-administered questionnaires. Deaths were ascertained up to March 31, 2021, via death registry linkage. Cox proportional hazards were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the aforementioned association.

Results: A total of 130 women died during the median follow-up of 37.2 months (interquartile: 24.7–50.2 months). We found no evidence that any pre-diagnostic dietary supplements intake compared with never is associated with OC survival (HR = 0.75, 95%CI: 0.47–1.18). Furthermore, our study suggested no association for ever supplements intakes of vitamin A (HR = 0.48, 95%CI: 0.07–3.46), vitamin C (HR = 0.64, 95%CI: 0.27–1.54), vitamin D (HR = 1.19, 95%CI: 0.28–5.03), vitamin E (HR = 0.47, 95%CI: 0.06–3.87), multivitamin (HR = 0.49, 95%CI: 0.14–1.67), calcium (HR = 0.96, 95%CI: 0.53–1.72), and fish oil/DHA (HR = 0.31, 95%CI: 0.04–2.37) with OC survival. Interestingly, we only found a detrimental effect of vitamin B supplementation intake (HR = 3.78, 95%CI: 1.33–0.69) on OC survival.

Conclusions: We found no evidence that any pre-diagnostic dietary supplements intake is associated with OC survival. Considering lower exposure of dietary supplements before OC diagnosis in the present study, further studies are warranted to confirm these findings.
Sea Cucumber Intestinal Peptide Induces the Apoptosis of MCF-7 Cells by Inhibiting PI3K/AKT Pathway
Authors: Wei Wei , Fan Xiao-Man , Jia Shao-Hui , Zhang Xi-Ping , Zhang Zhao , Zhang Xue-Jun , Zhang Jiu-Xun , Zhang Ye-Wang
Published: December 2021

Sea cucumbers are one of many marine echinoderm animals that contain valuable nutrients and medicinal compounds. The bioactive substances in sea cucumbers make them have promising biological and pharmacological properties, including antioxidant, anti-bacterial, and anti-tumor effects. In this study, sea cucumber intestinal peptide (SCIP) is a small molecular oligopeptide (<1,000 Da) extracted from sea cucumber intestines hydrolyzed by alkaline protease. The analysis of amino acid composition showed that hydrophobic amino acids and branched-chain amino acids were rich in SCIP. Nowadays, although increasing studies have revealed the biological functions of the sea cucumber active substances, there are few studies on the function of SCIP. Furthermore, due to the anti-cancer activity being an essential characteristic of sea cucumber active substances, we also investigated the anti-cancer potential and the underlying mechanism of SCIP in vivo and in vitro. The results indicate that SCIP inhibits the growth of MCF-7 tumor cells in zebrafish and increases the apoptosis of human breast cancer MCF-7 cells. Further mechanism studies confirm that SCIP promotes the expression of apoptosis-related proteins and thus promotes the breast cancer cells (MCF-7) apoptosis via inhibition of PI3K/AKT signal transduction pathway.
The Pyruvate Dehydrogenase Complex in Sepsis: Metabolic Regulation and Targeted Therapy
Authors: Zeng Zhenhua , Huang Qiaobing , Mao Liangfeng , Wu Jie , An Sheng , Chen Zhongqing , Zhang Weijin
Published: December 2021

Anaerobic glycolysis is the process by which glucose is broken down into pyruvate and lactate and is the primary metabolic pathway in sepsis. The pyruvate dehydrogenase complex (PDHC) is a multienzyme complex that serves as a critical hub in energy metabolism. Under aerobic conditions, pyruvate translocates to mitochondria, where it is oxidized into acetyl-CoA through the activation of PDHC, thereby accelerating aerobic oxidation. Both phosphorylation and acetylation affect PDHC activity and, consequently, the regulation of energy metabolism. The mechanisms underlying the protective effects of PDHC in sepsis involve the regulation on the balance of lactate, the release of inflammatory mediators, the remodeling of tricarboxylic acid (TCA) cycle, as well as on the improvement of lipid and energy metabolism. Therapeutic drugs that target PDHC activation for sepsis treatment include dichloroacetate, thiamine, amrinone, TNF-binding protein, and ciprofloxacin. In this review, we summarize the recent findings regarding the metabolic regulation of PDHC in sepsis and the therapies targeting PDHC for the treatment of this condition.
Revealing the Hypoglycemic Effects and Mechanism of GABA-Rich Germinated Adzuki Beans on T2DM Mice by Untargeted Serum Metabolomics
Authors: Jiang Xiujie , Xu Qingpeng , Zhang Aiwu , Liu Yong , Li Zhijiang , Tang Huacheng , Cao Dongmei , Zhang Dongjie
Published: December 2021

Type 2 diabetes mellitus (T2DM) is one of the most common metabolic diseases, and exploring strategies to prevent and treat diabetes has become extremely important. In recent decades the search for new therapeutic strategies for T2DM involving dietary interventions has attracted public attention. We established a diabetic mouse model by feeding mice a high-fat diet combined with injection of low-dose streptozotocin, intending to elucidate the effects and possible mechanisms of different dosages of γ-aminobutyric acid (GABA)-rich germinated adzuki beans on the treatment of diabetes in mice. The mice were treated for 6 weeks either with increasing doses of GABA-enriched germinated adzuki beans, with non-germinated adzuki beans, with GABA, or with the positive control drug metformin. Then, the blood glucose levels and blood lipid biochemical indicators of all the mice were measured. At the same time, serum differential metabolite interactions were explored by UPLC-Q/TOF-MS-based serum metabolomic analysis. The results showed that body weight and fasting blood glucose levels were significantly reduced (P < 0.05). We also report improved levels of total cholesterol, triglycerides, aspartate aminotransferase, alanine aminotransferase, urea, and serum creatinine. We observed a significant improvement in the homeostasis model assessment of the beta cell function and insulin resistance (HOMA-β and HOMA-IR) scores (P < 0.05) in the group of mice treated with the highest dose of GABA-enriched germinated adzuki beans. In addition, the metabolic profiles of the serum were analyzed, and 31 differential metabolites including amino acids and lipids were obtained. According to the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, this was found to be correlated with nine significantly enriched metabolic pathways involving the up-regulation of levels of L-serine, SM (d18:1/22:1(13Z)), L-histidine, creatine, and 3-indoleacetic acid. Our data suggest that the hypoglycemic effect of GABA-enriched germinated adzuki beans on diabetic mice may be related to improving tryptophan metabolism, glycerol phospholipid metabolism, sphingosline metabolism, and the glycine, serine, and threonine metabolic pathways. This study provides a reference for the application of GABA-enriched germinated foods in type 2 diabetes and could provide a cue for searching biomarkers to be adopted for T2DM diagnosis.
Gemcitabine Maintenance Therapy in Patients With Metastasized Soft Tissue Sarcomas
Authors: Harrer Dennis Christoph , Buschauer Sebastian , Sterz Ulrich , Menhart Karin , Wendl Christina , Heudobler Daniel , Grube Matthias , Pukrop Tobias , Herr Wolfgang , Vogelhuber Martin
Published: December 2021

Background

Metastasized soft-tissue sarcomas still pose a significant therapeutic challenge given the limited efficacy of currently available multimodal treatment strategies. Recent progress in molecular characterization of sarcoma subtypes has enabled successful personalized therapy approaches in a minority of selected patients with targetable mutations. However, in the majority of patients with refractory soft tissue sarcomas, long-term survival remains poor.

Methods

We report on three adult patients with various soft tissue sarcomas subjected to Gemcitabine maintenance therapy. Tumor entities included leiomyosarcoma of the pancreas (patient 1), undifferentiated pleomorphic sarcoma of the right femur (patient 2), and peri-aortic leiomyosarcoma (patient 3). Metastatic sites encompassed liver, lung, and bones. All patients received Gemcitabine maintenance therapy until disease progression following prior salvage chemotherapy with Docetaxel and Gemcitabine. Patients were treated outside of clinical trials. Response assessment was based on radiological imaging.

Results

In response to salvage chemotherapy with Docetaxel and Gemcitabine, one patient exhibited a partial remission, and two patients showed stable disease. Patient 1 exhibited stable disease for 6 months during Gemcitabine maintenance therapy before suffering rapid progression of hepatic metastases. Patient 2 underwent 21 months of Gemcitabine maintenance therapy, which was discontinued after progressive pulmonary metastases were detected. Patient 3 is still being treated with Gemcitabine maintenance therapy. Remarkably, owing to significant chemotherapy-associated hematotoxicity, the dose of Gemcitabine dose was reduced by two-thirds. Nevertheless, stable disease with constant pulmonary metastases has been maintained in this patient for 14 months.

Conclusions

Gemcitabine maintenance therapy following prior Docetaxel and Gemcitabine chemotherapy is manageable and reveals potential benefits for patients with aggressive metastasized soft tissue sarcomas. Prospective trials evaluating Gemcitabine maintenance therapy are encouraged.
LncRNA FOXP4-AS1 Promotes the Progression of Esophageal Squamous Cell Carcinoma by Interacting With MLL2/H3K4me3 to Upregulate FOXP4
Authors: Niu Yunfeng , Wang Gaoyan , Li Yan , Guo Wei , Guo Yanli , Dong Zhiming
Published: December 2021

Malignant tumors are a grave threat to human health. Esophageal squamous cell carcinoma (ESCC) is a common gastrointestinal malignant tumor. China has a high incidence of ESCC, and its morbidity and mortality are higher than the global average. Increasingly, studies have shown that long noncoding RNAs (lncRNAs) play a vital function in the occurrence and development of tumors. Although the biological function of FOXP4-AS1 has been demonstrated in various tumors, the potential molecular mechanism of FOXP4-AS1 in ESCC is still poorly understood. The expression of FOXP4 and FOXP4-AS1 was detected in ESCC by quantitative real-time PCR (qRT–PCR) or SP immunohistochemistry (IHC). shRNA was used to silence gene expression. Apoptosis, cell cycle, MTS, colony formation, invasion and migration assays were employed to explore the biological functions of FOXP4 and FOXP4-AS1. The potential molecular mechanism of FOXP4-AS1 in ESCC was determined by dual-luciferase reporter, RNA immunoprecipitation (RIP) and chromatin immunoprecipitation (ChIP). Here, we demonstrated that FOXP4-AS1 was significantly increased in ESCC tissues and cell lines, associated with lymph node metastasis and TNM staging. Cell function experiments showed that FOXP4-AS1 promoted the proliferation, invasion and migration ability of ESCC cells. The expression of FOXP4-AS1 and FOXP4 in ESCC tissues was positively correlated. Further research found that FOXP4-AS1, upregulated in ESCC, promotes FOXP4 expression by enriching MLL2 and H3K4me3 in the FOXP4 promoter through a “molecular scaffold”. Moreover, FOXP4, a transcription factor of β-catenin, promotes the transcription of β-catenin and ultimately leads to the malignant progression of ESCC. Finally, FOXP4-AS1 may be a new therapeutic target for ESCC.
Impact of Androgen Suppression Therapy on the Risk and Prognosis of Bladder Cancer: A Systematic Review and Meta-Analysis
Authors: Xiang Peng , Du Zhen , Hao Yongxiu , Guan Di , Liu Dan , Yan Wei , Wang Mingdong , Liu Yutong , Ping Hao
Published: December 2021

Purpose

The purpose of this study was to summarize the existing evidence and develop a comprehensive systematic review of the impact of androgen suppression therapy (AST) on the incidence or clinical outcomes of bladder cancer.

Methods

We systematically searched the PubMed and Embase databases from inception to June 20, 2021 to identify all observational studies examining the incidence or clinical outcomes of bladder cancer in patients who received AST. AST is defined as the use of 5-alpha reductase inhibitors (5-ARIs) or androgen deprivation therapy (ADT).

Results

A total of 18 observational studies were included. Our results showed that AST was not significantly associated with a reduced risk of BCa incidence (OR: 0.92, 95% CI: 0.68–1.24) compared with the lack of AST. The subgroup analysis revealed that finasteride use was significantly associated with a reduction in the risk of BCa incidence (OR: 0.75, 95% CI: 0.64–0.88). Recurrence-free survival (RFS) was improved among AST users compared with nonusers (HR: 0.68, 95% CI: 0.48–0.95), while no significant difference between AST users versus nonusers was identified for cancer-specific survival (CSS), overall survival (OS) or progression-free survival (PFS).

Conclusion

Current evidence indicates that therapy with finasteride may represent a potential strategy aimed at reducing BCa incidence. Moreover, AST has a beneficial effect on the recurrence of bladder cancer. Further well-designed randomized trials or cohort studies with better characterized study populations are needed to validate our preliminary findings.

Systematic Review Registration

International Prospective Register of Systematic Reviews database [https://www.crd.york.ac.uk/PROSPERO/], identifier CRD42021261685.
Clinical Presentations, Diagnosis, and Management for Pediatric Antral Web—A 20-Year Experience of a Referral Center
Authors: Yeh Pai-Jui , Chao Hsun-Chin , Chen Chien-Chang , Lai Jin-Yao , Lai Ming-Wei
Published: December 2021

Background: Antral web is a rare cause of gastric outlet obstruction in children. The presentation is diverse, depending on the degree of obstruction. Unfortunately, the guidance of management is still lacking.

Methods: This study retrospectively evaluated the presentations, management, and outcomes of the pediatric antral web based on a 20-year experience in a referral center.

Results: A total of 23 cases were included. The median age of diagnosis was 10 months (interquartile range, IQR, 0.8–23 months). Main presentations comprised vomiting (83%) and upper gastrointestinal (UGI) bleeding (48%). Concurrent gastric ulcers were common (68%). A total of 13 cases (57%) underwent interventional treatment. The median duration from diagnosis to intervention (DtI) was 10 days, but five with longer DtI, ranged from 30 to 755 days. Among the 15 cases with concurrent gastric ulcers, 10 patients received intervention, immediately in six but delayed in four. Surgical treatments (N = 12) achieved a cure in 11, with one rescued by endoscopic treatment.

Conclusions: Children who suffer from early gastric ulcers with outlet obstruction shall raise the suspicion of the antral web. Complete obstruction madates early intervention. Around half of the cases with adequate feeding and growth need no intervention. Recurrent obstructive symptoms or adjacent ulcers justify a switch from observation to intervention to avoid complications or growth faltering.
Case Report: Macrophage Activation Syndrome and Widespread Neuroimaging Abnormality in Childhood-Onset Systemic Lupus Erythematosus
Authors: Shi Nana , Wang Xiangying , Zou Lixia , Yang Xinghui , Ma Qian , Lu Meiping
Published: December 2021

Macrophage activation syndrome (MAS) and widespread brain lesions are rare and severe complications of childhood-onset systemic lupus erythematosus (SLE). We report an 11-year-old girl who presented with recurrent rashes for half a year and fever for 2 weeks. Clinical and laboratory features at admission pointed to the diagnosis of SLE and SLE-associated MAS. Cerebral magnetic resonance imaging taken on day 4 after admission showed abnormal signals. Glucocorticoid therapy was started on day 5. Two days later, the patient appeared weak and ill, then the next day she exhibited dizziness, drowsiness, apathia, and dysarthria. High-dose methylprednisolone, cyclophosphamide, and intravenous immunoglobulin were used to treat the patient, and intrathecal dexamethasone was given. The patient was discharged on day 30 after admission and showed complete clinical resolution and improved magnetic resonance imaging resolution.
The Attenuating Effect of Low-Intensity Pulsed Ultrasound on Hypoxia-Induced Rat Chondrocyte Damage in TMJ Osteoarthritis Based on TMT Labeling Quantitative Proteomic Analysis
Authors: Du Sa , Liang Chao , Sun Yujie , Ma Bowen , Gao Wenmo , Geng Wei
Published: December 2021

Temporomandibular joint osteoarthritis (TMJOA) is a degenerative disease with a complex and multifactorial etiology. An increased intrajoint pressure or weakened penetration can exacerbate the hypoxic state of the condylar cartilage microenvironment. Our group previously simulated the hypoxic environment of TMJOA in vitro. Low-intensity pulsed ultrasound (LIPUS) stimulation attenuates chondrocyte matrix degradation via a hypoxia-inducible factor (HIF) pathway-associated mechanism, but the mode of action of LIPUS is currently poorly understood. Moreover, most recent studies investigated the pathological mechanisms of osteoarthritis, but no biomarkers have been established for assessing the therapeutic effect of LIPUS on TMJOA with high specificity, which results in a lack of guidance regarding clinical application. Here, tandem mass tag (TMT)-based quantitative proteomic technology was used to comprehensively screen the molecular targets and pathways affected by the action of LIPUS on chondrocytes under hypoxic conditions. A bioinformatic analysis identified 902 and 131 differentially expressed proteins (DEPs) in the <1% oxygen treatment group compared with the control group and in the <1% oxygen + LIPUS stimulation group compared with the <1% oxygen treatment group, respectively. The DEPs were analyzed by gene ontology (GO), KEGG pathway and protein-protein interaction (PPI) network analyses. By acting on extracellular matrix (ECM)-associated proteins, LIPUS increases energy production and activates the FAK signaling pathway to regulate cell biological behaviors. DEPs of interest were selected to verify the reliability of the proteomic results. In addition, this experiment demonstrated that LIPUS could upregulate chondrogenic factors (such as Sox9, Collagen Ⅱ and Aggrecan) and increase the mucin sulfate content. Moreover, LIPUS reduced the hydrolytic degradation of the ECM by decreasing the MMP3/TIMP1 ratio and vascularization by downregulating VEGF. Interestingly, LIPUS improved the migration ability of chondrocytes. In summary, LIPUS can regulate complex biological processes in chondrocytes under hypoxic conditions and alter the expression of many functional proteins, which results in reductions in hypoxia-induced chondrocyte damage. ECM proteins such as thrombospondin4, thrombospondin1, IL1RL1, and tissue inhibitors of metalloproteinase 1 play a central role and can be used as specific biomarkers determining the efficacy of LIPUS and viable clinical therapeutic targets of TMJOA.
Spleen Perfusion as an Index of Gender Impact on Sympathetic Nervous System Response to Exercise
Authors: Lanfranchi Francesco , D'Amico Francesca , Raffa Stefano , Pennone Michele , Donegani Maria Isabella , Miceli Alberto , Chiola Silvia , Maggio Sara , Delucchi Carlo , Cossu Vanessa , Morbelli Silvia , Bauckneht Matteo , Sambuceti Gianmario , Marini Cecilia
Published: December 2021

Objective: Sympathetic nervous system (SNS) reaction to exercise is gender dependent. Nevertheless, clinically applicable methods to identify this difference are still missing. An organ largely sensitive to SNS is the spleen whose response to exercise can be easily evaluated, being included in the field of view of myocardial perfusion imaging (MPI). Here, we aimed to verify whether gender interferes with the spleen perfusion and its response to exercise.

Methods: For this purpose, we evaluated 286 original scans of consecutive patients submitted to MPI in the course of 2019. Our standard procedure implies a single-day stress-rest sequence with a gap of ≥2 h between the administrations of 180 and 500 MBq of 99mTc-Sestamibi, respectively. Imaging is performed 30 min after radiotracer administration, with scan duration set at 25 and 35 s per view, respectively. Non-gated scans were reconstructed with the filtered back-projection method. A volume of interest was drawn on the spleen and heart to estimate the dose-normalized average counting rate that was expressed in normalized counts per seconds (NCPS).

Results: In all subjects submitted to exercise MPI (n = 228), NCPS were higher during stress than at rest (3.52 ± 2.03 vs. 2.78 ± 2.07, respectively; p < 0.01). This effect was not detected in the 58 patients submitted to dipyridamole-stress. The response to exercise selectively involved the spleen, since NCPS in heart were unchanged irrespective of the used stressor. This same response was dependent upon gender, indeed spleen NCPS during stress were significantly higher in the 75 women than in the 153 men (3.86 ± 1.8 vs. 3.23 ± 1.6, respectively, p < 0.01). Again, this variance was not reproduced by heart. Finally, spleen NCPS were lower in the 173 patients with myocardial reversible perfusion defects (summed difference score ≥3) than in the remaining 55, despite similar values of rate pressure product at tracer injection.

Conclusion: Thus, exercise interference on spleen perfusion can be detected during MPI. This effect is dependent upon gender and ischemia confirming the high sensitivity of this organ to SNS activation.