Biology subjects

Gupta, N. K.

Publications and source records attributed to Gupta, N. K..

6 recordsLinked to original sources

bioRxiv2024

Implications of diabetes mellitus on pathophysiology of Tuberculosis: Role of AGE-RAGE Axis and Glycated Proteins

Chronic hyperglycemia in diabetes mellitus promotes the formation of advanced glycation end products (AGEs) via non-enzymatic glycation of plasma proteins. AGEs and their receptor RAGE are central to diabetic complications, as they activate inflammatory pathways and oxidative stress. We studied the AGE-RAGE axis in uncontrolled diabetic individuals having pulmonary TB (PTB+DM), uncontrolled diabetic individuals with no infection (DM), and pulmonary TB patients (PTB). Levels of AGEs and RAGE were measured across these groups and compared to controls. The results showed significantly higher AGEs and RAGE levels in the diabetic milieu, reflecting chronic hyperglycemia. These AGEs were shown to be associated with impaired macrophage function, evidenced by reduced phagocytic capacity. Increased AGEs correlated with disease severity in tuberculosis patients co-affected by diabetes, indicating compromised immune responses. RAGE expression also showed a higher trend in TB patients, although not statistically significant, potentially influencing infection outcomes. Glycated calmodulin was also elevated in diabetic and TB-diabetes comorbid patients and negatively correlated with nitric oxide (NO) levels, suggesting that calmodulin glycation hinders NO production in diabetic conditions. Molecular dynamic studies revealed that glycosylation disrupts calmodulins interaction with inducible nitric oxide synthase (iNOS), potentially explaining the decreased NO levels in TB-diabetes comorbid patients. These findings underscore the detrimental impact of AGEs and RAGE in diabetic immune dysregulation, highlighting the need for therapeutic strategies to mitigate their effects on macrophage function and restore immune responses. HighlightsO_LIWe conducted this study to examine how hyperglycemia-driven AGEs and RAGE contribute to immune dysfunction and disease severity in diabetic and TB-diabetes patients. C_LIO_LIHigh AGEs and RAGE impairs macrophage function, decreasing phagocytic capacity and worsening disease severity in TB-diabetes comorbidity. C_LIO_LIGlycosylation disrupts calmodulins interaction with iNOS, contributing to lower NO levels and weakened immune responses in TB-diabetes comorbidity. C_LIO_LIThe AGE-RAGE axis should be studied further for these comorbid conditions to assess and improve macrophage function and restore immune responses. C_LI

immunology↗

bioRxiv2024

Periventricular and Deep White Matter Hyperintensity Thresholds in Aging: Exponential Progression, Cognitive Decline, and Neuroanatomic Atrophy

White matter hyperintensities (WMH), which are brain lesions associated with cerebral small vessel disease and aging, signify fiber loss and pruning. Analysis of T2-FLAIR MRI data from the NACC cohort, including cognitively normal (CN), cognitively impaired (CI), and Alzheimers disease (CI-AD) subjects, revealed that a significant subset of participants, even those classified as CN, harbor substantial periventricular (PVWMH) and deep white matter hyperintensity (DWMH) loads, while others displayed minimal or no PVWMH and DWMH, across ages 50-94 years. In this study, we quantified the thresholds and progression kinetics of PVWMH and DWMH and their impact on cognitive performance and neuroanatomic changes in the aging cohort (NCN = 521, NCI = 146, NCI-AD = 319). Our findings explore the impact of PVWMH and DWMH loads on global and specific cognitive domains to determine whether cognitive impairments are directly induced by PVWMH and DWMH loads, or mediated through distinct neuroanatomic structures. PV and DWMH loads are higher in CI and CI-AD subjects compared to CN but the PVWMH and DWMH loads are not discriminative of CI and CI-AD. The progression kinetics of PVWMH and DWMH volume with age indicate an exponential rate of increase, with PVWMH escalating approximately twice as fast as DWMH particularly around an inflection point at 61 years of age. PVWMH load presents with increased probability of occurrence in frontal horn compared to occipital horn while DWMH is diffused and accumulates significantly at later age than that observed for PVWMH. Multivariate global regression suggested significant effect (p<0.01) of PVWMH on Trail making tests (TMTs)-A and B (executive function), animal naming tests (semantic memory), with no significant effects observed for DWMH load. Indeed, beyond a threshold of PVWMH volume >2.3 mL, significant deficits in TMTs were observed compared to the subjects without PVWMH load. A PVWMH volume >2.3 mL and DWMH >2.75 mL is significantly associated with impairments in attention & working memory (Digit Span Tests), and semantic memory. Noticeably, significant neuroanatomic atrophy in the cerebral cortex, nucleus accumbens, RMFG, precentral, and paracentral gyrus is observed for PVWMH load >2.3 mL, while DWMH load was not significantly associated with neuroanatomic loss. Furthermore, a mediation model employing neuroanatomic volumes as mediator, PVWMH load as predictor and cognitive tests as outcome suggested that PVWMH volume contributes significantly to deficits in TMT-B mediated through atrophy in precentral gyrus (64%), accumbens (39%), paracentral gyrus (32%), rostral middle frontal gyrus (31%), and lingual gyrus (30%), each contributing distinct proportions, alongside the direct effect. DWMH load did not emerge as a significant predictor (direct or indirect) for the cognitive deficits. Further, no significant neuroanatomic mediations from PVWMH load were observed for other cognitive tests indicative of direct involvement of PVWMH load. Global cognition like MMSE was affected only at a higher PVWMH accumulation (>6 ml). HighlightsO_LIPVWMH escalates exponentially twice as fast as DWMH with age. C_LIO_LIPVWMH >2.3 mL is linked to cognitive deficits in executive function, semantic memory and neuroanatomic atrophy; DWMH less impactful. C_LIO_LIPVWMH, not DWMH, significantly affects cognitive decline via a unique set of brain structural loss. C_LIO_LIPVWMH and DWMH loads are not discriminative of CI and AD subjects. C_LI Overview O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=128 SRC="FIGDIR/small/610993v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1ff66b2org.highwire.dtl.DTLVardef@af3852org.highwire.dtl.DTLVardef@19ab4c5org.highwire.dtl.DTLVardef@1d226a6_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

SbPIP2 Mediated Improvements in Plant Resilience: Physiological and Molecular Insights into Abiotic Stress Response

Understanding the mechanisms behind plant resilience to abiotic stresses is essential for enhancing crop yield and sustainability. This study integrates findings from a comprehensive investigation into the function of the SbPIP2 gene, which encodes an aquaporin protein, in improving the abiotic stress tolerance of transgenic plants. Our integrated approach revealed that transgenic plants overexpressing SbPIP2 significantly reduce reactive oxygen species (ROS) accumulation and exhibit enhanced physiological attributes, including higher seed germination rates, improved growth, early flowering, and better seed setting under stress conditions. Notably, these plants also showed a quicker recovery and completion of their lifecycle post-stress treatment. The transcriptomic analysis provided a deeper understanding of the genetic modifications contributing to stress resilience, highlighting the involvement of genes associated with oxidative stress response, calcium and sugar signaling pathways, stomatal regulation, phytohormone biosynthesis, and flower development. Additionally, the study underscores the central role of abscisic acid (ABA) in mediating stress responses through hormonal regulation, with transgenic plants displaying increased ABA levels due to the upregulation of biosynthesis genes and downregulation of catabolism genes. This hormonal adjustment is critical for stomatal closure, reducing water loss, and enhancing tolerance to abiotic stresses. Our findings elucidate the complex genetic and molecular pathways that underpin abiotic stress tolerance in plants, offering valuable insights for future research aimed at improving crop resilience through genetic engineering, thereby addressing the challenges of climate change and environmental stressors.

plant biology↗

bioRxiv2023

Magnitude and Kinetics of a set of Neuroanatomic Volume and Thickness together with White Matter Hyperintensity is definitive of Cognitive Status and Brain Age

In an aging population, a subset of individuals at a given age group have low white matter hyperintensity (WMH) while another subset has intermediate to high WMH load. WMH load quantification together with comprehensive neuroanatomic volumetry needs to be examined together for establishing a unique precise and optimal number of brain features as a noninvasive indicator of Brain Age and cognitive status. Here, a comprehensive neuroanatomic volumetry together with WMH quantification using longitudinal MRI and cognitive measurements from two aging cohorts have been performed together with machine learning modeling of the quantitative changes with aging to establish Optimal unique brain events discriminative of cognitive status and estimative of Brain Age. A set of Three optimal brain-associated quantities; wherein two are neuroanatomic features Total brain volume; CSF volume, and the third is the extent of microvascular pathology WMH load, provide highly precise discrimination of cognitive status as cognitively normal (CN), impaired (CI) and AD (CI-AD). While medial cortical thinning of Parahippocampal gyrus is an early age event discriminative between CI and CI-AD but loss of hippocampus, gray matter and white matter volume lacks sensitivity to discriminate between CI and CI-AD. The Brain Age estimation using the neuroanatomic volumetry and periventricular and deep WMH load indicates that elevated WMH load in the brain led to an increased Brain Age gap than the brain with low WMH at a given chronological age. Increased Brain Age gap with elevated WMH load at the early age groups is suggestive of profound vascular insult arising from WMH to the brain structure and function.

neuroscience↗

bioRxiv2022

Transgenic porcine model reveals two roles for LGR5 during lung development and homeostasis

Cells expressing LGR5 play a pivotal role in homeostasis, repair, and regeneration in multiple organs including skin and gastrointestinal tract, yet little is known about their role in the lung. Findings from mice, a widely used animal model, suggest that lung LGR5 expression differs from that of humans. In this work, using a new transgenic pig model, we identify two main populations of LGR5+ cells in the lung that are conserved in human, but not mouse lungs. Using RNA sequencing, 3D imaging and organoid models, we determine that in the fetal lung, epithelial LGR5 expression is transient in a subpopulation of SOX9+/ETV+/SFTPC+ progenitor lung tip cells. In contrast, epithelial LGR5 expression is absent from postnatal lung, but is reactivated in bronchioalveolar organoids derived from basal airway cells. We also describe a separate population of mesenchymal LGR5+ cells that surrounds developing and mature airways, lies adjacent to airway basal cells, and is closely associated with nerve fibers. Transcriptionally, mesenchymal LGR5+ cells include a subset of peribronchial fibroblasts (PBF) that express unique patterns of SHH, FGF, WNT and TGF-{beta} signaling pathway genes. These results support distinct roles for LGR5+ cells in the lung and describe a physiologically relevant animal model for further studies on the function of these cells in repair and regeneration.

cell biology↗

bioRxiv2022

Chronic hyperglycemia drives alterations in macrophage effector function in pulmonary tuberculosis

BackgroundThe rising prevalence of Diabetes mellitus (DM) in high TB endemic countries has the potential to adversely affect sustainability of TB control since DM can lead to alterations in both innate and adaptive immune response constituting as a risk factor for development of active tuberculosis (TB). The impact of hyperglycemia on TB specific innate immune response in terms of macrophage functions remains poorly addressed. Material and methodsMacrophage effector functions in diabetic and non-diabetic individuals with and without PTB infection as well as non-diabetic-uninfected controls (fifty individuals in each group) were assessed. Phagocytic capacity against BCG and surface expression of PRRs (CD11b, CD14, CD206, MARCO and TLR2) were measured via flow cytometry. Effector molecules (ROS and NO) were assessed via DCFDA and Griess reaction respectively. ResultsA systematic dysregulation in phagocytic capacity with concurrent alterations in expression pattern of key PRRs (CD11b, MARCO and CD206) and effector molecules (ROS and NO) was observed in diabetic individuals with PTB. These altered macrophage functions were positively correlated with increase in disease severity in diabetic individuals. ConclusionOur results highlight several key patterns of immune dysregulation against M.Tb under hyperglycemic conditions. A significant reduction in macrophage effector functions in infected diabetic individuals which further correlated with increase in disease severity reveals a negative impact of hyperglycemia with aetiology and pathological progression of TB.

immunology↗