👤 Sathyen A Prabhu

Hypertension is a global target for noncommunicable diseases, and meditation-based interventions (MBIs) benefit patients with hypertension (HTN). The primary objective of this scoping review is to map the globally published MBI studies on patients with HTN. The secondary goal is to identify the role of brain-derived neurotrophic factor (BDNF) in HTN. Based on the Arksey and O'Malley protocol of the Joanna Briggs Institute framework for scoping review, 5 electronic databases were searched with search terms related to HTN and meditation. The open-access articles in the English language published between 1985 and 2024 were selected. The selected articles involved MBIs. All the studies were uploaded to the Rayyan software. Two reviewers worked independently and in duplicate to screen the studies first for title and abstract, and then for full text. Data were extracted based on the template for the intervention description and replication checklist. The data were summarized and reported as a narrative summary. In total, 966 studies were identified. After removing 429 duplicates, 537 studies were screened for their titles and abstracts. 467 studies were excluded based on the inclusion and exclusion criteria, 18 were not retrieved, and 20 were excluded with reasons. Finally, the full texts of 70 studies were read. 32 eligible studies were included in this review. The studies were divided into 3 categories based on meditation and into 7 categories based on outcome. Moreover, no study involving human subjects has analyzed the level of BDNF in HTN patients receiving MBIs. MBIs have shown promising results among HTN patients. There is a research gap in studies related to BDNF and meditation among hypertensive patients. The limitation of the review is the inclusion of open-access articles published only in the English language. Hypertension, Meditation, Mindfulness, Brain-Derived Neurotrophic Factor. Show less

Genetic variants near LYPLAL1 are associated with Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) in humans, but their impact on LYPLAL1 function is unknown. We identified LYPLAL1 loss-of-function variants from UK BioBank (UKBB) whole-exome sequencing data that had AlphaMissense or GPN-MSA scores in the top 20% of LYPLAL1 variants for being disruptive. We aggregated these variants and carried out burden analysis for effects on MRI Proton Density-Fat Fraction (MRI-PDFF) and ICD-based MASLD in UKBB. Rare loss-of-function LYPLAL1 variants were associated with reduced MRI-PDFF and ICD diagnosed MASLD across sexes. We used CRISPR to knockout and overexpress LYPLAL1 in human hepatoma cells (HuH-7), measuring lipid content, lipid uptake/export, and changes in de novo lipogenesis and mitochondrial β-oxidation. LYPLAL1 subcellular localization was determined by overexpressing LYPLAL1-HA tagged protein. We purified GST tagged human LYPLAL1 protein and conducted in vitro tests for esterase and depalmitoylase activity. Knocking out LYPLAL1 reduced triglycerides biochemically as well as lipid intensity after oleic (18:1, n-9) acid treatment. LYPLAL1 KO cells had increased expression of PPARα and MLXIPL, increased mitochondrial β-oxidation, and reduced capacity to both import fatty acids (FAs) and export lipoproteins. Overexpression of LYPLAL1 increased lipid droplet accumulation and decreased PPARα and MLXIPL. LYPLAL1-HA is partly localized to mitochondria when treated with oleic acid. Biochemical analyses showed that LYPLAL1 has strong esterase activity but lacks depalmitoylase activity. Reduction of LYPLAL1 esterase function likely increases β-oxidation of FAs in mitochondria through PPARα and MLXIPL and decreases FA import to protect against lipid accumulation in human liver cancer cells. Together, our results indicate that LYPLAL1 loss-of-function protects against MASLD in Europeans and in vitro, LYPLAL1 is an esterase for short-chain substrates which is involved in the regulation of mitochondrial β-oxidation and uptake of fatty acids, influencing lipid accumulation in the liver. Show less

High-grade astrocytoma with piloid features (HGAP) is a recently described primary brain tumor and the first requiring a specific methylation pattern for diagnosis, as its histologic features are often compatible with other tumors such as glioblastoma (GBM). Characterized by molecular alterations in CDKN2A/B, NF1, BRAF, FGFR1, and ATRX, they may be located anywhere in the CNS but show a predilection for the posterior fossa. Reports are limited to retrospective case series, and the standard of care is not yet established. We performed a retrospective review of electronic medical records of all patients with HGAP at our institution. Records were queried for demographic, radiographic, clinical, surgical, pathologic, and outcome data. Eighteen patients were included with a median 17.1 months follow-up. Of these, 12 (63.2%) were women with a mean age of 43 years (range 24-67). The most common tumor locations were the cerebellum (8 patients, 42.1%) and thalamus (6 patients, 31.6%). On imaging, tumors were most commonly homogeneously contrast-enhancing (10 patients, 52.6%) or rim enhancing with central necrosis (5 patients, 26.3%). Ten patients (52.6%) underwent biopsy, while nine (47.4%) underwent resection, of which four (44.4%) underwent gross total resection. Adjuvant therapy included radiation in 16 patients (88.9%) and systemic treatment in 16 patients (88.9%). The initial systemic treatment was temozolomide in 14 patients (77.8%). One patient received upfront trametinib (a MEK1 inhibitor), and one patient received upfront dabrafenib (a BRAF inhibitor). At last follow up, 11 patients (57.9%) had progressive disease. Median progression-free survival (PFS) was 5.4 months (range 1.6-28.2 months), and median overall survival (OS) had not been reached. HGAP is a newly described rare glial tumor without an established standard of care. Its aggressive behavior and targetable mutations warrant further investigation regarding predictors of outcome for this entity. Show less

Alzheimer's disease (AD) is an extremely complex, heterogeneous, and multifactorial neurodegenerative disease clinically characterized by progressive memory loss and progressive decline in cognitive function. There is currently no effective treatment for the onset and/or progression of the pathophysiological diseases of AD. The global prevalence of this disease has increased in recent years due to modern lifestyle. Therefore, there is an urgent need to develop a drug with significant neuroprotective potential. Since plant metabolites, especially polyphenols, have important pharmacological properties acting against β-amyloid (Aβ), Tau, neuroinflammation, and oxidative stress, such phytochemicals were selected in the present research. Using the Schrödinger tool (Maestro V.13.6), the drug potency of these metabolites was studied after installation in the highly configured workstation. Among the 120 polyphenols docked, amygdalin showed notable docking values of - 11.2638, followed by eriocitrin (- 10.9569), keracyanin (- 10.7086), and amaroswerin (- 9.48126). The prominent MM-GBSA values of these molecules were - 62.8829, - 52.1914, - 68.6307, and - 63.1074, respectively. The MM-GBSA energy values demonstrated the drug stability of these molecules for β-site amyloid precursor protein-cleaving enzyme 1 (BACE1)-causing AD. In the absorption and distribution assessment, these phytochemicals showed significantly better values than the inhibitors CNP520. The chosen phytochemicals have been demonstrated as non-hepatotoxic; however, the BACE1 inhibitor CNP520 is hepatotoxic. In both the molecular docking and ADMET assessments, these natural chemicals have shown optimism as potential drug candidates for Alzheimer's disease. However, in order to understand the detailed biological metabolism of these compounds in AD, they need to be evaluated in in vivo studies to validate its efficacy. Show less

Cardiomyopathies are a leading cause of heart failure and are often caused by mutations in sarcomeric genes, resulting in contractile dysfunction and cellular damage. This may stimulate the production of a robust proinflammatory response. To determine whether myocardial inflammation is associated with cardiac dysfunction in dilated cardiomyopathy (DCM) caused by MYBPC3 mutation, we used the well-characterized cMyBP-C Show less

As individual naïve CD4 T lymphocytes circulate in the body after emerging from the thymus, they are likely to have individually varying microenvironmental interactions even in the absence of stimulation via specific target recognition. It is not clear if these interactions result in alterations in their activation, survival and effector programming. Naïve CD4 T cells show unimodal distribution for many phenotypic properties, suggesting that the variation is caused by intrinsic stochasticity, although underlying variation due to subsets created by different histories of microenvironmental interactions remains possible. To explore this possibility, we began examining the phenotype and functionality of naïve CD4 T cells differing in a basic unimodally distributed property, the CD4 levels, as well as the causal origin of these differences. We examined separated CD4hi and CD4lo subsets of mouse naïve CD4 cells. CD4lo cells were smaller with higher CD5 levels and lower levels of the dual-specific phosphatase (DUSP)6-suppressing micro-RNA miR181a, and responded poorly with more Th2-skewed outcomes. Human naïve CD4lo and CD4hi cells showed similar differences. Naïve CD4lo and CD4hi subsets of thymic single-positive CD4 T cells did not show differences whereas peripheral naïve CD4lo and CD4hi subsets of T cell receptor (TCR)-transgenic T cells did. Adoptive transfer-mediated parking of naïve CD4 cells in vivo lowered CD4 levels, increased CD5 and reactive oxygen species (ROS) levels and induced hyporesponsiveness in them, dependent, at least in part, on availability of major histocompatibility complex class II (MHCII) molecules. ROS scavenging or DUSP inhibition ameliorated hyporesponsiveness. Naïve CD4 cells from aged mice showed lower CD4 levels and cell sizes, higher CD5 levels, and hyporesponsiveness and Th2-skewing reversed by DUSP inhibition. Our data show that, underlying a unimodally distributed property, the CD4 level, there are subsets of naïve CD4 cells that vary in the time spent in the periphery receiving MHCII-mediated signals and show resultant alteration of phenotype and functionality via ROS and DUSP activity. Our findings also suggest the feasibility of potential pharmacological interventions for improved CD4 T cell responses during vaccination of older people via either anti-oxidant or DUSP inhibitor small molecules. Show less