Targeting Abnormal Tau Phosphorylation for Alzheimer's Therapeutics.

Alzheimer's disease (AD) is a widespread neurodegenerative disorder characterized by progressive memory and cognitive decline, posing a formidable public health challenge. This review explores the intricate interplay between two pivotal players in AD pathogenesis: ß-amyloid (Aß) and tau protein. While the amyloid cascade theory has long dominated AD research, recent developments have ignited debates about its centrality. Aß plaques and tau NFTs are hallmark pathologies in AD. Aducanumab and lecanemab, monoclonal antibodies targeting Aß, have been approved, albeit amidst controversy, raising questions about the therapeutic efficacy of Aß-focused interventions. On the other hand, tau, specifically its hyperphosphorylation, disrupts microtubule stability and contributes to neuronal dysfunction. Various post-translational modifications of tau drive its aggregation into NFTs. Emerging treatments targeting tau, such as GSK-3ß and CDK5 inhibitors, have shown promise in preclinical and clinical studies. Restoring the equilibrium between protein kinases and phosphatases, notably protein phosphatase-2A (PP2A), is a promising avenue for AD therapy, as tau is primarily regulated by its phosphorylation state. Activation of tau-specific phosphatases offers potential for mitigating tau pathology. The evolving landscape of AD drug development emphasizes tau-centric therapies and reevaluation of the amyloid cascade hypothesis. Additionally, exploring the role of neuroinflammation and its interaction with tau pathology present promising research directions.

Effect of Benidipine Alone and in Combination With Bosentan and Sildenafil in Amelioration of Pulmonary Arterial Hypertension in Experimental Model in Rats.

ABSTRACT: Pulmonary arterial hypertension (PAH) is a persistent condition affecting the pulmonary arteries' endothelium. Benidipine, a calcium channel blocker, possesses vasodilatory, anti-inflammatory activity, reduces oxidative stress, and inhibits the activity of Transforming growth factor-ß (TGF-ß) and α-smooth muscle actin (α-SMA). The present study was designed to investigate the effect of benidipine alone and in combination with bosentan and sildenafil on monocrotaline (MCT)-induced pulmonary hypertension in a rat model. PAH was induced by a single-dose administration of MCT in rats. Animals were randomized into different groups and treated with benidipine alone and in combination with bosentan or sildenafil. Various parameters such as hemodynamic parameters, Fulton's index and oxidative stress parameters were performed. Additionally, histopathology of lung and right ventricular of heart tissue, immunohistochemistry, expression of α-SMA, endothelial nitric oxide synthase (eNOS), TGF-ß, and RT-PCR, and an in vitro study using human umbilical vein endothelial cells (HUVECs) was also carried out. Treatment of benidipine and its combination exhibited better prevention in the elevated right ventricular systolic pressure, right ventricular hypertrophy, rise in oxidative stress, and increase in expression of α-SMA and TGF-ß receptor 1 compared with MCT control group rats. In HUVECs, the expression of α-SMA was increased, whereas that of eNOS decreased after TGF-ß exposure and was substantially reversed after pretreatment with benidipine. We concluded that benidipine and its combination with bosentan and sildenafil exhibit beneficial effects in MCT-induced PAH through the eNOS/TGF-ß/α-SMA signaling pathway.

Removal of arsenic from jarosite waste using hydrometallurgical treatment.

The jarosite waste used during this study consists of minute amount of arsenic that has a potential to be leached into environment when kept in open area. This study tried to recover arsenic from jarosite waste using hydrometallurgical treatment. The comprehensive characterization of jarosite samples was performed using various analytical techniques, including X-ray diffraction (XRD), Fourier transform Infrared (FTIR), scanning electron microscopy (SEM), and energy-dispersive X-ray spectroscopy (EDX), and it was characterized as natrojarosite. For optimal removal of arsenic, the response surface methodology (RSM) was applied with the key factors, including dosage (A), time (B), temperature (C), and acid concentration (D) on the recovery of arsenic. The results indicated that the dosage (A) and acid concentration (D) demonstrated significant positive effects on arsenic recovery. As expected, the higher dosage and acid concentration was associated with increased recovery percentages for the arsenic from jarosite. Whereas time (B) and temperature (C) did not exhibit statistically significant recovery of arsenic within the specified experimental range. The contour plots showed the optimal operating conditions for the highest recovery percentage was approximately 52.61% when 2.5 g of jarosite was treated with 10 mol/L acid for 150 min at operating temperature of 80°. Although our study showed very moderate recovery of arsenic, it is first report where arsenic has been removed from jarosite waste. Readjustment of range of operating parameters would provide more insight into the further optimization of the yield.

Hydration effects on the vibrational properties of carboxylates: From continuum models to QM/MM simulations.

The presence of carboxyl groups in a molecule delivers an affinity to metal cations and a sensitivity to the chemical environment, especially for an environment that can give rise to intermolecular hydrogen bonds. Carboxylate groups can also induce intramolecular interactions, such as the formation of hydrogen bonds with donor groups, leading to an impact on the conformational space of biomolecules. In the latter case, the protonation state of the amino groups plays an important role. In order to provide an accurate description of the modifications induced in a carboxylated molecule by the formation of hydrogen bonds, one needs a compromise between a quantum chemical description of the system and the necessity to take into account explicit solvent molecules. In this work, we propose a bottom-up approach to study the conformational space and the carboxylate stretching band of (bio)organic anions. Starting from the anions in a continuum solvent, we then move to calculations using a microsolvation approach including one explicit water molecule per polar group, immersed in a continuum. Finally, we run QM/MM molecular dynamics simulations to analyze the solvation properties and to explore the anions conformational space. The results thus obtained are in good agreement with the description given by the microsolvation approach and they bring a more detailed description of the solvation shell and of the intermolecular hydrogen bonds.

Gold-Zinc Cooperative Catalysis for Seven-exo-dig Hydrocarboxylation of Internal Alkynes.

Seven-exo-dig hydrocarboxylation of nonactivated internal alkynes with conformationally flexible linker chains was achieved with cooperative gold-zinc catalysts composed of an imidazo[1,5-a]pyridinylidene ligand including a bipyridine coordination site at the C5 position. A proximity effect of the gold and zinc sites was essential for their high catalytic activity, in which the internal alkyne activated by the cationic gold species was attacked by the carboxylic acid deprotonated by the basic zinc site. Using a gold(I)-complex with a bulky aromatic N-substituent, 2,6-dibenzhydryl-4-methylphenyl group, for the NHC ligand facilitated seven-membered ring formation while minimizing intermolecular hydrocarboxylation as an undesired side reaction. The reaction mechanism was investigated by quantum chemical calculations.

Visible Light-Assisted Degradation of Sulfamethoxazole on 2D/0D Sulfur-Doped Bi2O3/MnO2 Z-Scheme Heterojunction Immobilized Photocatalysts.

Retrieving the spent photocatalysts from the reaction system is always a challenging task. Therefore, the present work is focused on immobilizing sulfur-doped-Bi2O3/MnO2 (S-BOMO) heterojunction photocatalysts over different support matrices and evaluating their performance for the removal of sulfamethoxazole (SMX) in water under visible light. Our findings revealed S-BOMO coated clay beads (S-BOMO CCB) achieving more than 86% (240 min) SMX degradation ∼3, ∼1.3, and ∼2 times higher compared to S-BOMO coated on the different substrates, including glass beads, floating stones, and polymer material substrates, respectively. Mott-Schottky measurements confirmed the construction of the Z-scheme heterojunction involving MnO2 and 2S-Bi2O3. This Z-scheme mechanism, along with its narrow band gap of 1.58 eV, resulted in a rapid spatial transfer of the photogenerated charge carriers between the semiconductors and is believed to enhance the overall photocatalytic activity of the nanocomposite. Radical trapping and electron paramagnetic resonance results clearly established the active role of hydroxyl radicals and hydrogen peroxide in the degradation of SMX. Further, the 2S-BOMO CCB demonstrated excellent stability and photocatalytic activity over multiple runs. According to the sensitivity analysis and the results of anion effect experiments, phosphate and sulfate ions exhibit a significant impact on sulfamethoxazole degradation. Toxicity analysis revealed that 2S-BOMO CCB and sulfamethoxazole degradation byproducts were apparently innocuous. Additionally, the practical applicability of 2S-BOMO CCB was examined in various real water matrices, with the degradation efficiency followed the order: tap water < groundwater < surface water < hospital wastewater < municipal wastewater < pharmaceutical industry wastewater. The economic assessment revealed the reduction in the overall cost of the immobilized 2S-BOMO following the recovery process. Overall, the findings of this work provided critical insights into the synthesis and performance of incredibly effective and stable immobilized photocatalysts for the degradation of pharmaceutical pollutants.

Physical properties and photocatalytic activity of Cr-doped TiO2 nanoparticles.

Nanocrystalline Ti1- x Crx O2 (0 ≤ x ≤ 0.20) samples were synthesised via acid-modified sol-gel process and characterised with various techniques, such as HRTEM, FESEM, Raman, XPS, DTA and VSM. The TEM image of TiO2 exhibits elongated nanoparticles with an average size of 10 nm. The HRTEM in combination with selected area electron diffraction (SAED) reveals the interplanar spacing and polycrystalline nature of the samples, respectively. FESEM micrographs divulge nonuniform morphologies and less aggregation of the particles in the doped sample. Raman spectra ensure the phase purity of the samples and a blue shift on Cr doping. X-ray photoelectron spectra (XPS) predict the chemical state of the elements and oxygen vacancies in the prepared samples. Room temperature magnetic measurements exhibit a significant variation in the magnetic parameters on Cr doping in TiO2 . The differential thermal analysis (DTA) shows the structural phase transition at ∼630°C. The photocatalytic performance is studied for the degradation of methylene blue (MB) dye under visible light irradiation. A higher photocatalytic efficiency is found for the 20% of Cr-doped TiO2 . These studies propose that the appropriate incorporation of Cr ions makes TiO2 very efficient for visible light-driven photocatalysts required for applications in wastewater treatment. LAY DESCRIPTION: In the present study, nanoparticles of TiO2 and Cr-doped TiO2 have been synthesised by a cost-effective acid-modified sol-gel process. The effect of Cr doping on the microstructure, thermal, magnetic and photocatalytic properties of TiO2 were explored in detail. The transmission electron microscopy (TEM) images exhibit the presence of elongated nanoparticles with an average size of 10 nm. Field emission scanning electron microscopy (FESEM) was used to study the surface morphology of the synthesised materials, which revealed nonuniform morphologies and less aggregation of the particles in the Cr-doped sample. Energy dispersive x-ray spectroscopy (EDS) confirms the elemental compositions with the appropriate stoichiometry of the elements. Raman spectra ensure the phase purity of the materials and also a blue shift with the incorporation of Cr ions in TiO2 . X-ray photoelectron spectra (XPS) predict the chemical state of the elements and oxygen vacancies in the prepared samples. The magnetic nature of all the synthesised samples was examined through the vibrating sample magnetometer (VSM) and revealed weak ferromagnetic behaviour of the samples. These results signify that the oxygen vacancies and defects play a crucial role in developing the ferromagnetic nature of oxide semiconductors. The differential thermal analysis (DTA) shows the structural phase transition at ∼630°C. The photocatalytic performance of the prepared samples was studied for the degradation of methylene blue (MB) dye under irradiation of visible light. A higher photocatalytic efficiency was found for the 20% of Cr-doped TiO2 . These studies propose that the appropriate incorporation of Cr ions makes TiO2 very efficient for visible light-driven photocatalysts required for applications in wastewater treatment.

Insights of Endocytosis Signaling in Health and Disease.

Endocytosis in mammalian cells is a fundamental cellular machinery that regulates vital physiological processes, such as the absorption of metabolites, release of neurotransmitters, uptake of hormone cellular defense, and delivery of biomolecules across the plasma membrane. A remarkable characteristic of the endocytic machinery is the sequential assembly of the complex proteins at the plasma membrane, followed by internalization and fusion of various biomolecules to different cellular compartments. In all eukaryotic cells, functional characterization of endocytic pathways is based on dynamics of the protein complex and signal transduction modules. To coordinate the assembly and functions of the numerous parts of the endocytic machinery, the endocytic proteins interact significantly within and between the modules. Clathrin-dependent and -independent endocytosis, caveolar pathway, and receptor mediated endocytosis have been attributed to a greater variety of physiological and pathophysiological roles such as, autophagy, metabolism, cell division, apoptosis, cellular defense, and intestinal permeabilization. Notably, any defect or alteration in the endocytic machinery results in the development of pathological consequences associated with human diseases such as cancer, cardiovascular diseases, neurological diseases, and inflammatory diseases. In this review, an in-depth endeavor has been made to illustrate the process of endocytosis, and associated mechanisms describing pathological manifestation associated with dysregulated endocytosis machinery.

Effect of stress on contextual pain sensitivity in the preoperative period- A proof of concept study.

Background and Aims: The importance of non-noxious contextual inputs in the interplay of pain with neurophysiologic and behavioral factors is gaining recognition. Stress of impending surgery can act as a negative context, leading to a decrease in pain threshold in patients. This study was conducted to assess the influence of stress conferred by the imminent and other contextual inputs such as anxiety, socioeconomic status, prior painful experience, and the effect of gender on modulation of pain perception in patients undergoing elective surgery. Material and Methods: In total, 120 patients aged between 18 and 60 years of either gender posted for elective gastrointestinal surgery under general anesthesia were recruited. Data were collected on preoperative anxiety level, socioeconomic status, education, and any prior painful experience. A pressure algometer was used to measure the pressure pain thresholds and pain tolerance on the day before surgery and on the morning of surgery in the preoperative suite. Results: There was a statistically significant decrease in both pain threshold (P < 0.0001) and pain tolerance in the immediate preoperative period in comparison to the baseline readings taken the day before surgery (P = 0.048). The magnitude of change in pain scalars was greater in females (P < 0.001), those with a high anxiety score, and a history of severe painful experience in the past. Conclusion: Preoperative surgical stress lowers the pain threshold and pain tolerance. Contextual modulation of pain by factors such as anxiety and memory of prior painful experience, especially in the female gender, could influence postoperative patient outcomes and warrants further research.

Environment-Driven Coherent Population Transfer Governs the Ultrafast Photophysics of Tryptophan.

By combining UV transient absorption spectroscopy with sub-30-fs temporal resolution and CASPT2/MM calculations, we present a complete description of the primary photoinduced processes in solvated tryptophan. Our results shed new light on the role of the solvent in the relaxation dynamics of tryptophan. We unveil two consecutive coherent population transfer events involving the lowest two singlet excited states: a sub-50-fs nonadiabatic La → Lb transfer through a conical intersection and a subsequent 220 fs reverse Lb → La transfer due to solvent-assisted adiabatic stabilization of the La state. Vibrational fingerprints in the transient absorption spectra provide compelling evidence of a vibronic coherence established between the two excited states from the earliest times after photoexcitation and lasting until the back-transfer to La is complete. The demonstration of response to the environment as a driver of coherent population dynamics among the excited states of tryptophan closes the long debate on its solvent-assisted relaxation mechanisms and extends its application as a local probe of protein dynamics to the ultrafast time scales.

Targeting lysophosphatidic acid receptor with Ki16425 impedes T cell lymphoma progression through apoptosis induction, glycolysis inhibition, and activation of antitumor immune response.

Lysophosphatidic acid (LPA) is a small phospholipid that acts as an extracellular lipid mediator. It promotes cancer progression by altering a wide array of cellular processes, including apoptosis, survival, angiogenesis, invasion, and migration through binding with its cognate receptors. Intriguingly, our previous study showed that in vitro treatment of LPA induced survival of T lymphoma cells. Hence, the present investigation was designed to investigate the antitumor potential of Ki16425, an antagonist of LPA receptors, against T cell lymphoma. Our in vitro results showed inhibition of LPA-mediated survival and metabolic activity of T lymphoma cells by Ki16425. Further, in vivo experimental findings indicated the tumor retarding potential of Ki16425 against T cell lymphoma through apoptosis induction, glycolysis inhibition, and immunoactivation. The administration of Ki16425 triggered apoptosis by down-regulating the expression of Bcl2 and up-regulating p53, Bax, cleaved caspase-3, and Cyt c expression. Further, Ki16425 suppressed glycolytic activity with concomitantly decreased expression of GLUT3 and MCT1. Moreover, we also noticed an elevated level of NO and iNOS in tumor cells after Ki16425 administration which might also be responsible for apoptosis induction and suppressed glycolysis. Additionally, we observed an increased population of total leukocytes, lymphocytes, and monocytes along with increased thymocytes count and IL-2 and IFN-γ levels. Besides, we observed amelioration of tumor-induced kidney and liver damages by Ki16425. Taken together, this is the first study that demonstrates that LPA receptors could be potential future therapeutic targets for designing promising therapeutic strategies against T cell lymphoma.

Phosphodiesterase 5 inhibitor sildenafil potentiates the antitumor activity of cisplatin by ROS-mediated apoptosis: a role of deregulated glucose metabolism.

Cyclic nucleotide phosphodiesterase 5 (PDE5) has been recently identified to play a crucial role in the progression of many cancers. PDE5 promotes tumorigenesis by dysregulating various cellular processes such as proliferation, apoptosis, angiogenesis, and invasion and migration. Interestingly, multiple studies have reported the promising chemosensitizing potential of PDE5 inhibitor sildenafil in breast, colon, prostate, glioma, and lung cancers. However, to date, the chemosensitizing action of sildenafil is not evaluated in T cell lymphoma, a rare and challenging neoplastic disorder. Hence, the present investigation was undertaken to examine the chemosensitizing potential of sildenafil against T cell lymphoma along with elucidation of possible involvement of altered apoptosis and glucose metabolism. The experimental findings of this study showed that sildenafil enhances the cytotoxic ability of cisplatin by apoptosis induction through altering the levels of apoptosis regulatory molecules: Bcl-2, Bax, cytochrome c (Cyt c), cleaved caspase-3, and poly (ADP-ribose) polymerase (PARP). These molecular alterations were possibly driven by sildenafil through reactive oxygen species (ROS). Sildenafil deregulates glucose metabolism by markedly lowering the expression of glycolysis regulatory molecules, namely glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), hexokinase II (HKII), pyruvate kinase M2 (PKM2), and pyruvate dehydrogenase kinase 1 (PDK1) via suppressing hypoxia-inducible factor 1-alpha (HIF-1α) expression. Hence, sildenafil potentiates the tumor cell killing ability of cisplatin by augmenting ROS production through switching the glucose metabolism from glycolysis to oxidative phosphorylation (OXPHOS). Overall, our study demonstrates that sildenafil might be a promising adjunct therapeutic candidate in designing novel combinatorial chemotherapeutic regimens against T cell lymphoma.

Esophageal Microbiome in Healthy Children and Esophageal Eosinophilia.

OBJECTIVES: There is limited knowledge about the role of esophageal microbiome in pediatric esophageal eosinophilia (EE). We aimed to characterize the esophageal microbiome in pediatric patients with and without EE. METHODS: In the present prospective study, esophageal mucosal biopsies were obtained from 41 children. Of these, 22 had normal esophageal mucosal biopsies ("healthy"), 6 children had reflux esophagitis (RE), 4 had proton pump inhibitor (PPi)-responsive esophageal eosinophilia (PPi-REE), and 9 had eosinophilic esophagitis (EoE). The microbiome composition was analyzed using 16S rRNA gene sequencing. The age median (range) in years for the healthy, RE, PPi-REE, and EoE group were 10 (1.5-18), 6 (2-15), 6.5 (5-15), and 9 (1.5-17), respectively. RESULTS: The bacterial phylum Actinobacteria, Bacteroidetes, Firmicutes, Fusobacteria, and Proteobacteria were the most predominant. The Epsilonproteobacteria, Betaproteobacteria, Flavobacteria, Fusobacteria, and Sphingobacteria class were underrepresented across groups. The Vibrionales was predominant in healthy and EoE group but lower in RE and PPi-REE groups. The genus Streptococcus, Rahnella, and Leptotrichia explained 29.65% of the variation in the data with an additional 10.86% variation in the data was explained by Microbacterium, Prevotella, and Vibrio genus. The healthy group had a higher diversity and richness index compared to other groups, but this was not statistically different. CONCLUSIONS: The pediatric esophagus has an abundant and diverse microbiome, both in the healthy and diseased states. The healthy group had a higher, but not significantly different, diversity and richness index compared to other groups.

An assessment of hospital wastewater and biomedical waste generation, existing legislations, risk assessment, treatment processes, and scenario during COVID-19.

Hospitals release significant quantities of wastewater (HWW) and biomedical waste (BMW), which hosts a wide range of contaminants that can adversely affect the environment if left untreated. The COVID-19 outbreak has further increased hospital waste generation over the past two years. In this context, a thorough literature study was carried out to reveal the negative implications of untreated hospital waste and delineate the proper ways to handle them. Conventional treatment methods can remove only 50%-70% of the emerging contaminants (ECs) present in the HWW. Still, many countries have not implemented suitable treatment methods to treat the HWW in-situ. This review presents an overview of worldwide HWW generation, regulations, and guidelines on HWW management and highlights the various treatment techniques for efficiently removing ECs from HWW. When combined with advanced oxidation processes, biological or physical treatment processes could remove around 90% of ECs. Analgesics were found to be more easily removed than antibiotics, ß-blockers, and X-ray contrast media. The different environmental implications of BMW have also been highlighted. Mishandling of BMW can spread infections, deadly diseases, and hazardous waste into the environment. Hence, the different steps associated with collection to final disposal of BMW have been delineated to minimize the associated health risks. The paper circumscribes the multiple aspects of efficient hospital waste management and may be instrumental during the COVID-19 pandemic when the waste generation from all hospitals worldwide has increased significantly.

FGF signaling promotes myoblast proliferation through activation of wingless signaling.

Indirect flight muscles (IFMs) are the largest muscles in Drosophila and are made up of hundreds of myonuclei. The generation of these giant muscles requires a large pool of wing disc associated adult muscle precursors (AMPs), however the factors that control proliferation to form this myoblast pool are incompletely known. Here, we examine the role of fibroblast growth factor (FGF) signaling in the proliferation of wing disc associated myoblasts. We find that the components of FGF signaling are expressed in myoblasts and surrounding epithelial cells of the wing disc. Next, we show that attenuation of FGF signaling results in a diminished myoblast pool. This reduction in the pool size is due to decreased myoblast proliferation. By contrast, activating the FGF signaling pathway increases the myoblast pool size and restores the proliferative capacity of FGF knockdown flies. Finally, our results demonstrate that the FGF receptor Heartless acts through up-regulating ß-catenin/Armadillo signaling to promote myoblast proliferation. Our studies identify a novel role for FGF signaling during IFM formation and uncover the mechanism through which FGF coordinates with Wingless signaling to promote myoblast proliferation.

An inquest into regulatory mechanism of caveolin by ischemic preconditioning against orchidectomy-challenged rat heart.

Lower level of testosterone in men is related to major risks of cardiovascular diseases. This risk may increase due to the opening of mitochondrial permeability transition pore (mPTP). The mPTP is also regulated by ischemic preconditioning (IPC) and a membrane protein known as caveolin. The cardioprotective effect of IPC is the most effective methodologies used in testosterone deficiency. Daidzein (DDZ) a caveolin inhibitor shows cardioprotective action. The experiment has been designed to evaluate the pretreated DDZ effect in IPC-mediated cardioprotective action in orchidectomy (OCZ)-challenged rat heart. The experiment was designed on male Wistar rats with/without OCZ. The level of testosterone is decreased by OCZ which reduces general body growth. Isolated heart from normal and OCZ rat was tied up on Langendorff's perfused apparatus and followed by ischemic reperfusion (IR) and IPC cycle. To investigate the cardioprotective effect of DDZ in heart with testosterone deficiency, a total of nine groups, each consisting of six rats (n = 6) were as follows: Sham, IR, IPC, IPC + OCZ, IPC + DDZ, IPC + OCZ + DDZ, IPC + sodium nitrite, IPC + OCZ + sodium nitrite, IPC + OCZ + DDZ + sodium nitrite. Hemodynamic parameters, cellular injury (infarct size, LDH, CKMB and cardiac troponin-T), oxidative stress, mitochondrial function, integrity and immunoblot analysis were assessed for each group. The experimental data showed that DDZ potentiated IPC-mediated increase in the heart rate, left ventricular diastolic pressure, coronary flow; + dp/dtmax, and - dp/dtmax. The pretreated DDZ decreases the action of LDH and CKMB, myocyte size, cardiac collagen content, infarct size and ventricular fibrillation and attenuation in oxidative stress and mitochondrial dysfunction in OCZ-challenged rat heart in all sets of experiments. Sodium nitrite, a producer of nitric oxide (NO), enhanced potentiating effects of DDZ on IPC-mediated cardioprotection in OCZ-challenged rats. These observations show that the downregulation of caveolin through impaired opening of mPTP during reperfusion and caveolin might be a potential adjuvant to IPC against cardiac injury in OCZ-challenged rats.

Integration of proteomic and genetic approaches to assess developmental muscle atrophy.

Muscle atrophy, or a decline in muscle protein mass, is a significant problem in the aging population and in numerous disease states. Unraveling molecular signals that trigger and promote atrophy may lead to a better understanding of treatment options; however, there is no single cause of atrophy identified to date. To gain insight into this problem, we chose to investigate changes in protein profiles during muscle atrophy in Manduca sexta and Drosophila melanogaster. The use of insect models provides an interesting parallel to probe atrophic mechanisms as these organisms undergo a normal developmental atrophy process during the pupal transition stage. Leveraging the inherent advantages of each model organism, we first defined protein signature changes during M. sexta intersegmental muscle (ISM) atrophy and then used genetic approaches to confirm their functional importance in the D. melanogaster dorsal internal oblique muscles (DIOMs). Our data reveal an upregulation of proteasome and peptidase components and a general downregulation of proteins that regulate actin filament formation. Surprisingly, thick filament proteins that comprise the A-band are increased in abundance, providing support for the ordered destruction of myofibrillar components during developmental atrophy. We also uncovered the actin filament regulator ciboulot (Cib) as a novel regulator of muscle atrophy. These insights provide a framework towards a better understanding of global changes that occur during atrophy and may eventually lead to therapeutic targets.

Nimbolide induces cell death in T lymphoma cells: Implication of altered apoptosis and glucose metabolism.

Nimbolide is a tetranortriterpenoid derived from the leaves and flowers of Azadirachta indica (Neem). It exhibits anticancer activity against a variety of cancers by modulating various crucial features, including cell proliferation, apoptosis, and invasion and metastasis. More importantly, the cytotoxic effect of nimbolide has also been observed against T cell lymphoma, but the underlying mechanisms are still unexplored. So far, no study has been conducted to observe the effect of nimbolide on cancer cell metabolism. Therefore, the present investigation was designed to explore the molecular mechanisms of the antitumor potential of nimbolide against T cell lymphoma, a neoplastic disorder of thymic origin. In addition, we also unraveled the anti-glycolytic activity of nimbolide against T lymphoma cells with possible molecular mechanisms. Our results showed the cytotoxic action of nimbolide against three different cell lines of T cell lymphoma, namely Dalton's lymphoma, HuT-78, and J6. Nimbolide-induced apoptosis in T lymphoma cells by altering the level of reactive oxygen species, p53, Bcl2, Bax, and cytochrome c, with subsequent cleavage of caspase 3. Remarkably, nimbolide inhibited the expression of hypoxia-inducible factor-1α, glucose transporter 3, hexokinase II, and pyruvate dehydrogenase kinase 1, which led to the suppression of glycolysis with concomitant activation of oxidative phosphorylation. Hence, the results of the present investigation demonstrate that nimbolide exerts tumoricidal activity against T lymphoma cells via augmentation of apoptosis and reversal of altered cell metabolism. Thus, the present study provides a new insight for the therapeutic utilization of nimbolide against T cell lymphoma.

SCSIM: Jointly simulating correlated single-cell and bulk next-generation DNA sequencing data.

BACKGROUND: Recently, it has become possible to collect next-generation DNA sequencing data sets that are composed of multiple samples from multiple biological units where each of these samples may be from a single cell or bulk tissue. Yet, there does not yet exist a tool for simulating DNA sequencing data from such a nested sampling arrangement with single-cell and bulk samples so that developers of analysis methods can assess accuracy and precision. RESULTS: We have developed a tool that simulates DNA sequencing data from hierarchically grouped (correlated) samples where each sample is designated bulk or single-cell. Our tool uses a simple configuration file to define the experimental arrangement and can be integrated into software pipelines for testing of variant callers or other genomic tools. CONCLUSIONS: The DNA sequencing data generated by our simulator is representative of real data and integrates seamlessly with standard downstream analysis tools.

Lysophosphatidic acid promotes survival of T lymphoma cells by altering apoptosis and glucose metabolism.

Lysophosphatidic acid (LPA) is a bioactive lipid, which plays an indispensable role in various physiological and pathological processes. Moreover, an elevated level of LPA has been observed in malignancies of different origins and implicated in their progression via modulation of proliferation, apoptosis, invasion and metastasis. Interestingly, few recent reports suggest a pivotal role of LPA-modulated metabolism in oncogenesis of ovarian cancer. However, little is understood regarding the role of LPA in the development and progression of T cell malignancies, which are considered as one of the most challenging neoplasms for clinical management. Additionally, mechanisms underlying the LPA-dependent modulation of glucose metabolism in T cell lymphoma are also not known. Therefore, the present study was undertaken to explore the role of LPA-altered apoptosis and glucose metabolism on the survival of T lymphoma cells. Observations of this investigation suggest that LPA supports survival of T lymphoma cells via altering apoptosis and glucose metabolism through changing the level of reactive species, namely nitric oxide and reactive oxygen species along with expression of various survival and glucose metabolism regulatory molecules, including hypoxia-inducible factor 1-alpha, p53, Bcl2, and glucose transporter 3, hexokinase II, pyruvate kinase muscle isozyme 2, monocarboxylate transporter 1, pyruvate dehydrogenase kinase 1. Taken together' the results of the present investigation decipher the novel mechanisms of LPA-mediated survival of T lymphoma cells via modulation of apoptosis and glucose metabolism.