Induction Of Heat Shock Proteins Research Articles

Brain-penetrant heat shock protein amplifier arimoclomol enhances GCase activity in in vitro Gaucher disease models

Brain-penetrant heat shock protein amplifier arimoclomol enhances GCase activity in in vitro Gaucher disease models

Neuroprotective effects of a novel carnosine-hydrazide derivative on hippocampal CA1 damage after transient cerebral ischemia

Ischemia-reperfusion injuries produce reactive oxygen species that promote the peroxide lipid oxidation process resulting in the production of an endogenic lipid peroxide, 4-hydroxy-trans-2-nonenal (4-HNE), a highly cytotoxic aldehyde that induces cell death. We synthesized a novel 4-HNE scavenger – a carnosine-hydrazide derivative, l-carnosine hydrazide (CNN) – and examined its neuroprotective effect in a model of transient ischemia.PC-12 cells were pre-incubated with various doses (0–50 mmol/L) of CNN for 30 min, followed by incubation with 4-HNE (250 μM). An MTT assay was performed 24 h later to examine cell survival. Transient ischemia was induced by bilateral common carotid artery occlusion (BCCO) in the Mongolian gerbil. Animals were assigned to sham-operated (n = 6), placebo-treated (n = 12), CNN pre-treated (20 mg/kg; n = 12), CNN post-treated (100 mg/kg; n = 11), and histidyl hydrazide (a previously known 4-HNE scavenger) post-treated (100 mg/kg; n = 7) groups. Heat shock protein 70 immunoreactivity in the hippocampal CA1 region was evaluated 24 h later, while delayed neuronal death using 4-HNE staining was evaluated 7 days later.Pre-incubation with 30 mmol/L CNN completely inhibited 4-HNE-induced cell toxicity. CNN prevented delayed neuronal death by >60% in the pre-treated group (p < 0.001) and by >40% in the post-treated group (p < 0.01). Histidyl hydrazide post-treatment elicited no protective effect. CNN pre-treatment resulted in high heat shock protein 70 and low 4-HNE immunoreactivity in CA1 pyramidal neurons. Higher 4-HNE immunoreactivity was also found in the placebo-treated animals than in the CNN pre-treated animals.Our novel compound, CNN, elicited highly effective 4-HNE scavenging activity in vitro. Furthermore, CNN administration both pre- and post-BCCO remarkably reduced delayed neuronal death in the hippocampal CA1 region via its induction of heat shock protein 70 and scavenging of 4-HNE.

The Inner Ear Heat Shock Transcriptional Signature Identifies Compounds That Protect Against Aminoglycoside Ototoxicity.

Mechanosensory hair cells of the inner ear transduce auditory and vestibular sensory input. Hair cells are susceptible to death from a variety of stressors, including treatment with therapeutic drugs that have ototoxic side effects. There is a need for co-therapies to mitigate drug-induced ototoxicity, and we showed previously that induction of heat shock proteins (HSPs) protects against hair cell death and hearing loss caused by aminoglycoside antibiotics in mouse. Here, we utilized the library of integrated cellular signatures (LINCS) to identify perturbagens that induce transcriptional profiles similar to that of heat shock. Massively parallel sequencing of RNA (RNA-Seq) of heat shocked and control mouse utricles provided a heat shock gene expression signature that was used in conjunction with LINCS to identify candidate perturbagens, several of which were known to protect the inner ear. Our data indicate that LINCS is a useful tool to screen for compounds that generate specific gene expression signatures in the inner ear. Forty-two LINCS-identified perturbagens were tested for otoprotection in zebrafish, and three of these were protective. These compounds also induced the heat shock gene expression signature in mouse utricles, and one compound protected against aminoglycoside-induced hair cell death in whole organ cultures of utricles from adult mice.

Neuroprotective Effects of Heat Shock Protein70.

Heat Shock Proteins (HSPs) increase response to many stresses in cells. Stroke is a neural shock that leads to the destruction of a large number of brain cells, whereas induction and expression of HSPs can decrease the amount of damage, and in some conditions can cure damaged cells. HSP70 family is considered as the most important member of HSPs in normal and stress condition of cells. They are strongly up-regulated by stresses and have protective roles in under stressed cells. Therefore, in this review, we briefly consider the association between HSP70 and stroke. We searched in Pubmed and Scopus databases using the specified keywords and selected the articles based on the certain association between HSP70 and stroke. HSP70 protects cells from damage through a variety of cellular and biochemical processes such as chaperone function, anti-apoptotic, anti-necrotic and anti-inflammatory mechanisms. Protective effects of HSP70 in neurodegenerative shocks are illustrated in the review, and it can be concluded that the induction of HSP70 in stresses can be considered as a therapeutic factor, although it needs further studies.

Pharmacological induction of Heat Shock Protein 70 by celastrol protects motoneurons from excitotoxicity in rat spinal cord in vitro

The secondary phase of spinal cord injury arising after the primary lesion largely extends the damage severity with delayed negative consequences for sensory-motor pathways. It is, therefore, important to find out if enhancing intrinsic mechanisms of neuroprotection can spare motoneurons that are very vulnerable cells. This issue was investigated with an in vitro model of rat spinal cord excitotoxicity monitored for up to 24hr after the primary injury evoked by kainate. This study sought to pharmacologically boost the expression of heat shock proteins (HSP) to protect spinal motoneurons using celastrol to investigate if the rat spinal cord can upregulate HSP as neuroprotective mechanism. Despite its narrow range of drug safety in vitro, celastrol was not toxic to the rat spinal cord at 0.75μM concentration and enhanced the expression of HSP70 by motoneurons. When celastrol was applied either before or after kainate, the number of dead motoneurons was significantly decreased and the nuclear localization of the cell death biomarker AIF strongly inhibited. Nevertheless, electrophysiological recording showed that protection of lumbar motor networks by celastrol was rather limited as reflex activity was impaired and fictive locomotion largely depressed, suggesting that functional deficit persisted, though the networks could express slow rhythmic oscillations. While our data do not exclude further recovery at later times beyond the experimental observations, the present results indicate that the upregulated expression of HSP in the aftermath of acute injury may be an interesting avenue for early protection of spinal motoneurons.

High doses of sodium ascorbate act as a prooxidant and protect gnotobiotic brine shrimp larvae (Artemia franciscana) against Vibrio harveyi infection coinciding with heat shock protein 70 activation

Ascorbate is an essential nutrient commonly regarded as an antioxidant. In this study, using axenic brine shrimp and pathogenic strain Vibrio harveyi as the host-pathogen model, we confirmed that pretreatment of sodium ascorbate (NaAs), at an optimum concentration, was a prooxidant by generation of hydrogen peroxide, inducing protective effects in the brine shrimp against V. harveyi infection. Such a protective effect could be neutralized by the addition of an antioxidant enzyme catalase. We further showed that generation of oxygen radicals is linked to the induction of heat shock protein 70 (Hsp70), which is involved in eliciting the antioxidant protection system including superoxidase dismutase (SOD) and possibly many other immune responses. Furthermore, using RNA interference technique, we found that the pretreatment of sodium ascorbate increased the survival significantly in the control knockdown groups (using green fluorescent protein, GFP) but not in Hsp70 knockdown groups and the result directly suggested that the up-regulated Hsp70 induced by sodium ascorbate pretreatment induced the protective effect. These results provide a mechanistic rationale for exploring the further use of ascorbate for antimicrobial therapy in aquaculture.

Heat stress upregulates G-T mismatch binding activities in zebrafish (Danio rerio) embryos preexposed and nonexposed to a sublethal level of cadmium (Cd)

G-T mispair frequently appears in eukaryotic DNA due to the spontaneous deamination of 5-methylcytosine paired with guanine and is therefore an important target for DNA mismatch repair (MMR). Our earlier studies showed the downregulation of G-T binding activities in cadmium (Cd)-exposed (Danio rerio) embryos. Since elevation of water temperature was reported to increase Cd toxicity in zebrafish, this study explored whether heat stress affected zebrafish mismatch binding capacity in the absence or presence of Cd. Heat stress (37 °C for 30 min) induced heat shock protein 70 mRNA expression in embryos at 10 and 24 h post fertilization (hpf). Heat stress weakly upregulated normal G-T sensing machinery and inhibited G-T recognition activity in embryos preexposed to 3 μM Cd for 9 h. Either heat shock or a 23-h Cd treatment alone caused a 1.7-fold stimulation of G-T binding capacity in 24 hpf embryos and heat stress of Cd-preexposed embryos further enhanced G-T binding activity to 2.5 fold of control. Normal and Cd-downregulated loop binding activities in 10 and 24 hpf embryos were almost unreactive to heat shock. Heat stress-upregulated G-T sensing in nonexposed, but not in Cd-preexposed, 24 hpf embryos correlated with stronger gene activities encoding MMR-linked mismatch detecting factors MutS homolog 2 and 6 plus a higher DNA binding activity of the transcription factor Sp1 that regulates msh2/msh6 expression. Our results suggested the importance of heat shock response in facilitating the correction of G-T mismatch in developing zebrafish even under Cd exposure.

Genetic and Pharmacological Targeting of Heat Shock Protein 70 in the Mouse Amygdala-Kindling Model.

Inflammatory responses involving Toll-like receptor signaling represent a key factor contributing to epileptogenesis. Thus, it is of particular interest to explore the relevance of toll-like receptor ligands and modulators, such as heat shock protein 70 (HSP70). Motivated by recent findings demonstrating an upregulation of HSP70 in a model of epileptogenesis, we analyzed the consequences of genetic and pharmacological targeting of HSP70 expression in a mouse kindling paradigm. Lack of inducible HSP70 resulted in increased prekindling seizure thresholds. However, at threshold stimulation the deficiency-promoted seizure spread, as indicated by an increased seizure severity. Subsequent kindling stimulations elicited more severe seizures in knockout mice, whereas endogenous termination of seizure activity remained unaffected with duration of behavioral and electrographic seizure activity comparable to that of wild-type mice. Interestingly, HSP70 deficiency resulted in enhanced microglia activation in the CA1 region. Next, we assessed a pharmacological targeting approach aiming to promote HSP70 expression. Celastrol treatment had no impact on kindling progression but reduced postkindling seizure thresholds and enhanced microglia activation in CA1 and CA3. In conclusion, the findings from HSP70-knockout mice support a protective role of HSP70 with an effect on microglia activation and spread of seizure activity. Unexpectedly, celastrol administration resulted in detrimental consequences. These findings should be considered as a warning about the general safety of celastrol as a drug candidate. The impact of pathophysiological mechanisms on the quality of celastrol effects requires comprehensive future studies exploring influencing factors. Moreover, alternate strategies to increase HSP70 expression should be further developed and validated.

Thermal stress induces heat shock protein 70 and apoptosis during embryo development in a Neotropical freshwater fish.

Fish embryos are particularly vulnerable to temperature changes, with the effects varying with developmental stage. The major aim of the present study was to analyse the relationship between apoptosis and heat shock protein (HSP) 70 during embryo development under thermal stress conditions. To this end, Prochilodus lineatus embryos at the blastopore closure stage were subjected to one of three thermal treatments for 1h (Group 1, 25°C (control); Group 2, 20°C; Group 3, 30°C) and then examined at 0, 4 and 8h posttreatment (h.p.t.). The viability of embryos was highest in Group 1 (81.33±16.65%), followed by Group 3 and Group 2 (75.33±12.10% and 68.67±16.86% respectively), with significant difference between Groups 1 and 2 (P<0.05). At 0h.p.t., embryos subjected to thermal stress (Group 3) had a significantly higher number of terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling (TUNEL)- and caspase-3-labelled cells, and a lower number of HSP70-positive cells than those in the control group. At 4h.p.t., there was a decrease in the TUNEL reaction and an increase in HSP70 in embryos in Group 3. At 8h.p.t., the size of Group 3 embryos was significantly smaller than that of Group 1 embryos. The results indicate a cytoprotective role for HSP70, regulating caspase-3-mediated apoptosis during embryo development of P. lineatus; however, this mechanism is not effective in controlling embryo viability and larval malformations.

Vorinostat enhances gefitinib‑induced cell death through reactive oxygen species‑dependent cleavage of HSP90 and its clients in non‑small cell lung cancer with the EGFR mutation.

Although different mechanisms of acquired resistance to epidermal growth factor receptor (EGFR)‑tyrosine kinase inhibitors (TKIs) have been reported in non‑small cell lung cancers (NSCLCs), the optimal treatment for patients with acquired resistance has not been clearly defined. The purpose of this study was to investigate the antitumor effects of gefitinib in combination with vorinostat, a potent histone deacetylase inhibitor (HDACI), and their associated molecular mechanisms in relation to activating apoptosis in NSCLC. The treatment using a combination of vorinostat and gefitinib was more potent in promoting cell death by activating apoptosis than gefitinib alone in parental PC9 cells that harbor an EGFR‑activating mutation (EGFR exon 19 deletion) and gefitinib‑resistant PC9 cells (PC9GR) with an EGFR T790M mutation. This combination induced heat shock protein 90 (HSP90) cleavage and reduced the level of HSP90 client proteins, including EGFR, MET and AKT, in PC9 and PC9GR cells. The addition of 4‑(2‑aminoethyl) benzenesulfonyl fluoride hydrochloride, a scavenger of reactive oxygen species (ROS), inhibited the degradation of HSP90 client proteins and HSP90 cleavage that was induced by co‑treatment as well as the cleavage of caspase‑3, caspase‑8, and caspase‑9 and cell death. We also observed that cleavage of HSP90 and its clients were blocked when caspases were inhibited. These results revealed that co‑treatment with vorinostat and gefitinib induced ROS‑dependent caspase activation, leading to the downregulation of HSP90 clients through HSP90 cleavage. Collectively, our findings provide a new basis for strategies that combine vorinostat with an EGFR‑TKI to reverse EGFR‑TKI resistance in NSCLC.

The repressor and co-activator HsfB1 regulates the major heat stress transcription factors in tomato.

Plants code for a multitude of heat stress transcription factors (Hsfs). Three of them act as central regulators of heat stress (HS) response in tomato (Solanum lycopersicum). HsfA1a regulates the initial response, and HsfA2 controls acquired thermotolerance. HsfB1 is a transcriptional repressor but can also act as co-activator of HsfA1a. Currently, the mode of action and the relevance of the dual function of HsfB1 remain elusive. We examined this in HsfB1 overexpression or suppression transgenic tomato lines. Proteome analysis revealed that HsfB1 overexpression stimulates the co-activator function of HsfB1 and consequently the accumulation of HS-related proteins under non-stress conditions. Plants with enhanced levels of HsfB1 show aberrant growth and development but enhanced thermotolerance. HsfB1 suppression has no significant effect prior to stress. Upon HS, HsfB1 suppression strongly enhances the induction of heat shock proteins due to the higher activity of other HS-induced Hsfs, resulting in increased thermotolerance compared with wild-type. Thereby, HsfB1 acts as co-activator of HsfA1a for several Hsps, but as a transcriptional repressor on other Hsfs, including HsfA1b and HsfA2. The dual function explains the activation of chaperones to enhance protection and regulate the balance between growth and stress response upon deviations from the homeostatic levels of HsfB1.

Augmentation of vaccine-induced humoral and cellular immunity by a physical radiofrequency adjuvant

Protein/subunit vaccines often require external adjuvants to induce protective immunity. Due to the safety concern of chemical adjuvants, physical adjuvants were recently explored to boost vaccination. Physical adjuvants use physical energies rather than chemicals to stimulate tissue stress and endogenous danger signal release to boost vaccination. Here we present the safety and potency of non-invasive radiofrequency treatment to boost intradermal vaccination in murine models. We show non-invasive radiofrequency can increase protein antigen-induced humoral and cellular immune responses with adjuvant effects comparable to widely used chemical adjuvants. Radiofrequency adjuvant can also safely boost pandemic 2009 H1N1 influenza vaccination with adjuvant effects comparable to MF59-like AddaVax adjuvant. We find radiofrequency adjuvant induces heat shock protein 70 (HSP70) release and activates MyD88 to mediate the adjuvant effects. Physical radiofrequency can potentially be a safe and potent adjuvant to augment protein/subunit vaccine-induced humoral and cellular immune responses.

Pharmacological induction of heat shock proteins ameliorates toxicity of mutant PKCγ in spinocerebellar ataxia type 14

Amyloid and amyloid-like protein aggregations are hallmarks of multiple, varied neurodegenerative disorders, including Alzheimer's and Parkinson's diseases. We previously reported that spinocerebellar ataxia type 14 (SCA14), a dominant-inherited neurodegenerative disease that affects cerebellar Purkinje cells, is characterized by the intracellular formation of neurotoxic amyloid-like aggregates of genetic variants of protein kinase Cγ (PKCγ). A number of protein chaperones, including heat shock protein 70 (Hsp70), promote the degradation and/or refolding of misfolded proteins and thereby prevent their aggregation. Here, we report that, in various SCA14-associated, aggregating PKCγ variants, endogenous Hsp70 is incorporated into aggregates and that expression of these PKCγ mutants up-regulates Hsp70 expression. We observed that PKCγ binds Hsp70 and that this interaction is enhanced in the SCA14-associated variants, mediated by the kinase domain that is involved in amyloid-like fibril formation as well as the C2 domain of PKCγ. Pharmacological up-regulation of Hsp70 by the Hsp90 inhibitors celastrol and herbimycin A attenuated the aggregation of mutant PKCγ in primary cultured Purkinje cells. Up-regulation of Hsp70 diminished net PKCγ aggregation by preventing aggregate formation, resulting in decreased levels of apoptotic cell death among primary cultured Purkinje cells expressing the PKCγ variant. Of note, herbimycin A also ameliorated abnormal dendritic development. Extending our in vitro observations, administration of celastrol to mice up-regulated cerebellar Hsp70. Our findings identify heat shock proteins as important endogenous regulators of pathophysiological PKCγ aggregation and point to Hsp90 inhibition as a potential therapeutic strategy in the treatment of SCA14.

Reduction of Thermotolerance by Heat Shock Protein 90 Inhibitors in Murine Erythroleukemia Cells.

Cells induce heat shock proteins (HSPs) against various stress. However, murine erythroleukemia (MEL) cells do not express HSP72, a heat-inducible member of HSP70 family. So, it is of interest to examine how MEL cells respond to heat stress (44°C, 30 min). Heat stress-induced apoptosis was suppressed by pretreatment of heat shock (44°C, 10 min). Such suppressive effects were maximal at 6 h after heat shock and remained up to 12 h. Interestingly, such effects of heat shock were abrogated by specific inhibitors of HSP90 such as 17-allylamino-17-demethoxygeldanamycin (17-AAG) and novobiocin. From flow cytometric analysis, it was found that MEL cells arrest in G2 phase at 6 h after heat shock, but restore original cell cycle at 12 h. High expression level of HSP90 was maintained before and after heat shock. Phosphorylation of HSP90α was observed in apoptotic cells induced by heat stress, but inhibited by pretreatment of heat shock. Such inhibition was abrogated by 17-AAG. Moreover, c-Jun NH2-terminal kinase (JNK) was activated in heat stress-induced apoptotic cells. Taken together, these results suggest that HSP90α in MEL cells plays an important role in the thermotolerance, i.e., suppression of heat stress-induced apoptosis by heat shock.

Small interfering RNA based knock down of acute heat shock and or GGA inducible bovine heat shock protein 70 may interfere invitro expression pattern of TLR2/4 and NOD1/2

Heat shock protein 70 (Hsp70) is a widely known mammalian stress-inducible protein critical for cytoprotection against different stressors. Despite the chaperone based cytoprotective functions, intracellular Hsp70 also participates in diverse immune modulatory activities. To investigate the immune modulatory effect of inducible bovine Hsp70, we examined the expression profile of four major pattern recognition receptors (PRRs) viz. TLR2/4 and NOD1/2 using two different invitro cell cultured models. We observed that, invitro acute heat stress and Geranylgeranylacetone (GGA) induction increased the level of Hsp70 which upregulated the expression of all the four PRRs in both the cell cultured models. However, the expression level of TLR4 was found to be highest followed by NOD2, TLR2 and NOD1. Conversely, specific siRNA based knockdown of Hsp70 showed a decreased expression level of all the four PRRs. This study may add some references pertaining to the innate immune modulatory effects of bovine heat shock protein 70.

Abstract B19: Compound 23 inhibits high glucose-induced breast cancer progression in vivo through regulating activity and expression of PP2Cδ

Abstract Epidemiologic evidence suggests that women with diabetes have increased risk of breast cancer. Moreover, diabetes may dramatically increase mortality in patients with cancer, and there exists some important distinction between the breast cancer patients with and without diabetes in the regimen selection and outcomes of cancer therapy. There is an urgent need for more effective and specific clinical treatment for diabetes-associated breast cancer. Our previous studies have suggested that hyperglycemia, via PKC/GSK3β and ROS/NF-κB pathways that are involved in PP2Cδ activation, suppresses the tumor-suppressor p53 function and inhibits DNA damage-induced apoptosis, inducing proliferation in the epithelium and the development of breast cancer. HG inhibition of p53 activity and induction of cancer cell proliferation, migration, and invasion were significantly blocked by CCT007093, a known PP2Cδ inhibitor. The structure similarity between a group of curcumin mimics (compounds 1-33) and CCT007093 spurred us to investigate the inhibitory ability of compounds 1-33 on PP2Cδ. The growth inhibition assay screening identified that compound 23 (C19H26N4O) has a striking cytotoxicity on MCF-7 cells instead of MCF-12A cells versus CCT007093. More interestingly, the impressive cytotoxicity of 23 is fully mirrored by their much stronger inhibitory ability on PP2Cδ in cells (as assessed by phospho-P38 measurement) than CCT007093. Docking simulation for binding modes of these inhibitors to PP2Cδ phosphatase domain suggests that the carbonyl oxygen and the nitrogen on the heteroaromatic ring of compound 23 form two hydrogen bonds with side chains of Arg258 and Asp105, respectively. This leads to a stable binding model of compound 23, which is inconsistent with its stronger inhibition on PP2Cδ. Furthermore, compound 23 dramatically induces heat shock protein 27 (Hsp27), ablating HG-induced ROS production and NF-κB activation, which partially blocked HG induction of PP2Cδ protein expression. Thus, compound 23 significantly blocked HG inhibition of p53 activity and induction of cancer cell proliferation, migration, and invasion. Finally, using streptozotocin (STZ)-induced diabetic nude mice bearing MCF-7 cells, we demonstrate that hyperglycemia promoted the development of breast cancer in vivo and that compound 23 significantly inhibited xenografted breast cancer growth in mice. Taken together, these results suggest that the identified novel PP2Cδ inhibitor compound 23 inhibits HG-induced breast cancer progression in vivo through regulating expression and activity of PP2Cδ. These findings provide the first evidence proposing an alternative approach for the therapy of breast cancer patients with diabetes. Citation Format: Ke Wu, Xiaoting Yu, Xianghua Yi, Zhimin Huang, Ying-Li Wu, Yahya Elshimali, Yanjun Liu, Donghui Zhu, Shilong Zheng, Qiao-Hong Chen, Guangdi Wang, Yong Wu, Jaydutt V. Vadgama. Compound 23 inhibits high glucose-induced breast cancer progression in vivo through regulating activity and expression of PP2Cδ [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr B19.

Transcriptional response of the heat shock gene hsp70 aligns with differences in stress susceptibility of shallow-water corals from the Mediterranean Sea

Shallow-water corals of the Mediterranean Sea are facing a dramatic increase in water temperature due to climate change, predicted to increase the frequency of bleaching and mass mortality events. However, supposedly not all corals are affected equally, as they show differences in stress susceptibility, as suggested by physiological outputs of corals along temperature gradients and under controlled conditions in terms of reproduction, demography, growth, calcification, and photosynthetic efficiency. In this study, gene expression and induction of a 70-kDa heat shock protein (HSP70) was analyzed in five common shallow-water hard corals in the Mediterranean Sea, namely Astroides calycularis, Balanophyllia europaea, Caryophyllia inornata, Cladocora caespitosa, and Leptopsammia pruvoti. The main aim was to assess the contribution of this evolutionary conserved cytoprotective mechanism to the physiological plasticity of these species that possess different growth modes (solitary vs colonial) and trophic strategies (zooxanthellate vs azooxanthellate). Using quantitative real-time PCR, in situ hsp70 baseline levels and expression profiles after a heat-shock exposure were assessed.Levels of hsp70 and heat stress induction were higher in zooxanthellate than in azooxanthellate species, and different heat stress transcriptional profiles were observed between colonial and solitary zooxanthellate corals. On the whole, the hsp70 transcriptional response to heat stress aligns with stress susceptibility of the species and suggests a contribution of trophic strategy and morphology in shaping coral resilience to stress. Understanding these molecular processes may contribute to assess the potential effects and relative resilience of Mediterranean corals under climate change.

Inducible HSP70 antagonizes cisplatin‑induced cell apoptosis through inhibition of the MAPK signaling pathway in HGC‑27 cells.

Inducible heat shock protein 70 (HSP70; also known as HSPA1 or HSP72) is implicated in cancer. As a stress-inducible heat shock protein, HSP70 is highly expressed in a variety of cancers and correlates with metastasis, chemotherapy resistance and tumor prognosis. The present study demonstrated that suppression of HSP70 through the specific inhibitor pifithrin-µ or by HSP70 knockdown enhanced cisplatin-induced apoptosis in HGC-27 gastric cancer cells. By contrast, upregulation of HSP70 through transfection of a HSP70 overexpressing plasmid decreased cisplatin-induced HGC-27 cell apoptosis. In exploring the underlying molecular mechanisms, the present results revealed that HSP70 antagonized cisplatin-induced HGC-27 cell apoptosis by regulating the mitogen-activated protein kinase (MAPK) signaling pathway. In addition, suppressing the MAPK pathway enhanced cisplatin-induced HGC-27 cell apoptosis. Collectively, the present findings suggest that inhibition of HSP70 expression enhanced the sensitivity of HGC-27 cells to cisplatin via the MAPK signaling pathway, and that HSP70 may serve as a potential therapeutic target in gastric cancer.

Poly(ADP-Ribose) Polymerase 1 Promotes the Human Heat Shock Response by Facilitating Heat Shock Transcription Factor 1 Binding to DNA

The heat shock response (HSR) is characterized by the rapid and robust induction of heat shock proteins (HSPs), including HSP70, in response to heat shock and is regulated by heat shock transcription factor 1 (HSF1) in mammalian cells. Poly(ADP-ribose) polymerase 1 (PARP1), which can form a complex with HSF1 through the scaffold protein PARP13, has been suggested to be involved in the HSR. However, its effects on and the regulatory mechanisms of the HSR are not well understood. Here we show that prior to heat shock, the HSF1-PARP13-PARP1 complex binds to the HSP70 promoter. In response to heat shock, activated and auto-PARylated PARP1 dissociates from HSF1-PARP13 and is redistributed throughout the HSP70 locus. Remarkably, chromatin in the HSP70 promoter is initially PARylated at high levels and decondensed, whereas chromatin in the gene body is moderately PARylated afterwards. Activated HSF1 then binds to the promoter efficiently and promotes the HSR. Chromatin PARylation and HSF1 binding to the promoter are also facilitated by the phosphorylation-dependent dissociation of PARP13. Furthermore, the HSR and proteostasis capacity are reduced by pretreatment with genotoxic stresses, which disrupt the ternary complex. These results illuminate one of the priming mechanisms of the HSR that facilitates the binding of HSF1 to DNA during heat shock.

Heat shock protein inducer reverses the contractile and structural remodeling of HL-1 cardiomyocytes in experimental model of Atrial Fibrillation

Background: Atrial Fibrillation (AF) is the most common tachyarrhythmia associated with electrical, structural remodeling and contractile dysfunction, which is rooted in an impaired protein quality control (PQC) system. PQC regulates the correct folding, trafficking and degradation of proteins in cells. Heat shock proteins (HSPs) play a critical role in facilitating the PQC. Our previous studies showed that the HSP inducers geranylgeranylaceton (GGA) and its derivatives prevent contractile dysfunction in tachypaced atrial cardiomyocyte and Drosophila model for AF. Here we tested whether the potent HSP inducer GGA59 also restores contractile dysfunction in tachypaced cardiomyocytes and explored the underlying mechanisms.