Recent findings on stress induced structural plasticity in rodents have identified important differences between the hippocampus and amygdala. The same chronic immobilization stress (CIS, 2h/day) causes growth of dendrites and spines in the basolateral amygdala (BLA), but dendritic atrophy in hippocampal area CA3. CIS induced morphological changes also differ in their temporal longevity- BLA hypertrophy, unlike CA3 atrophy, persists even after 21 days of stress-free recovery. Furthermore, a single session of acute immobilization stress (AIS, 2h) leads to a significant increase in spine density 10 days, but not 1 day, later in the BLA. However, little is known about the molecular correlates of the differential effects of chronic and acute stress. Because BDNF is known to be a key regulator of dendritic architecture and spines, we investigated if the levels of BDNF expression reflect the divergent effects of stress on the hippocampus and amygdala. CIS reduces BDNF in area CA3, while it increases it in the BLA of male Wistar rats. CIS-induced increase in BDNF expression lasts for at least 21 days after the end of CIS in the BLA. But CIS-induced decrease in area CA3 BDNF levels, reverses to normal levels within the same period. Finally, BDNF is up regulated in the BLA 1 day after AIS and this increase persists even 10 days later. In contrast, AIS fails to elicit any significant change in area CA3 at either time points. Together, these findings demonstrate that both acute and chronic stress trigger opposite effects on BDNF levels in the BLA versus area CA3, and these divergent changes also follow distinct temporal profiles. These results point to a role for BDNF in stress-induced structural plasticity across both hippocampus and amygdala, two brain areas that have also been implicated in the cognitive and affective symptoms of stress-related psychiatric disorders.
In Parkinson’s disease (PD), fibrillar forms of α-synuclein are hypothesized to propagate through synaptically coupled networks, causing Lewy pathology (LP) and neurodegeneration. To more rigorously characterize the determinants of spreading, preformed α-synuclein fibrils were injected into the mouse pedunculopontine nucleus (PPN), a brain region that manifests LP in PD patients and the distribution of developing α-synuclein pathology compared to that ascertained by anterograde and retrograde connectomic mapping. Within the PPN, α-synuclein pathology was cell-specific, being robust in PD-vulnerable cholinergic neurons but not in neighboring noncholinergic neurons. While nearly all neurons projecting to PPN cholinergics manifested α-synuclein pathology, the kinetics, magnitude, and persistence of the propagated pathology were unrelated to the strength of those connections. Thus, neuronal phenotype governs the somatodendritic uptake of pathological α-synuclein, and while the afferent connectome restricts the subsequent spreading of pathology, its magnitude and persistence is not a strict function of the strength of coupling.
Endoplasmic reticulum (ER) stress-mediated apoptosis is a well-known factor in the pathogenesis of age-related macular degeneration (AMD). ER stress leads to accumulation of misfolded proteins, which in turn activates unfolded protein response (UPR) of the cell for its survival. The prolonged UPR of ER stress promotes cell death; however, the transition between adaptation and ER stress-induced apoptosis has not been clearly understood. Hence, the present study investigates the regulatory effect of (-)-epigallocatechin gallate (EGCG) on ER stress-induced by hydrogen peroxide (HO) and disturbance of calcium homeostasis by thapsigargin (TG) in mouse retinal pigment epithelial (MRPE) cells. The oxidant molecules influenced MRPE cells showed an increased level of intracellular calcium [Ca] in ER and transferred to mitochondria through ER-mitochondrial tether site then increased ROS production. EGCG restores [Ca] homeostasis by decreasing ROS production through inhibition of prohibitin1 which regulate ER-mitochondrial tether site and inhibit apoptosis. Effect of EGCG on ER stress-mediated apoptosis was elucidated by exploring the UPR signalling pathways. EGCG downregulated GRP78, CHOP, PERK, ERO1α, IRE1α, cleaved PARP, cleaved caspase 3, caspase 12 and upregulated expression of calnexinin MRPE cells. In addition to this, inhibition of apoptosis by EGCG was also confirmed with expression of proteins Akt, PTEN and GSK3β. MRPE cells with EGCG upregulates phosphorylation of Akt at ser473 and phospho ser380 of PTEN, but phosphorylation at ser9 of GSK3β was inhibited. Further, constitutively active (myristoylated) CA-Akt transfected in MRPE cells had an increased Akt activity in EGCG influenced cells. These findings strongly suggest that antioxidant molecules inhibit cell death through the proper balancing of [Ca] and ROS production in order to maintain UPR of ER in MRPE cells. Thus, modulation of UPR signalling may provide a potential target for the therapeutic approaches of AMD.
Curcumin delivery to cancer cells is challenging due to its hydrophobic nature, low bio distribution and low availability. Many nano vehicles suffer from low stability and toxicity, and hence the prerequisite of a non-toxic nano vehicle with effective drug delivery is still being delved. The present study investigates the delivery efficiency of curcumin with non-spherical mesoporous silica nanoparticles (MSNAs). Their mechanism of drug delivery and signalling proteins activated to induce apoptosis was further explored in MCF-7 cells. A non-spherical MSN was synthesised, functionalised with PEI (MSNAP) and analysed its intracellular behaviour. Our result indicates that MSNAP was non-toxic until 20 µg/mL and likely localizes in cytoplasmic vesicles. On contrast, well-known MCM-41P induced autophagosome formation, indicating cellular toxicity. Curcumin was loaded on MSNAP and its effectiveness in inducing cell death was studied in MCF-7 and in MCF-7R cells. Curcumin loading on MSNAP induces better cell death with 30 µM curcumin, better than unbounded curcumin. Western blot analysis suggest, curcumin induce apoptosis through the activation of caspase 9, 6, 12, PARP, CHOP and PTEN. The cell survival protein Akt1 was downregulated by curcumin with and without the nanostructure. Interestingly, cleaved caspase 9 was activated in higher amount in nano-conjugated curcumin compared to the free curcumin. But other ER resident protein like IRE1α, PERK and GRP78 were downregulated indicating curcumin disturbs ER homeostasis. Further, electron microscopic analysis reveled that nanocurcumin induced apoptosis by disrupting mitochondria and nucleus. Our results with doxorubicin resistant MCF-7 cell lines confirm nanodelivery of doxorubicin and curcumin sensitised cells effectively at lesser concentration. Further docking studies of curcumin indicate it interacts with the apoptotic proteins through hydrogen bonding formation and with higher binding energy.
The multiple properties of zinc sulphide nanoparticles (ZnS-NPs) are attracting great attention in the field of chemical and biological research. ZnS-NPs also find their application in biosensor and photocatalysis. Zinc is an important metal ion in retina and its deficiency leads to age-related macular degeneration. As of now, not much research is available on bio-interaction of ZnS as nanoform with retinal pigment epithelial (RPE) cells. RPE cells in the retina help in maintaining normal photoreceptor function and vision. To begin with, ZnS-NPs were synthesized and characterized using UV-visible spectra, X-ray diffraction, Fourier transform infrared spectrum, transmission electron microscopy and dynamic light scattering. Followed by the confirmation of nanoparticles, our study extended to investigate the impact of ZnS-NPs in primary mouse RPE (MRPE) cells at different concentrations. ZnS-NPs showed dose-dependent cytotoxicity in MRPE cells and no changes were observed in cells' tight intactness at minimal concentration. In addition, exposure to ZnS-NPs increased cellular permeability in dose- and time-dependent manner in MRPE cells. The findings from DCFH-DA analysis revealed that ZnS-NPs-treated cells had elevated level of reactive oxygen species and partial activation of cell apoptosis was identified after exposure to ZnS-NPs at higher concentration. Furthermore, pre-treatment of the primary MRPE cells with ZnS-NPs led to phosphorylation of Akt (Ser 473), which indicates the crucial role of ZnS-NPs in regulating cell survival at minimal concentration. Altogether, this study enumerates requisite dose of using ZnS-NPs to maintain healthy RPE cells and contributes to future studies in development of therapeutic drug and drug carrier for ocular-related disorders.
Breast cancer accounts for the first highest mortality rate in India and second in world. Though current treatment strategies are effectively killing cancer cells, they also end in causing severe side effects and drug resistance. Curcumin is a nutraceutical with multipotent activity but its insolubility in water limits its therapeutic potential as an anti-cancer drug. The hydrophilicity of curcumin could be increased by nanoformulation or changing its functional groups. In this study, curcumin is loaded on mesoporous silica nanoparticle and its anti-cancer activity is elucidated with MCF-7 cell death. Structural characteristics of Mobil Composition of Matter - 41(MCM-41) as determined by high-resolution transmission electron microscopy (HR-TEM) shows that MCM-41 size ranges from 100 to 200 nm diameters with pore size 2-10 nm for drug adsorption. The authors found 80-90% of curcumin is loaded on MCM-41 and curcumin is released efficiently at pH 3.0. The 50 µM curcumin-loaded MCM-41 induced 50% mortality of MCF-7 cells. Altogether, their results suggested that increased curcumin loading and sustained release from MCM-41 effectively decreased cell survival of MCF-7 cells in vitro.
Doxorubicin (DOX), a common chemotherapeutic agent, impairs synaptic plasticity. DOX also causes a persistent increase in basal neuronal excitability, which occludes serotonin-induced enhanced excitability. Therefore, we sought to characterize and reverse DOX-induced physiological changes and modulation of molecules implicated in memory induction using sensory neurons from the marine mollusk Aplysia californica. DOX produced two mechanistically distinct phases of extracellular signal-regulated kinase (ERK) activation, an early and a late phase. Inhibition of MEK (mitogen-activated protein kinase (MAPK)/ERK kinase) after DOX treatment reversed the late ERK activation. MEK inhibition during treatment enhanced the late ERK activation possibly through prolonged downregulation of MAPK phosphatase-1 (MKP-1). Unexpectedly, the late ERK activation negatively correlated with excitability. MEK inhibition during DOX treatment simultaneously enhanced the late activation of ERK and blocked the increase in basal excitability. In summary, we report DOX-mediated biphasic activation of ERK and the reversal of the associated changes in neurons, a potential strategy for reversing the deleterious effects of DOX treatment.
Age-related macular degeneration (AMD) is the leading cause for irreversible visual impairment affecting 30-50 million individuals every year. Oxidative stress and endoplasmic reticulum stress have been identified as crucial factors for the pathogenesis of AMD. Current treatments do not focus on underlying stimuli responsible for the disease like AMD. Zinc is an important trace metal in retina and its deficiency leads to AMD. Recent studies on zinc sulphide nanoparticles (ZnS-NPs) are gaining attention in the field of physical and biological research. In this present study, in investigating the role of ZnS-NPs on hydrogen peroxide and thapsigargin-treated primary mice retinal pigment epithelial (MRPE) cells, we synthesized ZnS-NPs and characterized using atomic force microscope (AFM) and SEM-EDX. The ZnS-NPs abrogate the primary MRPE cell death through inhibition of oxidative stress-induced reactive oxygen species production and cell permeability. Oxidant molecules hydrogen peroxide and thapsigargin alter unfolded protein response such as glucose-regulated protein 78 (GRP78) and C/EBP homology protein (CHOP) expressions, whereas ZnS-NPs-pre-treated primary MRPE cells downregulated the overexpression of such proteins. The expressions of apoptotic proteins caspase 12 and cleaved caspase 9 and caspase 3 were also significantly controlled in ZnS-NPs-treated primary MRPE cells when comparing with thapsigargin- and hydrogen peroxide-treated cells. From these results, ZnS-NPs stabilize reactive oxygen species elevation, when subjected to hydrogen peroxide- and thapsigargin-mediated oxidant injury and helps in maintaining normal homeostasis through regulating endoplasmic reticulum (ER) stress response proteins which is the lead cause for apoptosis-mediated pathogenesis of AMD.
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