26 research outputs found
Bortezomib Eliminates Persistent Chlamydia trachomatis Infection through Rapid and Specific Host Cell Apoptosis
No full textChlamydia trachomatis, a parasitic intracellular bacterium, is a major human pathogen that causes millions of trachoma, sexually transmitted infections, and pneumonia cases worldwide. Previously, peptidomimetic inhibitors consisting of a hydrophobic dipeptide derivative exhibited significant inhibitory effects against chlamydial growth. Based on this finding, this study showed that both bortezomib (BTZ) and ixazomib (IXA), anticancer drugs characterized by proteasome inhibitors, have intensive inhibitory activity against Chlamydia. Both BTZ and IXA consisted of hydrophobic dipeptide derivatives and strongly restricted the growth of Chlamydia (BTZ, IC(50) = 24 nM). In contrast, no growth inhibitory effect was observed for other nonintracellular parasitic bacteria, such as Escherichia coli. BTZ and IXA appeared to inhibit chlamydial growth bacteriostatically via electron microscopy. Surprisingly, Chlamydia-infected cells that induced a persistent infection state were selectively eliminated by BTZ treatment, whereas uninfected cells survived. These results strongly suggested the potential of boron compounds based on hydrophobic dipeptides for treating chlamydial infections, including persistent infections, which may be useful for future therapeutic use in chlamydial infectious diseases
Seasonal variations in planktonic foraminiferal flux and oxygen isotopic composition in the western North Pacific : Implications for paleoceanographic reconstruction
No full textThe oxygen isotopic composition (delta O-18) of planktonic foraminiferal shells in seafloor sediment provides information on past surface oceanography. Knowledge of seasonal and depth habitat, as well as the delta O-18 disequilibrium (vital effect), is essential to constrain the interpretation of sedimentary delta O-18. Here, we present a 1-year time series of planktonic foraminiferal shell fluxes and delta(18)Ofrom a sediment trap moored in the northwestern margin of the North Pacific. The vital effect and calcification depth for four species were estimated by comparing shell delta O-18 and the predicted values of equilibrium calcite calculated from temperature and estimated delta O-18 in seawater. Six major species (Neogloboquadrina incompta, Nedgloboquadrina dutertrei, Neogloboquadrina pachyderma, Globigerina quinqueloba, Globigerina bulloides, and Globorotalia scitula) constituted 97% of the total foraminiferal flux. Most major species showed large fluxes in June and December, corresponding to periods of the development and disruption of the seasonal thermocline, implying the importance of nutrient injection and/or circulation for foraminiferal fluxes. Additional peaks in N. dutertrei and N. pachyderma were observed in August. The seasonal successions of foraminiferal fluxes corresponded to surface ocean stratification conditions and food availability, which are closely related to circulation of local currents. Vital effect estimations suggest that shells calcified in equilibrium for G. bulloides and N. pachyderma [sinistral (s)1 and with a -0.7% offset for N. dutertrei [dextral (d)], a -1.0%, offset for N. incompta (d), and a -03% offset for N. pachyderma (d). The calculation of flux-weighted delta O-18 values reveals that the sedimentary delta O-18 values of G. bulloides, N. dutertrei (d), and N. incompta (d) reflect surface temperature in winter season, and those of N. pachyderma (s) and N. pachyderma (d) reflect summer and annual mean subsurface temperature, respectively. The shallow calcification depths for the four species suggest that delta O-18 between different species (Delta delta O-18) in the western North Pacific does not work for reconstructing past stratification conditions, unlike in other regions. Rather, the delta O-18 between N. pachyderma (s) and G. bulloides, N. dutertrei (d) or N. incompta (d) may be a more suitable proxy for past seasonality. (C) 2013 Elsevier B.V. All rights reserved
Intracellular Survival of Biofilm-Forming MRSA OJ-1 by Escaping from the Lysosome and Autophagosome in J774A Cells Cultured in Overdosed Vancomycin
No full textWe investigated the drug-resistant mechanisms of intracellular survival of methicillin-resistant S. aureus (MRSA). Our established MRSA clinical strain, OJ-1, with high biofilm-forming ability, and a macrophage cell line, J774A, were used. After ingestion of OJ-1 by J774A, the cells were incubated for ten days with vancomycin at doses 30 times higher than the minimum inhibitory concentration. The number of phagocytosed intracellular OJ-1 gradually decreased during the study but plateaued after day 7. In J774A cells with intracellular OJ-1, the expression of LysoTracker-positive lysosomes increased until day 5 and then declined from day 7. In contrast, LysoTracker-negative and OJ-1-retaining J774A cells became prominent from day 7, and intracellular OJ-1 also escaped from the autophagosome. Electron microscopy also demonstrated that OJ-1 escaped the phagosomes and was localized in the J774A cytoplasm. At the end of incubation, when vancomycin was withdrawn, OJ-1 started to grow vigorously. The present results indicate that intracellular phagocytosed biofilm-forming MRSA could survive for more than ten days by escaping the lysosomes and autophagosomes in macrophages. Intracellular MRSA may survive in macrophages, and accordingly, they could be resistant to antimicrobial drug treatments. However, the mechanisms their escape from the lysosomes are still unknown. Additional studies will be performed to clarify the lysosome-escaping mechanisms of biofilm-forming MRSA
Multiple mutations of Mycobacterium intracellulare subsp. chimaera causing false-negative reaction to the transcription-reverse transcription concerted method for pathogen detection
No full textObjectives: To report an isolate of Mycobacterium intracellulare subsp. chimaera with multiple mutations in 16S ribosomal RNA (rRNA) gene, resulting in the false-negative reaction to the transcription-reverse transcription concerted (TRC) method for Mycobacterium avium-intracellulare complex. Methods: We used TRC, polymerase chain reaction (PCR), and Matrix-assisted laser desorption/ionization Time-of-Flight/Mass Spectrometry (MALDI-TOF/MS) methods to identify a clinical isolate in 2021. Due to the discordant results between TRC and PCR or MALDI-TOF MS methods, 16S rRNA sequencing, whole-genome shotgun (WGS) sequencing, and average nucleotide identity (ANI) analysis were employed to identify the isolate. Results: A mycobacterial isolate from a sputum sample gave negative results for the detection of Mycobacterium tuberculosis complex or M. avium-intracellulare complex by the TRC method. However, the isolate was identified as M. intracellulare by both PCR method and MALDI-TOF MS method. WGS sequencing of 16S rRNA genome revealed eight substitution mutations and one insertion mutation within the region, which could hamper the correct reaction to TRC method. Subsequent ANI analysis between the isolate and various species of nontuberculosis mycobacteria revealed that the isolate could be identified as M. intracellulare subsp. chimaera. Conclusion: Rare mutations within the 16S rRNA genome resulted in the false-negative identification of Mycobacterium chimaera by the TRC method. WGS sequencing and ANI analysis was necessary to identify the isolate
Co-infection of human papillomavirus and other sexually transmitted bacteria in cervical cancer patients in the Philippines
No full textCervical cancer is the fourth most common cancer in women globally. Based on several epidemiologic studies, human papillomavirus is strongly associated with cervical neoplasia. Aside from HPV, other bacterial infections in the genital tract were associated with cervical neoplasia. This study aimed to determine the prevalence of HPV infection; and co-infection with Ureaplasma spp., Mycoplasma spp., Chlamydia trachomatis, and Neisseria gonorrheae in Filipino cervical cancer patients. Forty-four patients (28 patients with cervical carcinoma and 16 patients with non-malignant cervix) who consulted in the Philippine General Hospital from 2016 to 2017 were included in this study. HPV genotyping and genetic detection of Ureaplasma spp., Mycoplasma spp., C. trachomatis, and N. gonorrheae were done using different PCR assays. The prevalence of HPV 16/18/33/52 was 75% in cervical cancer patients and 25% in control patients. Infection with HPV 16/18/33/52 was significantly associated with having cervical cancer (OR: 9.00; 95% CI: 2.18–37.18; p = 0.0024). HPV-16 was the most prevalent HPV genotype among Filipino cervical cancer patients. HPV-18 and HPV-52 were only detected from cervical cancer patients. Among HPV-positive patients, we noted a 22.73% co-infection with Ureaplasma spp. and 9.09% co-infection with Mycoplasma spp. To our knowledge, this is the first study on the co-infection of HPV and sexually transmitted infections among cervical cancer patients in the Philippines
Biofilm-Forming Methicillin-Resistant Staphylococcus aureus Survive in Kupffer Cells and Exhibit High Virulence in Mice
No full textAlthough Staphylococcus aureus is part of the normal body flora, heavy usage of antibiotics has resulted in the emergence of methicillin-resistant strains (MRSA). MRSA can form biofilms and cause indwelling foreign body infections, bacteremia, soft tissue infections, endocarditis, and osteomyelitis. Using an in vitro assay, we screened 173 clinical blood isolates of MRSA and selected 20 high-biofilm formers (H-BF) and low-biofilm formers (L-BF). These were intravenously administered to mice and the general condition of mice, the distribution of bacteria, and biofilm in the liver, lung, spleen, and kidney were investigated. MRSA count was the highest in the liver, especially within Kupffer cells, which were positive for acid polysaccharides that are associated with intracellular biofilm. After 24 h, the general condition of the mice worsened significantly in the H-BF group. In the liver, bacterial deposition and aggregation and the biofilm-forming spot number were all significantly greater for H-BF group than for L-BF. CFU analysis revealed that bacteria in the H-BF group survived for long periods in the liver. These results indicate that the biofilm-forming ability of MRSA is a crucial factor for intracellular persistence, which could lead to chronic infections
Longitudinal Dynamics of SARS-CoV-2 IgG Antibody Responses after the Two-Dose Regimen of BNT162b2 Vaccination and the Effect of a Third Dose on Healthcare Workers in Japan
No full textAnalysis of longitudinal dynamics of humoral immune responses to the BNT162b2 COVID-19 vaccine might provide useful information to predict the effectiveness of BNT162b2 in preventing SARS-CoV-2 infection. Herein, we measure anti-RBD IgG at 1, 3 and 6 months (M) after the second dose of BNT162b2, and at 1 M after a third dose of BNT162b2 vaccination in 431 COVID-19-naïve healthcare workers (HCWs) in Japan. All HCWs mounted high-anti-RBD IgG responses after the two-dose regimen of BNT162b2 vaccinations. Older persons and males presented lower anti-RBD IgG responses than younger adults and females, respectively. The decay in anti-RBD IgG started from 1 M after the second dose of BNT162b2 and anti-RBD IgG titers dropped to nearly one-tenth at 6 M after the second vaccination. Subsequently, the participants received a third dose of BNT162b2 at 8 M after the second dose of BNT162b2 vaccine. Anti-RBD antibody titers 1 M after the third dose of BNT162b2 increased seventeen times that of 6 M after the second dose, and was twice higher than the peak antibody titers at 1 M after the second dose of vaccination. The negative effect of age for the male gender on anti-RBD IgG antibody titers was not observed at 1 M after the third dose of BNT162b2 vaccine. There were no notable adverse events reported, which required hospitalization in these participants. These results suggest that the third dose of BNT162b2 safely improves humoral immunity against SARS-CoV-2 with no major adverse events
Mitochondrial ROS–ER Stress Axis Governs IL-10 Production in Neutrophils and Regulates Inflammation in Murine Chlamydia pneumoniae Lung Infection
No full textNeutrophils are among the first cells to be recruited to the lungs during Chlamydia pneumoniae infection in mouse models; however, their regulatory functions are not yet fully understood. This study examined the mechanisms and significance of IL-10-producing neutrophils throughout C. pneumoniae pulmonary infection in C57BL/6 mice. Our findings revealed that infection with C. pneumoniae induces IL-10 secretion in bone marrow-derived neutrophils, depending on Toll-like receptor 2 (TLR2) activation. This process involves TLR2-dependent mitochondrial reactive oxygen species (ROS) production, which triggers the endoplasmic reticulum (ER) stress pathway, including IRE1α and subsequent Xbp1 splicing. Inhibition of this pathway or depletion of neutrophils (using the 1A8 monoclonal antibody) significantly reduces IL-10 levels in bronchoalveolar lavage fluid (BALF) in vivo. Conversely, the absence of IL-10-producing neutrophils, whether through depletion or TLR2 deficiency, leads to increased IL-12p70 and IFN-γ-positive NK cells, along with decreased regulatory T cells and M2-like macrophages. This results in a lower bacterial burden in the lungs but causes more severe pulmonary damage and decreased survival rates. These findings highlight that IL-10 produced by neutrophils via the TLR2-mitochondrial ROS–ER stress pathway is essential for modulating pulmonary immune responses and maintaining immune homeostasis during C. pneumoniae infection, thereby preventing excessive inflammation and tissue damage
Athens and lasos : 412-394 BCE : A Reconstruction of IG II^2 3(In Commemoration of the Retirement of Professor Shunsuke Okuda, Michinobu Takagi and Tadashi Takahashi)
No full textP(論文)本論文では,イアソス出土のヘレニズム時代の碑文(lasos 3926)によって新たにもたらされたIG II^2 3+IG II^2 165に関する知見をもとに,碑文の新テキストを紹介するとともに,この碑文の決議年代が前394年ごろであること,およびその歴史的背景を考察した。顕彰された3名のイアソス人亡命者は,おそらく前412年以来,アテナイに身を寄せていたが,小アジア解放戦線にアテナイの将軍とともに加わって力を尽くしたものと思われる。彼らは,前394年に小アジアが開放され,イアソスが解放されると,アテナイから顕彰され,アテナイの保護のもと祖国にもどることに成功した。The author examines a new text of IG II^2 3+IG II^2 165, recently published by Fabiani, Habicht and Culasso Gastaldi, and considers its historical background and circumstance. This is an honorary decree for three lasians, Anaxagoras son of Apollonides, and Artemon and Kydias, sons of presumably Eumachos. The date of the decree is thought ca. 394 BCE through the analysis of lasian situation at that time. The three lasians were presumably expelled from lasos in 412 BCE and fled to Athens. They acted with Athenian generals who fought against the Spartans, and after the success of the liberation of the Greeks in Asia Minor in 394 BCE, they succeeded to return to their homeland lasos and were honored as proxenoi of the Athenians.departmental bulletin pape
Efficacy and safety of axitinib for metastatic renal cell carcinoma: Real-world data on patients with renal impairment
No full textObjectives Limited information is currently available on the efficacy and safety of axitinib for metastatic renal cell carcinoma (mRCC) patients with renal impairment. Therefore, the present study investigated the efficacy and toxicity of axitinib in patients with chronic kidney disease. Methods Post-hoc analyses were performed on a Japanese multicenter cohort study of 477 mRCC patients who received axitinib followed by 1 or 2 regimens of systemic antiangiogenic therapy between January 2012 and December 2016. Differences in clinical characteristics and the efficacy and safety of axitinib were assessed based on pretreatment renal function. Results Patients were categorized into the following 5 renal function groups according to baseline renal function: estimated glomerular filtration rate (eGFR) ≥60 ml/min (n = 133), 45 ml/min ≤eGFR <60 ml/min (n = 153), 30 ml/min ≤eGFR< 45 ml/min (n = 130), eGFR <30 ml/min (n = 45), and dialysis (n = 16). Median progression-free survival (PFS) (95% confidence interval [CI]) in the 5 groups was 11 (8−16), 14 (11−19), 14 (10–19), 12 (8−24), and 6 (3-NR) months, respectively (p = 0.781). After adjustments for treatment-related confounders, the renal function group was not a significant prognostic factor for PFS. Objective response rates in the 5 groups were 22%, 23%, 23%, 18%, 20%, and 38%, respectively (p = 0.468). Regarding adverse events of all grades, hypertension (p = 0.0006) and renal and urinary disorders (p < 0.0001) were more frequently observed in the eGFR <30 ml/min group than in the other groups. Conclusions Since renal function at the initiation of treatment with axitinib does not adversely affect the efficacy of VEGF-TKI therapy, clinicians do not need to avoid its administration to mRCC patients with impaired renal function in consideration of the risk of progression to end-stage renal disease
