Inhibition Of Protein Synthesis Research Articles

Natural Antimicrobial Agents from Algae: Current Advances and Future Directions

Infectious diseases have significantly shaped human history, leading to significant advancements in medical science. The discovery and development of antibiotics represented a critical breakthrough, but the rise of antibiotic-resistant pathogens now presents a serious global health threat. Due to the limitations of current synthetic antimicrobials, such as toxicity and environmental concerns, it is essential to explore alternative solutions. Algae, particularly microalgae and cyanobacteria, have emerged as promising sources of bioactive antimicrobial compounds. This review provides a comprehensive analysis of the antimicrobial properties of algal-derived compounds, including polysaccharides, fatty acids, and phenols, which have shown effectiveness against multi-drug-resistant bacteria. A co-occurrence bibliometric analysis using VOSviewer highlighted five key research clusters: antibiotic resistance, algal extracts, biosynthesis, water treatment, and novel pharmacological compounds. Furthermore, the primary mechanisms of action of these bioactive compounds, such as the inhibition of protein synthesis and cell membrane disruption, were identified, demonstrating their potential against both common and multi-resistant pathogens. Future research should prioritize optimizing algal biomass production, utilizing genetic and metabolic engineering, and creating innovative delivery systems to enhance the efficient production of bioactive compounds.

M2 macrophage exosome-derived Apoc1 promotes ferroptosis resistance in osteosarcoma by inhibiting ACSF2 deubiquitination.

Osteosarcoma (OS) is the most common primary malignant tumor of bone. The aim of this study was to investigate the regulatory mechanisms of M2 macrophage exosomes (M2-Exos) in ferroptosis in OS. A mouse model was established to investigate the in vivo role of M2-Exos. We investigated their effects on ferroptosis in OS using erastin, a ferroptosis activator, and deferoxamine mesylate, an iron chelator. In vitro, we investigated whether the Apoc1/Acyl-CoA Synthetase Family Member 2 (ACSF2) axis mediates these effects, using shApoc1 and shACSF2. The mechanisms whereby Apoc1 regulates ACSF2 were examined using cyclohexanone, a protein synthesis inhibitor, and MG132, a proteasomal inhibitor. M2-Exos reversed the inhibitory effects of erastin on OS cells, thus enhancing their viability, migration, invasion, proliferation, and reducing ferroptosis. Apoc1 was highly expressed in M2-Exos, and interfering with this expression reversed the effects of M2-Exos on OS cells. ACSF2 mediated the effects of M2-Exos-derived Apoc1. Apoc1 interacted with ACSF2, which, in turn, interacted with USP40. Apoc1 overexpression increased ACSF2 ubiquitination, promoting its degradation, whereas USP40 overexpression inhibited ACSF2 ubiquitination and promoted its expression. Apoc1 overexpression inhibited ACSF2 binding to USP40. M2-Exos-derived Apoc1 promoted ferroptosis resistance by inhibiting USP40 binding to ACSF2 and promoting ACSF2 ubiquitination and degradation, thus enhancing OS development.

The herbicidal activity and mechanism of Talaromyces purpureogenus CY-1 metabolites.

Studies have shown that Talaromyces can produce a large number of secondary metabolites in its metabolic process, many of which have good insecticidal, antibacterial, antitumor, antiviral and other biological activities. In order to explore the herbicidal activity and mechanism of Talaromyces purpureogenus CY-1, we determined the inhibitory effect of the fermentation broth of the CY-1 strain on weeds, identified the major active components, and further investigated the herbicidal mechanism. The results showed that CY-1, with IC50 values of 5.40 g/L and 4.39 g/L, respectively, exhibited good herbicidal activity against Xanthium sibiricum and Amaranthus lividus. Spraying CY-1 strain fermentation broth on redroot pigweed resulted in plant protection efficiencies and fresh weight protection efficiencies of 83.7% and 87%, respectively. The active component identified in the broth was 2-(3-hydroxybenzoyloxy) acrylic acid. Treatment of Amaranthus lividus with 2-(3-hydroxybenzoyloxy) acrylic acid resulted in trends of increasing superoxide dismutase activity, peroxidase activity, respiratory rate, cytochrome oxidase activity, and soluble protein content, followed by a decrease. Peroxidase activity, relative conductance and malondialdehyde content gradually increased, while acetyl lactate synthase and glutamine synthetase initially decreased and gradually returned to normal. The soluble sugar content showed a gradual decrease. The findings of the present study indicate that 2-(3-hydroxybenzoyloxy) acrylic acid can induce oxidative stress in plants, damaging plant cell walls, weakening respiratory activity, inhibiting protein synthesis and sugar metabolism, ultimately leading to weed wilting and death. © 2024 Society of Chemical Industry.

Paederus Dermatitis: Two Outbreaks of an Entomologic Disease in Austere Expeditionary Care.

Paederus dermatitis, also known as dermatitis linearis, is an acute cutaneous condition caused by contact with the potent vesicant toxin paederin, produced by endosymbiotic Pseudomonas-like bacteria within Paederus spp. beetles. Paederin is a protein synthesis inhibitor that halts cell division, leading to vesiculation and necrotic breakdown of the epidermis. The resultant damage facilitates secondary infection, especially in austere conditions. Between October 2022 and July 2023, several US special operations teams forward deployed to various countries in East Africa reported over 17 cases of painful, blistering skin eruptions consistent with Paederus dermatitis, 2 of which are summarized in this report. To confirm the best treatment approach, 1 team's medic reached back to a deployed infectious disease physician in the same Combatant Command as well as through the DoD ADVISOR line to a dermatologist in the United States. All cases were managed with irrigation, followed by a combination of topical steroid and antibacterial ointments, with resolution occurring after 3 to 7 days, whereas 38% of the cases in July 2023 developed secondary cellulitis by day 7, requiring oral antibiotic treatment. Strict preventative measures were implemented to limit exposure while carefully observing each case, as this was critical to optimize medical readiness of the team. Ultimately, we seek to highlight the identification of beetles specific to East Africa, seasonal prevalence, and the importance of preventative measures as they vary depending on specific beetle characteristics. Additionally, we reiterate classic presentation features that help avoid misdiagnosis for cases that occur outside of the typical epidemiologic criteria.

Structural insights into the toxicity of type II ribosome inactivating proteins (RIPs): a molecular dynamics study

Ribosome Inactivating Proteins (RIPs) act by irreversibly depurinating the 28S rRNA ricin-sarcin loop (SRL) of the eukaryotic ribosome resulting in protein synthesis inhibition. In general, they consist of two variants: Type I which is single chained (∼30 kDa), and Type II, a more toxic variant which is a Type I N-glycosidase chain covalently linked to a lectin chain. These proteins are believed to play a pivotal role in defence mechanisms. Intriguingly, non-toxic variants of such toxic proteins do exist in nature. To explore their mode of action, in the present study we have selected three toxic (Ricin, Ebulin and HmRIP) as well as two non-toxic (BGSL and SGSL) RIPs and performed molecular docking and molecular dynamic simulations with the SRL loop. This study throws light on the structural stability and plasticity of the toxic and non-toxic RIP complexes. Furthermore, analysis of the active site cavity volume and binding free energy calculations reveal that the SRL, particularly the specific adenine (A4605), is relatively unstable in the case of non-toxic RIPs which is also supported by the free binding energy calculations, and the pocket size analysis indicates the abnormal increase in active site cavity volume of non-toxic RIPs with time. This first-of-its-kind comprehensive study of toxic and non-toxic RIPs gives insights about the mode of action and the dynamic nature of their interaction with the SRL loop. These observations will be helpful in the development of toxoids against RIPs and also in designing novel therapeutic approaches against human diseases.

Targeting MuRF1 to Combat Skeletal Muscle Wasting in Cardiac Cachexia: Mechanisms and Therapeutic Prospects.

Cardiac cachexia, the terminal stage of chronic heart failure, is characterized by severe systemic metabolic imbalances and significant weight loss, primarily resulting from skeletal muscle mass depletion. Despite the detrimental consequences, there is no standardized and clinically-approved intervention currently available for cardiac cachexia. In the context of cardiac cachexia, accelerated protein turnover, that is, inhibited protein synthesis and enhanced protein degradation, plays a crucial role in skeletal muscle wasting. This process is primarily mediated by various proteins encoded by atrogenes. Among them, the atrogene Trim63 (tripartite motif family 63) and its encoded protein MuRF1 have been extensively studied. This review article aims to elucidate the pathogenic mechanisms underlying skeletal muscle wasting in cardiac cachexia, describe the biochemical characteristics of MuRF1, and provide an overview of the investigation into MuRF1-targeting inhibitors. The ultimate goal is to offer novel strategies for the clinical treatment for skeletal muscle wasting associated with cardiac cachexia.

Paenilamicins bind to a unique site on the ribosome to inhibit protein synthesis.

Paenilamicins bind to a unique site on the ribosome to inhibit protein synthesis.

Plastic Polymers and Antibiotic Resistance in an Antarctic Environment (Ross Sea): Are We Revealing the Tip of an Iceberg?

Microbial colonization of plastic polymers in Antarctic environments is an under-investigated issue. While several studies are documenting the spread of plastic pollution in the Ross Sea, whether the formation of a plastisphere (namely the complex microbial assemblage colonizing plastics) may favor the spread of antibiotic-resistant bacteria (ARB) in this marine environment is unknown yet. A colonization experiment was performed in this ecosystem, aiming at exploring the potential role of plastic polymers as a reservoir of antibiotic resistance. To this end, the biofilm-producing activity and the antibiotic susceptibility profiles of bacterial strains isolated from biofilms colonizing submerged polyvinylchloride and polyethylene panels were screened. The colonization experiment was carried out at two different sites of the Ross Sea, namely Road Bay and Tethys Bay. Most of bacterial isolates were able to produce biofilm; several multidrug resistances were detected in the bacterial members of biofilms associated to PVC and PE (also named as the plastisphere), as well as in the bacterial strains isolated from the surrounding water. The lowest percentage of ARB was found in the PE-associated plastisphere from the not-impacted (control) Punta Stocchino station, whereas the highest one was detected in the PVC-associated plastisphere from the Tethys Bay station. However, no selective enrichment of ARB in relation to the study sites or to either type of plastic material was observed, suggesting that resistance to antibiotics was a generalized widespread phenomenon. Resistance against to all the three classes of antibiotics assayed in this study (i.e., cell wall antibiotics, nucleic acids, and protein synthesis inhibitors) was observed. The high percentage of bacterial isolates showing resistance in remote environments like Antarctic ones, suffering increasing anthropic pressure, points out an emerging threat with a potential pathogenic risk that needs further deepening studies.

Paenilamicins are context-specific translocation inhibitors of protein synthesis.

The paenilamicins are a group of hybrid nonribosomal peptide-polyketide compounds produced by the honey bee pathogen Paenibacillus larvae that display activity against Gram-positive pathogens, such as Staphylococcus aureus. While paenilamicins have been shown to inhibit protein synthesis, their mechanism of action has remained unclear. Here we determine structures of paenilamicin PamB2-stalled ribosomes, revealing a unique binding site on the small 30S subunit located between the A- and P-site transfer RNAs (tRNAs). In addition to providing a precise description of interactions of PamB2 with the ribosome, the structures also rationalize the resistance mechanisms used by P. larvae. We further demonstrate that PamB2 interferes with the translocation of messenger RNA and tRNAs through the ribosome during translation elongation, and that this inhibitory activity is influenced by the presence of modifications at position 37 of the A-site tRNA. Collectively, our study defines the paenilamicins as a class of context-specific translocation inhibitors.

Physiological and Transcriptomic Analyses Reveal the Role of the Antioxidant System and Jasmonic Acid (JA) Signal Transduction in Mulberry (Morus alba L.) Response to Flooding Stress

In recent decades, the frequency of flooding has increased as a result of global climate change. Flooding has become one of the major abiotic stresses that seriously affect the growth and development of plants. Mulberry (Morus alba L.) is an important economic tree in China. Flooding stress is among the most severe abiotic stresses that affect the production of mulberry. However, the physiological and molecular biological mechanisms of mulberry responses to flooding stress are still unclear. In the present study, reactive oxygen species (ROS) metabolism, antioxidant mechanism, and plant hormones in mulberry associated with the response to flooding stress were investigated using physiological and transcriptomic analysis methods. The results showed significant increases in the production rate of superoxide anion (O2•−) and the content of hydrogen peroxide (H2O2) in leaves on the 5th day of flooding stress. This led to membrane lipid peroxidation and elevated malondialdehyde (MDA) levels. Antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), and peroxidase (POD) exhibited enhanced activities initially, followed by fluctuations. The ascorbic acid–glutathione (AsA-GSH) cycle played a crucial role in scavenging ROS, promoting the reduction of oxidized glutathione (GSSG) to reduced glutathione (GSH). Transcriptomic analysis revealed the up-regulation of the gene-encoding antioxidant enzymes (APX, MDHAR, GPX, GR, GST) involved in ROS scavenging and stress tolerance mechanisms. Jasmonic acid (JA) levels and the expression of JA synthesis-related genes increased significantly in mulberry leaves under flooding stress. This activation of the JA signaling pathway contributed to the plant’s adaptability to flooding conditions. Proline (Pro) and soluble sugar (SS) contents increased notably in response to flooding stress. Proline helped maintain cell turgor and protected enzymes and membranes from damage, while soluble sugars supported anaerobic respiration and energy supply. However, soluble protein (SP) content decreased, suggesting inhibition of protein synthesis. The study provides insights into mulberry’s flooding tolerance mechanisms, guiding future molecular breeding efforts. This summary captures the key findings and implications of the study on mulberry’s response to flooding stress, focusing on physiological and molecular mechanisms identified in the research.

The Role of MicroRNA in the Pathophysiology and Diagnosis of Viral Myocarditis

Myocarditis is a non-ischemic condition with a heterogeneous etiology, clinical course and prognosis. The most common etiology of myocarditis are viral infections, whereas the most severe complications are acute and chronic heart failure and sudden cardiac death. The heterogeneous clinical course of the disease, as well as the availability and costs of diagnostic tools such as cardiac magnetic resonance and endomyocardial biopsy, hinder the diagnosis of myocarditis and its underlying cause. Non-coding RNAs such as micro-RNAs (miRNAs; miR) have been shown to be involved in the disease’s pathophysiology; however, their potential in disease diagnosis and treatment should also be considered. Non-coding RNAs are RNAs that are not translated into proteins, and they have the ability to regulate several intracellular pathways. MiRNAs regulate gene expression by binding with their targets and inhibiting protein synthesis by interfering with the translation of coding genes or causing the degradation of messenger RNA. Several miRNAs, such as miR-1, -133, -21, -15, -98, -126, -155, -148, -203, -208, -221, -222, -203 and -590, have been shown to be involved in the pathophysiology of viral myocarditis (VMC), and some of them have been shown to have diagnostic abilities. This article summarizes the available data on miRNAs and their associations with VMC.

Lysine residues are not required for proteasome-mediated proteolysis of cellular prion protein

Cellular prion protein (PrPC) is a glycosylphosphatidylinositol (GPI)-anchored cell-surface protein. The mature cell-surface PrPC is internalized and subsequently degraded by lysosomes. Although, proteasomes are proposed to be involved, the precise mechanism of PrPC degradation remains uncertain. Given that proteins are ubiquitinated primarily on lysine residues, we sought to determine whether lysine residues within PrPC are involved in the ubiquitination and subsequent degradation of PrPC. We generated a plasmid vector expressing a mutant PrPC (called lysine-null PrPC) in which all lysine residues were replaced with arginine residues. Subsequently, we established stably transformed cell lines (designated HpL2-1 PrP-WT and HpL2-1 PrP-K/R, respectively) using the mouse PrPC-deficient neuronal cell line (HpL2-1) and plasmids expressing wild-type (WT) or lysine-null PrPC (PrP-K/R). We found that HpL2-1 PrP-WT and HpL2-1 PrP-K/R cells correctly expressed their respective PrPC which translocated efficiently to the plasma membrane. Subsequently, using immunoblotting and confocal microscopy, we found that treatment with cycloheximide (CHX; a protein synthesis inhibitor) significantly reduced PrPC expression in both these transformed cell lines, indicating that WT and lysine-null PrPC are degraded similarly. Taken together, these results indicate that the lysine residues of PrPC do not regulate its degradation.

A modified BPaL regimen for tuberculosis treatment replaces linezolid with inhaled spectinamides.

The Nix-TB clinical trial evaluated a new 6 month regimen containing three oral drugs; bedaquiline (B), pretomanid (Pa), and linezolid (L) (BPaL regimen) for the treatment of tuberculosis (TB). This regimen achieved remarkable results as almost 90% of the multidrug-resistant or extensively drug-resistant TB participants were cured but many patients also developed severe adverse events (AEs). The AEs were associated with the long-term administration of the protein synthesis inhibitor linezolid. Spectinamide 1599 is also a protein synthesis inhibitor of Mycobacterium tuberculosis with an excellent safety profile, but it lacks oral bioavailability. Here, we propose to replace L in the BPaL regimen with spectinamide (S) administered via inhalation and we demonstrate that inhaled spectinamide 1599, combined with BPa --BPaS regimen--has similar efficacy to that of the BPaL regimen while simultaneously avoiding the L-associated AEs. The BPaL and BPaS regimens were compared in the BALB/c and C3HeB/FeJ murine chronic TB efficacy models. After 4-weeks of treatment, both regimens promoted equivalent bactericidal effects in both TB murine models. However, treatment with BPaL resulted in significant weight loss and the complete blood count suggested the development of anemia. These effects were not similarly observed in mice treated with BPaS. BPaL and BPa, but not the BPaS treatment, also decreased myeloid to erythroid ratio suggesting the S in the BPaS regimen was able to recover this effect. Moreover, the BPaL also increased concentration of proinflammatory cytokines in bone marrow compared to mice receiving BPaS regimen. These combined data suggest that inhaled spectinamide 1599 combined with BPa is an effective TB regimen without L-associated AEs.

The fungal natural product fusidic acid demonstrates potent activity against Mycoplasma genitalium.

Antimicrobial resistance is extremely common in Mycoplasma genitalium, a frequent cause of urethritis in men and cervicitis, vaginitis, and pelvic inflammatory disease in women. Treatment of M. genitalium infections is difficult due to intrinsic and acquired resistance to many antibiotic classes. We undertook a program to identify novel antimicrobials with activity against M. genitalium from fungal natural products. Extracts of Ramularia coccinea contained a molecule with potent activity that was subsequently identified as fusidic acid, a fusidane-type antibiotic that has been in clinical use for decades outside the United States. We found that minimum inhibitory concentrations of fusidic acid ranged from 0.31 to 4 µg/mL among 17 M. genitalium strains including laboratory-passaged and low-passage clinical isolates. Time-kill data indicate that bactericidal killing occurs when M. genitalium is exposed to ≥10 µg/mL for 48 h, comparing favorably to serum concentrations obtained from typical loading dose regimens. Resistance to fusidic acid was associated with mutations in fusA consistent with the known mechanism of action in which fusidic acid inhibits protein synthesis by binding to elongation factor G. Interestingly, no mutants resistant to >10 µg/mL fusidic acid were obtained and a resistant strain containing a F435Y mutation in FusA was impaired for growth in vitro. These data suggest that fusidic acid may be a promising option for the treatment of M. genitalium infections.

Antibacterial and mechanism of action studies of boxazomycin A.

Boxazomycins A-C are potent broad-spectrum antibiotics isolated from Actinomycetes strain G495-1 in 1987. We now report that boxazomycin A inhibits bacterial growth by selectively inhibiting protein synthesis, its effect is bacteriostatic, and it is equally active against drug resistant bacterial strains. No cross-resistance to protein synthesis inhibitors was observed suggesting that its inhibition is distinct from clinical protein synthesis inhibitors. We also report in vivo efficacy in a Staphylococcus aureus murine infection model supported by corresponding pharmacokinetic studies.

Acute exercise performed during the late consolidation phase improves memory persistence by hippocampal protein synthesis and catecholamine modulation

Memory persistence is a crucial aspect of long-term memory (LTM) and involves late consolidation processes that modulate memory stability over time. Acute physical exercise (PE) has emerged as a potential strategy to modulate memory consolidation and enhance memory persistence. While its effects have been extensively explored in the early consolidation phase, its impact on the late phase remains unexplored. In this study, we investigated the effects and mechanisms of an acute PE on the late consolidation window of novel object recognition (NOR) memory in rats. A 30-minute running session applied 11 h after NOR memory acquisition significantly increased memory persistence for at least 7 days. The inhibition of hippocampal protein synthesis immediately after acute PE using anisomycin (a ribosomal inhibitor) or rapamycin (an mTOR pathway inhibitor) impaired the effect of PE on memory persistence. Animals only presented memory 1 day after acquisition. The same effect was observed with the inhibition of beta-adrenergic receptors by timolol. Although there were no differences between the groups' comparison, blocking D1/D5 receptors after acute PE resulted in a lack of memory persistence in the dichotomous testing (remember/non-remember). Therefore, our exploration of the mechanisms underlying this enhancement revealed the involvement of protein synthesis and the requirement of beta-adrenergic and dopaminergic D1/D5 receptors in the dorsal hippocampus. These findings provide valuable insights into PE as a potential memory modulator, contributing to expanding our understanding of memory consolidation dynamics and acute PE effects.

Fabrication of MnSnO2 intercalated TA-rGO modified sensor for selective electrochemical detection of chloramphenicol in real samples

Chloramphenicol (CAP), a potent antibiotic capable of inhibiting protein synthesis, presents significant challenges related to long-term dosing and its persistent leaching into the environment, raising concerns about environmental contamination and resistance development. To address this issue, we developed a reliable, low-cost, and biocompatible nanocomposite material comprising tannic acid (TA)-reduced graphene oxide (rGO) intercalated into manganese-doped tin oxide nanoparticles (MnSnO₂ NPs). The structural formation and catalytic activity of the MnSnO₂ NPs/TA-rGO nanocomposite were characterized using field emission-scanning electron microscopy (FE-SEM), high-resolution transmission electron microscopy (HR-TEM), X-ray diffraction (XRD), Fourier-transform infrared spectroscopy (FT-IR), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), and electrochemical techniques. This material exhibits robust interfacial interactions and synergistic effects, resulting in an admirable electrocatalytic reduction response for CAP sensing. The presence of co-interference molecules improved the selectivity performance of the MnSnO2 NPs/TA-rGO-modified glassy carbon electrode. The fabricated exhibited a two linear determination range (0.011–103.43 μmol L−1 and 103.43–1924.16 μmol L−1), with a detection limit (LOD) is 6.7 nmol L−1 and limit of quantification (LOQ) is 12.3 nmol L−1. Furthermore, this sensor demonstrated good sensitivity, admirable reproducibility, repeatability, and storage stability. Finally, the practicability of the fabricated MnSnO2 NPs/TA-rGO glassy carbon electrode sensor was evaluated by analyzing the CAP content in milk, honey, eye drops, biofluids (human serum and urine), and river water, and satisfactory recovery rates of 95.4 %–100.3 % were noted.

Toxicity and Efficacy Evaluation of Soluble Recombinant Ricin Vaccine

Background: Ricin, a toxin extracted from the seeds of Ricinus communis, is classified as a ribosome-inactivating protein. The A-subunit of ricin shows RNA N-glycosidase activity that cleaves ribosomal RNA (rRNA) and exhibits toxicity by inhibiting protein synthesis and inducing vascular leak syndrome. Methods: In this study, we created a truncated version of the previously developed R51 ricin vaccine (RTA 1-194 D75C Y80C) through in silico analysis. Results: The resulting R51-3 vaccine showed a more-than-six-fold increase in soluble protein expression when compared to R51, with over 85% solubility. In a pilot toxicity test, no toxicity was observed in hematological and biochemical parameters in BALB/c mice and New Zealand white rabbits following five repeated administrations of R51-3. Furthermore, R51-3 successfully protected mice and rabbits from a 20 × LD50 ricin challenge after three intramuscular injections spaced 2 weeks apart. Similarly, monkeys that received three injections of R51-3 survived a 60 µg/kg ricin challenge. Conclusions: These findings support R51-3 as a promising candidate antigen for ricin vaccine development.

Involvement of kinases in memory consolidation of inhibitory avoidance training.

The inhibitory avoidance (IA) task is a paradigm widely used to investigate the molecular and cellular mechanisms involved in the formation of long-term memory of aversive experiences. In this review, we discuss studies on different brain structures in rats associated with memory consolidation, such as the hippocampus, striatum, and amygdala, as well as some cortical areas, including the insular, cingulate, entorhinal, parietal and prefrontal cortex. These studies have shown that IA training triggers the release of neurotransmitters, hormones, growth factors, etc., that activate intracellular signaling pathways related to protein kinases, which induce intracellular non-genomic changes or transcriptional mechanisms in the nucleus, leading to the synthesis of proteins. We have summarized the temporal dynamics and crosstalk among protein kinase A, protein kinase C, mitogen activated protein kinase, extracellular-signal-regulated kinase, and Ca2+/calmodulin-dependent protein kinase II described in the hippocampus. Protein kinase activity has been associated with structural changes and synaptic strengthening, resulting in memory storage. However, little is known about the molecular mechanisms involved in intense IA training, which protects memory from typical amnestic treatments, such as protein synthesis inhibitors, and induces increased spinogenesis, suggesting an unexplored mechanism independent of the genomic pathway. This highly emotional experience causes an extinction-resistant memory, as has been observed in some pathological states such as post-traumatic stress disorder. We propose that the changes in spinogenesis observed after intense IA training could be generated by protein kinases via non-genomic pathways.

The Proteostasis Network is a Therapeutic Target in Acute Myeloid Leukemia.

Oncogenic growth places great strain and dependence on the proteostasis network. This has made proteostasis pathways attractive therapeutic targets in cancer, but efforts to drug these pathways have yielded disappointing clinical outcomes. One exception is proteasome inhibitors, which are approved for frontline treatment of multiple myeloma. However, proteasome inhibitors are largely ineffective for treatment of other cancers, including acute myeloid leukemia (AML), although reasons for these differences are unknown. Here, we determined that proteasome inhibitors are ineffective in AML due to inability to disrupt proteostasis. In response to proteasome inhibition, AML cells activated HSF1 and autophagy, two key stem cell proteostasis pathways, to prevent unfolded protein accumulation. Inactivation of HSF1 sensitized human AML cells to proteasome inhibition, marked by unfolded protein accumulation, activation of the PERK-mediated integrated stress response, severe reductions in protein synthesis, proliferation and cell survival, and significant slowing of disease progression and extension of survival in vivo . Similarly, combined autophagy and proteasome inhibition suppressed proliferation, synergistically killed AML cells, and significantly reduced AML burden and extended survival in vivo . Furthermore, autophagy and proteasome inhibition preferentially suppressed protein synthesis and induced apoptosis in primary patient AML cells, including AML stem/progenitor cells, without severely affecting normal hematopoietic stem/progenitor cells. Combined autophagy and proteasome inhibition also activated the integrated stress response, but surprisingly this occurred in a PKR-dependent manner. These studies unravel how proteostasis pathways are co-opted to promote AML growth, progression and drug resistance, and reveal that disabling the proteostasis network is a promising strategy to therapeutically target AML.