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2021 ◽  
Vol 11 ◽  
Author(s):  
Francesca Bibbò ◽  
Carmen Sorice ◽  
Veronica Ferrucci ◽  
Massimo Zollo

We analyze the fundamental functions of Prune_1 in brain pathophysiology. We discuss the importance and maintenance of the function of Prune_1 and how its perturbation influences both brain pathological conditions, neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA; OMIM: 617481), and tumorigenesis of medulloblastoma (MB) with functional correlations to other tumors. A therapeutic view underlying recent discoveries identified small molecules and cell penetrating peptides to impair the interaction of Prune_1 with protein partners (e.g., Nm23-H1), thus further impairing intracellular and extracellular signaling (i.e., canonical Wnt and TGF-β pathways). Identifying the mechanism of action of Prune_1 as responsible for neurodevelopmental disorders (NDDs), we have recognized other genes which are found overexpressed in brain tumors (e.g., MB) with functional implications in neurodevelopmental processes, as mainly linked to changes in mitotic cell cycle processes. Thus, with Prune_1 being a significant target in NDDs, we discuss how its network of action can be dysregulated during brain development, thus generating cancer and metastatic dissemination.


2021 ◽  
pp. 204589402110568
Author(s):  
Vijaya Karoor ◽  
Delaney Swindle ◽  
David Pak ◽  
Derek Strassheim ◽  
Mehdi A Fini ◽  
...  

Macrophages are a heterogeneous population with both pro, and anti-inflammatory functions play an essential role in maintaining tissue homeostasis, promoting inflammation under pathological conditions, and tissue repair after injury. In pulmonary hypertension (PH), the M1 phenotype is more pro-inflammatory compared to the M2 phenotype, which is involved in tissue repair. The role of macrophages in the initiation and progression of PH is well studied. However, their role in the regression of established PH is not well known. Rats chronically exposed to hemoglobin (Hb) plus hypoxia (HX) share similarities to humans with PH associated with hemolytic disease, including the presence of a unique macrophage phenotype surrounding distal vessels that are associated with vascular remodeling. These lung macrophages are characterized by high iron content, HO-1, ET-1, and IL-6 and are recruited from the circulation. Depletion of macrophages in this model prevents the development of PH and vascular remodeling. In this study, we specifically investigate the regression of PH over a four-week duration after rats were removed from Hb+HX exposure with and without gadolinium chloride administration. Withdrawal of Hb+HX reversed systolic pressures and right ventricular function after Hb+Hx exposure in 4 weeks. Our data show that depleting circulating monocytes/macrophages during reversal prevents complete recovery of right ventricular systolic pressure and vascular remodeling in this rat model of PH at 4 weeks post exposure. The data presented offer a novel insight into the role of macrophages in the processes of PH regression in a rodent model of Hb+Hx-driven disease


2021 ◽  
Author(s):  
Wei Sun ◽  
Tao Nie ◽  
Kuai Li ◽  
Wenjie Wu ◽  
Qiaoyun Long ◽  
...  

<b>Background & Aims</b> <p>Hepatosteatosis, defined as excessive intrahepatic lipid accumulation, represents the first step of NAFLD. When combined with additional cellular stress, this benign status progresses to local and systemic pathological conditions such as NASH and insulin resistance. However, the molecular events directly caused by hepatic lipid build-up, in terms of its impact on liver biology and other peripheral organs, remain unclear. Carnitine palmitoyltransferase 1A (CPT1A) is the rate limiting enzyme for long chain fatty acid beta-oxidation in the liver. Here we utilise hepatocyte-specific <i>Cpt1a</i> knockout (LKO) mice to investigate the physiological consequences of abolishing hepatic long chain fatty acid metabolism.</p> <p><b>Approach & Results </b></p> <p>Compared to the wild-type (WT) littermates, high fat diet (HFD)-fed LKO mice displayed more severe hepatosteatosis but were otherwise protected against diet-induced weight gain, insulin resistance, hepatic ER stress, inflammation and damage. Interestingly, increased energy expenditure was observed in LKO mice, accompanied by enhanced adipose tissue browning. RNAseq analysis revealed that the peroxisome proliferator activator alpha (PPARα)- fibroblast growth factor 21 (FGF21) axis was activated in liver of LKO mice. Importantly, antibody-mediated neutralization of FGF21 abolished the healthier metabolic phenotype and adipose browning in LKO mice, indicating that the elevation of FGF21 contributes to the improved liver pathology and adipose browning in HFD-treated LKO mice. </p> <p><b>Conclusions</b></p> Liver with deficient CPT1A expression adopts a healthy steatotic status that protects against HFD-evoked liver damage and potentiates adipose browning in an FGF21-dependent manner. Inhibition of hepatic CPT1A may serve as a viable strategy for the treatment of obesity and NAFLD.


2021 ◽  
Author(s):  
Wei Sun ◽  
Tao Nie ◽  
Kuai Li ◽  
Wenjie Wu ◽  
Qiaoyun Long ◽  
...  

<b>Background & Aims</b> <p>Hepatosteatosis, defined as excessive intrahepatic lipid accumulation, represents the first step of NAFLD. When combined with additional cellular stress, this benign status progresses to local and systemic pathological conditions such as NASH and insulin resistance. However, the molecular events directly caused by hepatic lipid build-up, in terms of its impact on liver biology and other peripheral organs, remain unclear. Carnitine palmitoyltransferase 1A (CPT1A) is the rate limiting enzyme for long chain fatty acid beta-oxidation in the liver. Here we utilise hepatocyte-specific <i>Cpt1a</i> knockout (LKO) mice to investigate the physiological consequences of abolishing hepatic long chain fatty acid metabolism.</p> <p><b>Approach & Results </b></p> <p>Compared to the wild-type (WT) littermates, high fat diet (HFD)-fed LKO mice displayed more severe hepatosteatosis but were otherwise protected against diet-induced weight gain, insulin resistance, hepatic ER stress, inflammation and damage. Interestingly, increased energy expenditure was observed in LKO mice, accompanied by enhanced adipose tissue browning. RNAseq analysis revealed that the peroxisome proliferator activator alpha (PPARα)- fibroblast growth factor 21 (FGF21) axis was activated in liver of LKO mice. Importantly, antibody-mediated neutralization of FGF21 abolished the healthier metabolic phenotype and adipose browning in LKO mice, indicating that the elevation of FGF21 contributes to the improved liver pathology and adipose browning in HFD-treated LKO mice. </p> <p><b>Conclusions</b></p> Liver with deficient CPT1A expression adopts a healthy steatotic status that protects against HFD-evoked liver damage and potentiates adipose browning in an FGF21-dependent manner. Inhibition of hepatic CPT1A may serve as a viable strategy for the treatment of obesity and NAFLD.


2021 ◽  
Vol 27 (4) ◽  
pp. 390-401
Author(s):  
A. M. Chaulin ◽  
D. V. Duplyakov

The understanding of the diagnostic and prognostic value of many biomarkers of cardiovascular diseases (CVD), including cardiac troponins (cTnT and cTnI), is changing significantly with the development of methods for their determination. New highly sensitive immunoassays can detect minimal concentrations of cardiac troponin protein molecules in biological fluids (several ng/L or less), allowing the detection of cTnT and cTnI in all healthy individuals. Along with this, there are opportunities to use cTnT and cTnI both to assess the risk of developing CVD in healthy people, and to identify and monitor many early pathological conditions that pose a risk to the cardiovascular system and the life of patients. These pathological conditions include hypertension (HTN), which is the direct cause leading to coronary heart disease, acute myocardial infarction, stroke, and other CVD. A number of recent studies reported the possibility of using highly sensitive cTnT and cTnI in the management of HTN patients. In this article, we consider in detail the diagnostic and prognostic value of cardiac troponins in HTN, we also discuss the main possible mechanisms underlying the increase in cTnT and cTnI in human body fluids.


2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Jiankai Fang ◽  
Chao Feng ◽  
Wangwang Chen ◽  
Pengbo Hou ◽  
Zhanhong Liu ◽  
...  

AbstractSkeletal muscle has an extraordinary regenerative capacity reflecting the rapid activation and effective differentiation of muscle stem cells (MuSCs). In the course of muscle regeneration, MuSCs are reprogrammed by immune cells. In turn, MuSCs confer immune cells anti-inflammatory properties to resolve inflammation and facilitate tissue repair. Indeed, MuSCs can exert therapeutic effects on various degenerative and inflammatory disorders based on their immunoregulatory ability, including effects primed by interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α). At the molecular level, the tryptophan metabolites, kynurenine or kynurenic acid, produced by indoleamine 2,3-dioxygenase (IDO), augment the expression of TNF-stimulated gene 6 (TSG6) through the activation of the aryl hydrocarbon receptor (AHR). In addition, insulin growth factor 2 (IGF2) produced by MuSCs can endow maturing macrophages oxidative phosphorylation (OXPHOS)-dependent anti-inflammatory functions. Herein, we summarize the current understanding of the immunomodulatory characteristics of MuSCs and the issues related to their potential applications in pathological conditions, including COVID-19.


Author(s):  
Nicole A. Jastremski ◽  
Alejandra Sánchez-Polo

There is very little published literature regarding pre-Columbian burial practices that include human skeletal remains of the Napo culture (A.D. 1188–1480) in the western Amazon. Due to poor bone preservation and a history of looting practices, bioarchaeologists have rarely been able to collect, analyze, and interpret skeletal remains. Here, we provide the initial publication of a human skeleton from the Ecuadorian Amazon belonging to the Napo culture, preserved in a funerary urn acquired by the Museo de Arte Precolombino Casa del Alabado in Quito, Ecuador. This partial adult skeleton, radiocarbon dated to cal A.D. 1021–1155, consists primarily of broken long bones that indicate a robust individual with a height range of 160–170 cm. Although no trauma was observed, pathological conditions including cysts and likely Osgood-Schlatter’s disease were present and robust muscle insertions were noted. Taphonomic damage from termite osteophagy was inferred by the presence of round bore holes, cavities, tunneling, and cortical etching on the humerus, femur, and tibia. The urn itself is an anthropomorphic polychrome vessel that opens at the bottom, with six equally spaced holes to facilitate closure. The urn burial is similar to those of other Amazonian Polychrome Tradition cultures located to the east in Brazil.   Las prácticas funerarias precolombinas que incluyen restos humanos esqueléticos de la cultura Napo (1188–1480 D.C.), en el oeste de la Amazonía, han sido escasamente dadas a conocer en la literatura arqueológica. Debido a la pobre preservación de los huesos en ese medio y a una dilatada trayectoria de huaquerismo, desde la bioarqueología no ha sido posible recoger, analizar e interpretar restos humanos. Este artículo trata de solventar este vacío al atender desde una perspectiva bioarqueológica los restos óseos humanos provenientes de la Amazonía ecuatoriana pertenecientes a la cultura Napo, preservados en una urna funeraria que se conserva en el Museo de Arte Precolombino Casa del Alabado en Quito, Ecuador. Por un lado, este esqueleto parcial del que se conservan huesos largos fragmentados de un adulto fue datado mediante técnicas radiométricas entre 1021 y 1155 cal D.C.Habría sido una persona robusta, con una altura que oscilaría entre los 160 y 170 cm. Aunque no se ha observado ningún traumatismo, las patologías registradas incluyen quistes, como los debidos a la enfermedad de Osgood-Schlatter, e inserciones musculares robustas. Entre las afecciones tafonómicas más relevantes, se han apreciado las causadas por osteofagia de termitas, las cuales se infieren por la presencia de perforaciones redondas, cavidades, túneles y decapado cortical en húmero, fémur y tibia. Por otro lado, la urna es un ejemplar antropomorfo policromado de apertura basal con seis orificios espaciados que ayudaban a cerrarla. El entierro en urna es similar a aquellos otros de las culturas de la Tradición Polícroma Amazónica localizadas al este en Brasil.


2021 ◽  
Vol 27 (4) ◽  
pp. 390-401
Author(s):  
A. M. Chaulin ◽  
D. V. Duplyakov

The understanding of the diagnostic and prognostic value of many biomarkers of cardiovascular diseases (CVD), including cardiac troponins (cTnT and cTnI), is changing significantly with the development of methods for their determination. New highly sensitive immunoassays can detect minimal concentrations of cardiac troponin protein molecules in biological fluids (several ng/L or less), allowing the detection of cTnT and cTnI in all healthy individuals. Along with this, there are opportunities to use cTnT and cTnI both to assess the risk of developing CVD in healthy people, and to identify and monitor many early pathological conditions that pose a risk to the cardiovascular system and the life of patients. These pathological conditions include hypertension (HTN), which is the direct cause leading to coronary heart disease, acute myocardial infarction, stroke, and other CVD. A number of recent studies reported the possibility of using highly sensitive cTnT and cTnI in the management of HTN patients. In this article, we consider in detail the diagnostic and prognostic value of cardiac troponins in HTN, we also discuss the main possible mechanisms underlying the increase in cTnT and cTnI in human body fluids.


2021 ◽  
Vol 12 ◽  
Author(s):  
Hongjing Zhou ◽  
Shiyun Pu ◽  
Houfeng Zhou ◽  
Yuanxin Guo

The protein Klotho can significantly delay aging, so it has attracted widespread attention. Abnormal downregulation of Klotho has been detected in several aging-related diseases, such as Alzheimer’s disease, kidney injury, cancer, chronic obstructive pulmonary disease (COPD), vascular disease, muscular dystrophy and diabetes. Conversely, many exogenous and endogenous factors, several drugs, lifestyle changes and genetic manipulations were reported to exert therapeutic effects through increasing Klotho expression. In recent years, Klotho has been identified as a potential autophagy regulator. How Klotho may contribute to reversing the effects of aging and disease became clearer when it was linked to autophagy, the process in which eukaryotic cells clear away dysfunctional proteins and damaged organelles: the abovementioned diseases involve abnormal autophagy. Interestingly, growing evidence indicates that Klotho plays a dual role as inducer or inhibitor of autophagy in different physiological or pathological conditions through its influence on IGF-1/PI3K/Akt/mTOR signaling pathway, Beclin 1 expression and activity, as well as aldosterone level, which can help restore autophagy to beneficial levels. The present review examines the role of Klotho in regulating autophagy in Alzheimer’s disease, kidney injury, cancer, COPD, vascular disease, muscular dystrophy and diabetes. Targeting Klotho may provide a new perspective for preventing and treating aging-related diseases.


2021 ◽  
Vol 5 ◽  
pp. 45-52
Author(s):  
Grace Ben Inah ◽  
Samuel Archibong Efanga

Objectives: Radiology education in the undergraduate level imparts in medical students the basic knowledge to interpret common pathological conditions, know the right imaging requests to make and the right order in which they should be made when they become physicians and the degree of this knowledge is influenced by several factors. The aim of this study was to evaluate the knowledge of radiology in exiting medical students and to identify the challenges of undergraduate radiology education. Material and Methods: This was a prospective cross-sectional observational study that was conducted in a 2-month period in the Radiology Department of the University of Calabar Teaching Hospital. The year 6 medical students of the University of Calabar, who were 79 in number, participated in the study. Relevant questions covering the major areas of radiology were presented to each participant by the use of a pre-test questionnaire. SPSS version 23.0., Pearson’s Chi-square test, and t-tests were used to analyze the data. Results: The medical students had a mean score of 66.5% in radiology knowledge. A significant relationship was observed between diagnostic radiology knowledge and the duration of radiology posting (P = 0.029), radiology teaching methods (P = 0.001), and the quality of learning environment (P = 0.002), respectively. Conclusion: The final year medical students in University of Calabar have an appreciable knowledge of radiology. This can be improved if the duration of radiology education increases by early introduction into the pre-clinical class or other clinical courses, if the radiology teaching methods are updated, and if the quality of the learning environment is improved.


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