M(en)TORship lessons on life and death by the integrated stress response

Cells employ pro-survival and pro-adaptive pathways to cope with different forms of environmental stress. When stress is excessive, and the damage caused by it is unsustainable, cells engage pro-death pathways, which are in place to protect the host from the deleterious effects of harmed cells. Two important pathways that determine the balance between survival and death of stressed cells are the integrated stress response (ISR) and the mammalian target of rapamycin (mTOR), both of which converge at the level of mRNA translation. The two pathways have established avenues of communication to control their activity and determine the fate of stressed cells in a context-dependent manner. The functional interplay between the ISR and mTOR may have significant ramifications in the development and treatment of human diseases such as diabetes, neurodegeneration and cancer.     

TRAIL Receptors Serve as Stress-Associated Molecular Patterns to Promote ER-Stress-Induced Inflammation

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Reaction of small heat-shock proteins to different kinds of cellular stress in cultured rat hippocampal neurons

Upregulation of small heat-shock proteins (sHsps) in response to cellular stress is one mechanism to increase cell viability. We previously described that cultured rat hippocampal neurons express five of the 11 family members but only upregulate two of them (HspB1 and HspB5) at the protein level after heat stress. Since neurons have to cope with many other pathological conditions, we investigated in this study the expression of all five expressed sHsps on mRNA and protein level after sublethal sodium arsenite and oxidative and hyperosmotic stress. Under all three conditions, HspB1, HspB5, HspB6, and HspB8 but not HspB11 were consistently upregulated but showed differences in the time course of upregulation. The increase of sHsps always occurred earlier on mRNA level compared with protein levels. We conclude from our data that these four upregulated sHsps (HspB1, HspB5, HspB6, HspB8) act together in different proportions in the protection of neurons from various stress conditions.     

Screening of rice cultivars for Cr-stress response by using the parameters of seed germination,morpho-physiological and antioxidant analysis

Rice is the most important crop for the majority of population across the world with sensitive behavior toward heavy metals such as chromium (Cr) in polluted regions. Although, there is no information on the Cr resistance phenotyping in rice. Herein, two different groups of rice cultivars (normal, and hybrid) were used, each group with 14 different rice cultivars. Firstly, seed germination analysis was conducted by evaluating various seed germination indices to identify the rice cultivars with greatest seed germination vigor. Furthermore, exposure of chromium (Cr) toxicity to 28 different rice varieties (NV1-NV14, HV1-HV14) caused noticeable plant biomass reduction. Subsequently, NV2, NV6, NV10, NV12, NV13 (normal type), HV1, HV4, HV8, and HV9 (hybrid types) were pragmatic as moderately sensitive varieties, while NV3, NV4, NV9, and NV14 (normal type), HV3, HV6, HV7, and HV13 were observed as moderately tolerant. Although, NV7, and HV10 were ranked most sensitive cultivars, and NV11, and HV14 were considered as most tolerant varieties as compared to the other rice (both groups) genotypes. Afterward, Cr induced reduction in chlorophyll pigments were significantly lesser in HV14 relative to NV11, NV7, and especially HV10, and as a result HV14 modulated the total soluble sugar level as well as reduced ROS accumulation, and MDA contents production by stimulating the antioxidant defense mechanism conspicuously which further reduced the electrolyte leakage as well. Our outcomes provide support to explore the Cr tolerance mechanism in cereal crops as well as knowledge about rice breeding with increased tolerance against Cr stress.     

Molecular basis of the Keap1–Nrf2 system

Nrf2 (NF-E2-related factor 2) is a master regulator of cellular responses against environmental stresses. Nrf2 induces the expression of detoxification and antioxidant enzymes, and Keap1 (Kelch-like ECH-associated protein 1), an adaptor subunit of Cullin 3-based E3 ubiquitin ligase, regulates Nrf2 activity. Keap1 also acts as a sensor for oxidative and electrophilic stresses. Keap1 retains multiple sensor cysteine residues that detect various stress stimuli. Increasing attention has been paid to the roles that Nrf2 plays in the protection of our bodies against drug toxicity and stress-induced diseases. On the other hand, Nrf2 is found to promote both oncogenesis and cancer cell resistance against chemotherapeutic drugs. Thus, although Nrf2 acts to protect our body from deleterious stresses, cancer cells hijack the Nrf2 activity to support their malignant growth. Nrf2 has emerged as a new therapeutic target, and both inducers and inhibitors of Nrf2 are awaited. Studies challenging the molecular basis of the Keap1–Nrf2 system functions are now critically important to improve translational studies of the system. Indeed, recent studies identified cross talk between Nrf2 and other signaling pathways, which provides new insights into the mechanisms by which the Keap1–Nrf2 system serves as a potent regulator of our health and disease.     

Characterization of the passive mechanical properties of spine muscles across species

Passive mechanical properties differ between muscle groups within a species. Altered functional demands can also shift the passive force-length relationship. The extent that passive mechanical properties differ within a muscle group (e.g. spine extensors) or between homologous muscles of different species is unknown. It was hypothesized that multifidus, believed to specialize in spine stabilization, would generate greater passive tensile stresses under isometric conditions than erector spinae, which have more generalized functions of moving and stabilizing the spine; observing greater multifidus moduli in different species would strengthen this hypothesis. Permeabilized fibre bundles (n = 337) from the multifidus and erector spinae of mice, rats, and rabbits were mechanically tested. A novel logistic function was fit to the experimental data to fully characterize passive stress and modulus. Species had the greatest effect on passive muscle parameters with mice having the largest moduli at all lengths. Rats generated less passive stress than rabbits due to a shift of the passive force-length relationship towards longer muscle lengths. Rat multifidus generated slightly greater stresses than erector spinae, but no differences were observed between mouse muscles. The secondary objective was to determine the parameters required to simulate the passive force-length relationship. Experimental data were compared to the passive muscle model in OpenSim. The default OpenSim model, optimized for hindlimb muscles, did not fit any of the spine muscles tested; however, the model could accurately simulate experimental data after adjusting the input parameters. The optimal parameters for modelling the passive force-length relationships of spine muscles in OpenSim are presented.     

Endogenous opiates: 1986

This is the ninth installment of our annual review of research involving the endogenous opiate peptides. It is restricted to the non-analgesic and behavioral studies of the opiate peptides published in 1986. The specific topics this year include stress; tolerance and dependence; eating; drinking; gastrointestinal, renal, and hepatic processes; mental illness; learning, memory, and reward; cardiovascular responses; respiration and thermoregulation; seizures and other neurological disorders; activity; sex, pregnancy, and development; and some other behaviors.     

Comparative responses of Achillea millefolium ecotypes to competition and soil type

Summary Achillea millefolium populations from adjacent sites with zonal and serpentime soil were used to test predictions about the relation between growth and the competitive ability of plants in productive and unproductive environments. Under greenhouse conditions, individually-grown plants from both sources grew larger in serpentine soil than in zonal soil; serpentine plants accumulated 72% more biomass than zonal plants. In zonal soil, zonal plants were 71% larger than serpentine plants, although these differences were not statistically significant, and plants from both sources accumulated much less biomass and were shorter than plants growing in serpentine soil. In a high density, fertilized replacement series, zonal plants were taller and heavier but exhibited no more competitive ability than serpentine plants. The predictions that rapid height growth and biomass accumulation contribute significantly to competitive ability are not supported by our results. Although ecotypic differentiation has occurred between these A. millefolium populations, apparently in response to different soil types, the expression of these heritable differences can be masked by other environmental effects. There has been no apparent trade-off in these ecotypes between their response to the physical environment and their competitive ability.     

Stress-Induced Changes in t-[35S]Butylbicyclophosphorothionate Binding to γ-Aminobutyric Acid-Gated Chloride Channels Are Mimicked by In Vitro Occupation of Benzodiazepine Receptors

The allosteric modulation of t-[35S]butylbicyclophosphorothionate binding by flunitrazepam was studied in well-washed brain membranes prepared from control and swim-stressed rats. Swim stress has been reported to decrease the KD and increase the Bmax of this radioligand. Flunitrazepam increased radioligand binding with equal potency (EC50 approximately 11 nM) in both groups, but the maximal enhancement (efficacy) produced by this drug was significantly greater in control than in swim-stressed rats. Ro 15-1788 (a benzodiazepine receptor antagonist) blocked the effect of flunitrazepam on t-[35S]butylbicyclophosphorothionate binding in both groups. This increase in t-[35S]butylbicyclophosphorothionate binding resulted from a significant reduction in KD with no alteration in Bmax. The KD values obtained in cortical membranes of control rats after addition of flunitrazepam were not significantly different from those in the swim-stressed group. Preincubation of cortical homogenates from control animals with flunitrazepam prior to extensive tissue washing resulted in Bmax and KD values of t-[35S]butylbicyclophosphorothionate similar to those obtained in stressed animals. These findings suggest that stress and flunitrazepam may share a common mechanism in regulating t-[35S]butylbicyclophosphorothionate binding and support the concept that stress-induced modification of gamma-aminobutyric acid (GABA)-gated chloride channels in the CNS results from the release of an endogenous modulator (with benzodiazepine-like properties) of the benzodiazepine-GABA receptor chloride ionophore receptor complex.