As demands for new antibiotics and strategies to control methicillin-resistant
(MRSA) increase, there have been efforts to obtain more accurate and abundant information about the mechanism of the ...bacterial responses to antibiotics. However, most of the previous studies have investigated responses to antibiotics without considering the genetic differences between MRSA and methicillin-susceptible
(MSSA). Here, we initially applied a multi-omics approach into the clinical isolates (
,
WKZ-1 (MSSA) and
WKZ-2 (MRSA)) that are isogenic except for the mobile genetic element called staphylococcal cassette chromosome
(SCC
) type IV to explore the response to β-lactam antibiotics (oxacillin). First, the isogenic pair showed a similar metabolism without oxacillin treatment. The quantitative proteomics demonstrated that proteins involved in peptidoglycan biosynthesis (MurZ, PBP2, SgtB, PrsA), two-component systems (VrsSR, WalR, SaeSR, AgrA), oxidative stress (MsrA1, MsrB), and stringent response (RelQ) were differentially regulated after the oxacillin treatment of the isogenic isolates. In addition, targeted metabolic profiling showed that metabolites belonging to the building blocks (lysine, glutamine, acetyl-CoA, UTP) of peptidoglycan biosynthesis machinery were specifically decreased in the oxacillin-treated MRSA. These results indicate that the difference in metabolism of this isogenic pair with oxacillin treatment could be caused only by SCC
type IV. Understanding and investigating the antibiotic response at the molecular level can, therefore, provide insight into drug resistance mechanisms and new opportunities for antibiotics development.
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IJS, KILJ, NUK, UL, UM, UPUK
Summary
To explore whether bacterial secreted 4‐hydroxy‐2‐alkylquinolines (HAQs) can regulate host innate immune responses, we used the extracts of bacterial culture supernatants from a wild‐type ...(PA14) and two mutants of Pseudomonas aeruginosa that have defects in making HAQs. Surprisingly, the extract of supernatants from the P. aeruginosa pqsA mutant that does not make HAQs showed strong stimulating activity for the production of innate cytokines such as tumour necrosis factor‐α and interleukin‐6 in the J774A.1 mouse monocyte/macrophage cell line, whereas the extract from the wild‐type did not. The addition of 4‐hydroxy‐2‐heptylquinoline (HHQ) or 2‐heptyl‐3,4‐dihydroxyquinoline (PQS, Pseudomonas quinolone signal) to mammalian cell culture media abolished this stimulating activity of the extracts of supernatants from the pqsA mutant on the expression of innate cytokines in J774A.1 cells and in the primary bronchoalveolar lavage cells from C57BL/6 mice, suggesting that HHQ and PQS can suppress the host innate immune responses. The pqsA mutant showed reduced dissemination in the lung tissue compared with the wild‐type strain in a mouse in vivo intranasal infection model, suggesting that HHQ and PQS may play a role in the pathogenicity of P. aeruginosa. HHQ and PQS reduced the nuclear factor‐κB (NF‐κB) binding to its binding sites and the expression of NF‐κB target genes, and PQS delayed inhibitor of κB degradation, indicating that the effect of HHQ and PQS was mediated through the NF‐κB pathway. Our results suggest that HHQ and PQS produced by P. aeruginosa actively suppress host innate immune responses.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Recurrent implantation failure (RIF) refers to two or more unsuccessful in vitro fertilization embryo transfers in the same individual. Embryonic characteristics, immunological factors, and ...coagulation factors are known to be the causes of RIF. Genetic factors have also been reported to be involved in the occurrence of RIF, and some single nucleotide polymorphisms (SNPs) may contribute to RIF. We examined SNPs in
,
,
, and
, which have been associated with primary ovarian failure. A cohort of 133 RIF patients and 317 healthy controls consisting of all Korean women was included. Genotyping was performed by Taq-Man genotyping assays to determine the frequency of the following polymorphisms:
rs6165,
rs11893842 and rs35118453,
rs9340799 and rs2234693, and
rs17003221 and rs3810682. The differences in these SNPs were compared between the patient and control groups. Our results demonstrate a decreased prevalence of RIF in subjects with the
rs6165 A>G polymorphism AA vs. AG adjusted odds ratio (AOR) = 0.432; confidence interval (CI) = 0.206-0.908;
= 0.027, AA+AG vs. GG AOR = 0.434; CI = 0.213-0.885;
= 0.022. Based on a genotype combination analysis, the GG/AA (
rs6165/ESR1 rs9340799: OR = 0.250; CI = 0.072-0.874;
= 0.030) and GG-CC (
rs6165/
rs3810682: OR = 0.466; CI = 0.220-0.987;
= 0.046) alleles were also associated with a decreased RIF risk. Additionally, the
rs6165GG and
rs17003221TT+TC genotype combination was associated with a decreased RIF risk (OR = 0.430; CI = 0.210-0.877;
= 0.020) and increased FSH levels, as assessed by an analysis of variance. The
rs6165 polymorphism and genotype combinations are significantly associated with RIF development in Korean women.
Fucoidan, a sulfated polysaccharide, is an active component found in various species of seaweed. Although this compound has a strong anti-inflammatory activity, the underlying mechanisms exerted by ...fucoidan have not been fully elucidated. In the present study, the anti-inflammatory effects of fucoidan on lipopolysaccharide (LPS)-stimulated macrophages and zebrafish larvae were examined. The present data indicated that fucoidan significantly suppressed the secretion of pro-inflammatory mediators including nitric oxide (NO ) and prostaglandin E
2
(PGE
2
), and cytokines, such as tumor necrosis factor-α and interleukin-1β in RAW 264.7 macrophages without any significant cytotoxicity, the protective effects of which were accompanied by a marked reduction in their regulatory gene expression at the transcription levels. Fucoidan also inhibited translocation of the nuclear factor-kappa B from the cytoplasm to the nucleus and attenuated LPS-induced production of intracellular reactive oxygen species (ROS) in RAW 264.7 macrophages. Moreover, fucoidan reduced NO and PGE
2
production and ROS accumulation in LPS-stimulated zebrafish larvae, which was associated with a diminished recruitment of neutrophils and macrophages. Based on the results of this study, we suggest that fucoidan has excellent potential as a therapeutic agent for inflammatory disorders.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The COHORT trial was conducted to compare the efficacy of androgen deprivation therapy (ADT) alone versus combined with radiation therapy (ADT + RT) for clinically node-positive prostate cancer. We ...reported adverse events and quality of life between the two treatment groups. Fifty-nine patients were randomized to receive ADT alone or ADT + RT and analyzed as per-protocol. Patients allocated to the ADT alone arm received ADT for at least 2 years. Patients in the ADT + RT arm received additional pelvic RT. Higher rates of grade ≥ 2 acute genitourinary (0% vs. 7.1%) and late gastrointestinal adverse events (0% vs. 14.3%) were reported in the ADT + RT arm compared with the ADT alone. However, grade ≥ 2 late genitourinary toxicity was more common in the ADT alone than the ADT + RT arm (9.7% vs. 3.6%). No grade ≥ 3 adverse events were reported. There was no statistically significant difference in EPIC scores between two treatment arms. However, the urinary and bowel domains tended to decrease and recover in the ADT + RT arm. In conclusion, ADT + RT demonstrated higher rates of adverse events compared to ADT alone. However, the addition of RT did not significantly impact the quality of life.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
We have identified missense mutations at conserved amino acids in the
PRPS1 gene on Xq22.3 in two families with a syndromic form of inherited peripheral neuropathy, one of Asian and one of European ...descent. The disease is inherited in an X-linked recessive manner, and the affected male patients invariably develop sensorineural hearing loss of prelingual type followed by gating disturbance and visual loss. The family of European descent was reported in 1967 as having Rosenberg-Chutorian syndrome, and recently a Korean family with the same symptom triad was identified with a novel disease locus CMTX5 on the chromosome band Xq21.32-q24.
PRPS1 (phosphoribosyl pyrophosphate synthetase 1) is an isoform of the
PRPS gene family and is ubiquitously expressed in human tissues, including cochlea. The enzyme mediates the biochemical step critical for purine metabolism and nucleotide biosynthesis. The mutations identified were E43D, in patients with Rosenberg-Chutorian syndrome, and M115T, in the Korean patients with CMTX5. We also showed decreased enzyme activity in patients with M115T.
PRPS1 is the first CMT gene that encodes a metabolic enzyme, shedding a new light on the understanding of peripheral nerve-specific metabolism and also suggesting the potential of
PRPS1 as a target for drugs in prevention and treatment of peripheral neuropathy by antimetabolite therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Trastuzumab (TZMB) is widely used as first line therapy for breast cancer (BC) patients overexpressing human epidermal growth factor receptor 2 (HER2). Despite its clinical benefits, many patients ...suffer from primary or secondary resistance to this drug within one year. As diverse molecular mechanisms occur contemporaneously during the resistance development, we focused on elucidating the role of heat shock protein 27 (HSP27) in TZMB-resistance, as this protein simultaneously regulates the function of diverse client molecules that are involved in the resistance mechanism. By extensively utilizing TZMB-refractory breast cancer cell lines transduced with diverse phosphovariants of HSP27, our study newly revealed that specific phosphorylation of HSP27 at S15 promoted its S78 phosphorylation and served as key mediator to promote direct interactions that increase the stability of HER2 and protein kinase B (AKT). This phosphorylation promoted nuclear translocation of HER2, enhancing the distinct nuclear function of HER2 that promoted AKT activation and cyclin D1 expression. Co-administration of TZMB and a functional inhibitor of HSP27, J2, significantly reduced the S15/78 phosphorylation of HSP27, which downregulated HER2 and its downstream signals, sensitizing TZMB-refractory cell, and JIMT1-xenograft mouse models to TZMB. Collectively, p-HSP27S15 could serve as a valuable predictive marker and also a therapeutic target for TZMB-resistance.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Prosaposin (PSAP) is a precursor of saposin (SAP), which is present in lysosomal and secreted proteins. PSAP is a member of the SAP-like protein families, which comprise multifunctional proteins. In ...particular, their antimicrobial activity has been reported. We identified PSAP-like (PsPSAPL) sequences from starry flounder and analysed their expression and antimicrobial activity based on cDNA and amino acid sequences. PsPSAPL showed conservation of three saposin B type domains at high levels, and PsPSAPL mRNA was relatively abundantly distributed in the brain and gills of healthy starry founders. PsPSAPL mRNA showed significant expression changes in response to viral haemorrhagic septicaemia virus and Streptococcus parauberis. Synthetic peptides (PsPSAPL-1 and -2), prepared based on amino acid sequences, were used to confirm as well as analyse the antimicrobial activity against bacteria and parasites. Consequently, PsPSAPL-1 and -2 were found to significantly inhibit the growth of various bacteria and kill the Miamiensis avidus. In addition, bacterial biofilm formation was significantly inhibited. Safety was also confirmed by analysing cell haemolysis. These results indicate the immunological function of PsPSAP and the potential antimicrobial activity of the AMPs PsPSAPL-1 and -2.
•The Prosaposin-like (PSAPL) was identified by NGS analysis from Platichthys stellatus.•PsPSAPL showed high homology and sequence conservation with other species PSAPL.•PsPSAPL mRNA showed significant expression change due to pathogen infection.•The antimicrobial function and in vivo safety of PsPSAPL peptides were confirmed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
An exceptionally low interfacial tension of a dense fluid of concentrated polyelectrolyte complexes, phase-separated from a biphasic fluid known as complex coacervates, represents a unique and highly ...sought-after materials property that inspires novel applications from superior coating to wet adhesion. Despite extensive studies and broad interest, the molecular and structural bases for the unique properties of complex coacervates are unclear. Here, a microphase-separated complex coacervate fluid generated by mixing a recombinant mussel foot protein-1 (mfp-1) as the polycation and hyaluronic acid (HA) as the polyanion at stoichiometric ratios was macroscopically phase-separated into a dense complex coacervate and a dilute supernatant phase to enable separate characterization of the two fluid phases. Surprisingly, despite up to 4 orders of magnitude differing density of the polyelectrolytes, the diffusivity of water in these two phases was found to be indistinguishable. The presence of unbound, bulk-like, water in the dense fluid can be reconciled with a water population that is only weakly perturbed by the polyelectrolyte interface and network. This hypothesis was experimentally validated by cryo-TEM of the macroscopically phase-separated dense complex coacervate phase that was found to be a bicontinuous and biphasic nanostructured network, in which one of the phases was confirmed by staining techniques to be water and the other polyelectrolyte complexes. We conclude that a weak cohesive energy between water–water and water–polyelectrolytes manifests itself in a bicontinuous network, and is responsible for the exceptionally low interfacial energy of this complex fluid phase with respect to virtually any surface within an aqueous medium.
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IJS, KILJ, NUK, PNG, UL, UM
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