Publications by authors named "Santosh K Yadav"

52 Publications

Diacylglycerol Kinase Inhibition Reduces Airway Contraction by Negative Feedback Regulation of Gq-signaling.

Am J Respir Cell Mol Biol 2021 Jul 22. Epub 2021 Jul 22.

Thomas Jefferson University, 6559, Center for Translational Medicine, Philadelphia, Pennsylvania, United States;

Exaggerated airway smooth muscle (ASM) contraction regulated by the Gq family of G protein-coupled receptors (GPCRs) causes airway hyperresponsiveness (AHR) in asthma. Activation of Gq-coupled GPCRs leads to phospholipase C (PLC)-mediated generation of inositol triphosphate (IP3) and diacylglycerol (DAG). DAG signaling is terminated by the action of DAG kinase (DGK) that converts DAG into phosphatidic acid (PA). Our previous study demonstrated that DGKα and ζ isoform knockout mice are protected from the development of allergen-induced AHR. Here we aimed at determining the mechanism by which DGK regulates ASM contraction. Activity of DGK isoforms was inhibited in human ASM cells by siRNA-mediated knockdown of DGKα and ζwhile pharmacological inhibition was achieved by pan DGK inhibitor I (R59022). Effects of DGK inhibition on contractile agonist-induced activation of PLC and myosin light chain (MLC) kinase, elevation of IP3, and calcium levels were assessed. Further, we employed human precision-cut lung slices and assessed the role of DGK in agonist-induced bronchoconstriction. DGK inhibitor I attenuated histamine- and methacholine-induced bronchoconstriction. DGKα and ζ knockdown or pre-treatment with DGK inhibitor I resulted in attenuated agonist-induced phosphorylation of MLC and myosin light chain phosphatase in ASM cells. Further, DGK inhibition decreased Gq agonist-induced calcium elevation, generation of IP3, and increased histamine-induced production of PA. Finally, DGK inhibition or treatment with DAG analog resulted in attenuation of activation of PLC in human ASM cells. Our findings suggest that DGK inhibition perturbed the DAG:PA ratio resulting in inhibition of Gq-PLC activation in a negative feedback manner, resulting in protection against ASM contraction.
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http://dx.doi.org/10.1165/rcmb.2021-0106OCDOI Listing
July 2021

Autocrine regulation of airway smooth muscle contraction by diacylglycerol kinase.

J Cell Physiol 2021 Jul 18. Epub 2021 Jul 18.

Division of Pulmonary, Allergy and Critical Care Medicine, Center for Translational Medicine, Jane & Leonard Korman Respiratory Institute, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.

Diacylglycerol kinase (DGK), a lipid kinase, catalyzes the conversion of diacylglycerol (DAG) to phosphatidic acid, thereby terminating DAG-mediated signaling by Gq-coupled receptors that regulate contraction of airway smooth muscle (ASM). A previous study from our laboratory demonstrated that DGK inhibition or genetic ablation leads to reduced ASM contraction and provides protection for allergen-induced airway hyperresponsiveness. However, the mechanism by which DGK regulates contractile signaling in ASM is not well established. Herein, we investigated the role of prorelaxant cAMP-protein kinase A (PKA) signaling in DGK-mediated regulation of ASM contraction. Pretreatment of human ASM cells with DGK inhibitor I activated PKA as demonstrated by the phosphorylation of PKA substrates, VASP, Hsp20, and CREB, which was abrogated when PKA was inhibited pharmacologically or molecularly using overexpression of the PKA inhibitor peptide, PKI. Furthermore, inhibition of DGK resulted in induction of cyclooxygenase (COX) and generation of prostaglandin E (PGE ) with concomitant activation of Gs-cAMP-PKA signaling in ASM cells in an autocrine/paracrine fashion. Inhibition of protein kinase C (PKC) or extracellular-signal-regulated kinase (ERK) attenuated DGK-mediated production of PGE and activation of cAMP-PKA signaling in human ASM cells, suggesting that inhibition of DGK activates the COX-PGE pathway in a PKC-ERK-dependent manner. Finally, DGK inhibition-mediated attenuation of contractile agonist-induced phosphorylation of myosin light chain 20 (MLC-20), a marker of ASM contraction, involves COX-mediated cAMP production and PKA activation in ASM cells. Collectively these findings establish a novel mechanism by which DGK regulates ASM contraction and further advances DGK as a potential therapeutic target to provide effective bronchoprotection in asthma.
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http://dx.doi.org/10.1002/jcp.30528DOI Listing
July 2021

Body mass-normalized moderate dose of dietary nitrate intake improves endothelial function and walking capacity in patients with peripheral artery disease.

Am J Physiol Regul Integr Comp Physiol 2021 08 23;321(2):R162-R173. Epub 2021 Jun 23.

School of Health & Kinesiology, University of Nebraska at Omaha, Omaha, Nebraska.

Peripheral artery disease (PAD) is characterized by the accumulation of atherosclerotic plaques in the lower extremity conduit arteries, which impairs blood flow and walking capacity. Dietary nitrate has been used to reduce blood pressure (BP) and improve walking capacity in PAD. However, a standardized dose for PAD has not been determined. Therefore, we sought to determine the effects of a body mass-normalized moderate dose of nitrate (0.11 mmol nitrate/kg) as beetroot juice on serum nitrate/nitrite, vascular function, walking capacity, and tissue oxygen utilization capacity in patients with PAD. A total of 11 patients with PAD received either nitrate supplement or placebo in a randomized crossover design. Total serum nitrate/nitrite, resting BP, brachial and popliteal artery endothelial function (flow-mediated dilation, FMD), arterial stiffness (pulse-wave velocity, PWV), augmentation index (AIx), maximal walking distance and time, claudication onset time, and skeletal muscle oxygen utilization were measured pre- and postnitrate and placebo intake. There were significant group × time interactions ( < 0.05) for serum nitrate/nitrite, FMD, BP, walking distance and time, and skeletal muscle oxygen utilization. The nitrate group showed significantly increased serum nitrate/nitrite (Δ1.32 μM), increased brachial and popliteal FMD (Δ1.3% and Δ1.7%, respectively), reduced peripheral and central systolic BP (Δ-4.7 mmHg and Δ-8.2 mmHg, respectively), increased maximal walking distance (Δ92.7 m) and time (Δ56.3 s), and reduced deoxygenated hemoglobin during walking. There were no changes in PWV, AIx, or claudication ( > 0.05). These results indicate that a body-mass normalized moderate dose of nitrate may be effective and safe for reducing BP, improving endothelial function, and improving walking capacity in patients with PAD.
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http://dx.doi.org/10.1152/ajpregu.00121.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8409914PMC
August 2021

Genetic variations influence brain changes in patients with attention-deficit hyperactivity disorder.

Transl Psychiatry 2021 06 5;11(1):349. Epub 2021 Jun 5.

Laboratory of Molecular and Metabolic Imaging, Sidra Medicine, Doha, Qatar.

Attention-deficit hyperactivity disorder (ADHD) is a neurological and neurodevelopmental childhood-onset disorder characterized by a persistent pattern of inattentiveness, impulsiveness, restlessness, and hyperactivity. These symptoms may continue in 55-66% of cases from childhood into adulthood. Even though the precise etiology of ADHD is not fully understood, it is considered as a multifactorial and heterogeneous disorder with several contributing factors such as heritability, auxiliary to neurodevelopmental issues, severe brain injuries, neuroinflammation, consanguineous marriages, premature birth, and exposure to environmental toxins. Neuroimaging and neurodevelopmental assessments may help to explore the possible role of genetic variations on ADHD neuropsychobiology. Multiple genetic studies have observed a strong genetic association with various aspects of neuropsychobiological functions, including neural abnormalities and delayed neurodevelopment in ADHD. The advancement in neuroimaging and molecular genomics offers the opportunity to analyze the impact of genetic variations alongside its dysregulated pathways on structural and functional derived brain imaging phenotypes in various neurological and psychiatric disorders, including ADHD. Recently, neuroimaging genomic studies observed a significant association of brain imaging phenotypes with genetic susceptibility in ADHD. Integrating the neuroimaging-derived phenotypes with genomics deciphers various neurobiological pathways that can be leveraged for the development of novel clinical biomarkers, new treatment modalities as well as therapeutic interventions for ADHD patients. In this review, we discuss the neurobiology of ADHD with particular emphasis on structural and functional changes in the ADHD brain and their interactions with complex genomic variations utilizing imaging genetics methodologies. We also highlight the genetic variants supposedly allied with the development of ADHD and how these, in turn, may affect the brain circuit function and related behaviors. In addition to reviewing imaging genetic studies, we also examine the need for complementary approaches at various levels of biological complexity and emphasize the importance of combining and integrating results to explore biological pathways involved in ADHD disorder. These approaches include animal models, computational biology, bioinformatics analyses, and multimodal imaging genetics studies.
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http://dx.doi.org/10.1038/s41398-021-01473-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179928PMC
June 2021

Intestinal Carriage of Extended-Spectrum -Lactamase- (ESBL-) Possessing and Species among Nepalese Health Science and Non-Health Science Students.

Can J Infect Dis Med Microbiol 2021 9;2021:4767429. Epub 2021 Apr 9.

Department of Microbiology, Maharajgunj Medical Campus, Institute of Medicine, Tribhuvan University, Kathmandu, Nepal.

Infections due to extended-spectrum -lactamase- (ESBL-) producing Gram-negative bacteria have led to increased mortality, morbidity, and economic burden worldwide. These bacteria can colonize the healthy intestine of human beings and can disseminate in communities and hospital. This study aimed to investigate the prevalence of fecal carriage of ESBL-producing and species among health science (HS) and non-health science (NHS) students. This descriptive cross-sectional study was conducted on 104 HS and 104 NHS students in which one stool sample from each student was collected and processed for bacterial culture and sensitivity testing according to standard bacteriological procedures. Each morphotype was identified and characterized phenotypically. The antimicrobial sensitivity profile of bacterial isolates was determined by the Kirby-Bauer disk diffusion technique. ESBL production was tested by combination disk method as recommended by the Clinical and Laboratory Standards Institute. Out of 208 stool samples, and spp. were recovered from 203 (86.8%) and 31 (13.2%) stool samples, respectively. Among those 234 isolates, 69 were positive for ESBL which included ( = 66, 95.7%) and spp. ( = 3, 4.3%). Fifty (42.4%) out of 118 isolates from HS students and 19 (16.4%) out of 116 from NHS students were colonized by ESBL-producers. Compared to non-ESBL producers, a higher number of ESBL-producing isolates were resistant to ciprofloxacin (14.5% vs. 1.8%, < 0.001), cotrimoxazole (59.4% vs. 16.4%, < 0.001), and amikacin (10.1% vs 4.2%, < 0.001). All and species isolates were susceptible to meropenem. The prevalence of fecal carriage of ESBL-producing bacteria was higher in HS students; however, there was a considerable number of these strains colonizing NHS students as well. This "iceberg phenomenon" of asymptomatic carriage of ESBL-producing pathogens might act as a source of infection in both the community and hospitals. Therefore, surveillance of carriage of drug-resistant bacteria should be performed regularly.
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http://dx.doi.org/10.1155/2021/4767429DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052163PMC
April 2021

Impact of attention deficit hyperactivity disorder and gender differences on academic and social difficulties among adolescents in Qatari Schools.

Qatar Med J 2021 15(1):11. Epub 2021 Mar 15.

Sidra Medicine, Doha, Qatar E-mail:

Background: To evaluate the social and academic impact of adolescents with Attention Deficit Hyperactivity Disorder (ADHD) and gender differences compared with their non-ADHD peers.

Methods: A cross-sectional descriptive study using a standardized rating scale of teacher observations was conducted in the schools of Qatar from 7 to 12 grades. Teachers completed Swanson, Nolan, and Pelham (SNAP-IV) rating scale questionnaires for the ADHD core symptoms together with nine questions to evaluate the academic and social difficulties in all participants.

Results: A total of 1775 students (mean age: 15 ± 1.5 years; boys/girls: 717/1058) were included in this study. Based on the SNAP-IV rating scale, 150 students were showing core symptoms of ADHD and classified as having ADHD (8.5%; boys/girls; 93/57) and 1625 students as non-ADHD peers (91.5%; boys/girls; 624/1001). Prevalence of ADHD among adolescent students is 8.5%, and it varied significantly between genders with 13% of boys and 5.4% of girls affected by this disorder. Adolescents with ADHD had more academic and social difficulties than their non-ADHD peers, the boys more so than the girls. Boys with inattentive subtype of ADHD had more academic difficulties than girls, while girls had more social difficulties than boys.

Conclusion: The results of this study revealed that ADHD among adolescents is substantially associated with academic and social difficulties in the school environment. Gender differences among students with ADHD should be considered in the school and clinical environment.
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http://dx.doi.org/10.5339/qmj.2021.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961152PMC
March 2021

Generating Ins2/miR-133aTg Mice to Model miRNA-Driven Cardioprotection of Human Diabetic Heart.

Methods Mol Biol 2021 ;2224:113-121

Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, USA.

Diabetes mellitus (DM) is caused either due to insulin deficiency (T1DM) or insulin resistance (T2DM). DM increases the risk of heart failure by diabetic cardiomyopathy (DMCM), a cardiac muscle disorder that leads to a progressive decline in diastolic function, and ultimately systolic dysfunction. Mouse models of T1DM and T2DM exhibit clinical signs of DMCM. Growing evidence implicates microRNA (miRNA), an endogenous, non-coding, regulatory RNA, in the pathogenesis and signaling of DMCM. Therefore, inhibiting deleterious miRNAs and mimicking cardioprotective miRNAs could provide a potential therapeutic intervention for DMCM. miRNA-133a (miR-133a) is a highly abundant miRNA in the human heart. It is a cardioprotective miRNA, which is downregulated in the DM heart. It has anti-hypertrophic and anti-fibrotic effects. miR-133a mimic treatment after the onset of early DMCM can reverse histological and clinical signs of the disease in mice. We hypothesized that overexpression of cardiac-specific miR-133a in Ins2 Akita (T1DM) mice can prevent progression of DMCM. Here, we describe a method to create and validate cardiac-specific Ins2/miR-133aTg mice to determine whether cardiac-specific miR-133a overexpression prevents development of DMCM. These strategies demonstrate the value of genetic modeling of human disease such as DMCM and evaluate the potential of miRNA as a therapeutic intervention.
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http://dx.doi.org/10.1007/978-1-0716-1008-4_8DOI Listing
April 2021

Intracellular matrix metalloproteinase-9 mediates epigenetic modifications and autophagy to regulate differentiation in human cardiac stem cells.

Stem Cells 2021 04 12;39(4):497-506. Epub 2021 Jan 12.

Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska, USA.

Epigenetic reprogramming and autophagy have critical roles in differentiation of stem cells. However, very little is known about how epigenetic modifications are mediated and how they contribute to autophagy and differentiation in human cardiac stem cells (hCSCs). Previously, we have reported that intracellular matrix metalloproteinase-9 (MMP9), a collagenase, mediates cell death in hCSCs. Here, we investigated whether intracellular MMP9 mediates epigenetic modifications and autophagy in hCSCs. We created MMP9KO hCSCs and treated them with 5-azacytidine, an inhibitor of DNA methylation, and bafilomycin A1, an inhibitor of autophagosome degradation, and evaluated epigenetic modifications, autophagic flux, and differentiation. Our results showed compromised epigenetic modifications, reduced autophagy, and impaired differentiation in MMP9KO hCSCs. Remarkably, paracrine MMP9 supplementation restored epigenetic modifications but further reduced autophagy in MMP9KO hCSCs. We conclude that intracellular MMP9 is a critical mediator of epigenetic modifications and autophagy in hCSCs. Furthermore, the endocrine and paracrine effects of MMP9 vary for regulating autophagy in hCSCs. These novel roles of MMP9 are valuable for stem cell therapy.
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http://dx.doi.org/10.1002/stem.3330DOI Listing
April 2021

A Whole-Genome Sequencing Association Study of Low Bone Mineral Density Identifies New Susceptibility Loci in the Phase I Qatar Biobank Cohort.

J Pers Med 2021 Jan 7;11(1). Epub 2021 Jan 7.

Biomedical Research Center, College of Health Sciences-QU Health, Qatar University, Doha 2713, Qatar.

Bone density disorders are characterized by a reduction in bone mass density and strength, which lead to an increase in the susceptibility to sudden and unexpected fractures. Despite the serious consequences of low bone mineral density (BMD) and its significant impact on human health, most affected individuals may not know that they have the disease because it is asymptomatic. Therefore, understanding the genetic basis of low BMD and osteoporosis is essential to fully elucidate its pathobiology and devise preventative or therapeutic approaches. Here we sequenced the whole genomes of 3000 individuals from the Qatar Biobank and conducted genome-wide association analyses to identify genetic risk factors associated with low BMD in the Qatari population. Fifteen variants were significantly associated with total body BMD ( < 5 × 10). Of these, five variants had previously been reported by and were directionally consistent with previous genome-wide association study data. Ten variants were new: six intronic variants located at six gene loci (MALAT1/TALAM1, FASLG, LSAMP, SAG, FAM189A2, and LOC101928063) and four intergenic variants. This first such study in Qatar provides a new insight into the genetic architecture of low BMD in the Qatari population. Nevertheless, more studies are needed to validate these findings and to elucidate the functional effects of these variants on low BMD and bone fracture susceptibility.
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http://dx.doi.org/10.3390/jpm11010034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825795PMC
January 2021

Non-invasive biomarkers for monitoring the immunotherapeutic response to cancer.

J Transl Med 2020 12 9;18(1):471. Epub 2020 Dec 9.

Functional and Molecular Imaging Laboratory, Cancer Research Department, Sidra Medicine, P.O. Box 26999, Doha, Qatar.

Immunotherapy is an efficient way to cure cancer by modulating the patient's immune response. However, the immunotherapy response is heterogeneous and varies between individual patients and cancer subtypes, reinforcing the need for early benefit predictors. Evaluating the infiltration of immune cells in the tumor and changes in cell-intrinsic tumor characteristics provide potential response markers to treatment. However, this approach requires invasive sampling and may not be suitable for real-time monitoring of treatment response. The recent emergence of quantitative imaging biomarkers provides promising opportunities. In vivo imaging technologies that interrogate T cell responses, metabolic activities, and immune microenvironment could offer a powerful tool to monitor the cancer response to immunotherapy. Advances in imaging techniques to identify tumors' immunological characteristics can help stratify patients who are more likely to respond to immunotherapy. This review discusses the metabolic events that occur during T cell activation and differentiation, anti-cancer immunotherapy-induced T cell responses, focusing on non-invasive imaging techniques to monitor T cell metabolism in the search for novel biomarkers of response to cancer immunotherapy.
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http://dx.doi.org/10.1186/s12967-020-02656-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727217PMC
December 2020

Successful Establishment of the First Neonatal Respiratory Extracorporeal Membrane Oxygenation (ECMO) Program in the Middle East, in Collaboration With Pediatric Services.

Front Pediatr 2020 11;8:506. Epub 2020 Sep 11.

Weill Cornell Medicine, Doha, Qatar.

Extracorporeal membrane oxygenation (ECMO) is a complex life-saving support for acute cardio-respiratory failure, unresponsive to medical treatment. Starting a new ECMO program requires synergizing different aspects of organizational infrastructures and appropriate extensive training of core team members to deliver the care successfully and safely. To describe the process of establishing a new neonatal ECMO program and to evaluate the program by benchmarking the ECMO respiratory outcomes and mechanical complications to the well-established Extracorporeal Life Support Organization (ELSO) registry data. We reviewed the processes and steps involved in planning and setting up the new ECMO program. To assess the success of the ECMO implementation program, we retrospectively reviewed data of clinical outcomes and technical complications for the first 11 patients who have received ECMO therapy for respiratory indications since program activation (July 2018-May 2020). We analyzed mechanical complications as a tool to measure infrastructures and our effective training for the core team of ECMO specialists. We also looked at all clinical complications and benchmarked these numbers with the last 10 years of ELSO registry data (2009-2019) in the corresponding categories for comparison. Chi-square test was used to compare, and outcomes are presented in percentage; a -value of <0.05 is considered significant. A total of 27 patients underwent ECMO in the hospital, out of which 11 (six neonatal and five pediatric) patients had acute respiratory failure treated with venovenous (VV) ECMO or veno-arterial (VA) ECMO over a 22-month period. We had a total of 3,360 h of ECMO run with a range from 1 day to 7 weeks on ECMO. Clinical outcomes and mechanical complications are comparable to ELSO registry data (no significant difference); there were no pump failure, oxygenator failure, or pump clots. Establishing the ECMO program involved a multisystem approach with particular attention to the training of ECMO team members. The unified protocols, equipment, and multistep ECMO team training increased staff knowledge, technical skills, and teamwork, allowing the successful development of a neonatal respiratory ECMO program with minimal mechanical complications during ECMO runs, showing a comparable patient flow and mechanical complications.
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http://dx.doi.org/10.3389/fped.2020.00506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516255PMC
September 2020

Acute mitochondrial antioxidant intake improves endothelial function, antioxidant enzyme activity, and exercise tolerance in patients with peripheral artery disease.

Am J Physiol Heart Circ Physiol 2020 08 24;319(2):H456-H467. Epub 2020 Jul 24.

Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska.

Peripheral artery disease (PAD) is a manifestation of atherosclerosis in the leg arteries, which causes claudication. This may be in part due to vascular mitochondrial dysfunction and excessive reactive oxygen species (ROS) production. A mitochondrial-targeted antioxidant (MitoQ) has been shown to improve vascular mitochondrial function that, in turn, led to improved vascular function in older adults and animal models. However, the roles of vascular mitochondria in vascular function including endothelial function and arterial stiffness in patients with PAD are unknown; therefore, with the use of acute MitoQ intake, this study examined the roles of vascular mitochondria in endothelial function, arterial stiffness, exercise tolerance, and skeletal muscle function in patients with PAD. Eleven patients with PAD received either MitoQ or placebo in a randomized crossover design. At each visit, blood samples, brachial and popliteal artery flow-mediated dilation (FMD), peripheral and central pulse-wave velocity (PWV), blood pressure (BP), maximal walking capacity, time to claudication (COT), and oxygen utility capacity were measured pre- and-post-MitoQ and placebo. There were significant group by time interactions ( < 0.05) for brachial and popliteal FMD that both increased by Δ2.6 and Δ3.3%, respectively, and increases superoxide dismutase (Δ0.03 U/mL), maximal walking time (Δ73.8 s), maximal walking distance (Δ49.3 m), and COT (Δ44.2 s). There were no changes in resting heart rate, BP, malondialdehyde, total antioxidant capacity, PWV, or oxygen utility capacity ( > 0.05). MitoQ intake may be an effective strategy for targeting the vascular mitochondrial environment, which may be useful for restoring endothelial function, leg pain, and walking time in patients with PAD. The results of this study reveal for the first time that acute oral intake of mitochondrial-targeted antioxidant (MitoQ, 80 mg) is effective for improving vascular endothelial function and superoxide dismutase in patients with peripheral artery disease (PAD). Acute MitoQ intake is also effective for improving maximal walking capacity and delaying the onset of claudication in patients with PAD. These findings suggest that the acute oral intake of MitoQ-mediated improvements in vascular mitochondria play a pivotal role for improving endothelial function, the redox environment, and skeletal muscle performance in PAD.
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http://dx.doi.org/10.1152/ajpheart.00235.2020DOI Listing
August 2020

Combined anthocyanins and bromelain supplement improves endothelial function and skeletal muscle oxygenation status in adults: a double-blind placebo-controlled randomised crossover clinical trial.

Br J Nutr 2021 01 14;125(2):161-171. Epub 2020 Jul 14.

School of Health and Kinesiology, University of Nebraska Omaha, Omaha, NE 68182, USA.

Anthocyanins and bromelain have gained significant attention due to their antioxidative and anti-inflammatory properties. Both have been shown to improve endothelial function, blood pressure (BP) and oxygen utility capacity in humans; however, the combination of these two and the impacts on endothelial function, BP, total antioxidant capacity (TAC) and oxygen utility capacity have not been previously investigated. The purpose of this study was to investigate the impacts of a combined anthocyanins and bromelain supplement (BE) on endothelial function, BP, TAC, oxygen utility capacity and fatigability in healthy adults. Healthy adults (n 18, age 24 (sd 4) years) received BE or placebo in a randomised crossover design. Brachial artery flow-mediated dilation (FMD), BP, TAC, resting heart rate, oxygen utility capacity and fatigability were measured pre- and post-BE and placebo intake. The BE group showed significantly increased FMD, reduced systolic BP and improved oxygen utility capacity compared with the placebo group (P < 0·05). Tissue saturation and oxygenated Hb significantly increased following BE intake, while deoxygenated Hb significantly decreased (P < 0·05) during exercise. Additionally, TAC was significantly increased following BE intake (P < 0·05). There were no significant differences for resting heart rate, diastolic BP or fatigability index. These results suggest that BE intake is an effective nutritional therapy for improving endothelial function, BP, TAC and oxygen utility capacity, which may be beneficial to support vascular health in humans.
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http://dx.doi.org/10.1017/S0007114520002548DOI Listing
January 2021

Genetic and Neuroimaging Approaches to Understanding Post-Traumatic Stress Disorder.

Int J Mol Sci 2020 Jun 24;21(12). Epub 2020 Jun 24.

Functional and Molecular Imaging Department, Research Branch, Sidra Medicine, Doha 26999, Qatar.

Post-traumatic stress disorder (PTSD) is a highly disabling condition, increasingly recognized as both a disorder of mental health and social burden, but also as an anxiety disorder characterized by fear, stress, and negative alterations in mood. PTSD is associated with structural, metabolic, and molecular changes in several brain regions and the neural circuitry. Brain areas implicated in the traumatic stress response include the amygdala, hippocampus, and prefrontal cortex, which play an essential role in memory function. Abnormalities in these brain areas are hypothesized to underlie symptoms of PTSD and other stress-related psychiatric disorders. Conventional methods of studying PTSD have proven to be insufficient for diagnosis, measurement of treatment efficacy, and monitoring disease progression, and currently, there is no diagnostic biomarker available for PTSD. A deep understanding of cutting-edge neuroimaging genetic approaches is necessary for the development of novel therapeutics and biomarkers to better diagnose and treat the disorder. A current goal is to understand the gene pathways that are associated with PTSD, and how those genes act on the fear/stress circuitry to mediate risk vs. resilience for PTSD. This review article explains the rationale and practical utility of neuroimaging genetics in PTSD and how the resulting information can aid the diagnosis and clinical management of patients with PTSD.
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http://dx.doi.org/10.3390/ijms21124503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352752PMC
June 2020

Diagnostic performance of multi-parametric MRI to differentiate benign sex cord stromal tumors from malignant (non-stromal and stromal) testicular neoplasms.

Abdom Radiol (NY) 2021 01 22;46(1):319-330. Epub 2020 Jun 22.

Department of Radiology, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada.

Purpose: Testicular stromal tumors are uncommon, although mostly benign. The purpose of this study is to assess the role of multi-parametric MRI in differentiating benign testicular stromal tumors from malignant testicular neoplasms (non-stromal and stromal).

Methods: A single-center retrospective study comparing benign stromal tumors (STs) to malignant testicular neoplasms (MTNs) was conducted. MR imaging assessment included tumor size, T2- and T1-weighted signal intensity, T2- and T1-weighted texture pattern, diffusion restriction, presence of hemorrhage and/or necrosis, and measurement of apparent diffusion coefficient and dynamic contrast enhancement (DCE). Inter-observer agreement was assessed using Cohen's kappa and Bland-Altman and data were compared using independent t-tests or χ. Receiver operating characteristic curve analysis was used to test models incorporating various imaging features.

Results: Radical orchiectomy and histopathology revealed 20 testicular neoplasms: seven STs (35%) and thirteen MTNs (65%). MTNs were significantly larger in size than STs (5.1 ± 2.36 cm vs. 1.27 ± 0.56 cm; p-value < 0.001). STs demonstrated more hypointense T2W signal (85.7% vs. 46.2%; p-value < 0.09), less T2W heterogeneous texture (14.3% vs. 61.5%; p-value < 0.04), and less diffusion restriction (16.7% vs. 83.3%; p-value < 0.01) in comparison to MTNs. STs demonstrated mainly homogenous post-contrast enhancement pattern (71.4% vs. 7.7%; p-value < 0.004), while MTNs showed primarily heterogeneous enhancement pattern (77% vs. 14.3%; p-value < 0.02). STs revealed greater corrected venous phase enhancement (STs: 0.59 ± 0.29; MTNs: 0.25 ± 0.25; p-value < 0.03). STs showed higher ADC values, though the difference was not statistically significant (p-value < 0.25). A model combining T2W, DWI, and DCE features showed the best overall diagnostic accuracy with area under ROC curve of 0.99 and confidence interval ranging from 0.94 to 1.

Conclusion: Multi-parametric MRI can potentially differentiate benign stromal tumors from malignant testicular neoplasms, which can help to avoid radical orchiectomy. However, future studies using larger sample sizes are needed to validate our results.
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http://dx.doi.org/10.1007/s00261-020-02621-4DOI Listing
January 2021

Therapeutic Effects of Curcumol in Several Diseases; An Overview.

Nutr Cancer 2021 14;73(2):181-195. Epub 2020 Apr 14.

Translational Medicine, Research Branch, Sidra Medical and Research Center, Doha, Qatar.

also known as is a traditional Chinese medicine that has been used for many centuries against several diseases. The rhizome of the plant is composed of curcuminoids (curcumin, demethoxycurcumin, and bisdemethoxycurcumin), and essential volatile oils including curcumol, curdione, and germacrone. While curcuminoids have been extensively studied for their antimicrobial, antioxidant, anti-inflammatory and anticancer properties, the therapeutic efficacy of curcumol is still emerging. Recent studies have shown anticancer properties of curcumol against multiple solid tumors such as breast, colorectal, head and neck, and lung adenocarcinomas. The underlying anti-tumor mechanisms revealed inhibition of several signaling pathways (NF-κB, MAPK, PI-3K/AKT, and GSK-3β) associated with cell proliferation, survival, anti-apoptosis, invasion and metastasis. Besides curcumol, extracts from the roots possess many other terpenoids such as β-elemene, δ-elemene, germacrone, furanodiene and furanodienone with known anticancer properties. In this review, we comprehensively focused on the composition of essential oils, their structure, isolation and therapeutic uses of curcumol to aid in the improvement and development of novel drugs with minimal cytotoxicity, enhanced efficacy, and less cost.
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http://dx.doi.org/10.1080/01635581.2020.1749676DOI Listing
August 2021

MMP9 mediates acute hyperglycemia-induced human cardiac stem cell death by upregulating apoptosis and pyroptosis in vitro.

Cell Death Dis 2020 03 13;11(3):186. Epub 2020 Mar 13.

Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, 985850, USA.

Providing a conducive microenvironment is critical to increase survival of transplanted stem cells in regenerative therapy. Hyperglycemia promotes stem cell death impairing cardiac regeneration in the diabetic heart. Understanding the molecular mechanisms of high glucose-induced stem cell death is important for improving cardiac regeneration in diabetic patients. Matrix metalloproteinase-9 (MMP9), a collagenase, is upregulated in the diabetic heart, and ablation of MMP9 decreases infarct size in the non-diabetic myocardial infarction heart. In the present study, we aim to investigate whether MMP9 is a mediator of hyperglycemia-induced cell death in human cardiac stem cells (hCSCs) in vitro. We created MMP9 hCSCs to test the hypothesis that MMP9 mediates hyperglycemia-induced oxidative stress and cell death via apoptosis and pyroptosis in hCSCs, which is attenuated by the lack of MMP9. We found that hyperglycemia induced oxidative stress and increased cell death by promoting pyroptosis and apoptosis in hCSCs, which was prevented in MMP9 hCSCs. These findings revealed a novel intracellular role of MMP9 in mediating stem cell death and provide a platform to assess whether MMP9 inhibition could improve hCSCs survival in stem cell therapy at least in acute hyperglycemic microenvironment.
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http://dx.doi.org/10.1038/s41419-020-2367-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7070071PMC
March 2020

Role of non-coding RNA networks in leukemia progression, metastasis and drug resistance.

Mol Cancer 2020 03 12;19(1):57. Epub 2020 Mar 12.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar.

Early-stage detection of leukemia is a critical determinant for successful treatment of the disease and can increase the survival rate of leukemia patients. The factors limiting the current screening approaches to leukemia include low sensitivity and specificity, high costs, and a low participation rate. An approach based on novel and innovative biomarkers with high accuracy from peripheral blood offers a comfortable and appealing alternative to patients, potentially leading to a higher participation rate.Recently, non-coding RNAs due to their involvement in vital oncogenic processes such as differentiation, proliferation, migration, angiogenesis and apoptosis have attracted much attention as potential diagnostic and prognostic biomarkers in leukemia. Emerging lines of evidence have shown that the mutational spectrum and dysregulated expression of non-coding RNA genes are closely associated with the development and progression of various cancers, including leukemia. In this review, we highlight the expression and functional roles of different types of non-coding RNAs in leukemia and discuss their potential clinical applications as diagnostic or prognostic biomarkers and therapeutic targets.
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http://dx.doi.org/10.1186/s12943-020-01175-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069174PMC
March 2020

Claudin-1, A Double-Edged Sword in Cancer.

Int J Mol Sci 2020 Jan 15;21(2). Epub 2020 Jan 15.

Division of Translational Medicine, Research Branch, Sidra Medicine, Doha 26999, Qatar.

Claudins, a group of membrane proteins involved in the formation of tight junctions, are mainly found in endothelial or epithelial cells. These proteins have attracted much attention in recent years and have been implicated and studied in a multitude of diseases. Claudins not only regulate paracellular transepithelial/transendothelial transport but are also critical for cell growth and differentiation. Not only tissue-specific but the differential expression in malignant tumors is also the focus of claudin-related research. In addition to up- or down-regulation, claudin proteins also undergo delocalization, which plays a vital role in tumor invasion and aggressiveness. Claudin (CLDN)-1 is the most-studied claudin in cancers and to date, its role as either a tumor promoter or suppressor (or both) is not established. In some cancers, lower expression of CLDN-1 is shown to be associated with cancer progression and invasion, while in others, loss of CLDN-1 improves the patient survival. Another topic of discussion regarding the significance of CLDN-1 is its localization (nuclear or cytoplasmic vs perijunctional) in diseased states. This article reviews the evidence regarding CLDN-1 in cancers either as a tumor promoter or suppressor from the literature and we also review the literature regarding the pattern of CLDN-1 distribution in different cancers, focusing on whether this localization is associated with tumor aggressiveness. Furthermore, we utilized expression data from The Cancer Genome Atlas (TCGA) to investigate the association between CLDN-1 expression and overall survival (OS) in different cancer types. We also used TCGA data to compare CLDN-1 expression in normal and tumor tissues. Additionally, a pathway interaction analysis was performed to investigate the interaction of CLDN-1 with other proteins and as a future therapeutic target.
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http://dx.doi.org/10.3390/ijms21020569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013445PMC
January 2020

Exploring Dysregulated Signaling Pathways in Cancer.

Curr Pharm Des 2020 ;26(4):429-445

Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar.

Cancer cell biology takes advantage of identifying diverse cellular signaling pathways that are disrupted in cancer. Signaling pathways are an important means of communication from the exterior of cell to intracellular mediators, as well as intracellular interactions that govern diverse cellular processes. Oncogenic mutations or abnormal expression of signaling components disrupt the regulatory networks that govern cell function, thus enabling tumor cells to undergo dysregulated mitogenesis, to resist apoptosis, and to promote invasion to neighboring tissues. Unraveling of dysregulated signaling pathways may advance the understanding of tumor pathophysiology and lead to the improvement of targeted tumor therapy. In this review article, different signaling pathways and how their dysregulation contributes to the development of tumors have been discussed.
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http://dx.doi.org/10.2174/1381612826666200115095937DOI Listing
November 2020

Exercise Training Promotes Cardiac Hydrogen Sulfide Biosynthesis and Mitigates Pyroptosis to Prevent High-Fat Diet-Induced Diabetic Cardiomyopathy.

Antioxidants (Basel) 2019 Dec 11;8(12). Epub 2019 Dec 11.

Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE 68198, USA.

Obesity increases the risk of developing diabetes and subsequently, diabetic cardiomyopathy (DMCM). Reduced cardioprotective antioxidant hydrogen sulfide (HS) and increased inflammatory cell death via pyroptosis contribute to adverse cardiac remodeling and DMCM. Although exercise training (EX) has cardioprotective effects, it is unclear whether EX mitigates obesity-induced DMCM by increasing H₂S biosynthesis and mitigating pyroptosis in the heart. C57BL6 mice were fed a high-fat diet (HFD) while undergoing treadmill EX for 20 weeks. HFD mice developed obesity, hyperglycemia, and insulin resistance, which were reduced by EX. Left ventricle pressure-volume measurement revealed that obese mice developed reduced diastolic function with preserved ejection fraction, which was improved by EX. Cardiac dysfunction was accompanied by increased cardiac pyroptosis signaling, structural remodeling, and metabolic remodeling, indicated by accumulation of lipid droplets in the heart. Notably, EX increased cardiac H₂S concentration and expression of H₂S biosynthesis enzymes. HFD-induced obesity led to features of type 2 diabetes (T2DM), and subsequently DMCM. EX during the HFD regimen prevented the development of DMCM, possibly by promoting H₂S-mediated cardioprotection and alleviating pyroptosis. This is the first report of EX modulating H₂S and pyroptotic signaling in the heart.
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http://dx.doi.org/10.3390/antiox8120638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6943713PMC
December 2019

Hydrogen Sulfide Ameliorates Homocysteine-Induced Cardiac Remodeling and Dysfunction.

Front Physiol 2019 24;10:598. Epub 2019 May 24.

Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, United States.

Patients with diabetes, a methionine-rich meat diet, or certain genetic polymorphisms show elevated levels of homocysteine (Hcy), which is strongly associated with the development of cardiovascular disease including diabetic cardiomyopathy. However, reducing Hcy levels with folate shows no beneficial cardiac effects. We have previously shown that a hydrogen sulfide (HS), a by-product of Hcy through transsulfuration by cystathionine beta synthase (CBS), donor mitigates Hcy-induced hypertrophy in cardiomyocytes. However, the cardiac effects of HS in the context of hyperhomocysteinemia (HHcy) have not been studied. We tested the hypothesis that HHcy causes cardiac remodeling and dysfunction , which is ameliorated by HS. Twelve-week-old male CBS (a model of HHcy) and sibling CBS (WT) mice were treated with SG1002 (a slow release HS donor) diet for 4 months. The left ventricle of CBS mice showed increased expression of early remodeling signals c-Jun and c-Fos, increased interstitial collagen deposition, and increased cellular hypertrophy. Notably, SG1002 treatment slightly reduced c-Jun and c-Fos expression, decreased interstitial fibrosis, and reduced cellular hypertrophy. Pressure volume loop analyses in CBS mice revealed increased end systolic pressure with no change in stroke volume (SV) suggesting increased afterload, which was abolished by SG1002 treatment. Additionally, SG1002 treatment increased end-diastolic volume and SV in CBS mice, suggesting increased ventricular filling. These results demonstrate SG1002 treatment alleviates cardiac remodeling and afterload in HHcy mice. HS may be cardioprotective in conditions where HS is reduced and Hcy is elevated.
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http://dx.doi.org/10.3389/fphys.2019.00598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544124PMC
May 2019

Transgenic Expression of miR-133a in the Diabetic Akita Heart Prevents Cardiac Remodeling and Cardiomyopathy.

Front Cardiovasc Med 2019 24;6:45. Epub 2019 Apr 24.

Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NE, United States.

Advanced diabetes mellitus (DM) may have both insulin resistance and deficiency (double DM) that accelerates diabetic cardiomyopathy (DMCM), a cardiac muscle disorder. Reduced cardiac miR-133a, a cardioprotective miRNA, is associated with DMCM. However, it is unclear whether increasing miR-133a levels in the double DM heart could prevent DMCM. We hypothesized that increasing cardiac levels of miR-133a could prevent DMCM in Akita, a mouse model of double DM. To test the hypothesis, we created Akita/miR-133aTg mice, a new strain of Akita where miR-133a is overexpressed in the heart, by crossbreeding male Akita with female cardiac-specific miR-133a transgenic mice. We validated Akita/miR-133aTg mice by genotyping and phenotyping (miR-133a levels in the heart). To determine whether miR-133a overexpression could prevent cardiac remodeling and cardiomyopathy, we evaluated cardiac fibrosis, hypertrophy, and dysfunction (P-V loop) in 13-15 week male WT, Akita, Akita/miR-133aTg, and miR-133aTg mice. Our results revealed that miR-133a overexpression in the Akita heart prevents DM-induced cardiac fibrosis (reduced collagen deposition), hypertrophy (decreased beta-myosin heavy chain), and impaired contractility (downregulated calcium handling protein sarco-endoplasmic reticulum-ATPase-2a). These results demonstrate that increased levels of miR-133a in the DM heart could prevent cardiac remodeling. Our P-V loop analysis showed a trend of decreased cardiac output, stroke volume, and ± dp/dt in Akita, which were blunted in Akita/miR-133aTg heart. These findings suggest that 13-15 week Akita heart undergoes adverse remodeling toward cardiomyopathy, which is prevented by miR-133a overexpression. In addition, increased cardiac miR-133a in the Akita heart did not change blood glucose levels but decreased lipid accumulation in the heart, suggesting inhibition of metabolic remodeling in the heart. Thus, miR-133a could be a promising therapeutic candidate to prevent DMCM.
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http://dx.doi.org/10.3389/fcvm.2019.00045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6491745PMC
April 2019

Tight Junction Proteins and Signaling Pathways in Cancer and Inflammation: A Functional Crosstalk.

Front Physiol 2018 23;9:1942. Epub 2019 Jan 23.

Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.

The ability of epithelial cells to organize through cell-cell adhesion into a functioning epithelium serves the purpose of a tight epithelial protective barrier. Contacts between adjacent cells are made up of tight junctions (TJ), adherens junctions (AJ), and desmosomes with unique cellular functions and a complex molecular composition. These proteins mediate firm mechanical stability, serves as a gatekeeper for the paracellular pathway, and helps in preserving tissue homeostasis. TJ proteins are involved in maintaining cell polarity, in establishing organ-specific apical domains and also in recruiting signaling proteins involved in the regulation of various important cellular functions including proliferation, differentiation, and migration. As a vital component of the epithelial barrier, TJs are under a constant threat from proinflammatory mediators, pathogenic viruses and bacteria, aiding inflammation and the development of disease. Inflammatory bowel disease (IBD) patients reveal loss of TJ barrier function, increased levels of proinflammatory cytokines, and immune dysregulation; yet, the relationship between these events is partly understood. Although TJ barrier defects are inadequate to cause experimental IBD, mucosal immune activation is changed in response to augmented epithelial permeability. Thus, the current studies suggest that altered barrier function may predispose or increase disease progression and therapies targeted to specifically restore the barrier function may provide a substitute or supplement to immunologic-based therapies. This review provides a brief introduction about the TJs, AJs, structure and function of TJ proteins. The link between TJ proteins and key signaling pathways in cell proliferation, transformation, and metastasis is discussed thoroughly. We also discuss the compromised intestinal TJ integrity under inflammatory conditions, and the signaling mechanisms involved that bridge inflammation and cancer.
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http://dx.doi.org/10.3389/fphys.2018.01942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351700PMC
January 2019

Isolation, Characterization, and Differentiation of Cardiac Stem Cells from the Adult Mouse Heart.

J Vis Exp 2019 01 7(143). Epub 2019 Jan 7.

Department of Cellular and Integrative Physiology, University of Nebraska Medical Center; Department of Anesthesiology, University of Nebraska Medical Center;

Myocardial infarction (MI) is a leading cause of morbidity and mortality around the world. A major goal of regenerative medicine is to replenish the dead myocardium after MI. Although several strategies have been used to regenerate myocardium, stem cell therapy remains a major approach to replenish the dead myocardium of an MI heart. Accumulating evidence suggests the presence of resident cardiac stem cells (CSCs) in the adult heart and their endocrine and/or paracrine effects on cardiac regeneration. However, CSC isolation and their characterization and differentiation toward myocardial cells, especially cardiomyocytes, remains a technical challenge. In the present study, we provided a simple method for the isolation, characterization, and differentiation of CSCs from the adult mouse heart. Here, we describe a density gradient method for the isolation of CSCs, where the heart is digested by a 0.2% collagenase II solution. To characterize the isolated CSCs, we evaluated the expression of CSCs/cardiac markers Sca-1, NKX2-5, and GATA4, and pluripotency/stemness markers OCT4, SOX2, and Nanog. We also determined the proliferation potential of isolated CSCs by culturing them in a Petri dish and assessing the expression of the proliferation marker Ki-67. For evaluating the differentiation potential of CSCs, we selected seven- to ten-days cultured CSCs. We transferred them to a new plate with a cardiomyocyte differentiation medium. They are incubated in a cell culture incubator for 12 days, while the differentiation medium is changed every three days. The differentiated CSCs express cardiomyocyte-specific markers: actinin and troponin I. Thus, CSCs isolated with this protocol have stemness and cardiac markers, and they have a potential for proliferation and differentiation toward cardiomyocyte lineage.
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http://dx.doi.org/10.3791/58448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7207148PMC
January 2019

Give Me a Fork: Can Autophagy Research Solve the Riddle of Airway Remodeling in Asthma?

Am J Respir Cell Mol Biol 2019 May;60(5):494-496

1 Jane and Leonard Korman Lung Institute Thomas Jefferson University Philadelphia, Pennsylvania.

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http://dx.doi.org/10.1165/rcmb.2018-0353EDDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6503612PMC
May 2019

Changes in resting-state functional brain activity are associated with waning cognitive functions in HIV-infected children.

Neuroimage Clin 2018 29;20:1204-1210. Epub 2018 Oct 29.

Division of Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar; Laboratory Animal Research Center, Qatar University, Doha, Qatar.

Delayed brain development in perinatally HIV-infected children may affect the functional brain activity and subsequently cognitive function. The current study evaluated the functional brain activity in HIV-infected children by quantifying the amplitude of low frequency fluctuations (ALFF) and functional connectivity (FC). Additionally, correlation of ALFF and FC with cognitive measures was performed. Twenty-six HIV-infected children and 20 control children underwent neuropsychological (NP) assessment and resting-state functional magnetic resonance imaging (rs-fMRI). ALFF and FC maps were generated and group differences were analyzed using two-sample t-test. Furthermore, ALFF and FC showing significant group differences were correlated with NP scores using Pearson's correlation. Significantly lower ALFF in the left middle temporal gyrus, precentral and post central gyrus was observed in HIV-infected children compared to controls. FC was significantly reduced in the right inferior parietal, vermis, middle temporal and left postcentral regions, and significantly increased in the right precuneus, superior parietal and left middle frontal regions in HIV-infected children as compared to control. HIV-infected children showed significantly lower NP scores in various domains including closure, exclusion, memory, verbal meaning, quantity and hidden figure than controls. These waning cognitive functions were significantly associated with changes in ALFF and FC in HIV-infected children. The findings suggest that abnormal ALFF and FC may responsible for cognitive deficits in HIV-infected children. ALFF and FC in association with cognitive evaluation may provide a clinical biomarker to evaluate functional brain activity and to plan neurocognitive intervention in HIV-infected children undergoing standard treatment.
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http://dx.doi.org/10.1016/j.nicl.2018.10.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6224323PMC
February 2019

Toughening Anhydride-Cured Epoxy Resins Using Fatty Alkyl-Anhydride-Grafted Epoxidized Soybean Oil.

ACS Omega 2018 Mar 6;3(3):2641-2651. Epub 2018 Mar 6.

Department of Chemical & Biological Engineering, Drexel University, Philadelphia, Pennsylvania 19104, United States.

The aim of this work is to develop a series of advanced biobased tougheners for thermosetting epoxy resins suitable for high-performance applications. These bio-rubber (BR) tougheners were prepared via a one-step chemical modification of epoxidized soybean oil using biobased hexanoic anhydride. To investigate their toughening performance, these BR tougheners were blended with diglycidyl ether of bisphenol A epoxy monomers at various weight fractions and cured with anhydride hardeners. Significant improvements in fracture toughness properties, as well as minimal reductions in glass transition temperature (), were observed. When 20 wt % of a BR toughener was utilized, the critical stress intensity factor and critical strain energy release rate of a thermosetting matrix were enhanced by >200 and >500%, respectively, whereas the was reduced by only 20 °C. The phase-separated domains were evenly dispersed across the fracture surfaces as observed through scanning electron microscopy and atomic force microscopy. Moreover, domain sizes were demonstrated to be tunable within the micrometer range by altering the toughener molecular structure and weight fractions. These BR tougheners demonstrate the possibility of achieving toughness while having the thermal properties of standard bisphenol epoxy thermosetting resins.
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http://dx.doi.org/10.1021/acsomega.7b02042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6045475PMC
March 2018

The thermo-sensitive gene expression signatures of spermatogenesis.

Reprod Biol Endocrinol 2018 Jun 2;16(1):56. Epub 2018 Jun 2.

Division of Endocrinology, CSIR-Central Drug Research Institute, BS-10/1, Sector-10, Jankipuram Extension, Sitapur Road, Lucknow, 226031, India.

Background: Spermatogenesis in most mammals (including human and rat) occurs at ~ 3 °C lower than body temperature in a scrotum and fails rapidly at 37 °C inside the abdomen. The present study investigates the heat-sensitive transcriptome and miRNAs in the most vulnerable germ cells (spermatocytes and round spermatids) that are primarily targeted at elevated temperature in a bid to identify novel targets for contraception and/or infertility treatment.

Methods: Testes of adult male rats subjected to surgical cryptorchidism were obtained at 0, 24, 72 and 120 h post-surgery, followed by isolation of primary spermatocytes and round spermatids and purification to > 90% purity using a combination of trypsin digestion, centrifugal elutriation and density gradient centrifugation techniques. RNA isolated from these cells was sequenced by massive parallel sequencing technique to identify the most-heat sensitive mRNAs and miRNAs.

Results: Heat stress altered the expression of a large number of genes by ≥2.0 fold, out of which 594 genes (286↑; 308↓) showed alterations in spermatocytes and 154 genes (105↑; 49↓) showed alterations in spermatids throughout the duration of experiment. 62 heat-sensitive genes were common to both cell types. Similarly, 66 and 60 heat-sensitive miRNAs in spermatocytes and spermatids, respectively, were affected by ≥1.5 fold, out of which 6 were common to both the cell types.

Conclusion: The study has identified Acly, selV, SLC16A7(MCT-2), Txnrd1 and Prkar2B as potential heat sensitive targets in germ cells, which may be tightly regulated by heat sensitive miRNAs rno-miR-22-3P, rno-miR-22-5P, rno-miR-129-5P, rno-miR-3560, rno-miR-3560 and rno-miR-466c-5P.
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http://dx.doi.org/10.1186/s12958-018-0372-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5985054PMC
June 2018
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