Heat Shock Protein 90 as Therapeutic Target for CVDs and Heart Ageing

Cardiovascular diseases (CVDs) are the leading cause of death globally, representing approximately 32% of all deaths worldwide. Molecular chaperones are involved in heart protection against stresses and age-mediated accumulation of toxic misfolded proteins by regulation of the protein synthesis/degradation balance and refolding of misfolded proteins, thus supporting the high metabolic demand of the heart cells. Heat shock protein 90 (HSP90) is one of the main cardioprotective chaperones, represented by cytosolic HSP90a and HSP90b, mitochondrial TRAP1 and ER-localised Grp94 isoforms. Currently, the main way to study the functional role of HSPs is the application of HSP inhibitors, which could have a different way of action. In this review, we discussed the recently investigated role of HSP90 proteins in cardioprotection, atherosclerosis, CVDs development and the involvements of HSP90 clients in the activation of different molecular pathways and signalling mechanisms, related to heart ageing.

STATUS OF OXIDANT (MDA) ANTIOXIDANT (SOD) IN FIRST AND THIRD TRIMESTER OF NORMAL PREGNANCY IN TERTIARY CENTER OF CENTRAL INDIA

INTRODUCTION: Pregnancy is associated with high metabolic demand and increased demand for tissue oxygen. Consequently increased production of reactive oxygen species. This leads in increased oxidative stress and decreases antioxidant status during gestational age of normal pregnant women. Aim: Aim of this study was to evaluate the level of oxidant and antioxidant in 1st and 3rd trimester of normal pregnant women. MATERIAL AND METHODS: The present study included total 150 cases attended ANC Clinic at the department of Gynae LNMC & J K Hospital was screened for the study. Level of MDA was estimated by Jean et al and SOD was Marklund and Marklund. RESULTS: Findings were, that there was signicantly increase in Malondialdehyde levels (p<0.001) and signicantly decrease in superoxide dismutase activities (P<0.001) in 1st and 3rd trimester of normal pregnant women. Conclusion: present study concludes that there was difference in oxidative status due to dynamic changes. During pregnancy oxidative stress is increased and antioxidant decreased that can be fatal to the health of the mother and the fetus. Therefore antioxidant supplements should be prescribed in early pregnancy to prevent the overwhelming of oxidative stress in pregnant females.

The balance of mitochondrial fission and fusion in cortical axons depends on the kinases SadA and SadB

Neurons are highly polarized cells that display characteristic differences in the organization of their organelles in axons and dendrites. Mitochondria are of particular importance for neuronal homeostasis due to their high metabolic demand. The kinases SadA and SadB (SadA/B) promote the formation of distinct axonal and dendritic extensions during the development of cortical and hippocampal neurons. Here, we show that SadA/B are required for the axon-specific dynamics of mitochondria. The interaction with Ankyrin B (AnkB) stimulates the activity of SadA/B that function as regulators of mitochondrial dynamics through the phosphorylation of Tau. Suppression of SadA/B or AnkB in cortical neurons induces the elongation of mitochondria by disrupting the balance of fission and fusion. The normal dynamics of axonal mitochondria could be restored by mild actin destabilization. Thus, the elongation after a loss of SadA/B results from an excessive stabilization of actin filaments and reduction of Drp1 recruitment to mitochondria.

Optimizing mitochondrial maintenance in extended neuronal projections

Neurons rely on localized mitochondria to fulfill spatially heterogeneous metabolic demands. Mitochondrial aging occurs on timescales shorter than the neuronal lifespan, necessitating transport of fresh material from the soma. Maintaining an optimal distribution of healthy mitochondria requires an interplay between a stationary pool localized to sites of high metabolic demand and a motile pool capable of delivering new material. Interchange between these pools can occur via transient fusion / fission events or by halting and restarting entire mitochondria. Our quantitative model of neuronal mitostasis identifies key parameters that govern steady-state mitochondrial health at discrete locations. Very infrequent exchange between stationary and motile pools optimizes this system. Exchange via transient fusion allows for robust maintenance, which can be further improved by selective recycling through mitophagy. These results provide a framework for quantifying how perturbations in organelle transport and interactions affect mitochondrial homeostasis in neurons, a key aspect underlying many neurodegenerative disorders.

Oxidative stress and impaired oligodendrocyte precursor cell differentiation in neurological disorders

Oligodendrocyte precursor cells (OPCs) account for 5% of the resident parenchymal central nervous system glial cells. OPCs are not only a back-up for the loss of oligodendrocytes that occurs due to brain injury or inflammation-induced demyelination (remyelination) but are also pivotal in plastic processes such as learning and memory (adaptive myelination). OPC differentiation into mature myelinating oligodendrocytes is controlled by a complex transcriptional network and depends on high metabolic and mitochondrial demand. Mounting evidence shows that OPC dysfunction, culminating in the lack of OPC differentiation, mediates the progression of neurodegenerative disorders such as multiple sclerosis, Alzheimer’s disease and Parkinson’s disease. Importantly, neurodegeneration is characterised by oxidative and carbonyl stress, which may primarily affect OPC plasticity due to the high metabolic demand and a limited antioxidant capacity associated with this cell type. The underlying mechanisms of how oxidative/carbonyl stress disrupt OPC differentiation remain enigmatic and a focus of current research efforts. This review proposes a role for oxidative/carbonyl stress in interfering with the transcriptional and metabolic changes required for OPC differentiation. In particular, oligodendrocyte (epi)genetics, cellular defence and repair responses, mitochondrial signalling and respiration, and lipid metabolism represent key mechanisms how oxidative/carbonyl stress may hamper OPC differentiation in neurodegenerative disorders. Understanding how oxidative/carbonyl stress impacts OPC function may pave the way for future OPC-targeted treatment strategies in neurodegenerative disorders.

A hybrid semiconducting organosilica-based O2 nanoeconomizer for on-demand synergistic photothermally boosted radiotherapy

The outcome of radiotherapy is significantly restricted by tumor hypoxia. To overcome this obstacle, one prevalent solution is to increase intratumoral oxygen supply. However, its effectiveness is often limited by the high metabolic demand for O2 by cancer cells. Herein, we develop a hybrid semiconducting organosilica-based O2 nanoeconomizer pHPFON-NO/O2 to combat tumor hypoxia. Our solution is twofold: first, the pHPFON-NO/O2 interacts with the acidic tumor microenvironment to release NO for endogenous O2 conservation; second, it releases O2 in response to mild photothermal effect to enable exogenous O2 infusion. Additionally, the photothermal effect can be increased to eradicate tumor residues with radioresistant properties due to other factors. This “reducing expenditure of O2 and broadening sources” strategy significantly alleviates tumor hypoxia in multiple ways, greatly enhances the efficacy of radiotherapy both in vitro and in vivo, and demonstrates the synergy between on-demand temperature-controlled photothermal and oxygen-elevated radiotherapy for complete tumor response.

Unique Members of the Adipokinetic Hormone Family in Butterflies and Moths (Insecta, Lepidoptera)

Lepidoptera is amongst one of the four most speciose insect orders and ecologically very successful because of their ability to fly. Insect flight is always aerobic and exacts a high metabolic demand on the animal. A family of structurally related neuropeptides, generically referred to as adipokinetic hormones (AKHs), play a key role in triggering the release of readily utilizable fuel metabolites into the hemolymph from the storage forms in the fat body. We used mass spectrometry to elucidate AKH sequences from 34 species of Lepidoptera and searched the literature and publicly available databases to compile (in a phylogenetic context) a comprehensive list of all Lepidoptera sequences published/predicted from a total of 76 species. We then used the resulting set of 15 biochemically characterized AKHs in a physiological assay that measures lipid or carbohydrate mobilization in three different lepidopteran species to learn about the functional cross-activity (receptor-ligand interactions) amongst the different butterfly/moth families. Our results include novel peptide structures, demonstrate structural diversity, phylogenetic trends in peptide distribution and order-specificity of Lepidoptera AKHs. There is almost an equal occurrence of octa-, nona-, and decapeptides, with an unparalleled emphasis on nonapeptides than in any insect order. Primitive species make Peram-CAH-II, an octapeptide found also in other orders; the lepidopteran signature peptide is Manse-AKH. Not all of the 15 tested AKHs are active in Pieris brassicae; this provides insight into structure-activity specificity and could be useful for further investigations into possible biorational insecticide development.

Emerging Nutritional Interventions for Age-Associated Cellular Decline

Aging is associated with a progressive decline in cellular health leading to dysfunction in organs with a high metabolic demand. A key feature of age associated cellular decline is impairment of mitochondrial quality control pathways such as mitophagy. Deficits in optimal functioning of these pathways results in a compromise in cellular bioenergetics that ultimately leads to mitochondrial dysfunction. Promising nutritional interventions have emerged that boost mitochondrial health such as nicotinamide riboside (vitamin B3 precursor) and Urolithin A (gut metabolite of compounds found in pomegranates), that act via different mechanisms of action to improve overall mitochondrial health. Recent literature on the evidence behind these interventions will be presented and discussed during this symposium. We will also share recent clinical evidence from double-blind placebo-controlled studies with Urolithin A. Our results suggest that nutritional interventions such as Urolithin A are promising approaches that can be employed to manage age associated cellular decline.

Optimizing Mitochondrial Maintenance in Extended Neuronal Projections

Neurons rely on localized mitochondria to fulfill spatially heterogeneous metabolic demands. Mi-tochondrial aging occurs on timescales shorter than the neuronal lifespan, necessitating transport of fresh material from the soma. Maintaining an optimal distribution of healthy mitochondria requires an interplay between a stationary pool localized to sites of high metabolic demand and a motile pool capable of delivering new material. Interchange between these pools can occur via transient fusion / fission events or by halting and restarting entire mitochondria. Our quantitative model of neuronal mitostasis identifies key parameters that govern steady-state mitochondrial health at discrete locations. Very infrequent exchange between stationary and motile pools optimizes this system. Exchange via transient fusion allows for robust maintenance, which can be further improved by selective recycling through mitophagy. These results provide a framework for quantifying how perturbations in organelle transport and interactions affect mitochondrial homeostasis in neurons, an key aspect underlying many neurodegenerative disorders.

Stabilization of myeloid-derived HIFs promotes vascular regeneration in retinal ischemia

The retinal vasculature is tightly organized in a structure that provides for the high metabolic demand of neurons while minimizing interference with incident light. The adverse impact of retinal vascular insufficiency is mitigated by adaptive vascular regeneration but exacerbated by pathological neovascularization. Aberrant growth of neovessels in the retina is responsible for impairment of sight in common blinding disorders including retinopathy of prematurity, proliferative diabetic retinopathy, and age-related macular degeneration. Myeloid cells are key players in this process, with diverse roles that can either promote or protect against ocular neovascularization. We have previously demonstrated that myeloid-derived VEGF, HIF1, and HIF2 are not essential for pathological retinal neovascularization. Here, however, we show by cell-specific depletion of Vhl in a mouse model of retinal ischemia (oxygen-induced retinopathy, OIR) that myeloid-derived HIFs promote VEGF and bFGF expression and enhance vascular regeneration in association with improved density and organization of the astrocytic network.