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The presence of HSPs in female reproductive and their relationship with the steroid hormone fluctuation have been reported in several mammals but not in non-human primates. The present research dealt with the oviductal expression and localization of the more studied HSPs (60, 70, and 90) as well as the morphological changes in the Hamadryas baboon (Papio hamadryas) during the follicular, preovulatory, and luteal phases of the menstrual cycle. Therefore, western blots, histomorphological, and immunohistochemical analyses were carried out. The results of western blot analysis displayed the lowest HSP expression in the luteal phase. The histomorphology showed that the mucosal epithelium consisted of undifferentiated cuboidal cells in follicular and luteal phases and well-distinguishable columnar ciliated and non-ciliated cells during the preovulatory phase. Immunohistochemistry evidenced that the mucosal epithelium contained cytoplasmic and nuclear HSP60, 70, and 90 immunostaining in the follicular and luteal phases. During the preovulatory phase, the non-ciliated cells showed: (i) cytoplasmic HSP60; (ii) nuclear and cytoplasmic HSP90. Ciliated cells showed cytoplasmic and ciliary HSP70 and ciliary HSP90. The stromal cells and myocytes of muscular layer displayed a decreased cytoplasmic HSP60 in the preovulatory phase and nuclear and low cytoplasmic HSP70 throughout the menstrual cycle. Nuclear HSP90 decreased in ampulla stromal cells and the follicular phase myocytes. These findings indicate that the expression pattern of HSP60,70, and 90 is related to the morphofunctional features of the baboon oviductal ampulla during the menstrual cycle and could represent a referent point for further studies in the oviduct of Primates., (© 2023. The Author(s).)

Tumors often overexpress glucose-regulated proteins, and agents that interfere with the production or activity of these proteins may represent novel cancer treatments. The chlorpromazine derivative JX57 exhibits promising effects against endometrial cancer with minimal extrapyramidal side effects; however, its mechanisms of action are currently unknown. Here, glucose-regulated protein 75 kD (GRP75) is identified as a direct target of JX57 using activity-based protein profiling and loss-of-function experiments. The findings show that GRP75 is necessary for the biological activity of JX57, as JX57 exhibits moderate anticancer properties in GRP75-deficient cancer cells, both in vitro and in vivo. High GRP75 expression is correlated with poor differentiation and poor survival in patients with endometrial cancer, whereas the knockdown of GRP75 can significantly suppress tumor growth. Mechanistically, the direct binding of JX57 to GRP75 impairs the structure of the mitochondria-associated endoplasmic reticulum membrane and disrupts the endoplasmic reticulum-mitochondrial calcium homeostasis, resulting in a mitochondrial energy crisis and AMP-activated protein kinase activation. Taken together, these findings highlight GRP75 as a potential prognostic biomarker and direct therapeutic target in endometrial cancer and suggest that the chlorpromazine derivative JX57 can potentially be a new therapeutic option for endometrial cancer., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Glioblastoma multiforme (GBM) is a highly aggressive and lethal form of primary brain tumour. Borax has been demonstrated to exhibit anti-cancer activity through cell death pathways. However, the specific impact of borax on ferroptosis in GBM is not well-established, and the underlying regulatory mechanisms remain unclear. Initially, the effective concentration of borax on cell viability and proliferation in U251 and A172 cells was determined. Subsequently, the effects of borax on the wound healing were analysed. Nuclear factor erythroid 2-related factor 2 (NRF2), glutathione peroxidase 4 (GPx4), glutathione (GSH), HSP70 protein 5 (HSPA5), malondialdehyde (MDA) levels and caspase-3/7 activity were determined in borax-treated and untreated cells. Finally, the protein expression levels of HSPA5, NRF2 and GPx4 were analysed. Borax suppressed cell viability and proliferation in U251 and A172 cells in a concentration- and time-dependent manner. In addition, borax treatment decreased GPx4, GSH, HSPA5 and NRF2 levels in U251 and A172 cells while increasing MDA levels and caspase-3/7 activity. Moreover, borax reduced mRNA and protein levels of HSPA5, NRF2 and GPx4 in U251 and A172 cells. Consequently, borax may induce ferroptosis in GBM cells and regulate the associated regulatory mechanisms targeting NRF2 and HSPA5 pathways. This knowledge may contribute to the development of novel therapeutic approaches targeting ferroptosis in GBM and potentially improve patient outcomes., (© 2024 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

The review describes correlations between impaired functioning of chaperones and co-chaperones in Alzheimer's disease (AD) pathogenesis. The study aims to highlight significant lines of research in this field. Chaperones like Hsp90 or Hsp70 are critical agents in regulating cell homeostasis. Due to some conditions, like aging, their activity is damaged, resulting in β-amyloid and tau aggregation. This leads to the development of neurocognitive impairment. Dysregulation of co-chaperones is one of the causes of this condition. Disorders in the functioning of molecules like PP5, Cdc37, CacyBP/SIPTRAP1, CHIP protein, FKBP52, or STIP1 play a key role in AD pathogenesis. PP5, Cdc37, CacyBP/SIPTRAP1, and FKBP52 are Hsp90 co-chaperones. CHIP protein is a co-chaperone that switches Hsp70/Hsp90 complexes, and STIP1 binds to Hsp70. Recognition of precise processes allows for the invention of effective treatment methods. Potential drugs may either reduce tau levels or inhibit tau accumulation and aggregation. Some substances neuroprotect from Aβ toxicity. Further studies on chaperones and co-chaperones are required to understand the fundamental tenets of this topic more entirely and improve the prevention and treatment of AD.

Increasing temperature influences the habitats of various organisms, including microscopic invertebrates. To gain insight into temperature-dependent changes in tardigrades, we isolated storage cells exposed to various temperatures and conducted biochemical and ultrastructural analysis in active and tun-state Paramacrobiotus experimentalis Kaczmarek, Mioduchowska, Poprawa, & Roszkowska, 2020. The abundance of heat shock proteins (HSPs) and ultrastructure of the storage cells were examined at different temperatures (20 °C, 30 °C, 35 °C, 37 °C, 40 °C, and 42 °C) in storage cells isolated from active specimens of Pam. experimentalis. In the active animals, upon increase in external temperature, we observed an increase in the levels of HSPs (HSP27, HSP60, and HSP70). Furthermore, the number of ultrastructural changes in storage cells increased with increasing temperature. Cellular organelles, such as mitochondria and the rough endoplasmic reticulum, gradually degenerated. At 42 °C, cell death occurred by necrosis. Apart from the higher electron density of the karyoplasm and the accumulation of electron-dense material in some mitochondria (at 42 °C), almost no changes were observed in the ultrastructure of tun storage cells exposed to different temperatures. We concluded that desiccated (tun-state) are resistant to high temperatures, but not active tardigrades (survival rates of tuns after 24 h of rehydration: 93.3% at 20 °C, 60.0% at 35 °C, 33.3% at 37 °C, 33.3% at 40 °C, and 20.0% at 42 °C)., (© 2024. The Author(s).)

Cancer metastasis, a highly complex process wherein cancer cells move from the primary site to other sites in the body, is a major hurdle in its therapeutics. A large array of synthetic chemotherapeutic molecules used for the treatment of metastatic cancers, besides being extremely expensive and unaffordable, are known to cause severe adverse effects leading to poor quality of life (QOL) of the patients. In this premise, natural compounds (considered safe, easily available and economic) that possess the potential to inhibit migration of cancer cells are deemed useful and hence are on demand. Cucurbitacin-B (19-(10→9β)-abeo-10-lanost-5-ene triterpene, called Cuc-B) is a steroid mostly found in plants of Cucurbitaceae family. It has been shown to possess anticancer activity although the molecular mechanism remains poorly defined. We present evidence that Cuc-B has the ability to interact with mortalin and HDM2 proteins that are enriched in cancer cells, suppress wild type p53 function and promote cancer cell migration. Computational analyses showed that Cuc-B interacts with mortalin similar to MKT077 and Withanone, both have been shown to reactivate p53 function and inhibit cell migration. Furthermore, Cuc-B interacted with HDM2 similar to Y30, a well-known inhibitor of HDM2. Experimental cell and molecular analyses demonstrated the downregulation of several proteins, critically involved in cell migration in Cuc-B (low non-toxic doses)-treated cancer cells and exhibited inhibition of cell migration. The data suggested that Cuc-B is a potential natural drug that warrants further mechanistic and clinical studies for its use in the management of metastatic cancers.Communicated by Ramaswamy H. Sarma.

A widely used type II pyrethroid pesticide cypermethrin (CYP) is one of endocrine disrupting chemicals (EDCs) with anti-androgenic activity to induce male reproductive toxicology. However, the mechanisms have not been fully elucidated. This study was to explore the effects of CYP on apoptosis of mouse Sertoli cells (TM4) and the roles of endoplasmic reticulum (ER)-mitochondria coupling involving 1,4,5-trisphosphate receptor type1-glucose-regulated protein 75-voltage-dependent anion channel 1 (IP3R1-GRP75-VDAC1). TM4 were cultured with different concentrations of CYP. Flow cytometry, calcium (Ca 2+ ) fluorescent probe, transmission electron microscopy and confocal microscopy, and western blot were to examine apoptosis of TM4, mitochondrial Ca 2+ , ER-mitochondria coupling, and expressions of related proteins. CYP was found to increase apoptotic rates of TM4 significantly. CYP was shown to significantly increase expressions of cleaved caspase-3, cleaved poly ADP-ribose polymerase (PARP). Concentration of mitochondrial Ca 2+ was increased by CYP treatment significantly. CYP significantly enhanced ER-mitochondria coupling. CYP was shown to increase expressions of IP3R, Grp75 and VDAC1 significantly. We suggest that CYP induces apoptosis in TM4 cells by facilitating mitochondrial Ca 2+ overload regulated by ER-mitochondria coupling involving IP3R1-GRP75-VDAC1. This study identifies a novel mechanism of CYP-induced apoptosis in Sertoli cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Considering the wide application of nanoparticles in various fields of life and growing concern regarding their toxic effects, the present study was designed with the aim to evaluate the potential risks of using copper sulfate nanoparticles (CuSO 4 -NPs) in comparison to bulk form. Nanoparticles of CuSO 4 , having mean size of 73 nm were prepared by ball milling method, and fingerlings of Labeo rohita were exposed to two levels, 20 and 100 μg L -1 of CuSO 4 in both bulk and nano forms for 28 days and their comparative effects on the metallothioneins (MTs), heat shock proteins 70 (HSP 70), lipid profile, cholesterol (CHOL) and triglyceraldehyde (TG) levels, activities of some metabolic enzymes Alanine transaminase (ALT), Aspartate transaminase (AST) Akaline phosphatase (ALP), and genes expressions of HSP-70, TNF-α and IL1-ß were investigated. CuSO 4 showed the concentration and particle type dependent effects. The over expression of HSPs and MTs, significant decreases in CHOL, TG, low density lipid (LDL) levels and ALP activity, while significant increases in high density lipid (HDL)level as well as ALT and AST activities and HSP-70, TNF-α and IL1-β expressions were observed in response to higher concentration of both bulk and nano form of copper sulfate. At lower concentration (20 μg L -1 ), however, only bulk form showed toxicity. Thus, low concentrations of CuSO 4 -NPs pose negligible threat to freshwater fish., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Inflammatory processes are often accompanied by oxidative stress and lipid peroxidation, which might lead to cellular and organ damage. Carnosic acid (CA), an active component found in rosemary, exhibits pharmacological properties including antioxidative, anti-inflammatory, and antiviral effects. The aim of this research was to investigate whether CA can mitigate lipopolysaccharide (LPS)-induced oxidative stress and inflammatory responses in poultry and to understand its underlying mechanisms. We administered CA to broiler chickens via oral gavage and treated them with LPS, followed by analysis of the effects of different dosages of CA on body weight, antioxidative capacity, and inflammatory factors. Carnosic acid had no significant impact on the body weight of broiler chickens. However, serum analysis indicated that the middle dose of CA effectively enhanced the antioxidative capacity and reduced levels of oxidative stress and inflammation-related factors. Moreover, in the liver, CA demonstrated the ability to regulate the expression of proteins such as heat shock protein 60 (HSP60), heat shock protein 70 (HSP70), and P38 mitogen-activated protein kinase (P38), suggesting its protective role against liver damage induced by LPS. In the intestinal tract of broiler chickens, CA regulated the expression and localization of proteins including HSP60, HSP70, NFE2 like bZIP transcription factor 2 (Nrf2), and P38, while also influencing the expression of inflammatory markers such as protein tyrosine phosphatase receptor type C (CD45), and connexin (Cx). These findings revealed the potential protective mechanisms of CA in alleviating oxidative stress and inflammatory damage induced by LPS in poultry. Carnosic acid notably enhanced the chickens' antioxidative capacity by modulating the expression of key proteins, thereby reducing oxidative stress and inflammatory response levels. This study provides a deeper comprehension of the protective mechanisms of CA and its potential impact on avian health., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The heat shock protein 70 (Hsp70) family of molecular chaperones has important functions in maintaining proteostasis under stress conditions. Several Hsp70 isoforms, especially Hsp72 (HSPA1A), are dramatically upregulated in response to stress; however, it is unclear whether these family members have biochemical properties that are specifically adapted to these scenarios. The redox-active compound, methylene blue (MB), has been shown to inhibit the ATPase activity of Hsp72 in vitro, and it promotes degradation of the Hsp72 substrate, tau, in cellular and animal models. Here, we report that MB irreversibly inactivates Hsp72 but not the nearly identical, constitutively expressed isoform, heat shock cognate 70 (Hsc70; HSPA8). Mass spectrometry results show that MB oxidizes Cys306, which is not conserved in Hsc70. Molecular models suggested that oxidation of Cys306 exposes Cys267 to modification and that both events contribute to loss of ATP binding in response to MB. Consistent with this model, mutating Cys267 and Cys306 to serine made Hsp72 largely resistant to MB in vitro, and overexpression of the C306S mutant blocked MB-mediated loss of tau in a cellular model. Furthermore, mutating Cys267 and Cys306 to the pseudo-oxidation mimic, aspartic acid, mirrored MB treatment: the C267D and C306D mutants had reduced ATPase activity in vitro, and overexpression of the C267/306D double mutant significantly reduced tau levels in cells. Together, these results suggest that redox sensing by specific cysteine residues in Hsp72, but not Hsc70, may be an important component of the chaperone response to oxidative stress.

The microtubule associated protein tau (MAPT/tau) aberrantly accumulates in 15 neurodegenerative diseases, termed tauopathies. One way to treat tauopathies may be to accelerate tau clearance, but the molecular mechanisms governing tau stability are not yet clear. We recently identified chemical probes that markedly accelerate the clearance of tau in cellular and animal models. In the current study, we used one of these probes in combination with immunoprecipitation and mass spectrometry to identify 48 proteins whose association with tau changes during the first 10 min after treatment. These proteins included known modifiers of tau proteotoxicity, such as ILF-2 (NFAT), ILF-3, and ataxin-2. A striking observation from the data set was that tau binding to heat shock protein 70 (Hsp70) decreased, whereas binding to Hsp90 significantly increased. Both chaperones have been linked to tau homeostasis, but their mechanisms have not been established. Using peptide arrays and binding assays, we found that Hsp70 and Hsp90 appeared to compete for binding to shared sites on tau. Further, the Hsp90-bound complex proved to be important in initiating tau clearance in cells. These results suggest that the relative levels of Hsp70 and Hsp90 may help determine whether tau is retained or degraded. Consistent with this model, analysis of reported microarray expression data from Alzheimer's disease patients and age-matched controls showed that the levels of Hsp90 are reduced in the diseased hippocampus. These studies suggest that Hsp70 and Hsp90 work together to coordinate tau homeostasis.

Nine neurodegenerative disorders are caused by the abnormal expansion of polyglutamine (polyQ) regions within distinct proteins. Genetic and biochemical evidence has documented that the molecular chaperone, heat shock protein 70 (Hsp70), modulates polyQ toxicity and aggregation, yet it remains unclear how Hsp70 might be used as a potential therapeutic target in polyQ-related diseases. We have utilized a pair of membrane-permeable compounds that tune the activity of Hsp70 by either stimulating or by inhibiting its ATPase functions. Using these two pharmacological agents in both yeast and PC12 cell models of polyQ aggregation and toxicity, we were surprised to find that stimulating Hsp70 solubilized polyQ conformers and simultaneously exacerbated polyQ-mediated toxicity. By contrast, inhibiting Hsp70 ATPase activity protected against polyQ toxicity and promoted aggregation. These findings clarify the role of Hsp70 as a possible drug target in polyQ disorders and suggest that Hsp70 uses ATP hydrolysis to help partition polyQ proteins into structures with varying levels of proteotoxicity. Our results thus support an emerging concept in which certain kinds of polyQ aggregates may be protective, while more soluble polyQ species are toxic.

Protein function is often regulated by posttranslational modifications (PTMs), and recent advances in mass spectrometry have resulted in an exponential increase in PTM identification. However, the functional significance of the vast majority of these modifications remains unknown. To address this problem, we compiled nearly 200,000 phosphorylation, acetylation, and ubiquitination sites from 11 eukaryotic species, including 2,500 newly identified ubiquitylation sites for Saccharomyces cerevisiae. We developed methods to prioritize the functional relevance of these PTMs by predicting those that likely participate in cross-regulatory events, regulate domain activity, or mediate protein-protein interactions. PTM conservation within domain families identifies regulatory "hot spots" that overlap with functionally important regions, a concept that we experimentally validated on the HSP70 domain family. Finally, our analysis of the evolution of PTM regulation highlights potential routes for neutral drift in regulatory interactions and suggests that only a fraction of modification sites are likely to have a significant biological role.

Rosa damascena, or Damask rose, is a rose hybrid commonly harvested for rose oil used in perfumery and for rose water used to flavor food. The petal extract of R. damascena was recently found to decrease Drosophila melanogaster mortality without impairing reproductive fitness or metabolic rate. Here, we report that R. damascena extended both mean and maximum lifespan of the fly. The extract also protected against oxidative stress in flies, predominantly in females. However, it did not alter mitochondrial respiration or content, superoxide production, or the major antioxidant defenses, superoxide dismutase and catalase. The extract increased survival in both sexes when exposed to reduced iron, though surprisingly, it sensitized both sexes to heat stress (survival at 37°C), and appeared to down-regulate the major heat shock protein HSP70 and the small mitochondrial heat shock protein HSP22, at 25°C and after heat shock (4 h at 37°C). We hypothesize that R. damascena extends lifespan by protecting against iron, which concomitantly leads to decreased HSP expression and compromising heat tolerance.

J proteins are a diverse family of co-chaperones that cooperate with heat shock protein 70 (Hsp70) to coordinate protein quality control, especially in response to cellular stress. Current models suggest that individual J proteins might play roles in recruiting Hsp70s to specific functions, such as maintaining cell wall integrity or promoting ribosome biogenesis. However, relatively few stresses have been used to test this model and, as a result, only a few specific activities have been identified. To expand our understanding of the J protein network, we used a synthetic lethal approach in which 11 Saccharomyces cerevisiae deletion strains were treated with 12 well-characterized chemical inhibitors. The results defined new roles for specific J proteins in major signaling pathways. For example, an important role for Swa2 in cell wall integrity was identified and activities of the under-explored Jjj1, Apj1, Jjj3 and Caj1 proteins were suggested. More generally, these findings support a model in which some J proteins, such as Ydj1 and Zuo1, play "generalist" roles, while others, such as Apj1 and Jjj2, are "specialists", having roles in relatively few pathways. Together, these results provide new insight into the network of J proteins.

In Escherichia coli, the molecular chaperones DnaK and DnaJ cooperate to assist the folding of newly synthesized or unfolded polypeptides. DnaK and DnaJ bind to hydrophobic motifs in these proteins and they also bind to each other. Together, this system is thought to be sufficiently versatile to act on the entire proteome, which creates interesting challenges in understanding the interactions between DnaK, DnaJ and their thousands of potential substrates. To address this question, we computationally predicted the number and frequency of DnaK- and DnaJ-binding motifs in the E. coli proteome, guided by free energy-based binding consensus motifs. This analysis revealed that nearly every protein is predicted to contain multiple DnaK- and DnaJ-binding sites, with the DnaJ sites occurring approximately twice as often. Further, we found that an overwhelming majority of the DnaK sites partially or completely overlapped with the DnaJ-binding motifs. It is well known that high concentrations of DnaJ inhibit DnaK-DnaJ-mediated refolding. The observed overlapping binding sites suggest that this phenomenon may be explained by an important balance in the relative stoichiometry of DnaK and DnaJ. To test this idea, we measured the chaperone-assisted folding of two denatured substrates and found that the distribution of predicted DnaK- and DnaJ-binding sites was indeed a good predictor of the optimal stoichiometry required for folding. These studies provide insight into how DnaK and DnaJ might cooperate to maintain global protein homeostasis.

Candida albicans Ssa1 and Ssa2 are members of the HSP70 family of heat shock proteins that are expressed on the cell surface and function as receptors for antimicrobial peptides such as histatins. We investigated the role of Ssa1 and Ssa2 in mediating pathogenic host cell interactions and virulence. A C. albicans ssa1Δ/Δ mutant had attenuated virulence in murine models of disseminated and oropharyngeal candidiasis, whereas an ssa2Δ/Δ mutant did not. In vitro studies revealed that the ssa1Δ/Δ mutant caused markedly less damage to endothelial cells and oral epithelial cell lines. Also, the ssa1Δ/Δ mutant had defective binding to endothelial cell N-cadherin and epithelial cell E-cadherin, receptors that mediate host cell endocytosis of C. albicans. As a result, this mutant had impaired capacity to induce its own endocytosis by endothelial cells and oral epithelial cells. Latex beads coated with recombinant Ssa1 were avidly endocytosed by both endothelial cells and oral epithelial cells, demonstrating that Ssa1 is sufficient to induce host cell endocytosis. These results indicate that Ssa1 is a novel invasin that binds to host cell cadherins, induces host cell endocytosis, and is critical for C. albicans to cause maximal damage to host cells and induce disseminated and oropharyngeal disease.

The effects of exogenous recombinant human heat shock protein Hsp70 and hydrogen sulfide donor GYY4137 on the mechanisms of endocytosis of lipopolysaccharide (LPS) by human neuroblastoma cells SH-SY5Y were studied. Hsp70 and GYY4137 have been shown to significantly reduce LPS-induced production of inflammatory mediators by SH-SY5Y cells, including reactive oxygen species, nitric oxide, TNFα, IL-1β, and IL-6. Both the recombinant protein Hsp70 and the hydrogen sulfide donor GYY4137 exhibited significant protective effects; however, the combined use of these agents did not lead to a cumulative effect. It has been shown that pinocytosis, as well as clathrin-, caveolin-, tubulin- and receptor-dependent endocytosis were involved in protecting the cells by both the hydrogen sulfide donor and Hsp70 from LPS-induced production of reactive oxygen species and NO. [ABSTRACT FROM AUTHOR]

Vermicomposting is a process by which earthworms together with microorganisms degrade organic wastes into a humus-like material called vermicompost. This process does not include a thermophilic stage, and therefore, the possible presence of pathogens represents a potential health hazard. To elucidate the effect of earthworms in the selective reduction of pathogens, grape marc substrate was artificially inoculated with Escherichia coli, Enterococcus spp., thermotolerant coliform bacteria (TCB), and Salmonella spp., and their reduction during vermicomposting was monitored. Various defense mechanisms eliminating microorganisms in the earthworm gut were assumed to be involved in the process of pathogen reduction. Therefore, we followed the expression of three pattern recognition receptors (coelomic cytolytic factor (CCF), lipopolysaccharide-binding protein (LBP), and Toll-like receptor (v-TLR)), two antimicrobial molecules (fetidin/lysenins and lysozyme), and heat shock protein HSP70. We detected the significant decrease of some defense molecules (fetidin/lysenins and LBP) in all pathogen-inoculated substrates, and the increase of CCF and LBP in the Salmonella spp.-inoculated substrate. At the same time, the reduction of pathogens during vermicomposting was assessed. We observed the accelerated reduction of E. coli, Enterococcus spp., and TCB in pathogen-inoculated substrates with earthworms compared to that without earthworms. Moreover, the differences between the microbiome of grape marc substrate and earthworm intestines were determined by high throughput sequencing. This analysis revealed that the bacterial composition of grape marc substrate differed from the composition of the content of earthworm intestines, suggesting the elimination of specific bacterial species during food passage through the gut. [ABSTRACT FROM AUTHOR]

The heat shock protein Hsp70 is involved in cell defense from various types of stress, including the proteotoxic stress, which occurs during the development of many neurodegenerative diseases. This work presents data on the detection of small molecules, derivatives of indolyl- and pyrrolylazines, which can activate the synthesis of Hsp70 and cause its accumulation in the cell. The toxicity level of the new Hsp70 synthesis inducers was evaluated, and the safety of these compounds was demonstrated in experiments on SH-SY5Y neuroblastoma cell line. Derivatives of indolyl- and pyrrolylazines presented in this work can be potential therapeutic agents in models of neurodegenerative diseases that should be studied in more detail. [ABSTRACT FROM AUTHOR]

The accumulation and prion‐like propagation of α‐synuclein and other amyloidogenic proteins are associated with devastating neurodegenerative diseases. Metazoan heat shock protein HSP70 and its co‐chaperones DNAJB1 and HSP110 constitute a disaggregation machinery that is able to disassemble α‐synuclein fibrils in vitro, but its physiological effects on α‐synuclein toxicity are unknown. Here, we depleted Caenorhabditis elegans HSP‐110 and monitored the consequences on α‐synuclein‐related pathological phenotypes such as misfolding, intercellular spreading, and toxicity in C. elegans in vivo models. Depletion of HSP‐110 impaired HSP70 disaggregation activity, prevented resolubilization of amorphous aggregates, and compromised the overall cellular folding capacity. At the same time, HSP‐110 depletion reduced α‐synuclein foci formation, cell‐to‐cell transmission, and toxicity. These data demonstrate that the HSP70 disaggregation activity constitutes a double‐edged sword, as it is essential for maintaining cellular proteostasis but also involved in the generation of toxic amyloid‐type protein species. Synopsis: The HSP110/HSP70 chaperone system plays key roles in general protein folding and the disassembly of protein aggregates. A Caenorhabditis elegans model for α‐synuclein aggregation shows that this disaggregase function contributes to the formation of toxic, spreading‐competent amyloid species. Co‐chaperone HSP‐110 depletion impairs general cellular protein folding capacity and inhibits the HSP70 disaggregation machinery.HSP‐110 depletion impairs general cellular protein folding capacity.HSP‐110 depletion reduces α‐synuclein foci formation, cell‐to‐cell transmission, and in vivo toxicity.The negative effect of HSP‐110 depletion on cellular proteostasis overrides the beneficial effect on α‐synuclein toxicity in older animals. [ABSTRACT FROM AUTHOR]

The goal of the current investigation is to study the effect of vitamin C and acetylsalicylic acid in minimizing the effects of heat stress in terms of hematological values, growth hormone, HSP70 and glutathione. Broiler were randomly distributed into four groups: 1st group was served as the control, the 2nd group subjected to heat stress 40±2 ºC up to 4 hours/day, the 3rd group was subjected to heat stress and vitamin C 360 mg/L via drinking water and the 4th group was exposed to heat stress and acetylsalicylic acid 0.03% via drinking water. The result showed that exposure to heat stress decline in RBCs count, Hb concentration, PCV and percentage of lymphocyte, furthermore elevation in of MCV, heterophils, H/L ratio, and Hsp70 concentration. Administration of vitamin C caused a significant rise RBCs, percentage of lymphocyte and reduces in MCV, MCH value, percentage of heterophils and H/L ratio compared with the heat stress group. Administrations of acetylsalicylic acid were significantly increased the RBCs, and PCV and decrease in MCV, MCH, MCHC values, and H/L ratio compare with the heat stress group. The results did not show a significant change between the tested groups in the levels of glutathione and growth hormone. The study concluded that Vitamin C and acetylsalicylic acid administration as feed additive ameliorating the opposing effect caused by heat stress in the broiler; thus, its administration recommends when there is heat stress exposure. [ABSTRACT FROM AUTHOR]

The current study aimed to investigate the snail’s pathological changes and their relationship with the amount of gene expression of heat shock proteins HSP90 & HSP70 under the influence of lannate pesticide. P. canaliculata were collected during the period between 5th-10th May 2018. The laboratory generation snails were divided into 2 groups, the first was exposed to a concentration of 10 mg/L of the pesticide, as the lethal concentration of the pesticide was 12.6mg/L, and the second was left as a control group. After that, three snails from each group were dissected by the end of the following intervals (10mins, 1hr, 8hrs, 24hrs, 3days, 7days, and 15day). The gene expression was studies using qPCR method. Results of the genetic analysis for the abundance of the HSP70-HSP90 showed a clear effect of the pesticide on the treated snails during the above interval. On the other hand, the results of the histological study of the gills showed that the pathological changes varied in their intensity during the intervals, while there was no clear effect to variation of concentrations. These changes involve loss of cilia in the epithelial cells, infiltration of granulocytes in the cilia loss regions, hyperplasia, degradation and necrosis of cells as well as the accumulation of non-living brown and grey materials within the epithelial cells. Moreover, it was noticed that the mucous materials secreted from cystic cells has increased. [ABSTRACT FROM AUTHOR]

The article discusses the tissue- and cell-based analyses to confirm that the therapeutic intervention was mediated comprehensively by anti-inflammatory and antifibrotic effects of the therapy. It demonstrates that key pathology of allergic asthma can be almost completely resolved in a therapeutic manner by inhaled gene therapy.

Background: Rice is a chilling-sensitive crop that would suffer serious damage from low temperatures. Overexpression of the Lsi1 gene (Lsi1-OX) in rice enhances its chilling tolerance. This study revealed that a serine hydroxymethyltransferase (OsSHMT) mainly localised in the endoplasmic reticulum (ER) is involved in increasing tolerance to chilling. Results: A higher transcription level of OsSHMT was detected in Lsi1-OX rice than in the wild type. Histone H1 and nucleic acid binding protein were found to bind to the promoter region of OsSHMT and regulate its expression, and the transcription levels of these proteins were also up-regulated in the Lsi1-OX rice. Moreover, OsSHMT interacts with ATP synthase subunit α, heat shock protein Hsp70, mitochondrial substrate carrier family protein, ascorbate peroxidase 1 and ATP synthase subunit β. Lsi1-encoded protein OsNIP2;1 also interacts with ATP synthase subunit β, and the coordination of these proteins appears to function in reducing reactive oxygen species, as the H2O2 content of transgenic OsSHMT Arabidopsis thaliana was lower than that of the non-transgenic line under chilling treatment. Conclusions: Our results indicate that ER-localised OsSHMT plays a role in scavenging H2O2 to enhance the chilling tolerance of Lsi1-OX rice and that ATP synthase subunit β is an intermediate junction between OsNIP2;1 and OsSHMT. [ABSTRACT FROM AUTHOR]

Rotating and permanent night shiftwork schedules typically result in acute and sometimes chronic sleep deprivation plus acute and sometimes chronic disruption of the circadian time structure. Immune system processes and functionalities are organized as circadian rhythms, and they are also strongly influenced by sleep status. Sleep is a vital behavioral state of living beings and a modulator of immune function and responsiveness. Shiftworkers show increased risk for developing viral infections due to possible compromise of both innate and acquired immunity responses. Short sleep and sleep loss, common consequences of shiftwork, are associated with altered integrity of the immune system. We discuss the possible excess risk for COVID-19 infection in the context of the common conditions among shiftworkers, including nurses, doctors, and first responders, among others of high exposure to the contagion, of sleep imbalance and circadian disruption. ACE2: Angiotensin-converting enzyme 2; APC: Antigen.-presenting.cells; CCL: Chemokine (C-C motif) ligand; CD+:.Adhesion molecule expression; COVID-19: 2019 coronavirus disease; DCs: Dendritic cells; GH: Growth hormone; HPA: Hypothalamic-pituitary-adrenal; HSF: Heat shock factor; HSP70: Heat shock protein 70; HSP90: Heat shock protein 90; IL: Interleukin; INFγ: Interferon-gamma; LT/LB: T/B lymphocytes; MHC: Major histocompatibility complex; NK: Natural.killer; RAAS: renin–angiotensin–aldosterone system; SARS:.Severe acute respiratory syndrome; SCN: Suprachiasmatic nucleus;SD: Sleep deprivation; SNS: Sympathetic nervous system; Th1/Th2: T helper lymphocytes 1/2; TLR2/TLR4: Toll-like receptor 2/4; TNF-α: Tumor.necrosis.factor alpha; VEGF: Vascular endothelial growth factor [ABSTRACT FROM AUTHOR]

Citrus tristeza virus (CTV), a member of the family Closteroviridae, represents one of the most intricate viruses with an overwhelmingly complex biology. CTV is among viruses with largest RNA genomes CTV possesses a 19.3 kilobase (kb) positive-stranded RNA genome, which is nearly twice as large as the average sized RNA virus genome of 10 kb [[3]]. CTV produces a myriad of virus-specific RNA species in the infected cells During infection, CTV produces a plethora of different RNA species. [Extracted from the article]

Necroptosis is a regulated necrotic cell death pathway involved in development and disease. Its signaling cascade results in the formation of disulfide bond-dependent amyloid-like polymers of mixed lineage kinase domain-like protein (MLKL), which mediate proinflammatory cellmembrane disruption. We screened compound libraries provided by the National Cancer Institute and identified a small-molecule inhibitor of necroptosis named necroptosis-blocking compound 1 (NBC1). Biotin-labeled NBC1 specifically conjugates to heat shock protein Hsp70. NBC1 and PES-Cl, a known Hsp70 substrate-binding inhibitor, block the formation of MLKL polymers, but not MLKL tetramers in necroptosis-induced cells. In vitro, recombinant Hsp70 interacts with the N-terminal domain (NTD) of MLKL and promotes NTD polymerization, which has been shown to mediate the cell killing activity. Furthermore, the substrate-binding domain (SBD) of Hsp70 is sufficient to promote MLKL polymerization. NBC1 covalently conjugates cysteine 574 and cysteine 603 of the SBD to block its function. In addition, an SBD mutant with both cysteines mutated to serines loses its ability to promote MLKL polymerization. Interestingly, knockdown of Hsp70 in cells leads to MLKL destabilization, suggesting that MLKL might also be a client protein of Hsp70. In summary, using NBC1, an inhibitor of necroptosis, we identified Hsp70 as a molecular chaperone performing dual functions in necroptosis. It stabilizes MLKL protein under normal condition and promotes MLKL polymerization through its substrate-binding domain during necroptosis. [ABSTRACT FROM AUTHOR]

Exosomes are nano vesicles from the larger family named Extracellular Vesicle (EV)s which are released by various cells including tumor cells, mast cells, dendritic cells, B lymphocytes, neurons, adipocytes, endothelial cells, and epithelial cells. They are considerable messengers that can exchange proteins and genetic materials between the cells. Within the past decade, Tumor derived exosomes (TEX) have been emerged as important mediators in cancer initiation, progression and metastasis as well as host immune suppression and drug resistance. Although tumor derived exosomes consist of tumor antigens and several Heat Shock Proteins such as HSP70 and HSP90 to stimulate immune response against tumor cells, they contain inhibitory molecules like Fas ligand (Fas-L), Transforming Growth Factor Beta (TGF-β) and Prostaglandin E2 (PGE2) leading to decrease the cytotoxicity and establish immunosuppressive tumor microenvironment (TME). To bypass this problem and enhance immune response, some macromolecules such as miRNAs, HSPs and activatory ligands have been recognized as potent immune inducers that could be used as anti-tumor agents to construct a nano sized tumor vaccine. Here, we discussed emerging engineered exosomes as a novel therapeutic strategy and considered the associated challenges. Imbalance between immune suppression and immune response by tumor derived exosomes. Potential role of engineered tumor derived exosomes in changing the fate of immune response. Image designed by Adeleh Taghikhani. [ABSTRACT FROM AUTHOR]

Eusperm and parasperm ultrastructure have been studied for the first time in the neogastropod Plicopurpura patula. Eusperm structure is typical of many Neogastropoda, in which an apical bleb characterizes the conical acrosome with subacrosomal granule; the nucleus is tubular and penetrated to its tip by basal body and axoneme; the mid-piece comprises spiral mitochondria that ensheath the axoneme but terminate at the annulus, defining the junction with the end-piece. In the proximal portion of the end-piece dense tracts of glycogen match the axoneme but these disappear distally. The parasperm is unusual in having no axonemes and no motility was observed. Eusperm do not attach to parasperm, as occurs in the similar nurse cells of Littorinimorpha, thus potential functions may be limited to some form of paternity assurance as occurs in some insects. The nucleus of the parasperm is eliminated during paraspermiogenesis, but there is considerable post-transcriptional secretion activity resulting in the production of a variety of granules, some rich in glycoproteins. A prominent paracrystalline rod accumulates in the centre of the parasperm also from Golgi-derived secretions. Preliminary evidence from proteomics suggests that this parasperm carries the heat shock protein HSP70 that could play a role in fertilization inside the female. [ABSTRACT FROM AUTHOR]

The Hsp70 family of heat shock proteins plays a critical function in maintaining cellular homeostasis within various subcellular compartments. The human mitochondrial Hsp70 (HSPA9) has been associated with cellular death, senescence, cancer and neurodegenerative diseases, which is the rational for the name mortalin. It is well documented that mortalin, such as other Hsp70s, is prone to self-aggregation, which is related to mitochondria biogenesis failure. Here, we investigated the assembly, structure and function of thermic aggregates/oligomers of recombinant human mortalin and Hsp70-1A (HSPA1A). Summarily, both Hsp70 thermic aggregates have characteristics of supramolecular assemblies. They display characteristic organized structures and partial ATPase activity, despite their nanometric size. Indeed, we observed that the interaction of these aggregates/oligomers with liposomes is similar to monomeric Hsp70s and, finally, they were non-toxic over neuroblastoma cells. These findings revealed that high molecular mass oligomers of mortalin and Hsp70-1A preserved some of the fundamental functions of these proteins. Unlabelled Image [ABSTRACT FROM AUTHOR]

We studied the correlations of the expression of Ki-67 proliferation marker and localization of heat shock protein Hsp70 in tumor cells of papillary thyroid cancer with some clinical and morphological parameters and a 10-year survival prognosis. High variability of the proliferative activity (by Ki-67 index) of tumor cells was revealed. It was found that Hsp70 protein has different localization in tumor cells: cytoplasmic, nuclear, nucleolar, and mixed. Nuclear translocation of the Hsp70 protein correlated with the stage of the process and the prognosis of the disease, but did not correlate with sex, tumor size, capsule invasion, and lymph node metastasis. Ki-67 index of tumor cells correlated with sex, stage of the process, size of tumor formation and prognosis, but did not correlated with age, invasion into the capsule and metastasis to the lymph nodes. Depending on the variants of Hsp70 and Ki-67 co-expression, three molecular types of papillary thyroid cancer can be distinguished: favorable, intermediate, and poor prognosis. [ABSTRACT FROM AUTHOR]

Gene expression is a biological process regulated at different molecular levels, including chromatin accessibility, transcription, and RNA maturation and transport. In addition, these regulatory mechanisms have strong links with cellular metabolism. Here we present a multi-omics dataset that captures different aspects of this multi-layered process in yeast. We obtained RNA-seq, metabolomics, and H4K12ac ChIP-seq data for wild-type and mip6Δ strains during a heat-shock time course. Mip6 is an RNA-binding protein that contributes to RNA export during environmental stress and is informative of the contribution of post-transcriptional regulation to control cellular adaptations to environmental changes. The experiment was performed in quadruplicate, and the different omics measurements were obtained from the same biological samples, which facilitates the integration and analysis of data using covariance-based methods. We validate our dataset by showing that ChIP-seq, RNA-seq and metabolomics signals recapitulate existing knowledge about the response of ribosomal genes and the contribution of trehalose metabolism to heat stress. Raw data, processed data and preprocessing scripts are made available. Measurement(s) RNA • metabolite • histone_modification • epigenetic status Technology Type(s) RNA sequencing • nuclear magnetic resonance spectroscopy • ChIP-seq Factor Type(s) environmental stress • duration of heat shock • wild type vs Mip6 mutant strain Sample Characteristic - Organism Saccharomyces cerevisiae Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.11836743 [ABSTRACT FROM AUTHOR]

Objectives: To identify cytokines that can activate and expand NK cells in the presence of prostate cancer cells in order to determine whether these agents may be useful in future intra‐tumoural administration in pre‐clinical and clinical prostate cancer trials. Materials and Methods: Lymphocytes isolated from normal donor blood were set up in co‐cultures with either cancer or non‐cancerous prostate cell lines, together with each of the cytokines interleukin (IL)‐2, IL‐12, IL‐15, interferon (IFN)‐γ or IL‐21 for a period of 7 days. Then, expansion of NK cells, NKT cells and CD8 T cells was measured by flow cytometry and compared with the expansion of the same cells in the absence of prostate cells. The cytotoxic activity of NK cells, as measured by perforin and tumour cell killing, was also assessed. NK cell receptors and their corresponding ligands on prostate tumour cells were analysed to determine whether any of these were modulated by co‐culture. The role of the tumour‐secreted heat shock proteins HSP90 and HSP70 in the expansion of NK cells in the co‐cultures was also investigated because of their effects on NK and CD8 T‐cell activation. Results: We showed that, among a panel of cytokines known to cause NK cell activation and expansion, only IL‐15 could actively induce expansion of NK, NKT and CD8 T cells in the presence of prostate cancer cell lines. Furthermore, the expansion of NK cells was far greater (up to 50% greater) in the presence of the cancer cells (LNCaP, PC3) than when lymphocytes were incubated alone. In contrast, non‐cancerous cell lines (PNT2 and WPMY‐1) did not exert any expansion of NK cells. The cytolytic activity of the NK cells, as measured by perforin, CD107a and killing of tumour cells, was also greatest in co‐cultures with IL‐15. Examination of NK cell receptors shows that NKG2D is upregulated to a greater degree in the presence of prostate cancer cells, compared with the upregulation with IL‐15 in lymphocytes alone. However, blocking of NKG2D does not inhibit the enhanced expansion of NK cells in the presence of tumour cells. Conclusions: Among a panel of NK cell‐activating cytokines, IL‐15 was the only cytokine that could stimulate expansion of NK cells in the presence of prostate cancer cells; therefore IL‐15 may be a good candidate for novel future intra‐tumoural therapy of the disease. [ABSTRACT FROM AUTHOR]

Background: The aim of the study was to identify cytomegalovirus antibodies (IgM, IgG), heat shock protein 70 and to affect contact with animals on aborted women. This is Iraq's first study, no other studies to determine the relationship between CMV infection and HSP70 concentration in aborted women have been conducted. Method: During the duration from July to December (2018), 160 blood samples were obtained from women suffering from repeated embryo predictions, which were used by reviewers in privatelaboratories in the province of Basrah, Iraq to estimate the levels of cytomegalovirus (IgM, IGg) and heat shock protein 70. Result: The results showed that level IgM had higher rates in age (26-30) year at a rate of 26.7% with significantn difference compared to other age groups, whereas level IgG had higher rates in age (31-35 & 36-40) at rate of 100%. Also we found in this results significant relationship between IgM and primary abortion at rate 16.7% in the age group (26-30). But the results show that IgG had a higher rat in the age group (31-35) at rate 68.1% with significant diffrents compared with Primary abortion woman. In addition, the study showed that HSP70 concentration in aborted women was high rate of 38% and a higher concentration show in the 4th age group at rate of 56.3% in 320 ng/ml concentration. The study showed also that HSP70 concentration in aborted women was high rate of 38% and a higher concentration show in the 4th age group at rate of 56.3% in 320 ng/ml concentration, also we found that two and more abortions had the highest rate of 62 %, with significant differences relative to other abortions. The study also showed that aborted poultry breeders women were 42.6% higher with significant difference compared to other groups. Conclusion: Observed that the first age group is more vulnerable to HCMV infection during pregnancy in thistudy relationship between HSP70 and Poultry Breeders with abortion, too. [ABSTRACT FROM AUTHOR]

Considering the role played by the heat shock protein of 70 kDa (HSP70) in cancer, we characterized this protein and its major regulator, the heat shock factor 1 (HSF1), in chronic lymphocytic leukemia (CLL). We found both HSP70 and HSF1 overexpressed in CLL patients, correlated to poor prognosis and abnormally localized in the nucleus of leukemic B cells. The two proteins were strictly correlated each other and their levels decreased consensually in those patients responding to in vivo therapeutic regimens. HSP70 and HSF1 inhibition was proved to be effective in inducing a dose‐dependent in vitro apoptosis of CLL B cells. Considering that HSF1 is finely regulated by kinases belonging to pathways triggered by rat sarcoma (RAS), we benefited from a previous proteomic study performed in CLL patients aiming to assess the activation/expression of key signaling proteins. We found that patients showing high levels of HSP70 also expressed high Akt‐Ser473, thus activating HSF1. Inhibition of PI3K, which activates AKT, reduced the expression of HSF1 and HSP70. By contrast, HSP70‐low patients displayed high activation of MEK1/2 and ERK1/2, known to negatively regulate HSF1. These data demonstrate that the HSP70 expression is regulated by the modulation of HSF1 activity through the activation of RAS‐regulated pathways and suggest the HSP70/HSF1 interplay as an interesting target for antileukemic therapies. Finally, inhibition of PI3K, that activates AKT, reduced the expression of HSF1 and HSP70. What's new? The heat shock protein HSP70 is overexpressed in B cells from chronic lymphocytic leukemia (CLL) patients but how it contributes to leukemogenesis is unknown. Here, the authors identify its interaction with the heat shock factor HSF1 as a possible mechanism. HSF1 is activated by the phosphoinositide‐3‐kinase–protein kinase B (PI3K/AKT) signal transduction pathway, and inhibition of PI3K reduced the expression of both HSP70 and HSF1. Similarly, HSP70 or HSF1 inhibition induced cell death, supporting the notion that both represent possible targets in CLL treatment. [ABSTRACT FROM AUTHOR]

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The B-cell lymphoma 2 (Bcl-2)-associated athanogene (BAG) family is a relatively conserved and multifunctional co-chaperones in animals and plants, which can flexibly interact with a variety of proteins and regulate various processes from growth and development to stress response. However, compared with animals, the function of BAG family in plant remains largely unknown, especially in response to cold stress. In this study, we have found that the expression of BAG8 was significantly induced in tomato under cold stress. Results showed that bag8 mutants exhibit significantly reduced tolerance towards cold stress, while BAG8 overexpressing lines were relatively resistant as reflected by the phenotype and membrane peroxidation. Measuring of gas exchange parameters, photosystem I (PSI) and photosystem II (PSII) of tomato leaves under cold stress further revealed that BAG8 mitigated cold-induced damage in photosynthetic system. Additionally, bag8 mutants exhibited more cold-induced reactive oxygen species, which were substantially normalized in BAG8 overexpressing plants. Nevertheless, the activities of antioxidant enzymes which were compromised in bag8 mutants were improved in BAG8 overexpressing plants facing cold stress. Additionally, BAG8 interacted with heat shock protein Hsp70 and protein phosphatase PP2A both in vitro and in vivo. Our results demonstrate that BAG8 plays a positive role in cold tolerance in tomato probably by the improvement of photosystems and antioxidant systems, and by interacting with Hsp70 involved in photosynthesis and PP2A involved in stomatal development. [Display omitted] • The expression of BAG8 is significantly induced in tomato under cold stress. • BAG8 positively regulates tomato cold tolerance as reflected by the phenotype and membrane peroxidation. • BAG8 mitigates cold-induced damage in photosynthetic system. • BAG8 can reduce oxidative damage by increasing the activities of antioxidant enzymes in plants facing cold stress. • BAG8 interactes with heat shock protein Hsp70 and protein phosphatase PP2A both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

This study aimed to investigate the effects of 24 and 72 h exposure to environmentally relevant concentrations of tebuconazole (TEB) (10, 100 and 500 µg/L) fungicide on the freshwater snail Lymnaea stagnalis. The focus was induction of oxidative stress, alteration of gene expressions and histopathological changes in the kidney and digestive gland. TEB treatment induced a time- and concentration-dependent increase in intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels, while the total antioxidant capacity (TAC) was decreased. The activities of glutathione peroxidase (GPx), glutathione reductase (GR), and catalase (CAT) also increased in a time- and concentration-dependent manner in both tissues. TEB exposure significantly increased the mRNA levels of CAT, GPx, GR, heat shock proteins HSP40 and HSP70. Histological analysis revealed nephrocyte degeneration and disrupted digestive cells. The study concludes that acute exposure to TEB induces oxidative stress, alters antioxidant defense mechanisms, and leads to histopathological changes in L. stagnalis. • Effects of tebuconazole (TEB) on snail Lymnaea stagnalis were investigated. • Oxidative stress-related processes in the kidney and digestive gland were assessed. • ROS and malondialdehyde levels were induced but TAC was decreased. • TEB increased the mRNA levels of CAT, GPx, GR, heat shock proteins HSP40 and HSP70. • TEB induced nephrocyte degeneration in kidney tissue and disrupted digestive cells. [ABSTRACT FROM AUTHOR]

Neuregulins are a family of growth factor domain proteins that are structurally related to the epidermal growth factor. Accumulating evidence has shown that neuregulins have cyto- and neuroprotective properties in various cell types. In particular, the neuregulin-1 Beta (NRG1-Beta) isoform is well documented for its antiinflammatory properties in rat brain after acute stroke episodes. Pentachlorophenol (PCP) is an organochlorine compound that has been widely used as a biocide in several industrial, agricultural, and domestic applications. Previous investigations from our laboratory have demonstrated that PCP exerts both cytotoxic and mitogenic effects in human liver carcinoma (HepG2) cells, primary catfish hepatocytes and AML 12 mouse hepatocytes. We have also shown that in HepG2 cells, PCP has the ability to induce stress genes that may play a role in the molecular events leading to toxicity and tumorigenesis. In the present study, we hypothesize that NRG1-Beta will exert its cytoprotective effects in PCP-treated AML 12 mouse hepatocytes by its ability to suppress the toxic effects of PCP. To test this hypothesis, we performed the MTT-cell respiration assay to assess cell viability, and Western-blot analysis to assess stress-related proteins as a consequence of PCP exposure. Data obtained from 48 h-viability studies demonstrated a biphasic response; showing a dose-dependent increase in cell viability within the range of 0 to 3.87 microg/mL, and a gradual decrease within the concentration range of 7.75 to 31.0 microg/mL in concomitant treatments of NRG1-Beta+PCP and PCP. Cell viability percentages indicated that NRG1-Beta+PCPtreated cells were not significantly impaired, while PCP-treated cells were appreciably affected; suggesting that NRG1-Beta has the ability to suppress the toxic effects of PCP. Western Blot analysis demonstrated the potential of PCP to induce oxidative stress and inflammatory response (c-fos), growth arrest and DNA damage (GADD153), proteotoxic effects (HSP70), cell cycle arrest as consequence of DNA damage (p53), mitogenic response (cyclin- D1), and apoptosis (caspase-3). NRG1-Beta exposure attenuated stress-related protein expression in PCP-treated AML 12 mouse hepatocytes. Here we provide clear evidence that NRG1-Beta exerts cytoprotective effects in AML 12 mouse hepatocytes exposed to PCP.

Hyphomonas neptunium is a marine prosthecate alpha-proteobacterium currently classified as a member of the order 'Rhodobacterales'. Although this classification is supported by 16S rRNA gene sequence phylogeny, 23S rRNA gene sequence analysis, concatenated ribosomal proteins, HSP70 and EF-Tu phylogenies all support classifying Hyphomonas neptunium as a member of the Caulobacterales instead. The possible reasons why the 16S rRNA gene sequence gives conflicting results in this case are also discussed.

A growing number of human disorders have been associated with expansions of a tract of a single amino acid. Recently, polyalanine (polyA) tract expansions in the Aristaless-related homeobox (ARX) protein have been identified in a subset of patients with infantile spasms and mental retardation. How alanine expansions in ARX, or any other transcription factor, cause disease have not been determined. We generated a series of polyA expansions in Arx and expressed these in cell culture and brain slices. Transfection of these constructs results in nuclear protein aggregation, filamentous nuclear inclusions, and an increase in cell death. These inclusions are ubiquitinated and recruit Hsp70. Coexpressing Hsp70 decreases the percentage of cells with nuclear inclusions. Finally, we show that expressing mutant Arx in mouse brains results in neuronal nuclear inclusion formation. Our data suggest expansions in one of the ARX polyA tracts results in nuclear protein aggregation and an increase in cell death; likely underlying the pathogenesis of the associated infantile spasms and mental retardation.