Inhibition of VDAC1 Protects Against Glutamate-Induced Oxytosis and Mitochondrial Fragmentation in Hippocampal HT22 Cells.

The involvement of glutamate in neuronal cell death in neurodegenerative diseases and neurotrauma is mediated through excitotoxicity or oxytosis. The latter process induces oxidative stress via glutamate-mediated inhibition of cysteine transporter xCT, leading to depletion of the cellular glutathione pool. Mitochondrial damage, loss of mitochondrial membrane potential (MMP), and depletion of energy metabolites have been shown in this process. The Voltage-Dependent Anion Channel-1 (VDAC1) is one of the main components of the mitochondrial outer membrane and plays a gatekeeping role in mitochondria-cytoplasm transport of metabolites. In this study, we explored the possible participation of VDAC-1 in the pathophysiology of oxytosis. Administration of glutamate in HT22 cells that lack the glutamate ionotropic receptors induced an upregulation and oligomerization of VDAC1. This was associated with an increase in ROS and loss of cell survival. Glutamate-mediated oxytosis in this model also decreased MMP and promoted ATP depletion, resulting in translocation of cytochrome c (cyt C) and apoptosis inducing factor (AIF) from mitochondria into the cytosol. This was also accompanied by cleavage of AIF to form truncated AIF. Inhibition of VDAC1 oligomerization using 4,4'-Diisothiocyanatostilbene-2,2'-disulfonate (DIDS), significantly improved the cell survival, decreased the ROS levels, improved mitochondrial functions, and decreased the mitochondrial damage. Notably, DIDS also inhibited the mitochondrial fragmentation caused by glutamate, indicating the active role of VDAC1 oligomerization in the process of mitochondrial fragmentation in oxytosis. These results suggest a critical role for VDAC1 in mitochondrial fragmentation and its potential therapeutic value against glutamate-mediated oxidative neurotoxicity.

ß-Amyloid induces nuclear protease-mediated lamin fragmentation independent of caspase activation.

ß-Amyloid (Aß), a hallmark peptide of Alzheimer's disease, induces both caspase-dependent apoptosis and non-apoptotic cell death. In this study, we examined caspase-independent non-apoptotic cell death preceding caspase activation in Aß42-treated cells. We first determined the optimal treatment conditions for inducing cell death without caspase activation and selected a double-treatment method involving the incubation of cells with Aß42 for 4 and 6 h (4+6 h sample). We observed that levels of lamin A (LA) and lamin B (LB) were reduced in the 4+6 h samples. This reduction was decreased by treatment with suc-AAPF-CMK, an inhibitor of nuclear scaffold (NS) protease, but not by treatment with z-VAD-FMK, a pan-caspase inhibitor. In addition, suc-AAPF-CMK decreased the changes in nuclear morphology observed in cells in the 4+6 h samples, which were different from nuclear fragmentation observed in STS-treated cells. Furthermore, suc-AAPF-CMK inhibited cell death in the 4+6 h samples. LA and LB fragmentation occurred in the isolated nuclei and was also inhibited by suc-AAPF-CMK. Together, these data indicated that the fragmentation of LA and LB in the Aß42-treated cells was induced by an NS protease, whose identity is not clearly determined yet. A correlation between Aß42 toxicity and the lamin fragmentation by NS protease suggests that inhibition of the protease could be an effective method for controlling the pathological process of AD.

Amyloid ß binds procaspase-9 to inhibit assembly of Apaf-1 apoptosome and intrinsic apoptosis pathway.

Apoptosis is essential in the death process induced by Amyloid-ß (Aß), a major constituent of diffuse plaques found in Alzheimer's disease patients. However, we have found that caspase activation and cell death induced by staurosporine, employed to induce the intrinsic mitochondria-dependent apoptotic pathway, were significantly reduced by 42 amino-acid Aß42, implying that the peptide also has a negative effect on the apoptotic process. The inhibitory effect of Aß42 on the apoptotic pathway is associated with its interaction with procaspase-9 and consequent inhibition of Apaf-1 apoptosome assembly. We detected the inhibitory effect in the early stage (<8h) of apoptosis, but later caspase activation becomes obvious. Thus we inferred that the inhibitory process on apoptosis begins at an early stage, and the later robust activation surpasses it. We propose that the apoptotic manifestation in Aß-treated cells is a combined consequence of those anti- and pro-apoptotic processes.

Potential data for feasibility assessment and deployment of a 6.7 MW floating solar PV plant in Hatirjheel Lake, Dhaka, Bangladesh.

Floating solar photovoltaic has emerged as a highly sustainable and environmentally friendly solution worldwide from the various clean energy generation technologies. However, the installation of floating solar differs from rooftop or ground-mounted solar due to the significant consideration of the availability of water bodies and suitable climatic conditions. Therefore, conducting a feasibility analysis of the suitable climate is essential for installing a floating solar plant on water bodies. These data are evaluated for the viability of installing a 6.7 MW floating solar power plant on Hatirjheel Lake in Dhaka, Bangladesh. The feasibility analysis incorporated various climatic data, such as temperature, humidity, rainfall, sunshine hours, solar radiation, and windspeed, obtained from Meteonorm 8.1 software and the archive of the Bangladesh Meteorological Department. Besides, this study gathered and analyzed the energy demands of the local grid substation operated by Dhaka Power Distribution Company, to determine the appropriate capacity and architecture of the power plant. The power plant design was conducted using the PVsyst 7.3 software, which determined the necessary equipment quantities, DC energy generation capacity, and the energy injected into the grid in MWh. The study also calculated the Levelized Cost of Energy per kilowatt-hour and the payback period for the system, which indicates the economic viability of installing the system. Furthermore, the acquired dataset possesses significant potential and can be utilized for the establishment of all sorts of solar power plants, including floating solar plants, in any location or body of water within the Dhaka Metropolitan area.

Optimizing photovoltaic arrays: A tested dataset of newly manufactured PV modules for data-driven analysis and algorithm development.

This data article presents a comprehensive dataset comprising experimentally tested characteristics of newly manufactured photovoltaic (PV) modules, which have been collected by using a commercial PV testing system from a solar panel manufacturer company. The PV testing system includes an artificial sunlight simulator to generate input light for the PV and the outputs of the PV are tested by a professional IV tracer in a darkroom environment maintaining IEC60904-9 standard. The dataset encompasses modules with power ratings of 10 W, 85 W, and 247 W, each represented by 40 individual module records. The tested and collected characteristics of each module include open circuit voltage, short circuit current, maximum power point voltage, maximum power point current, maximum power point power, and fill factor. The motivation for this dataset lies in addressing the challenges posed by manufacturing defects and a ± 5 % manufacturing tolerance, which can lead to mismatch power losses in newly installed PV arrays. These losses result in lower current in series strings and lower voltage in parallel branches, ultimately decreasing the array's output power. The dataset serves as a valuable resource for academic research, particularly in the domain of PV array optimization. To facilitate optimization efforts, different algorithms have been explored in the literature. This dataset supports the exploration of these optimization algorithms to find solutions that enhance the position of each module within the array, consequently increasing the overall output power and efficiency of the PV system. The objective is to mitigate mismatch power losses, which, if unaddressed, can contribute to increased degradation rates and early aging of PV modules. This dataset lays the groundwork for addressing critical PV array performance and efficiency issues. In future research, this dataset can be reused to explore and implement optimization algorithms, to improve the overall output power and lifespan of newly installed PV arrays. The smart solution proposed in [1], utilizing a genetic algorithm-based module arrangement, demonstrates promising results for maximizing PV array output power using this dataset.

The inhibitory effects of Escherichia coli maltose binding protein on ß-amyloid aggregation and cytotoxicity.

The aggregation of ß-amyloid (Aß) peptide from its monomeric to its fibrillar form importantly contributes to the development of Alzheimer's disease. Here, we investigated the effects of Escherichia coli maltose binding protein (MBP), which has been previously used as a fusion protein, on Aß42 fibrillization, in order to improve understanding of the self-assembly process and the cytotoxic mechanism of Aß42. MBP, at a sub-stoichiometric ratio with respect to Aß42, was found to have chaperone-like inhibitory effects on ß-sheet fibril formation, due to the accumulation of Aß42 aggregates by sequestration of active Aß42 species as Aß42-MBP complexes. Furthermore, MBP increased the lag time of Aß42 polymerization, decreased the growth rate of fibril extension, and suppressed Aß42 mediated toxicity in human neuroblastoma SH-SY5Y cells. It appears that MBP decreases the active concentration of Aß42 by sequestering it as Aß42-MBP complex, and that this sequestration suppresses ongoing nucleation and retards the growth rate of Aß42 species required for fibril formation. We speculate that inhibition of the growth rate of potent Aß42 species by MBP suppresses Aß42-mediated toxicity in SH-SY5Y cells.

Electrical data of 10W, 40W, 80W, and 250W photovoltaic modules under the aging condition: Tested by a Solar Manufacturer Company in Bangladesh.

The health monitoring system of photovoltaic modules throughout their lifespan is an important research topic. The dataset of aged PV modules is required to investigate the performance of the aged PV array for simulation work. Different aging factors are responsible for decreasing the output power of aged PV modules and increasing the degradation rate. In addition, mismatch power losses are increases with the nonuniformity of aged PV modules due to different aging factors. In this work, four datasets of 10W, 40W, 80W, and 250W PV modules are collected under nonuniform aging conditions. Each dataset contains forty modules with a four-year aged average. The average deviation of each electrical parameter of the PV modules can be calculated from this data. Moreover, a correlation can be developed between the average deviation of electrical parameters and mismatch power loss in PV array modules under early aging conditions.

Evidence for a Strong Relationship between the Cytotoxicity and Intracellular Location of ß-Amyloid.

ß-Amyloid (Aß) is a hallmark peptide of Alzheimer's disease (AD). Herein, we explored the mechanism underlying the cytotoxicity of this peptide. Double treatment with oligomeric 42-amino-acid Aß (Aß42) species, which are more cytotoxic than other conformers such as monomers and fibrils, resulted in increased cytotoxicity. Under this treatment condition, an increase in intracellular localization of the peptide was observed, which indicated that the peptide administered extracellularly entered the cells. The cell-permeable peptide TAT-tagged Aß42 (tAß42), which was newly prepared for the study and found to be highly cell-permeable and soluble, induced Aß-specific lamin protein cleavage, caspase-3/7-like DEVDase activation, and high cytotoxicity (5-10-fold higher than that induced by the wild-type oligomeric preparations). Oligomeric species enrichment and double treatment were not necessary for enhancing the cytotoxicity and intracellular location of the fusion peptide. Taiwaniaflavone, an inhibitor of the cytotoxicity of wild-type Aß42 and tAß42, strongly blocked the internalization of the peptides into the cells. These data imply a strong relationship between the cytotoxicity and intracellular location of the Aß peptide. Based on these results, we suggest that agents that can reduce the cell permeability of Aß42 are potential AD therapeutics.

Electrical experimental data collection of polycrystalline and monocrystalline photovoltaic modules in an indoor environment using artificial sun simulator.

In the twenty-first century, energy sustainability and reliability are one of the major challenges in the world and prime factors of the national development plan. Recently, Solar PV is gaining popularity and making a significant effect as an alternative to fossil fuels due to reduction of cost and enhanced efficiency. However, the production performance of Solar PV over the period gets significantly impacted owing to a variety of problems such as dust, aging due to shading and soiling over the cell, hot spot, discoloration and corrosion for excessive atmospheric temperature, inadequate solar light, cell damage, and so on. In this research, a low-cost halogen-based artificial sun simulator is developed and deployed to examine the electrical properties of Solar PV in indoor conditions. Two monocrystalline and three polycrystalline PV panels under Standard Test Conditions, as well as a prototype 5 × 8 PV array, using this artificial light source, were evaluated rigorously for experimental purposes. With the help of a microcontroller-based I-V tracer and an actual data storage system, Open Circuit Voltage (Voc), Short Circuit Current (Isc), Maximum Power Voltage (Vmp), Maximum Power Current (Imp), and Maximum Power (Pmax) at three irradiance levels were measured and recorded. Utilizing Microsoft Excel software, the data logger's recorded data were analyzed and I-V and P-V curves were plotted. These data are extremely valuable for obtaining a good understanding of the validity of the Sun Simulator and the rate of deterioration of solar PV performance depending on irradiance. These data will aid the research community in future research regarding PV array performance monitoring, corresponding solution modeling, and developing cost-effective installation of large-scale PV arrays.

Regulatory role of cathepsin L in induction of nuclear laminopathy in Alzheimer's disease.

Experimental and clinical therapies in the field of Alzheimer's disease (AD) have focused on elimination of extracellular amyloid beta aggregates or prevention of cytoplasmic neuronal fibrillary tangles formation, yet these approaches have been generally ineffective. Interruption of nuclear lamina integrity, or laminopathy, is a newly identified concept in AD pathophysiology. Unraveling the molecular players in the induction of nuclear lamina damage may lead to identification of new therapies. Here, using 3xTg and APP/PS1 mouse models of AD, and in vitro model of amyloid beta42 (Aß42) toxicity in primary neuronal cultures and SH-SY5Y neuroblastoma cells, we have uncovered a key role for cathepsin L in the induction of nuclear lamina damage. The applicability of our findings to AD pathophysiology was validated in brain autopsy samples from patients. We report that upregulation of cathepsin L is an important process in the induction of nuclear lamina damage, shown by lamin B1 cleavage, and is associated with epigenetic modifications in AD pathophysiology. More importantly, pharmacological targeting and genetic knock out of cathepsin L mitigated Aß42 induced lamin B1 degradation and downstream structural and molecular changes. Affirming these findings, overexpression of cathepsin L alone was sufficient to induce lamin B1 cleavage. The proteolytic activity of cathepsin L on lamin B1 was confirmed using mass spectrometry. Our research identifies cathepsin L as a newly identified lamin B1 protease and mediator of laminopathy observed in AD. These results uncover a new aspect in the pathophysiology of AD that can be pharmacologically prevented, raising hope for potential therapeutic interventions.

Cathepsin B is an executioner of ferroptosis.

Ferroptosis is a necrotic form of cell death caused by inactivation of the glutathione system and uncontrolled iron-mediated lipid peroxidation. Increasing evidence implicates ferroptosis in a wide range of diseases from neurotrauma to cancer, highlighting the importance of identifying an executioner system that can be exploited for clinical applications. In this study, using pharmacological and genetic models of ferroptosis, we observed that lysosomal membrane permeabilization and cytoplasmic leakage of cathepsin B unleashes structural and functional changes in mitochondria and promotes a not previously reported cleavage of histone H3. Inhibition of cathepsin-B robustly rescued cellular membrane integrity and chromatin degradation. We show that these protective effects are independent of glutathione peroxidase-4 and are mediated by preventing lysosomal membrane damage. This was further confirmed when cathepsin B knockout primary fibroblasts remained unaffected in response to various ferroptosis inducers. Our work identifies new and yet-unrecognized aspects of ferroptosis and identifies cathepsin B as a mediator of ferroptotic cell death.

Differential involvement of caspase-6 in amyloid-ß-induced fragmentation of lamin A and B.

Amyloid-ß (Aß), a peptide implicated in Alzheimer's disease, was shown to cause specific fragmentation of lamin proteins, which was mediated by an unidentified protease named nuclear scaffold protease (NSP) independently of caspase-6. Because caspase-6 is responsible for the fragmentation process in many other damage-induced apoptosis, here we further investigated possible involvement of caspase-6 in Aß-induced lamin fragmentation under various conditions. We found that lamin A fragment generated by NSP (named fragment b) disappeared in cells incubated with Aß42 for prolonged periods and this product was preserved by a caspase-6 inhibitor. Furthermore, caspase-6 could remove fragment b in nuclei isolated from Aß42-treated cells (ANU). Lamin B in ANU was fragmented by caspase-6 only after treatment with an alkaline phosphatase. The caspase-mediated fragmentation of lamin B was also achieved with nuclei isolated from cells incubated with Aß42 plus a Cdk5 inhibitor. The results indicate that Aß42 induces NSP-mediated fragmentation of lamin A and the following removal process of fragment b by caspase-6 and an Aß-induced phosphorylation prevents the fragmentation of lamin B by caspase-6. The pathway leading to lamin protein fragmentation in this investigation appears to be specific for Aß and thus the data will provide novel insights into the toxicity of the peptide.

Simvastatin increases temozolomide-induced cell death by targeting the fusion of autophagosomes and lysosomes.

Temozolomide (TMZ) is a chemotherapy agent used to treat Grade IV astrocytoma, also known as glioblastoma (GBM). TMZ treatment causes DNA damage that results in tumor cell apoptosis and increases the survival rate of GBM patients. However, chemoresistance as a result of TMZ-induced autophagy significantly reduces this anticancer effects over time. Statins are competitive inhibitors of HMG-CoA reductase, the rate-limiting enzyme of the mevalonate (MEV) cascade. Statins are best known for their cholesterol (CH)-lowering effect. Long-term consumption of statins, prior to and in parallel with other cancer therapeutic approaches, has been reported to increase the survival rate of patients with various forms of cancers. In this study, we investigated the potentiation of TMZ-induced apoptosis by simvastatin (Simva) in human GBM cell lines and patient GBM cells, using cell monolayers and three-dimensional cell culture systems. The incubation of cells with a combination of Simva and TMZ resulted in a significant increase in apoptotic cells compared to cells treated with TMZ alone. Incubation of cells with CH or MEV cascade intermediates failed to compensate the decrease in cell viability induced by the combined Simva and TMZ treatment. Simva treatment inhibited the autophagy flux induced by TMZ by blocking autophago-lysosome formation. Our results suggest that Simva sensitizes GBM cells to TMZ-induced cell death in a MEV cascade-independent manner and identifies the inhibition of autophagosome-lysosome fusion as a promising therapeutic strategy in the treatment of GBM.

Thioredoxin system as a gatekeeper in caspase-6 activation and nuclear lamina integrity: Implications for Alzheimer's disease.

Recent reports in pathophysiology of neurodegenerative diseases (ND) have linked nuclear lamina degradation/deficits to neuronal cell death. Lamin-B1 damage is specifically involved in this process leading to nuclear envelope invagination and heterochromatin rearrangement. The underlying mechanisms involved in these events are not yet defined. In this study, while examining the effect of Thioredoxin-1(Trx1) inhibition on cell death in a model of oxidative stress, we noted robust nuclear invagination in SH-SY5Y cells. Evaluation of nuclear lamina proteins revealed lamin-B1 cleavage that was prevented by caspase-6 (CASP6) inhibitor and exacerbated after pharmacologic/genetic inhibition of Trx1 system, but not after glutathione depletion. Activation of CASP6 was upstream of CASP3/7 activation and its inhibition was sufficient to prevent cell death in our system. The effect of Trx1 redox status on CASP6 activation was assessed by administration of reduced/oxidized forms in cell-free nuclei preparation and purified enzymatic assays. Although reduced Trx1 decreased CASP6 enzymatic activity and lamin-B1 cleavage, the fully oxidized Trx1 showed opposite effects. The enhanced CASP6 activation was also associated with lower levels of DJ-1, a neuroprotective and master regulator of cellular antioxidants. The implication of our findings in ND pathophysiology was strengthened with detection of lower Trx1 levels in the hippocampi tissue of a mouse model of Alzheimer's disease. This coincided with higher CASP6 activation resulting in increased lamin-B1 and DJ-1 depletion. This study provides a first mechanistic explanation for the key regulatory role of Trx1 as a gatekeeper in activation of CASP6 and induction of nuclear invagination, an important player in ND pathophysiology.

Protective effect of chloroform extract of Stereospermum chelonoides bark against amyloid beta42 induced cell death in SH-SY5Y cells and against inflammation in Swiss albino mice.

Background This study was designed to evaluate the free radical scavenging property of chloroform extract of the bark of Stereospermum chelonoides (SCBC) and to investigate its potential in Alzheimer's disease and inflammation, two oxidative stress related disorders. Methods Preliminary phytochemical analysis and in vitro antioxidant potential of SCBC were evaluated using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assay, ferric reducing antioxidant power (FRAP) assay, cupric reducing antioxidant capacity (CUPRAC) and total antioxidant capacity determination assay. Total phenol and total flavonoid contents were also determined. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) based cytotoxicity and cyto-protective assays were performed on human neuroblastoma SH-SY5Y cells. Thioflavin-T assay and caspase activation measurement assay were carried out to elucidate the mechanism of cytoprotection of SCBC observed here. In vivo anti-inflammatory potential was measured using croton oil and xylene induced ear edema tests. Results Phytochemical screening of SCBC revealed the presence of various phytoconstituents. Dose-dependent in vitro antioxidant activity was observed. The extract was enriched in flavonoids and polyphenolic compounds too. SCBC was found to inhibit amyloid-ß peptide 1-42 (Aß42) induced cell death in a dose-dependent manner. Encouraged by the cyto-protective effect, its effects on Aß42 fibrillogenesis and caspase-3 activated apoptosis were observed. SCBC significantly slowed down the Aß42 fibrillogenesis and caspase-3 activation in a concentration-dependent manner indicating its probable mechanism of rendering cyto-protection. SCBC has been able to reduce inflammation significantly in croton oil induced ear edema in both doses. Conclusions Thus, this study could form the basis for further study for the potential use of SCBC in oxidative stress associated cell death and inflammation.

Limited activation of the intrinsic apoptotic pathway plays a main role in amyloid-ß-induced apoptosis without eliciting the activation of the extrinsic apoptotic pathway.

Amyloid-ß (Aß), a main pathogenic factor of Alzheimer's disease (AD), induces apoptosis accompanied by caspase activation. However, limited caspase activation and the suppression of the intrinsic apoptotic pathway (IAPW) are frequently observed upon Aß treatment. In this study, we investigated whether these suppressive effects of Aß can be overcome; we also examined the death-related pathways. Single treatments of cells with Aß42 for up to 48 h barely induced caspase activation. In cells treated with Aß42 twice for 2 h followed by 22 h (2+22 h) or for longer durations, the apoptotic protease activating factor-1 (Apaf-1) apoptosome was formed and caspases-3 and -9 were activated to a certain extent, suggesting the activation of the IAPW. However, the Aß42-induced activation of the IAPW differed from that induced by treatment with other agents, such as staurosporine (STS) in that lower amounts of cytochrome c were released from the mitochondria, the majority of procaspase-9 in the Apaf-1 complex was not processed and caspase-3 was activated to a lesser extent in the peptide-treated cells. Thus, it seemed that the IAPW was not fully activated by Aß42. The 30- and 41/43-kDa fragments derived from procaspase-8 were detected, which appear to be produced through the IAPW without death-inducing signaling-complex (DISC) formation, a key feature of the extrinsic apoptotic pathway (EAPW). Bid cleavage was observed only after caspase-3 activity reached its maximal levels, suggesting that the cleavage may contribute in a limited capacity to the amplification process of the IAPW in the Aß-treated cells. Taken together, our data suggest that the IAPW, albeit functional only to a limited extent, plays a major role in Aß42-induced apoptosis without the EAPW.