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Molecular Therapy. Methods & Clinical... Jun 2024Hematopoietic stem cell gene therapy (HSCGT) is a promising therapeutic strategy for the treatment of neurodegenerative, metabolic disorders. The approach involves the...
Hematopoietic stem cell gene therapy (HSCGT) is a promising therapeutic strategy for the treatment of neurodegenerative, metabolic disorders. The approach involves the introduction of a missing gene into patients' own stem cells via lentiviral-mediated transduction (TD). Once transplanted back into a fully conditioned patient, these genetically modified HSCs can repopulate the blood system and produce the functional protein, previously absent or non-functional in the patient, which can then cross-correct other affected cells in somatic organs and the central nervous system. We previously developed an HSCGT approach for the treatment of Mucopolysaccharidosis type II (MPSII) (Hunter syndrome), a debilitating pediatric lysosomal disorder caused by mutations in the iduronate-2-sulphatase (IDS) gene, leading to the accumulation of heparan and dermatan sulfate, which causes severe neurodegeneration, skeletal abnormalities, and cardiorespiratory disease. In HSCGT proof-of-concept studies using lentiviral IDS fused to a brain-targeting peptide ApoEII (IDS.ApoEII), we were able to normalize brain pathology and behavior of MPSII mice. Here we present an optimized and validated good manufacturing practice hematopoietic stem cell TD protocol for MPSII in preparation for first-in-man studies. Inclusion of TEs LentiBOOST and protamine sulfate significantly improved TD efficiency by at least 3-fold without causing adverse toxicity, thereby reducing vector quantity required.
PubMed: 38946936
DOI: 10.1016/j.omtm.2024.101271 -
World Journal of Gastroenterology Jun 2024Metabolic dysfunction-associated fatty liver disease (MAFLD) is a hepatic manifestation of the metabolic syndrome. It is one of the most common liver diseases worldwide... (Review)
Review
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a hepatic manifestation of the metabolic syndrome. It is one of the most common liver diseases worldwide and shows increasing prevalence rates in most countries. MAFLD is a progressive disease with the most severe cases presenting as advanced fibrosis or cirrhosis with an increased risk of hepatocellular carcinoma. Gut microbiota play a significant role in the pathogenesis and progression of MAFLD by disrupting the gut-liver axis. The mechanisms involved in maintaining gut-liver axis homeostasis are complex. One critical aspect involves preserving an appropriate intestinal barrier permeability and levels of intestinal lumen metabolites to ensure gut-liver axis functionality. An increase in intestinal barrier permeability induces metabolic endotoxemia that leads to steatohepatitis. Moreover, alterations in the absorption of various metabolites can affect liver metabolism and induce liver steatosis and fibrosis. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a class of drugs developed for the treatment of type 2 diabetes mellitus. They are also commonly used to combat obesity and have been proven to be effective in reversing hepatic steatosis. The mechanisms reported to be involved in this effect include an improved regulation of glycemia, reduced lipid synthesis, β-oxidation of free fatty acids, and induction of autophagy in hepatic cells. Recently, multiple peptide receptor agonists have been introduced and are expected to increase the effectiveness of the treatment. A modulation of gut microbiota has also been observed with the use of these drugs that may contribute to the amelioration of MAFLD. This review presents the current understanding of the role of the gut-liver axis in the development of MAFLD and use of members of the GLP-1 RA family as pleiotropic agents in the treatment of MAFLD.
Topics: Humans; Glucagon-Like Peptide-1 Receptor; Gastrointestinal Microbiome; Liver; Non-alcoholic Fatty Liver Disease; Animals; Metabolic Syndrome; Hypoglycemic Agents; Diabetes Mellitus, Type 2; Incretins; Intestinal Mucosa; Glucagon-Like Peptide-1 Receptor Agonists
PubMed: 38946874
DOI: 10.3748/wjg.v30.i23.2964 -
World Journal of Clinical Oncology Jun 2024Myeloproliferative neoplasms (MPNs) occur due to the abnormal proliferation of one or more terminal myeloid cell lines in peripheral blood. Subjects suffering from MPNs... (Review)
Review
Myeloproliferative neoplasms (MPNs) occur due to the abnormal proliferation of one or more terminal myeloid cell lines in peripheral blood. Subjects suffering from MPNs display a high burden of cardiovascular risk factors, and thrombotic events are often the cause of death in this population of patients. Herein, we provide a brief overview of dyslipidemia and metabolic syndrome and their epidemiology in MPNs and examine the common molecular mechanisms between dyslipidemia, metabolic syndrome, and MPNs, with a special focus on cardiovascular risk, atherosclerosis, and thrombotic events. Furthermore, we investigate the impact of dyslipidemia and metabolic syndrome on the occurrence and survival of thrombosis in MPN patients, as well as the management of dyslipidemia in MPNs, and the impact of MPN treatment on serum lipid concentrations, particularly as side/adverse effects reported in the context of clinical trials.
PubMed: 38946827
DOI: 10.5306/wjco.v15.i6.717 -
Journal of Cell Communication and... Jun 2024Obesity, a rapidly expanding epidemic worldwide, is known to exacerbate many medical conditions, making it a significant factor in multiple diseases and their associated... (Review)
Review
Obesity, a rapidly expanding epidemic worldwide, is known to exacerbate many medical conditions, making it a significant factor in multiple diseases and their associated complications. This threatening epidemic is linked to various harmful conditions such as type 2 diabetes mellitus, hypertension, metabolic dysfunction-associated steatotic liver disease, polycystic ovary syndrome, cardiovascular diseases (CVDs), dyslipidemia, and cancer. The rise in urbanization and sedentary lifestyles creates an environment that fosters obesity, leading to both psychosocial and medical complications. To identify individuals at risk and ensure timely treatment, it is crucial to have a better understanding of the pathophysiology of obesity and its comorbidities. This comprehensive review highlights the relationship between obesity and obesity-associated complications, including type 2 diabetes, hypertension, (CVDs), dyslipidemia, polycystic ovary syndrome, metabolic dysfunction-associated steatotic liver disease, gastrointestinal complications, and obstructive sleep apnea. It also explores the potential mechanisms underlying these associations. A thorough analysis of the interplay between obesity and its associated complications is vital in developing effective therapeutic strategies to combat the exponential increase in global obesity rates and mitigate the deadly consequences of this polygenic condition.
PubMed: 38946722
DOI: 10.1002/ccs3.12039 -
Food & Function Jul 2024: The Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet is emerging as a promising candidate for preventive measures against inflammatory bowel...
Greater adherence to the Mediterranean Dietary Approaches to Stop Hypertension Intervention for Neurodegenerative Delay (MIND) diet is associated with lower risk of inflammatory bowel disease: a prospective cohort study.
: The Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet is emerging as a promising candidate for preventive measures against inflammatory bowel disease (IBD), though there is currently no direct evidence from population-based studies. This study aims to bridge the gap in understanding of the association of the MIND diet with IBD risk. : We utilized data from 187 490 participants in the UK Biobank who provided dietary information and were free of IBD at baseline. Dietary information was obtained using a validated web-based 24-hour dietary recall questionnaire. A MIND diet score was evaluated based on the intake of ten beneficial and five unhealthy food groups and the scores were further grouped into tertiles. The outcome of interest was incident IBD, Crohn's disease (CD), and ulcerative colitis (UC). Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models adjusted for demographic characteristics, lifestyle factors, cancer history, and other dietary factors. Mediation analyses were performed to evaluate the role of systemic inflammation and metabolic disorders represented by the integrated biomarkers in the MIND diet-IBD association. : After a mean follow-up of 10.7 years, we documented 825 incident IBD cases (250 CD and 575 UC). The average age of the participants was 56.2 years, of which 55.0% were females. We found that greater adherence to the MIND diet, represented by a higher diet score, was associated with a lower risk of IBD (HR 0.74, 95% CI 0.62-0.90, = 0.002; for trend = 0.005), CD (HR 0.66, 95% CI 0.47-0.94, = 0.022; for trend = 0.023), and UC (HR 0.78, 95% CI 0.62-0.98, = 0.031; for trend = 0.022). The associations were partially mediated by metabolic and inflammation status (mediation proportion: 5.5-15.9%). : We found higher adherence to the MIND diet was associated with a lower risk of IBD, and that inflammatory and metabolic conditions may play an important role in the underlying mechanistic pathways.
PubMed: 38946529
DOI: 10.1039/d4fo00641k -
American Journal of Physiology. Cell... Jul 2024Type 2 diabetes (T2D) constitutes a major public health problem, and despite prevention efforts, this pandemic disease is 'one of the deadliest diseases in the world. In...
Type 2 diabetes (T2D) constitutes a major public health problem, and despite prevention efforts, this pandemic disease is 'one of the deadliest diseases in the world. In 2022, 6.7 million T2D patients died prematurely from vascular complications. Indeed, diabetes increases the risk of myocardial infarction or stroke eightfold. The identification of the molecular actors involved in the occurrence of cardiovascular complications and their prevention are therefore major axes. Our hypothesis is that factors brought into play during physiological aging appear prematurely with diabetes progression. Our study focused on the aging of the extracellular matrix (ECM), a major element in the maintenance of vascular homeostasis. We characterized the morphological and functional aspects of aorta, with a focus on the collagen and elastic fibers of diabetic mice aged from 6 months to non-diabetic mice aged 6 months and 20 months. The comparison with the two non-diabetic models (young and old) highlighted an exacerbated activity of proteases, which could explain a disturbance in the collagen accumulation and an excessive degradation of elastic fibers. Moreover, the generation of circulating elastin-derived peptides reflects premature aging of the ECM. These extracellular elements contribute to the appearance of vascular rigidity, often the origin of pathologies such as hypertension and atherosclerosis. In conclusion, we show that diabetic mice aged 6 months present the same characteristics of ECM wear as those observed in mice aged 20 months. This accelerated aortic wall remodeling could then explain the early onset of cardiovascular diseases and, therefore, the premature death of DT2 patients.
PubMed: 38946422
DOI: 10.1152/ajpcell.00615.2023 -
The American Journal of Psychiatry Jul 2024
Topics: Humans; Cardiovascular Diseases; Mental Disorders; Metabolic Syndrome
PubMed: 38946278
DOI: 10.1176/appi.ajp.20240370 -
Physical Medicine and Rehabilitation... Aug 2024Concussions are the most common type of traumatic brain injury. They result from external force to the head that causes a neuro-metabolic cascade to unfold. This can... (Review)
Review
Concussions are the most common type of traumatic brain injury. They result from external force to the head that causes a neuro-metabolic cascade to unfold. This can then lead to a variety of symptoms in the domains of physical, cognition, mood, and sleep. Concussions are a clinical diagnosis but it is important to rule out acute intracranial pathology through a detailed history and physical examination in addition to possible head imaging. Treatment should include an individualized approach that focuses on what domains are affected after concussion.
Topics: Humans; Brain Concussion
PubMed: 38945648
DOI: 10.1016/j.pmr.2024.02.005 -
Advances in Gerontology = Uspekhi... 2024Metabolic syndrome is a group of disorders that are closely related to both the risk of developing type 2 diabetes mellitus and cardiovascular diseases, and generally... (Review)
Review
[Markers of inflammation with decreased functionality in the cognitive and psychological domains of individual vitality in middle-aged and elderly patients with metabolic syndrome.].
Metabolic syndrome is a group of disorders that are closely related to both the risk of developing type 2 diabetes mellitus and cardiovascular diseases, and generally leading to the phenomenon of premature aging of the body. Excessive accumulation of adipose tissue contributes to the development of chronic immune inflammation and oxidative stress, which are both precursors to various disorders, such as insulin resistance, arterial hypertension and dyslipidemia, but also trigger inflammatory processes in patients. An increasing number of studies support the importance of chronic immune inflammation in the pathogenesis of metabolic syndrome, as pro-inflammatory markers such as TNF-α, IL-1β, IL-6, monocyte chemotactic protein-1 and growth of vascular endothelium. Among a wide range of cytokines, monocyte chemotactic protein-1 is considered one of the most important chemokines, which activates monocytes and other immune cells actively involved in inflammation. Another important point of chronic immune inflammation is its impact on the mental health of patients with metabolic syndrome. Increased levels of anxiety and depression are associated with levels of pro-inflammatory cytokines produced by adipose tissue, which ultimately has an adverse effect on the cognitive status of patients.
Topics: Humans; Metabolic Syndrome; Inflammation; Biomarkers; Aged; Cytokines; Middle Aged; Aging; Oxidative Stress
PubMed: 38944784
DOI: No ID Found -
Mymensingh Medical Journal : MMJ Jul 2024Metabolic Syndrome (METS) plays a pivotal role in the development of diabetes mellitus, coronary artery diseases and stroke. Due to the scarcity of data in this issue,...
Metabolic Syndrome (METS) plays a pivotal role in the development of diabetes mellitus, coronary artery diseases and stroke. Due to the scarcity of data in this issue, this study aims to assess the frequency and risk factors association of METS among the hypertensive patients. This cross-sectional study recruited 667 eligible hypertensive patients aged between 20 and 70 years using non-probability purposive sampling method conducted from 1st January 2019 to 30th June 2019. Hypertensive patients with the known history of diabetes, thyroid, renal, cardiac, or hepatic disease, Cushing syndrome or malignancy and secondary causes of obesity, confirmed pregnancy, bed ridden, taking lipid lowering drugs or drugs that affect lipid and glucose metabolism were excluded from the study. METS among the hypertensive patients (DE novo or established hypertensive patients) of this study was demonstrated by NCEP-ATPIII (National Cholesterol Education Program-Adult Treatment Panel III) criteria having two or more of the following points [a) increased waist circumference ≥102cm in men and ≥88cm in women, b) hypertriglyceridemia: ≥150mg/dl, c) reduced High density lipoprotein cholesterol (HDL-C) <40mg/dL (1.04mmol/L) in men and <50mg/dL (1.29mmol/L) in women, d) high fasting blood glucose: 110mg/dl]. Significantly high frequency (69.9%, p<0.001) of METS was found with a significant female preponderance (52.5%, p<0.001) where the mean age of the study population was 48±11 years. Sex (p<0.001), education (p=0.041), occupation (p<0.001), Body mass index (BMI) (p<0.001) and hypertensive status (p=0.002) showed a highly significant role in the development of METS. Following binary logistic regression analysis after adjusting for confounders, the female sex was 17 times higher than the male [Adjusted odd ratio (AOR) =16.96, 95% CI=4.91-58.66, p<0.001)], obesity 4 times higher than non-obese [BMI (obese AOR=4.24, 95% CI=2.55-7.98, p<0.001)], hypertensive status [established hypertension two times higher than de novo (de-novo AOR=0.60, 95% CI=0.037-0.97, p=0.037)] were significant and independent predictors of METS. Significantly high BMI (27.7±4.2 and p<0.001), high waist circumference (60.4%, p<0.001) and hyper tri-glyceridaemia and reduced HDL (46.0%, p<0.001 and 51.3%, p<0.001) were found in the subjects with METS. In conclusion, high frequency of METS among the hypertensive patients was found in Jashore, Bangladesh with significant risk factors related to female sex, education, occupation, BMI and hypertensive status. So, a holistic evaluation of metabolic components among the hypertensive patients may reduce premature cardiovascular morbidity and mortality.
Topics: Humans; Female; Male; Middle Aged; Metabolic Syndrome; Hypertension; Cross-Sectional Studies; Adult; Bangladesh; Risk Factors; Aged; Waist Circumference
PubMed: 38944728
DOI: No ID Found