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Cureus Oct 2022Hypertension (HTN) is one of the most prevalent and dangerous cardiovascular diseases worldwide. Recently, its direct or indirect association with gut dysbiosis has been... (Review)
Review
Hypertension (HTN) is one of the most prevalent and dangerous cardiovascular diseases worldwide. Recently, its direct or indirect association with gut dysbiosis has been an interest of study for many. It also includes the metabolomic and functional gene changes in hypertensives compared with healthy individuals. This systematic review aims to study quantitative and qualitative interactions between the two and re-defining the heart-gut axis. We have strictly followed the (PRISMA), 2020, guidelines. We conducted an in-depth search of databases such as PubMed, PubMed Central (PMC), Medline, and ScienceDirect to find relevant studies for our topic of interest. After the final quality check, we included eight articles in the systematic review. A significant difference in richness and diversity in gut microbiota was observed in hypertensive patients compared with healthy controls. There was an increased abundance of many bacteria such as , , , Enterobacteriaceae, , , , , and , while a decreased abundance of , , spp., and . Alteration of the composition also varied based on diet, age, ethnicity, and severity of HTN. Short-chain fatty acids (SCFAs)-producing bacteria are found to be on the lower side in hypertensives owing to the protective property of SCFAs against inflammation, especially butyric acid. From the perspective of metabolomic changes, harmful metabolites for cardiovascular health such as intestinal fatty acid binding protein (I-FABP), lipopolysaccharides (LPSs), zonulin, sphingomyelins, acylcarnitines, and trimethylamine -oxide (TMAO) were found to be increased in hypertensives. Changes in these biomarkers further establish the relation between gut epithelial health and high blood pressure (BP). Participants affected by diseases have an overall lower rate of acquiring new genes, which results in a low richness of genes in them compared with healthy individuals. There is increased expression of the choline utilization () gene and reduced expression of genes associated with biosynthesis and transport of amino acids in high-BP participants. The unique changes in the composition of the microbiota, functional changes in genes, and metabolome collectively help for a better understanding of the pathogenesis of HTN and also suggest the gut as a promising new therapeutic target for HTN. To establish a further causal relationship between the two, more research is required.
PubMed: 36381851
DOI: 10.7759/cureus.29927 -
Nutrients Jan 2024Epicatechin is a polyphenol compound that promotes skeletal muscle differentiation and counteracts the pathways that participate in the degradation of proteins. Several... (Review)
Review
Epicatechin is a polyphenol compound that promotes skeletal muscle differentiation and counteracts the pathways that participate in the degradation of proteins. Several studies present contradictory results of treatment protocols and therapeutic effects. Therefore, the objective of this systematic review was to investigate the current literature showing the molecular mechanism and clinical protocol of epicatechin in muscle atrophy in humans, animals, and myoblast cell-line. The search was conducted in Embase, PubMed/MEDLINE, Cochrane Library, and Web of Science. The qualitative analysis demonstrated that there is a commonness of epicatechin inhibitory action in myostatin expression and atrogenes MAFbx, FOXO, and MuRF1. Epicatechin showed positive effects on follistatin and on the stimulation of factors related to the myogenic actions (MyoD, Myf5, and myogenin). Furthermore, the literature also showed that epicatechin can interfere with mitochondrias' biosynthesis in muscle fibers, stimulation of the signaling pathways of AKT/mTOR protein production, and amelioration of skeletal musculature performance, particularly when combined with physical exercise. Epicatechin can, for these reasons, exhibit clinical applicability due to the beneficial results under conditions that negatively affect the skeletal musculature. However, there is no protocol standardization or enough clinical evidence to draw more specific conclusions on its therapeutic implementation.
Topics: Animals; Humans; Catechin; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscular Atrophy; MyoD Protein; TOR Serine-Threonine Kinases
PubMed: 38276564
DOI: 10.3390/nu16020326 -
Pulmonary Pharmacology & Therapeutics Aug 2023COPD pathogenesis is frequently associated with endoplasmic reticulum stress (ER stress) progression. Targeting the major unfolded protein response (UPR) branches in the... (Review)
Review
COPD pathogenesis is frequently associated with endoplasmic reticulum stress (ER stress) progression. Targeting the major unfolded protein response (UPR) branches in the ER stress pathway may provide pharmacotherapeutic selection strategies for treating COPD and enable relief from its symptoms. In this study, we aimed to systematically review the potential role of the ER stress inhibitors of major UPR branches (IRE1, PERK, and ATF6) in COPD-related studies and determine the current stage of knowledge in this field. The systematic review was carried out adhering to the PRISMA checklist based on published studies obtained from specific keyword searches of three databases, namely PubMed, ScienceDirect and Springer Database. The search was limited to the year 2000-2022 which includes all in vitro studies, in vivo studies and clinical trials related to the application of ER stress inhibitors toward COPD-induced models and disease. The risk of bias was evaluated using the QUIN, SYRCLE, revised Cochrane risk of bias tool for randomized trials (RoB 2.0) and NIH tool respectively. A total of 7828 articles were screened from three databases and a final total of 37 studies were included in the review. The ER stress and UPR pathways are potentially useful to prevent COPD progression and attenuate the exacerbation of COPD and related symptoms. Interestingly, the off-target effects from inhibition of the UPR pathway may be desirable or undesirable depending on context and therapeutic applications. Targeting the UPR pathway could have complex consequences as the production of ER molecules involved in folding may be impaired which could continuously provoke misfolding of proteins. Although several emerging compounds were noted to be potentially useful for targeted therapy against COPD, clinical studies have yet to be thoroughly explored.
Topics: Humans; eIF-2 Kinase; Endoplasmic Reticulum Stress; Unfolded Protein Response; Pulmonary Disease, Chronic Obstructive
PubMed: 37201652
DOI: 10.1016/j.pupt.2023.102218 -
Frontiers in Genetics 2022Heparan sulfate modified proteins or proteoglycans (HSPGs) are an abundant class of cell surface and extracellular matrix molecules. They serve important co-receptor...
Heparan sulfate modified proteins or proteoglycans (HSPGs) are an abundant class of cell surface and extracellular matrix molecules. They serve important co-receptor functions in the regulation of signaling as well as membrane trafficking. Many of these activities directly affect processes associated with neurodegeneration including uptake and export of Tau protein, disposition of Amyloid Precursor Protein-derived peptides, and regulation of autophagy. In this review we focus on the impact of HSPGs on autophagy, membrane trafficking, mitochondrial quality control and biogenesis, and lipid metabolism. Disruption of these processes are a hallmark of Alzheimer's disease (AD) and there is evidence that altering heparan sulfate structure and function could counter AD-associated pathological processes. Compromising presenilin function in several systems has provided instructive models for understanding the molecular and cellular underpinnings of AD. Disrupting presenilin function produces a constellation of cellular deficits including accumulation of lipid, disruption of autophagosome to lysosome traffic and reduction in mitochondrial size and number. Inhibition of heparan sulfate biosynthesis has opposing effects on all these cellular phenotypes, increasing mitochondrial size, stimulating autophagy flux to lysosomes, and reducing the level of intracellular lipid. These findings suggest a potential mechanism for countering pathology found in AD and related disorders by altering heparan sulfate structure and influencing cellular processes disrupted broadly in neurodegenerative disease. Vertebrate and invertebrate model systems, where the cellular machinery of autophagy and lipid metabolism are conserved, continue to provide important translational guideposts for designing interventions that address the root cause of neurodegenerative pathology.
PubMed: 36699460
DOI: 10.3389/fgene.2022.1012706 -
Current Diabetes Reviews 2020Protein carbamylation is a non-enzymatic and irreversible posttranslational process. It affects functions of numerous enzymes, hormones and receptors playing several...
INTRODUCTION & BACKGROUND
Protein carbamylation is a non-enzymatic and irreversible posttranslational process. It affects functions of numerous enzymes, hormones and receptors playing several roles in diabetes pathogenesis by changing their native structures. Detrimental consequences of oxidative protein damage comprise, but are not limited to glyoxidation, lipoxidation and carbonylation reactions. Since the carbamylated plasma proteins are strongly related to the glycemic control parameters of diabetes, they may have an additive value and emerge as potential biomarkers for the follow up, prognosis and treatment of diabetes mellitus.
METHODS & RESULTS
To conduct our systematic review, we used PubMed and Semantic Scholar, and used 'Protein carbamylation and diabetes' and 'Protein carbamylation and atherosclerosis' as keywords and looked into about five hundred manuscripts. Manuscripts that are not in English were excluded as well as manuscripts that did not mention carbamylation to maintain the focus of the present article. Similar to glycation, carbamylation is able to alter functions of plasma proteins and their interactions with endothelial cells and has been shown to be involved in the development of atherosclerosis.
CONCLUSION
At this stage, it seems clear that protein carbamylation leads to worse clinical outcomes. To improve patient care, but maybe more importantly to improve healthcare-prevention, we believe the next stage involves understanding how exactly protein carbamylation leads to worse outcomes and when and in what group of people anti-carbamylation therapies must be employed.
Topics: Atherosclerosis; Biomarkers; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelial Cells; Humans; Protein Carbamylation
PubMed: 31914914
DOI: 10.2174/1573399816666200107102918 -
Cytokine & Growth Factor Reviews Apr 2023Epidermal growth factor receptor (EGFR) mutation is the most common driver mutation in non-small cell lung cancer (NSCLC). The first-line therapy for advanced NSCLC... (Review)
Review
Epidermal growth factor receptor (EGFR) mutation is the most common driver mutation in non-small cell lung cancer (NSCLC). The first-line therapy for advanced NSCLC patients with EGFR-sensitive mutation is the EGFR tyrosine kinase inhibitor (EGFR-TKI). However, most NSCLC patients with EGFR mutation will develop resistant mutations in EGFR-TKI therapy. With further studies, resistance mechanisms represented by EGFR-T790M mutations have revealed the impact of EGFR mutations in situ on EGFR-TKIs sensitivity. The third-generation EGFR-TKIs inhibit both EGFR-sensitive mutations and T790M mutations. The emergence of novel mutations such as EGFR-C797S and EGFR-L718Q may decrease efficacy. Searching for new targets to overcome EGFR-TKI resistance becomes a key challenge. Therefore, an in-depth understanding of the regulatory mechanisms of EGFR is essential to find novel targets to overcome drug-resistant mutations in EGFR-TKIs. EGFR, as a receptor-type tyrosine kinase, undergoes homo/heterodimerization and autophosphorylation upon binding to ligands, which activates multiple downstream signaling pathways. Interestingly, there is growing evidence that the kinase activity of EGFR is affected not only by phosphorylation but also by various post-translational modifications (PTMs, such as S-palmitoylation, S-nitrosylation, Methylation, etc.). In this review, we systematically review the effects of different protein PTMs on EGFR kinase activity and its functionality and suggest that influencing EGFR kinase activity by modulating multiple EGFR sites are potential targets to overcome EGFR-TKIs resistance mutations.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; ErbB Receptors; Drug Resistance, Neoplasm; Protein Kinase Inhibitors; Mutation; Receptor Protein-Tyrosine Kinases; Protein Processing, Post-Translational
PubMed: 36934069
DOI: 10.1016/j.cytogfr.2023.03.003 -
Biochemical Society Transactions Jun 2021Hypoxia is a feature of most solid tumours and predicts for poor prognosis. In radiobiological hypoxia (<0.1% O2) cells become up to three times more resistant to...
Hypoxia is a feature of most solid tumours and predicts for poor prognosis. In radiobiological hypoxia (<0.1% O2) cells become up to three times more resistant to radiation. The biological response to radiobiological hypoxia is one of few physiologically relevant stresses that activates both the unfolded protein and DNA damage responses (UPR and DDR). Links between these pathways have been identified in studies carried out in normoxia. Based in part on these previous studies and recent work from our laboratory, we hypothesised that the biological response to hypoxia likely includes overlap between the DDR and UPR. While inhibition of the DDR is a recognised strategy for improving radiation response, the possibility of achieving this through targeting the UPR has not been realised. We carried out a systematic review to identify links between the DDR and UPR, in human cell lines exposed to <2% O2. Following PRISMA guidance, literature from January 2010 to October 2020 were retrieved via Ovid MEDLINE and evaluated. A total of 202 studies were included. LAMP3, ULK1, TRIB3, CHOP, NOXA, NORAD, SIAH1/2, DYRK2, HIPK2, CREB, NUPR1, JMJD2B, NRF2, GSK-3B, GADD45a, GADD45b, STAU1, C-SRC, HK2, CAV1, CypB, CLU, IGFBP-3 and SP1 were highlighted as potential links between the hypoxic DDR and UPR. Overall, we identified very few studies which demonstrate a molecular link between the DDR and UPR in hypoxia, however, it is clear that many of the molecules highlighted warrant further investigation under radiobiological hypoxia as these may include novel therapeutic targets to improve radiotherapy response.
Topics: Animals; Apoptosis; Cell Line, Tumor; DNA Damage; Humans; Hypoxia; Neoplasms; Protein Serine-Threonine Kinases; Signal Transduction; Unfolded Protein Response
PubMed: 34003246
DOI: 10.1042/BST20200861 -
Nutrients Apr 2023Tocotrienol, a type of vitamin E, is well known for its anti-cancer and other biological activities. This systematic review aims to summarize the involvement of... (Review)
Review
BACKGROUND
Tocotrienol, a type of vitamin E, is well known for its anti-cancer and other biological activities. This systematic review aims to summarize the involvement of endoplasmic reticulum stress (ERS) and subsequent unfolded protein response (UPR) as the underlying molecular mechanisms for the anticancer properties of tocotrienol.
METHOD
A comprehensive literature search was performed in March 2023 using the PubMed, Scopus, Web of Science, and EMBASE databases. In vitro, in vivo, and human studies were considered.
RESULT
A total of 840 articles were retrieved during the initial search, and 11 articles that fit the selection criteria were included for qualitative analysis. The current mechanistic findings are based solely on in vitro studies. Tocotrienol induces cancer cell growth arrest, autophagy, and cell death primarily through apoptosis but also through paraptosis-like cell death. Tocotrienol-rich fractions, including α-, γ- and δ-tocotrienols, induce ERS, as evidenced by upregulation of UPR markers and/or ERS-related apoptosis markers. Early endoplasmic reticulum calcium ion release, increased ceramide level, proteasomal inhibition, and upregulation of microRNA-190b were suggested to be essential in modulating tocotrienol-mediated ERS/UPR transduction. Nevertheless, the upstream molecular mechanism of tocotrienol-induced ERS is largely unknown.
CONCLUSION
ERS and UPR are essential in modulating tocotrienol-mediated anti-cancer effects. Further investigation is needed to elucidate the upstream molecular mechanism of tocotrienol-mediated ERS.
Topics: Humans; Tocotrienols; Endoplasmic Reticulum Stress; Unfolded Protein Response; Apoptosis; Cell Death
PubMed: 37111076
DOI: 10.3390/nu15081854 -
Journal of Science and Medicine in Sport Feb 2021The timing of protein intake over the day on muscle mass and strength gains have received interest in the literature. Thus, the aim of this systematic review is to...
OBJECTIVES
The timing of protein intake over the day on muscle mass and strength gains have received interest in the literature. Thus, the aim of this systematic review is to analyze clinical studies that evaluated the acute effects of pre-sleep protein consumption on overnight muscle protein synthesis and the chronic effects on muscle mass and strength.
DESIGNS
Systematic review.
METHODS
A literature search was conducted up to June 2020 according to PRISMA statement and nine articles were included to analyze.
RESULTS
The consumption of 20-40 g of casein approximately 30 min before sleep stimulates whole-body protein synthesis rates over a subsequent overnight period in young and elderly men (preceded or not by resistance exercise, respectively). In addition, pre-sleep protein consumption can augment the muscle adaptive response (muscle fiber cross-sectional area, strength and muscle mass) during 10-12 weeks of resistance exercise in young, but not in elderly men.
CONCLUSIONS
Based on current evidence, the consumption of 20-40 g of casein approximately 30 min before sleep improves protein synthetic response during an overnight recovery period in healthy young adult men, with possible positive effects on muscle mass and strength following prolonged resistance exercise. In elderly, despite the initial evidence regarding the pre-sleep protein enhances overnight muscle protein synthesis rates, the current available evidence is limited precluding to conclude about the chronic effects on skeletal muscle mass or strength. These conclusions need to be taken with caution due to uneven protein intakes between experimental groups. Therefore, more data are needed before further considering pre-sleep protein as an effective nutritional intervention.
Topics: Adult; Aged; Caseins; Humans; Muscle Proteins; Muscle Strength; Muscle, Skeletal; Resistance Training; Sleep; Time Factors
PubMed: 32811763
DOI: 10.1016/j.jsams.2020.07.016 -
Frontiers in Endocrinology 2021To explore the glycemic control [represented by glycated hemoglobin (HbA1c) concentrations] in children with diabetes mellitus (DM) in east China and middle- and...
Glycated Hemoglobin (HbA1c) Concentrations Among Children and Adolescents With Diabetes in Middle- and Low-Income Countries, 2010-2019: A Retrospective Chart Review and Systematic Review of Literature.
OBJECTIVES
To explore the glycemic control [represented by glycated hemoglobin (HbA1c) concentrations] in children with diabetes mellitus (DM) in east China and middle- and low-income countries, from 2010 to 2019.
METHODS
Retrospective data of children with DM from two hospital-based health records were reviewed. Data on HbA1c concentrations, hospitalization due to diabetic ketoacidosis, and patient demographics were collected and analyzed. A systematic review was subsequently performed to analyze publications that report HbA1c concentrations in patients aged <18 years. Patients' characteristics extracted from each publication were used to generate simulated individual data for pooled analysis. HbA1c estimates were derived from steady-state iterations.
RESULTS
Data of 843 diabetic children (aged 11.2 ± 3.9 years) with 2,658 HbA1c measures were retrieved from the two hospitals during the period 2010-2020. The duration of diabetes in the patients was 4.4 ± 2.8 years, and their HbA1c was 8.1 ± 2.2%. Patients who were internal migrants had significantly higher HbA1c concentration than resident patients (8.4 7.9%). The literature review yielded 1,164 publications, and the majority (74.1%) of patient data were published in high-income countries. The patient data extracted from these publications generated 486,416 HbA1c concentration estimates between 2005 and 2019. The average HbA1c concentration during the 15 years was 9.07 ± 2.15%. The mean HbA1c concentrations among children were 8.23, 8.73, 9.20, and 10.11% in high-income country (HIC), upper-middle income country (UMIC), lower-middle income country (LMIC), and low-income country (LIC) respectively. The mean rate of optimized glycemic control (HbA1c <7.5%) among children was 32.4, 27.5, 21.7, and 12.7% in HIC, UMIC, LMIC, and LIC, respectively.
CONCLUSIONS
The current study indicated that there is substantial room for improvement in glycemic control in children with DM worldwide, especially in middle- and low-income countries.
Topics: Adolescent; Child; Child, Preschool; China; Data Collection; Diabetes Mellitus; Diabetic Ketoacidosis; Electronic Health Records; Female; Glycated Hemoglobin; Hospitalization; Humans; Hypoglycemia; Infant; Infant, Newborn; Male; Models, Statistical; Retrospective Studies
PubMed: 33912137
DOI: 10.3389/fendo.2021.651589