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1.
ROS signaling in innate immunity via oxidative protein modifications.
Manoharan, RR, Prasad, A, Pospíšil, P, Kzhyshkowska, J
Frontiers in immunology. 2024;:1359600
Abstract
The innate immune response represents the first-line of defense against invading pathogens. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) have been implicated in various aspects of innate immune function, which involves respiratory bursts and inflammasome activation. These reactive species widely distributed within the cellular environment are short-lived intermediates that play a vital role in cellular signaling and proliferation and are likely to depend on their subcellular site of formation. NADPH oxidase complex of phagocytes is known to generate superoxide anion radical (O2 •-) that functions as a precursor for antimicrobial hydrogen peroxide (H2O2) production, and H2O2 is utilized by myeloperoxidase (MPO) to generate hypochlorous acid (HOCl) that mediates pathogen killing. H2O2 modulates the expression of redox-responsive transcriptional factors, namely NF-kB, NRF2, and HIF-1, thereby mediating redox-based epigenetic modification. Survival and function of immune cells are under redox control and depend on intracellular and extracellular levels of ROS/RNS. The current review focuses on redox factors involved in the activation of immune response and the role of ROS in oxidative modification of proteins in macrophage polarization and neutrophil function.
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2.
International consensus guidelines on robotic pancreatic surgery in 2023.
Liu, R, Abu Hilal, M, Besselink, MG, Hackert, T, Palanivelu, C, Zhao, Y, He, J, Boggi, U, Jang, JY, Panaro, F, et al
Hepatobiliary surgery and nutrition. 2024;(1):89-104
Abstract
BACKGROUND With the rapid development of robotic surgery, especially for the abdominal surgery, robotic pancreatic surgery (RPS) has been applied increasingly around the world. However, evidence-based guidelines regarding its application, safety, and efficacy are still lacking. To harvest robust evidence and comprehensive clinical practice, this study aims to develop international guidelines on the use of RPS. METHODS World Health Organization (WHO) Handbook for Guideline Development, GRADE Grid method, Delphi vote, and the AGREE-II instrument were used to establish the Guideline Steering Group, Guideline Development Group, and Guideline Secretary Group, formulate 19 clinical questions, develop the recommendations, and draft the guidelines. Three online meetings were held on 04/12/2020, 30/11/2021, and 25/01/2022 to vote on the recommendations and get advice and suggestions from all involved experts. All the experts focusing on minimally invasive surgery from America, Europe and Oceania made great contributions to this consensus guideline. RESULTS After a systematic literature review 176 studies were included, 19 questions were addressed and 14 recommendations were developed through the expert assessment and comprehensive judgment of the quality and credibility of the evidence. CONCLUSIONS The international RPS guidelines can guide current practice for surgeons, patients, medical societies, hospital administrators, and related social communities. Further randomized trials are required to determine the added value of RPS as compared to open and laparoscopic surgery.
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Milk fat globule-epidermal growth factor 8 (MFGE8) prevents intestinal fibrosis.
Lin, S, Wang, J, Mukherjee, PK, Mao, R, West, G, Czarnecki, D, Zhao, S, Nguyen, QT, Elias, M, Massey, WJ, et al
Gut. 2024
Abstract
OBJECTIVE Intestinal fibrosis is considered an inevitable consequence of chronic IBD, leading to stricture formation and need for surgery. During the process of fibrogenesis, extracellular matrix (ECM) components critically regulate the function of mesenchymal cells. We characterised the composition and function of ECM in fibrostenosing Crohn's disease (CD) and control tissues. DESIGN Decellularised full-thickness intestinal tissue platforms were tested using three different protocols, and ECM composition in different tissue phenotypes was explored by proteomics and validated by quantitative PCR (qPCR) and immunohistochemistry. Primary human intestinal myofibroblasts (HIMFs) treated with milk fat globule-epidermal growth factor 8 (MFGE8) were evaluated regarding the mechanism of their antifibrotic response, and the action of MFGE8 was tested in two experimental intestinal fibrosis models. RESULTS We established and validated an optimal decellularisation protocol for intestinal IBD tissues. Matrisome analysis revealed elevated MFGE8 expression in CD strictured (CDs) tissue, which was confirmed at the mRNA and protein levels. Treatment with MFGE8 inhibited ECM production in normal control HIMF but not CDs HIMF. Next-generation sequencing uncovered functionally relevant integrin-mediated signalling pathways, and blockade of integrin αvβ5 and focal adhesion kinase rendered HIMF non-responsive to MFGE8. MFGE8 prevented and reversed experimental intestinal fibrosis in vitro and in vivo. CONCLUSION MFGE8 displays antifibrotic effects, and its administration may represent a future approach for prevention of IBD-induced intestinal strictures.
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4.
Heart Failure With Preserved Ejection Fraction With CKD: A Narrative Review of a Multispecialty Disorder.
Patel, RN, Sharma, A, Prasad, A, Bansal, S
Kidney medicine. 2023;(12):100705
Abstract
Heart failure with preserved ejection fraction (HFpEF) is a heterogenous syndrome with varying phenotypic expression. The phenotype chronic kidney disease (CKD) associated HFpEF is increasing in prevalence globally and is associated with increased morbidity and mortality compared to other HFpEF variants. These 2 conditions share common risk factors, including obesity, diabetes, and metabolic syndrome, as well as similar pathophysiology, including systemic inflammation, oxidative stress, elevated neurohormones, mineralocorticoid-receptor activation, and venous congestion. Given the coexistence of CKD and HFpEF, the diagnosis of HFpEF can be difficult. Moreover, treatment options for HFpEF have remained limited despite the success seen in its counterpart, heart failure with reduced ejection fraction. HFpEF encompasses complex multisystem pathophysiological perturbations beyond neurohormones, it is unlikely that a single agent can have significant benefit in this population. Recent data on sodium-glucose cotransporter 2 (SGLT2) inhibitors in HFpEF and CKD, and on glucagon-like peptide-1 (GLP-1) agonists and mineralocorticoid-receptor antagonists in metabolic syndrome, which target multiple pathways simultaneously, have led to promising therapeutics for HFpEF and CKD. In this perspective, our goal is to increase awareness of HFpEF as a multisystem disorder that shares the same disease processes seen in CKD and to emphasize that its management in individuals with CKD warrants a collective and multidisciplinary approach.
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5.
Overview of the cardio-metabolic impact of the COVID-19 pandemic.
Barkhordarian, M, Behbood, A, Ranjbar, M, Rahimian, Z, Prasad, A
Endocrine. 2023;(3):477-490
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Abstract
Evidence has shown that cardiometabolic disorders (CMDs) are amongst the top contributors to COVID-19 infection morbidity and mortality. The reciprocal impact of COVID-19 infection and the most common CMDs, the risk factors for poor composite outcome among patients with one or several underlying diseases, the effect of common medical management on CMDs and their safety in the context of acute COVID-19 infection are reviewed. Later on, the changes brought by the COVID-19 pandemic quarantine on the general population's lifestyle (diet, exercise patterns) and metabolic health, acute cardiac complications of different COVID-19 vaccines and the effect of CMDs on the vaccine efficacy are discussed. Our review identified that the incidence of COVID-19 infection is higher among patients with underlying CMDs such as hypertension, diabetes, obesity and cardiovascular disease. Also, CMDs increase the risk of COVID-19 infection progression to severe disease phenotypes (e.g. hospital and/or ICU admission, use of mechanical ventilation). Lifestyle modification during COVID-19 era had a great impact on inducing and worsening of CMDs. Finally, the lower efficacy of COVID-19 vaccines was found in patients with metabolic disease.
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Detection and characterization of free oxygen radicals induced protein adduct formation in differentiating macrophages.
Manoharan, RR, Sedlářová, M, Pospíšil, P, Prasad, A
Biochimica et biophysica acta. General subjects. 2023;(5):130324
Abstract
Reactive oxygen species play a key role in cellular homeostasis and redox signaling at physiological levels, where excessive production affects the function and integrity of macromolecules, specifically proteins. Therefore, it is important to define radical-mediated proteotoxic stress in macrophages and identify target protein to prevent tissue dysfunction. A well employed, THP-1 cell line was utilized as in vitro model to study immune response and herein we employ immuno-spin trapping technique to investigate radical-mediated protein oxidation in macrophages. Hydroxyl radical formation along macrophage differentiation was confirmed by electron paramagnetic resonance along with confocal laser scanning microscopy using hydroxyphenyl fluorescein. Lipid peroxidation product, malondialdehyde, generated under experimental conditions as detected using swallow-tailed perylene derivative fluorescence observed by confocal laser scanning microscopy and high-performance liquid chromatography, respectively. The results obtained from this study warrant further corroboration and study of specific proteins involved in the macrophage activation and their role in inflammations.
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Imaging and Characterization of Oxidative Protein Modifications in Skin.
Prasad, A, Duchová, H, Manoharan, RR, Rathi, D, Pospíšil, P
International journal of molecular sciences. 2023;(4)
Abstract
Skin plays an important role in protection, metabolism, thermoregulation, sensation, and excretion whilst being consistently exposed to environmental aggression, including biotic and abiotic stresses. During the generation of oxidative stress in the skin, the epidermal and dermal cells are generally regarded as the most affected regions. The participation of reactive oxygen species (ROS) as a result of environmental fluctuations has been experimentally proven by several researchers and is well known to contribute to ultra-weak photon emission via the oxidation of biomolecules (lipids, proteins, and nucleic acids). More recently, ultra-weak photon emission detection techniques have been introduced to investigate the conditions of oxidative stress in various living systems in in vivo, ex vivo and in vitro studies. Research into two-dimensional photon imaging is drawing growing attention because of its application as a non-invasive tool. We monitored spontaneous and stress-induced ultra-weak photon emission under the exogenous application of a Fenton reagent. The results showed a marked difference in the ultra-weak photon emission. Overall, these results suggest that triplet carbonyl (3C=O∗) and singlet oxygen (1O2) are the final emitters. Furthermore, the formation of oxidatively modified protein adducts and protein carbonyl formation upon treatment with hydrogen peroxide (H2O2) were observed using an immunoblotting assay. The results from this study broaden our understanding of the mechanism of the generation of ROS in skin layers and the formation/contribution of various excited species can be used as tools to determine the physiological state of the organism.
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IMPROvE-CED Trial: Intracoronary Autologous CD34+ Cell Therapy for Treatment of Coronary Endothelial Dysfunction in Patients With Angina and Nonobstructive Coronary Arteries.
Corban, MT, Toya, T, Albers, D, Sebaali, F, Lewis, BR, Bois, J, Gulati, R, Prasad, A, Best, PJM, Bell, MR, et al
Circulation research. 2022;(3):326-338
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Abstract
BACKGROUND Coronary endothelial dysfunction (CED) causes angina/ischemia in patients with nonobstructive coronary artery disease (NOCAD). Patients with CED have decreased number and function of CD34+ cells involved in normal vascular repair with microcirculatory regenerative potential and paracrine anti-inflammatory effects. We evaluated safety and potential efficacy of intracoronary autologous CD34+ cell therapy for CED. METHODS Twenty NOCAD patients with invasively diagnosed CED and persistent angina despite maximally tolerated medical therapy underwent baseline exercise stress test, GCSF (granulocyte colony stimulating factor)-mediated CD34+ cell mobilization, leukapheresis, and selective 1×105 CD34+ cells/kg infusion into left anterior descending. Invasive CED evaluation and exercise stress test were repeated 6 months after cell infusion. Primary end points were safety and effect of intracoronary autologous CD34+ cell therapy on CED at 6 months of follow-up. Secondary end points were change in Canadian Cardiovascular Society angina class, as-needed sublingual nitroglycerin use/day, Seattle Angina Questionnaire scores, and exercise time at 6 months. Change in CED was compared with that of 51 historic control NOCAD patients treated with maximally tolerated medical therapy alone. RESULTS Mean age was 52±13 years; 75% were women. No death, myocardial infarction, or stroke occurred. Intracoronary CD34+ cell infusion improved microvascular CED (%acetylcholine-mediated coronary blood flow increased from 7.2 [-18.0 to 32.4] to 57.6 [16.3-98.3]%; P=0.014), decreased Canadian Cardiovascular Society angina class (3.7±0.5 to 1.7±0.9, Wilcoxon signed-rank test, P=0.00018), and sublingual nitroglycerin use/day (1 [0.4-3.5] to 0 [0-1], Wilcoxon signed-rank test, P=0.00047), and improved all Seattle Angina Questionnaire scores with no significant change in exercise time at 6 months of follow-up. Historic control patients had no significant change in CED. CONCLUSIONS A single intracoronary autologous CD34+ cell infusion was safe and may potentially be an effective disease-modifying therapy for microvascular CED in humans. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03471611.
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Resistance genes on the verge of plant-virus interaction.
Sett, S, Prasad, A, Prasad, M
Trends in plant science. 2022;(12):1242-1252
Abstract
Viruses are acellular pathogens that cause severe infections in plants, resulting in worldwide crop losses every year. The lack of chemical agents to control viral diseases exacerbates the situation. Thus, to devise proper management strategies, it is important that the defense mechanisms of plants against viruses are understood. Resistance (R) genes regulate plant defense against invading pathogens by eliciting a hypersensitive response (HR). Compatible interaction between plant R gene and viral avirulence (Avr) protein activates the necrotic cell death response at the site of infection, resulting in the cessation of disease. Here, we review different aspects of R gene-mediated dominant resistance against plant viruses in dicotyledonous plants and possible ways for developing crops with better disease resistance.
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DyeVert Contrast Reduction System Use in Patients Undergoing Coronary and/or Peripheral Angiography: A Systematic Literature Review and Meta-Analysis.
Tarantini, G, Prasad, A, Rathore, S, Bansal, S, Gottfried, R, Rosenkranz, AR, Briguori, C, Yaghoubi, M, Mashayekhi, A, Javanbakht, M, et al
Frontiers in medicine. 2022;:841876
Abstract
BACKGROUND Contrast-associated acute kidney injury (CA-AKI) is an important adverse effect associated with injecting iodinated intra-arterial contrast media (CM) during coronary angiography. The DyeVert™ Contrast Reduction System is a medical device intended to reduce the intra-arterial CM volume (CMV) administered. The aim of this study was to assess DyeVert System clinical effectiveness and safety by implementing a systematic review and meta-analysis of existing evidence. METHODS Systematic electronic literature searches were conducted in MEDLINE, Embase, the Cochrane Database of Systematic Reviews, ClinicalTrials.gov, and the International Clinical Trials Registry Platform database. Relevant data were extracted from included studies and meta-analyses were performed to synthesize evidence across studies. RESULTS The review included 17 eligible studies involving 1,731 DyeVert System cases and 1,387 control cases (without the use of DyeVert). Meta-analyses demonstrated use of the DyeVert System reduced CMV delivered to the patient by 39.27% (95% CI, 36.10-42.48%, P < 0.001), reduced CMV/baseline renal function ratios (Hedges's g, -0.56; 95% CI, -0.70 to -0.42, P < 0.001) and percentage of cases exceeding the maximum CMV threshold (risk difference -0.31, 95% CI, -0.48 to -0.13, P < 0.001) while maintaining adequate image quality in 98% of cases. DyeVert System cases demonstrated lower CA-AKI incidence vs. controls (absolute risk reduction 5.00% (95% CI, 0.40-9.80%; P = 0.03), relative risk 0.60 (95% CI, 0.40-0.90; P = 0.01) with a pooled estimate of the number needed to treat with the DyeVert System to avoid 1 CA-AKI event of 20. CONCLUSION DyeVert System use significantly reduces CMV delivered to the patient, CMV/baseline renal function ratios, and CA-AKI incidence while maintaining image quality. Accordingly, the device may serve as an adjunctive, procedure-based strategy to prevent CA-AKI. Future multi-center studies are needed to further assess effects of minimizing CMV on endpoints such as CA-AKI prevention, incidence of adverse cardiac and renal events, and health care costs.