Inhibition Of Protein Synthesis Research Articles

Isothiocyanates induce autophagy and inhibit protein synthesis in primary cells via modulation of AMPK-mTORC1-S6K1 signaling pathway, and protect against mutant huntingtin aggregation

PurposeAutophagy is a degradation process whose activation underlies beneficial effects of caloric restriction. Isothiocyanates (ITCs) induce autophagy in cancer cells, however, their impact on primary cells remains insufficiently explored, particularly in non-epithelial cells. The aim of this study was to investigate whether ITCs induce autophagy in primary (non-immortalized) mesenchymal cells and if so, to determine the molecular mechanism underlying its activation and consequences on cell functioning.MethodsPrimary human dermal fibroblasts (HDFa) and prostate cancer cells (PC3) as well as two ITCs, sulforaphane and phenethyl isothiocyanate, were applied. Cell viability was measured by the MTT test, protein synthesis - by 3H-leucine incorporation, and protein level - by immunoblotting. A number of mutant huntingtin (mHtt) aggregates was assessed by fluorescence microscopy.ResultsBoth ITCs efficiently induced autophagy in fibroblasts which coincided with suppression of mTORC1 – a negative autophagy regulator - and protein synthesis arrest. A dephosphorylation of mTORC1 substrate, S6K1, and ribosomal S6 protein was preceded by activation of AMPK, an inhibitor of mTORC1 and autophagy activator. A similar response was observed in phenethyl isothiocyanate-treated prostate cancer cells. We also showed that ITCs-induced autophagy and/or translation block do not affect cells viability and can protect cells against an accumulation of mHtt aggregates – a main cause of Huntington’s disease.ConclusionOur study showed that ITCs induce autophagy and inhibit protein synthesis in both primary mesenchymal and cancer cells via modulation of the AMPK-mTORC1-S6K1 pathway. Moreover, it suggests that ITCs might have a potential in developing therapeutics for Huntington’s disease.

Mode of Action and Mechanisms of Resistance to the Unusual Polyglycosylated Thiopeptide Antibiotic Persiathiacin A.

Persiathiacin A is a novel thiopeptide antibiotic produced by Actinokineospora species UTMC 2448. It has potent activity against methicillin-resistant Staphylococcus aureus (MRSA) and Mycobacterium tuberculosis. Thiopeptides, including persiathiacin A, exhibit antibacterial activity by inhibiting protein synthesis. In this study, we characterize the mechanism of action of persiathiacin A and investigate how resistance to this antibiotic can emerge. In vitro assays revealed that persiathiacin A inhibits translation elongation, leading to ribosome stalling. Genetic analysis of resistant Bacillus subtilis mutants identified mutations primarily in the rplK gene encoding ribosomal protein L11, which is the binding site for other 26-membered macrocycle-containing thiopeptides. The resistant mutants showed growth impairment and an increased lag time, even in the absence of persiathiacin. Comparative proteomic analysis of a resistant mutant versus the parental strain revealed multiple changes, indicative of negative effects on protein synthesis. Thus, although persiathiacin-resistant mutants can arise readily by the loss of L11 function, it is likely that such mutants would be severely compromised in pathogenesis. Furthermore, bioinformatics analysis identified differences in the key amino acids within the thiopeptide-binding region of L11 in the persiathiacin producer. These probably prevent the antibiotic from associating with its target, providing a mechanism for self-resistance.

Synthesis and Antibacterial Activity of New 6″-Modified Tobramycin Derivatives

Objectives: Aminoglycosides are one of the first classes of natural antibiotics which have not lost relevance due to their broad spectrum of action against Gram-positive, Gram-negative bacteria and mycobacteria. The high growth rate of antimicrobial resistance (AMR) together with the severe side effects of aminoglycosides increase the importance of developing improved semisynthetic derivatives. Methods: In this work, we proposed a synthetic route to new tobramycin derivatives modified at the 6″-position with aminoalkylamine or guanidinoalkylamine residues. Results: The antibacterial activity of the new compounds against reference strains of microorganisms was comparable to the parental tobramycin. In striking contrast to tobramycin (resistance index, >256), its 6″-modified derivatives were significantly more potent against resistant clinical isolates of P. aeruginosa strains (resistance index = 4–16) and they demonstrated a promising AMR circumvention in E. coli strains associated with mutations in the fusA gene encoding elongation factor G. All the obtained tobramycin derivatives exhibited reduced cytotoxicity for the eukaryotic HEK293T cells compared to the tobramycin and thereby they potentially may have improved therapeutic index. The proposed modification of the 6″-position of tobramycin does not change the mechanism of aminoglycoside’s antibacterial activity: new compounds induced translation errors which resulted in the inhibition of protein synthesis in bacterial cells. Conclusions: Taken together, we can suggest that further modifications of the 6″-position of tobramycin may be beneficial for circumvention of AMR to aminoglycosides or used for conjugation with other molecules of interest.

Melleatin, an antibiofilm multitasking protein with rRNA N-glycosylase and nuclease activity from Armillaria mellea fruiting bodies.

Several studies highlight the identification of some enzymes with additional abilities, especially those involved in metabolic pathways and/or host defence processes, classified as multitasking proteins. In this context, we report the characterization of melleatin (17.5-kDa), a multitasking enzyme isolated from Armillaria mellea fruiting bodies. Melleatin inhibits protein synthesis and displayed unexpected enzymatic action. Indeed, the structural characterization (primary structure and 3D model) showed that melleatin belongs to the His-Me finger endonucleases superfamily possessing a fold like the biofilm-dispersing nuclease NucB, the latter isolated from the marine Bacillus licheniformis. The enzymatic studies on melleatin showed that this enzyme is able to: i) inhibit protein synthesis in a rabbit reticulocyte lysate system (IC50 value 16.48 ± 3.71 nM); ii) damage rabbit and Trichoderma harzianum ribosomes as a ribosome inactivating protein (β-fragment release after Endo's assay); and iii) hydrolyse DNA. Functionally, melleatin has antibiofilm action and antifungal activity towards T. harzianum and Botrytis cinerea affecting fungal ribosomes, while it does not exhibit cytotoxicity against different human cell lines, being unable to enter the cells. Overall, melleatin represents a novel multitasking protein that could be used as a biotechnological tool for its antibiofilm and antifungal activity or as a toxic component of biomedical bioconstructs.

Boldenone and Testosterone Production from Phytosterol via One-Pot Cascade Biotransformations

Testosterone (TS) and its 1(2)-dehydrogenated derivative boldenone (BD) are widely used in medicine, veterinary science and as precursors in organic synthesis of many therapeutic steroids. Green production of these compounds is possible from androstenedione (AD) enzymatically, or from phytosterol (PS) using fermentation stages. In this study, the ascomycete Curvularia sp. VKM F-3040 was shown to convert androstadienedione (ADD, 4 and 10 g/L) to yield 97% and 78% (mol/mol) of BD, respectively. Based on its high 17β-hydroxysteroid dehydrogenase (17β-HSD) activity, a novel cascade biotransformation of PS was developed for production of TS and BD. At the first stage, the strains of Mycolicibacterium neoaurum VKM Ac-1815D or M. neoaurum VKM Ac-1816D converted PS (5 or 10 g/L) into AD or ADD (each in a concentration of 2.5 or 5 g/L), respectively. At the second stage, mycelium of the fungus under the revealed optimal conditions reduced AD or ADD with more than 90% efficiency to form TS or BD, respectively. Based on transcriptome analysis, six candidate genes that might encode 17β-HSDs in the Curvularia sp. genome were revealed. Along with 17β-HSDs, the fungus possessed inducible P450cur 7-monooxygenase, which led to the accumulation of 7α-hydroxytestosterone (7α-OH-TS) as a major product from AD (up to 83% within 24 h after mycelium addition at the second stage of cascade biotransformation). The presence of protein synthesis inhibitor cycloheximide (CHX) prevented 7α/β-hydroxylation due to inhibition of de novo synthesis of the enzyme in the fungal cells. The results demonstrate the high biotechnological potential of the Curvularia sp. strain and open up prospects for the synthesis of valuable 17β-reduced and 7-hydroxylated steroids by cascade biotransformations.

Repurposing Benzbromarone as an Antibacterial Agent against Gram-Positive Bacteria.

The rise of antibiotic-resistant Gram-positive pathogens, particularly methicillin-resistant Staphylococcus aureus (MRSA), presents a significant challenge in clinical settings. There is a critical need for new antibacterial agents to combat these resistant strains. Our study reveals that the uricosuric drug Benzbromarone (Benz) exhibits potent antibacterial activity against Gram-positive pathogens, with minimum inhibitory concentrations (MICs) ranging from 8 to 32 μg/mL and minimum bactericidal concentrations (MBCs) ranging from 32 to 128 μg/mL against clinical isolates of S. aureus, S. epidermidis, Enterococcus faecalis, and Streptococcus agalactiae. Furthermore, Benz significantly inhibits biofilm formation at subinhibitory concentrations and eradicates mature biofilms at higher concentrations. Benz also suppresses the hemolytic activity of S. aureus, indicating its potential to reduce virulence. Proteomic and in vitro induced resistance analyses indicate that Benz inhibits protein synthesis and turnover. Additionally, Benz induces membrane depolarization and increases membrane permeability, likely by targeting the membrane phospholipid phosphatidylethanolamine (PE). In the mouse wound infection model, Benz promotes wound healing and significantly reduces bacterial load. These findings suggest that Benz is a promising candidate for developing new antibacterial therapies against Gram-positive bacterial infections.

A Comprehensive Review on the Antibacterial, Antifungal, Antiviral, and Antiparasitic Potential of Silybin.

Silybin, a flavonolignan extracted from the seeds of the plant species Silybum marianum (L.) Gaertn., has a variety of pharmacological activities, including antimicrobial activity against several microorganisms of clinical interest. This review analyzes the existing studies on silybin's antimicrobial activity and possible mechanisms of action. Silybin has been shown to inhibit the growth of Gram-positive and Gram-negative bacteria, as well as some fungi, viruses, and protozoa. In general, possible mechanisms of antimicrobial action include the inhibition of efflux pumps, prevention of biofilm formation, reduction of the expression of virulence factors, induction of apoptosis-like effects, and plasma membrane damage, as well as the inhibition of nucleic acid and protein synthesis. Silybin has been shown to have synergistic effects when combined with conventional antibiotics against both drug-sensitive and drug-resistant microorganisms. However, the low bioavailability observed for this flavonolignan has been a challenge to its clinical use. In this context, nanotechnology has been used to increase silybin's bioavailability while enhancing its antimicrobial activity. Furthermore, certain structural modifications have been able to enhance its antimicrobial activity in comparison to that of the natural molecule. Overall, this review provides insights into the scientific understanding of the mechanism of action of silybin and its desired properties for the effective treatment of infections.

Oocyte death is triggered by the stabilization of TAp63α dimers in response to cisplatin

The TAp63α protein is highly expressed in primordial follicle oocytes, where it typically exists in an inactive dimeric form. Upon DNA damage, TAp63α undergoes hyperphosphorylation, transitioning from a dimeric to a tetrameric structure, which initiates oocyte apoptosis by upregulating pro-apoptotic gene. Our results demonstrate that cisplatin, an alkylating anti-cancer agent, predominantly produced the TAp63α dimer rather than the tetramer. We further observed that TAp63α protein accumulation occurred in primordial follicle oocytes following cisplatin treatment, and this accumulation was significantly reduced by cycloheximide, a protein synthesis inhibitor. These findings suggest that TAp63α accumulation is driven primarily by de novo protein synthesis in response to DNA damage. Notably, cycloheximide protected oocytes from cisplatin-induced apoptosis, as evidenced by reduced levels of both PUMA, a known pro-apoptotic target gene of TAp63α, and TAp63α itself. Additionally, TAp63α turnover appears to be regulated by ubiquitination and proteasome degradation, as evidenced by TAp63α accumulation without oocyte death when treated with PYR-41, a pharmacological inhibitor. However, when TAp63α was stabilized by PYR-41 and subsequently activated by cisplatin, oocyte death occurred, marked by increased γH2AX and Cleaved PARP. Moreover, the Casein kinase 1 inhibitor PF-670462 effectively blocked cisplatin-induced oocyte death, indicating that CK1-mediated phosphorylation is essential for TAp63α activation, even in the absence of tetramer formation. The ATR inhibitor BEZ235 prevented cisplatin-induced TAp63α accumulation, suggesting that TAp63α accumulation precedes its phosphorylation-driven activation. Collectively, our study reveals a novel mechanism of cisplatin-induced apoptosis in primordial follicle oocyte through TAp63α stabilization and accumulation, independent of tetramerization.

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.

Long-term leucine supplementation increases body weight in goats by controlling appetite and muscle protein synthesis under protein-restricted conditions

An inadequate amino acid (AA) supply in animals under protein-restricted conditions can slow skeletal muscle growth. Protein translation can be activated by short-term leucine (Leu) stimulation; however, whether muscle mass increases under long-term Leu supplementation and how the gut and muscle respond to Leu supplementation are largely unknown. In this study, we investigated if muscle mass increases with long-term Leu supplementation under protein-restricted conditions. We identified changes in the link between the gut and muscles under different amino acid supply conditions, using goats as the study object. A total of 27 Xiangdong black male goats with average initial body weight (BW) of 10.88 ± 1.22 kg were randomly divided into three dietary treatments: a normal protein diet (NP, 14.24% crude protein [CP]); a low protein diet (LP, 8.27% CP with supplemental 1.66% rumen-protected lysine [RPLys] and 0.09% rumen-protected methionine [RPMet]); and LP diet with rumen-protected Leu (RPLeu) (LP + RPLeu, 8.75% CP with supplemental 1.66% RPLys, 0.09% RPMet and 1.46% RPLeu). The animal trial lasted for 110 d, consisting of 20 d of adaptation and a 90 d of experimental period. The results showed that long-term protein restriction increased gut tryptophan hydroxylase 1 (TPH1) activity (P < 0.001), tryptophan (Trp) catabolism (P < 0.001), and 5-Hydroxytryptamine (5-HT) synthesis (P < 0.001), which all subsequently reduced goat appetite. Long-term Leu supplementation inhibited 5-HT synthesis (P < 0.001), decreased Trp catabolism in the gut, and increased appetite in goats. Long-term protein restriction enhanced jejunal and ileal branched-chain amino acid transferase (BCAT) (P < 0.001) and branched-chain α-Keto acid dehydrogenase (BCKD) (P = 0.048) activities, which increased branched-chain amino acid (BCAA) catabolism. Immunofluorescence results showed that protein restriction decreased the intestinal mucosal expression of solute carrier family 1 member 5 (SLC1A5) (P = 0.032) and solute carrier family 7 member 5 (SLC7A5) (P < 0.001), reduced BCAA transport from the mucosa to the blood, lowered BCAA levels in the blood (P < 0.001). Western blot results showed that protein restriction inhibited mammalian target of rapamycin (mTOR) pathway activation in goat muscles. Leu supplementation increased BCAA translocation from the intestine to the blood and promoted activation of the muscle mTOR pathway and protein synthesis. In conclusion, our results suggest that Leu supplementation in low-protein diets improves appetite and alleviates the inhibition of muscle protein synthesis in goats.

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.

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.

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.