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1.
Int J Microbiol ; 2024: 1329884, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38716459

RESUMEN

Background: Distinct bacterial strains may affect the prognosis of patients with chronic respiratory diseases. However, little is known about the clinical significance of respiratory bacteria in patients with chronic pulmonary aspergillosis (CPA), a progressive and debilitating disease caused by Aspergillus spp. Objectives: This study aimed to analyze data obtained from CPA patients and their sputum or bronchial washing samples and investigate the prevalence and composition of respiratory bacteria and clinical implications. Patients and Methods. We retrospectively reviewed the data of patients diagnosed with CPA between March 2019 and February 2023 in a tertiary referral hospital. We assessed the clinical characteristics and overall and pneumonia-specific survival rates of patients with CPA based on the presence of bacteria. Results and Conclusions. We included 142 patients with CPA. The most commonly identified bacteria were Klebsiella pneumoniae (22.5%), followed by Pseudomonas aeruginosa (21.8%) and Escherichia coli (4.2%). Patients with isolated bacteria had a higher prevalence of older age, female sex, diabetes, and a history of extrathoracic malignancy than those without isolated bacteria (P = 0.024, 0.013, 0.021, and 0.034, respectively). Furthermore, over a median follow-up of 11 (4-21) months, the pneumonia-specific mortality rate was 13.4% (19/142), which was higher in patients with isolated bacteria than in those without (P = 0.045, log-rank test). Particularly, patients with the presence of P. aeruginosa had a significantly higher mortality rate from pneumonia than those without the presence of P. aeruginosa (adjusted hazard ratio, 3.34; P = 0.015). In conclusion, CPA patients with isolated bacteria, especially P. aeruginosa, showed higher mortality rates due to pneumonia. Performing tests to identify bacteria in the lower respiratory tract of patients with CPA may be helpful in predicting future prognosis. Further studies are required to validate these findings in diverse ethnic groups.

2.
Carbohydr Res ; 540: 109125, 2024 Apr 26.
Artículo en Inglés | MEDLINE | ID: mdl-38703663

RESUMEN

Di-d-psicose anhydride (DPA), derived from functional rare saccharide as d-psicose, is investigated for its strong chelating ability. Methylglyoxal (MGO), an important precursor of advanced glycation end-products (AGEs), promotes obesity, and causes complications such as diabetic nephropathy. On mesangial cells, DPA can substantially reduce the negative effects of MGO. DPA effectively trapping MGO in mesangial cells. The bonding properties of the DPA-MGO adduct were discussed by mass spectrometry and nuclear magnetic resonance (NMR). The NMR spectra of the DPA-MGO adduct provide evidence for chelation bonding. The inhibition of AGE formation and the mass spectrometry results of the DPA-MGO adduct indicate that DPA can scavenge MGO at a molar ratio of 1:1. DPA suppressed 330 % of the up-regulated receptor for an AGEs protein expression to a normal level and restored the suppressed glyoxalase 1 level to 86 % of the normal group. This research provides important evidence and theoretical basis for the development of AGE inhibitors derived from rare saccharide.

3.
J Chemother ; : 1-9, 2024 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-38781042

RESUMEN

We developed a prediction model for cefotaxime resistance in patients with K. pneumoniae bacteremia. Adult patients with K. pneumoniae bacteremia were grouped into derivation (from March 2018 to December 2019) and validation (from January 2020 to August 2020) cohorts. The prediction scoring system was based on factors associated with cefotaxime resistance identified by the logistic regression model. A total of 358 patients were enrolled (256 for derivation, 102 for validation). In the multivariable analysis, age ≥65 years, hospital-acquired infection, prior antimicrobial use, and an updated Charlson comorbidity index ≥3 points were associated with cefotaxime resistance in the derivation cohort. When each variable was counted as 1 point, the values of the area under the curve were 0.761 in the derivation and 0.781 in the validation cohorts. The best cutoff value using the Youden index was ≥2 with 73.6% sensitivity and 67.5% specificity. Our simple scoring system favorably predicted cefotaxime resistance.

4.
Int J Gen Med ; 17: 1625-1633, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38706744

RESUMEN

Purpose: Clinical studies on dysbiosis and stroke outcomes has been insufficient to establish clear evidence. This study aimed to investigate the effects of pre-antibiotic use before a stroke event on secondary outcomes using a longitudinal population-level database. Patients and Methods: This retrospective cohort study included adults aged 55 years or older diagnosed with acute ischemic stroke (AIS) and acute hemorrhagic stroke (AHS) between 2004 and 2007. Patients were followed-up until the end of 2019, and the target outcomes were secondary AIS, AHS, and all-cause mortality. Multivariable Cox regression analyses were applied, and we adjusted covariates such as age, sex, socioeconomic status, hypertension, diabetes, and dyslipidemia. Pre-antibiotic use was identified from 7 days to 1 year before the acute stroke event. Results: We included 159,181 patients with AIS (AIS group) and 49,077 patients with AHS (AHS group). Pre-antibiotic use significantly increased the risk of secondary AIS in the AIS group (adjusted hazard ratio [aHR], 1.03; 95% confidence interval [CI], 1.01-1.05; p = 0.009) and secondary AHS in the AHS group (aHR, 1.08; 95% CI, 1.03-1.12; p <0.001). Furthermore, pre-antibiotic use in the AIS group was associated with a lower risk of mortality (aHR, 0.95; 95% CI, 0.94-0.96; p <0.001). Conclusion: Our population-based longitudinal study revealed that pre-antibiotic use was associated with a higher risk of secondary stroke and a lower risk of mortality in the AIS and AHS groups. Further studies are needed to understand the relationship between dysbiosis and stroke outcomes.

5.
Neurosci Biobehav Rev ; 162: 105719, 2024 May 16.
Artículo en Inglés | MEDLINE | ID: mdl-38759470

RESUMEN

To improve the initiation and speed of intended action, one of the crucial mechanisms is suppressing unwanted movements that interfere with goal-directed behavior, which is observed relatively aberrant in Parkinson's disease patients. Recent research has highlighted that dopamine deficits in Parkinson's disease predominantly occur in the caudal lateral part of the substantia nigra pars compacta (SNc) in human patients. We previously found two parallel circuits within the basal ganglia, primarily divided into circuits mediated by the rostral medial part and caudal lateral part of the SNc dopamine neurons. We have further discovered that the indirect pathway in caudal basal ganglia circuits, facilitated by the caudal lateral part of the SNc dopamine neurons, plays a critical role in suppressing unnecessary involuntary movements when animals perform voluntary goal-directed actions. We thus explored recent research in humans and non-human primates focusing on the distinct functions and networks of the caudal lateral part of the SNc dopamine neurons to elucidate the mechanisms involved in the impairment of suppressing involuntary movements in Parkinson's disease patients.

6.
Chemosphere ; : 142330, 2024 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-38759805

RESUMEN

Solar-driven artificial photosynthesis offers a promising avenue for hydrogen peroxide (H2O2) generation, an efficient and economical replacement for current methods. The efficiency and selectivity hurdles of the two-electron oxygen reduction reaction (ORR) in solar-to- H2O2 conversion are substantial barriers to large scale production. In this manuscript, a simple biomass-assisted synthesis was performed to produce oxygen-enriched carbon quantum dots (OE-CQDs) from spent coffee waste, acting as an efficient photocatalyst for solar-powered H2O2 production. OE-CQDs can stabilize and store light-generated electrons effectively, boosting charge separation and enhancing photocatalytic performance with longevity. The maximal photocatalytic H2O2 production was achieved viz the utilization of OE-CQDs with generation rate of 356.86 µmol g-1 h-1 by retaining 80% activity without any external sacrificial donors. The outstanding performance of synthesized OE-CQDs under light exposure at wavelength (λ) of 280 nm has been ensured by the quantum yield value of 9.4% upon H2O2 generation. The combinatorial benefits of OE-CQDs with their authentic crystalline structure and oxygen enrichment, is expected to be enhancing the ORR activity through accelerating charge transfer, and optimizing oxygen diffusion. Consequently, our eco-friendly method holds considerable promise for creating highly efficient, metal-free photocatalysts for artificial H2O2 production.

7.
Exp Mol Med ; 2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38760512

RESUMEN

Neuropathic pain is a debilitating condition caused by the hyperexcitability of spinal dorsal horn neurons and is often characterized by allodynia. Although neuron-independent mechanisms of hyperexcitability have been investigated, the contribution of astrocyte-neuron interactions remains unclear. Here, we show evidence of reactive astrocytes and their excessive GABA release in the spinal dorsal horn, which paradoxically leads to the tonic excitation of neighboring neurons in a neuropathic pain model. Using multiple electrophysiological methods, we demonstrated that neuronal hyperexcitability is attributed to both increased astrocytic GABA synthesis via monoamine oxidase B (MAOB) and the depolarized reversal potential of GABA-mediated currents (EGABA) via the downregulation of the neuronal K+/Cl- cotransporter KCC2. Furthermore, longitudinal 2-deoxy-2-[18F]-fluoro-D-glucose microPET imaging demonstrated increased regional glucose metabolism in the ipsilateral dorsal horn, reflecting neuronal hyperexcitability. Importantly, inhibiting MAOB restored the entire astrocytic GABA-mediated cascade and abrogated the increased glucose metabolism and mechanical allodynia. Overall, astrocytic GABA-mediated tonic excitation is critical for neuronal hyperexcitability, leading to mechanical allodynia and neuropathic pain.

8.
Free Radic Res ; 58(4): 276-292, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38613520

RESUMEN

It was demonstrated that ginsenosides exert anti-convulsive potentials and interleukin-6 (IL-6) is protective from excitotoxicity induced by kainate (KA), a model of temporal lobe epilepsy. Ginsenosides-mediated mitochondrial recovery is essential for attenuating KA-induced neurotoxicity, however, little is known about the effects of ginsenoside Re (GRe), one of the major ginsenosides. In this study, GRe significantly attenuated KA-induced seizures in mice. KA-induced redox changes were more evident in mitochondrial fraction than in cytosolic fraction in the hippocampus of mice. GRe significantly attenuated KA-induced mitochondrial oxidative stress (i.e. increases in reactive oxygen species, 4-hydroxynonenal, and protein carbonyl) and mitochondrial dysfunction (i.e. the increase in intra-mitochondrial Ca2+ and the decrease in mitochondrial membrane potential). GRe or mitochondrial protectant cyclosporin A restored phospho-signal transducers and activators of transcription 3 (STAT3) and IL-6 levels reduced by KA, and the effects of GRe were reversed by the JAK2 inhibitor AG490 and the mitochondrial toxin 3-nitropropionic acid (3-NP). Thus, we used IL-6 knockout (KO) mice to investigate whether the interaction between STAT3 and IL-6 is involved in the GRe effects. Importantly, KA-induced reduction of manganese superoxide dismutase (SOD-2) levels and neurodegeneration (i.e. astroglial inhibition, microglial activation, and neuronal loss) were more prominent in IL-6 KO than in wild-type (WT) mice. These KA-induced detrimental effects were attenuated by GRe in WT and, unexpectedly, IL-6 KO mice, which were counteracted by AG490 and 3-NP. Our results suggest that GRe attenuates KA-induced neurodegeneration via modulating mitochondrial oxidative burden, mitochondrial dysfunction, and STAT3 signaling in mice.


Asunto(s)
Ginsenósidos , Ácido Kaínico , Mitocondrias , Factor de Transcripción STAT3 , Transducción de Señal , Animales , Ácido Kaínico/toxicidad , Ratones , Mitocondrias/metabolismo , Mitocondrias/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo , Ginsenósidos/farmacología , Transducción de Señal/efectos de los fármacos , Masculino , Ratones Noqueados , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Estrés Oxidativo/efectos de los fármacos
9.
World J Urol ; 42(1): 228, 2024 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-38598022

RESUMEN

PURPOSE: Commercial double J stents (DJS) have a uniform shape regardless of the specific nature of various ureteral diseases. We tested renovated DJS and compared them with conventional DJS using ureter models. METHODS: One straight ureter model included stenosis at the distal ureter near the ureterovesical junction and the other did not. We used conventional DJS and renovated 5- and 6-Fr soft DJS for ureter stones and 6-, 7-, and 8.5-Fr hard DJS for tumors. The DJS comprised holes in the upper, middle, or lower one-third of the shaft (length, 24 cm; 2-cm-diameter coils at both ends). More holes were created along the shaft based on the ureteral disease location. Conventional DJS had holes spaced 1 cm apart along the shaft. Renovated DJS had holes spaced 1 cm apart along the shaft with 0.5-cm intervals on the upper, middle, or lower one-third of the shaft. Urine flow was evaluated. RESULTS: As the DJS diameter increased, the flow rate decreased. The flow rates of DJS with holes in the lower shaft were relatively lower than those of conventional DJS and DJS with holes in the upper and middle shafts. In the ureter model without stenosis, 6-, 7-, and 8.5-Fr renovated stents exhibited significantly higher flow rates than conventional stents. In the ureter model with stenosis, 5-, 6-, 7-, and 8.5-Fr renovated stents did not exhibit significantly higher flow rates than conventional stents. CONCLUSION: Renovated stents and conventional stents did not exhibit significant differences in urine flow with stenosis.


Asunto(s)
Uréter , Ureterolitiasis , Humanos , Uréter/cirugía , Constricción Patológica , Stents
10.
Eur J Surg Oncol ; 50(6): 108359, 2024 Apr 19.
Artículo en Inglés | MEDLINE | ID: mdl-38657377

RESUMEN

BACKGROUND: Peritoneal recurrence is a significant cause of treatment failure after radical gastrectomy for gastric cancer. The prediction of metachronous peritoneal recurrence would have a significantly impact risk stratification and tailored treatment planning. This study aimed to externally validate the previously established PERI-Gastric 1 and 2 models to assess their generalizability in an independent population. METHODS: Retrospective external validation was conducted on a cohort of 8564 patients who underwent elective gastrectomy for stage Ib-IIIc gastric cancer between 1998 and 2018 at the Yonsei Cancer Center. Discrimination was tested using the area under the receiver operating characteristic curves (AUROC). Accuracy was tested by plotting observations against the predicted risk of peritoneal recurrence and analyzing the resulting calibration plots. Clinical usefulness was tested with a decision curve analysis. RESULTS: In the validation cohort, PERI-Gastric 1 and PERI-Gastric 2 exhibited an AUROC of 0.766 (95 % C.I. 0.752-0.778) and 0.767 (95 % C.I. 0.755-0.780), a calibration-in-the-large of 0.935 and 0.700, a calibration belt with a 95 % C.I. over the bisector in the risk range of 24%-33 % and 35%-47 %. The decision curve analysis revealed a positive net benefit in the risk range of 10%-42 % and 15%-45 %, respectively. CONCLUSIONS: This study presents the external validation of the PERI-Gastric 1 and 2 scores in an Eastern population. The models demonstrated fair discrimination and satisfactory calibration for predicting the risk of peritoneal recurrence after radical gastrectomy, even in Eastern patients. PERI-Gastric 1 and 2 scores could also be applied to predict the risk of metachronous peritoneal recurrence in Eastern populations.

11.
J Med Food ; 2024 Apr 23.
Artículo en Inglés | MEDLINE | ID: mdl-38651680

RESUMEN

To probe the functions of Aster glehni (AG) extract containing various caffeoylquinic acids on dyslipidemia, obesity, and skeletal muscle-related diseases focused on the roles of skeletal muscle, we measured the levels of biomarkers involved in oxidative phosphorylation and type change of skeletal muscle in C2C12 cells and skeletal muscle tissues from apolipoprotein E knockout (ApoE KO) mice. After AG extract treatment in cell and animal experiments, western blotting, immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA) were used to estimate the levels of proteins that participated in skeletal muscle type change and oxidative phosphorylation. AG extract elevated protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), phosphorylated 5'-AMP-activated protein kinase (p-AMPK), peroxisome proliferator-activated receptor beta/delta (PPARß/δ), myoblast determination protein 1 (MyoD), and myoglobin in skeletal muscle tissues. Furthermore, it elevated the ATP concentration. However, protein expression of myostatin was decreased by AG treatment. In C2C12 cells, increments of MyoD, myoglobin, myosin, ATP-producing pathway, and differentiation degree by AG were dependent on PPARß/δ and caffeoylquinic acids. AG extract can contribute to the amelioration of skeletal muscle inactivity and sarcopenia through myogenesis in skeletal muscle tissues from ApoE KO mice, and function of AG extract may be dependent on PPARß/δ, and the main functional constituents of AG are trans-5-O-caffeoylquinic acid and 3,5-O-dicaffeoylquinic acid. In addition, in skeletal muscle, AG has potent efficacies against dyslipidemia and obesity through the increase of the type 1 muscle fiber content to produce more ATP by oxidative phosphorylation in skeletal muscle tissues from ApoE KO mice.

12.
Skin Res Technol ; 30(4): e413691, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38576226

RESUMEN

BACKGROUND: Botulinum toxin is a crucial therapeutic tool with broad indications in both cosmetic and medical fields. However, the expanding cosmetic use and increased dosages of botulinum toxin have raised concerns about resistance, making it essential to study the awareness and management practices among healthcare professionals. METHODS: A survey was conducted among clinical physicians using botulinum toxin. The study investigated their experiences, awareness, and management practices related to toxin resistance. Real-time mobile app-based surveys were administered to clinicians attending the 45th International Academic Conference of the Korean Academy of Laser and Dermatology (KALDAT) on December 3, 2023. RESULTS: Among 3140 participants, 673 clinical physicians completed the survey. Of these, 363 clinicians (53.9%) reported experiencing botulinum toxin resistance. Regarding the resistance rate, 59.4% indicated less than 1%, 36% reported approximately 1%-25%, and 95.4% reported less than 25%. Efforts to prevent resistance included maintaining intervals of over 3 months (54.8%), using products with lower resistance potential (47.0%), employing minimal effective doses (28.2%), and minimizing re-administration (14.9%). CONCLUSION: In the South Korean aesthetic medicine community, a majority of clinical physician's report encountering botulinum toxin resistance. Given the potential loss of various benefits associated with resistance, there is a need to establish appropriate guidelines based on mechanistic studies and current status assessments. Educating clinicians on applicable guidelines is crucial.


Asunto(s)
Toxinas Botulínicas Tipo A , Técnicas Cosméticas , Fármacos Neuromusculares , Médicos , Humanos , Toxinas Botulínicas Tipo A/uso terapéutico , Estética , Percepción , Fármacos Neuromusculares/uso terapéutico
13.
Ann Clin Microbiol Antimicrob ; 23(1): 35, 2024 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-38664689

RESUMEN

PURPOSE: The clinical significance of negative toxin enzyme immunoassays (EIA) for Clostridioides difficile infections (CDIs) is unclear. Our study aimed to investigate the significance of toxin EIA-negative in the diagnosis and prognosis of CDI. METHODS: All stool specimens submitted for C. difficile toxin EIA testing were cultured to isolate C. difficile. In-house PCR for tcdA, tcdB, cdtA, and cdtB genes were performed using C. difficile isolates. Stool specimens were tested with C. difficile toxins A and B using EIA kit (RIDASCREEN Clostridium difficile toxin A/B, R-Biopharm AG, Darmstadt, Germany). Characteristics and subsequent CDI episodes of toxin EIA-negative and -positive patients were compared. RESULTS: Among 190 C. difficile PCR-positive patients, 83 (43.7%) were toxin EIA-negative. Multivariate analysis revealed independent associations toxin EIA-negative results and shorter hospital stays (OR = 0.98, 95% CI 0.96-0.99, p = 0.013) and less high-risk antibiotic exposure in the preceding month (OR = 0.38, 95% CI 0.16-0.94, p = 0.035). Toxin EIA-negative patients displayed a significantly lower white blood cell count rate (11.0 vs. 35.4%, p < 0.001). Among the 54 patients who were toxin EIA-negative and did not receive CDI treatment, three (5.6%) were diagnosed with CDI after 7-21 days without complication. CONCLUSION: Our study demonstrates that toxin EIA-negative patients had milder laboratory findings and no complications, despite not receiving treatment. Prolonged hospitalisation and exposure to high-risk antibiotics could potentially serve as markers for the development of toxin EIA-positive CDI.


Asunto(s)
Proteínas Bacterianas , Toxinas Bacterianas , Clostridioides difficile , Infecciones por Clostridium , Heces , Humanos , Clostridioides difficile/genética , Heces/microbiología , Masculino , Femenino , Toxinas Bacterianas/análisis , Infecciones por Clostridium/diagnóstico , Infecciones por Clostridium/tratamiento farmacológico , Infecciones por Clostridium/microbiología , Anciano , Persona de Mediana Edad , Proteínas Bacterianas/genética , Proteínas Bacterianas/análisis , Enterotoxinas/análisis , Anciano de 80 o más Años , Antibacterianos/uso terapéutico , Técnicas para Inmunoenzimas , Adulto , Resultado del Tratamiento , Reacción en Cadena de la Polimerasa , Pronóstico
14.
Sci Rep ; 14(1): 9433, 2024 04 24.
Artículo en Inglés | MEDLINE | ID: mdl-38658592

RESUMEN

Selective retrieval of context-relevant memories is critical for animal survival. A behavioral index that captures its dynamic nature in real time is necessary to investigate this retrieval process. Here, we found a bias in eye gaze towards the locations previously associated with individual objects during retrieval. Participants learned two locations associated with each visual object and recalled one of them indicated by a contextual cue in the following days. Before the contextual cue presentation, participants often gazed at both locations associated with the given object on the background screen (look-at-both), and the frequency of look-at-both gaze pattern increased as learning progressed. Following the cue presentation, their gaze shifted toward the context-appropriate location. Interestingly, participants showed a higher accuracy of memory retrieval in trials where they gazed at both object-associated locations, implying functional advantage of the look-at-both gaze patterns. Our findings indicate that naturalistic eye movements reflect the dynamic process of memory retrieval and selection, highlighting the potential of eye gaze as an indicator for studying these cognitive processes.


Asunto(s)
Movimientos Oculares , Fijación Ocular , Recuerdo Mental , Humanos , Masculino , Femenino , Recuerdo Mental/fisiología , Adulto Joven , Fijación Ocular/fisiología , Adulto , Movimientos Oculares/fisiología , Señales (Psicología) , Memoria/fisiología , Aprendizaje/fisiología
16.
Korean J Physiol Pharmacol ; 28(3): 209-217, 2024 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-38682169

RESUMEN

In addition to cellular damage, ischemia-reperfusion (IR) injury induces substantial damage to the mitochondria and endoplasmic reticulum. In this study, we sought to determine whether impaired mitochondrial function owing to IR could be restored by transplanting mitochondria into the heart under ex vivo IR states. Additionally, we aimed to provide preliminary results to inform therapeutic options for ischemic heart disease (IHD). Healthy mitochondria isolated from autologous gluteus maximus muscle were transplanted into the hearts of Sprague-Dawley rats damaged by IR using the Langendorff system, and the heart rate and oxygen consumption capacity of the mitochondria were measured to confirm whether heart function was restored. In addition, relative expression levels were measured to identify the genes related to IR injury. Mitochondrial oxygen consumption capacity was found to be lower in the IR group than in the group that underwent mitochondrial transplantation after IR injury (p < 0.05), and the control group showed a tendency toward increased oxygen consumption capacity compared with the IR group. Among the genes related to fatty acid metabolism, Cpt1b (p < 0.05) and Fads1 (p < 0.01) showed significant expression in the following order: IR group, IR + transplantation group, and control group. These results suggest that mitochondrial transplantation protects the heart from IR damage and may be feasible as a therapeutic option for IHD.

17.
Apoptosis ; 2024 Apr 29.
Artículo en Inglés | MEDLINE | ID: mdl-38684550

RESUMEN

Mutations resulting in decreased activity of p53 tumor suppressor protein promote tumorigenesis. P53 protein levels are tightly regulated through the Ubiquitin Proteasome System (UPS). Several E3 ligases were shown to regulate p53 stability, including MDM2. Here we report that the ubiquitin E3 ligase XIAP (X-linked Inhibitors of Apoptosis) is a direct ligase for p53 and describe a novel approach for modulating the levels of p53 by targeting the XIAP pathway. Using in vivo (live-cell) and in vitro (cell-free reconstituted system) ubiquitylation assays, we show that the XIAP-antagonist ARTS regulates the levels of p53 by promoting the degradation of XIAP. XIAP directly binds and ubiquitylates p53. In apoptotic cells, ARTS inhibits the ubiquitylation of p53 by antagonizing XIAP. XIAP knockout MEFs express higher p53 protein levels compared to wild-type MEFs. Computational screen for small molecules with high affinity to the ARTS-binding site within XIAP identified a small-molecule ARTS-mimetic, B3. This compound stimulates apoptosis in a wide range of cancer cells but not normal PBMC (Peripheral Blood Mononuclear Cells). Like ARTS, the B3 compound binds to XIAP and promotes its degradation via the UPS. B3 binding to XIAP stabilizes p53 by disrupting its interaction with XIAP. These results reveal a novel mechanism by which ARTS and p53 regulate each other through an amplification loop to promote apoptosis. Finally, these data suggest that targeting the ARTS binding pocket in XIAP can be used to increase p53 levels as a new strategy for developing anti-cancer therapeutics.

18.
Gastric Cancer ; 27(3): 622-634, 2024 05.
Artículo en Inglés | MEDLINE | ID: mdl-38502275

RESUMEN

BACKGROUND: Fluorescent lymphography (FL) using indocyanine green (ICG) allows for the visualization of all draining lymph nodes (LNs), thereby increasing LN retrieval. However, no studies have assessed the efficacy of FL in high body mass index (BMI) gastric cancer patients, even as LN yield decreases with increasing BMI in gastrectomy. This study aimed to investigate the influence of FL on LN retrieval in high BMI gastric cancer patients. METHODS: Gastric cancer patients who underwent laparoscopic or robotic gastrectomies from 2013 to 2021 were included. Patients were classified into two groups, with FL (FL group) or without FL (non-FL group). The effect of FL on LN retrieval was assessed by BMI. Inverse probability of treatment weighting (IPTW) was used to ensure comparability between groups. RESULTS: Retrieved LN number decreased as BMI increased regardless of FL application (P < 0.001). According to the IPTW analysis, the mean retrieved LN number was significantly higher in the FL group (48.4 ± 18.5) than in the non-FL group (39.8 ± 16.3, P < 0.001), irrespective of BMI. The FL group exhibited a significantly higher proportion of patients with 16 or more LNs (99.5%) than the non-FL group (98.1%, P < 0.001). The FL group also had a significantly higher proportion of patients with 30 or more LNs (86.6%) than the non-FL group (72.2%, P < 0.001). In both the normal and high-BMI patients, the FL group had a significantly larger percentage of patients with a higher nodal classification than the non-FL group. CONCLUSION: FL resulted in more LN retrieval, even in high BMI patients. FL ensures accurate staging by maintaining the appropriate retrieved LN number in high BMI gastric cancer patients.


Asunto(s)
Linfografía , Neoplasias Gástricas , Humanos , Linfografía/métodos , Escisión del Ganglio Linfático/métodos , Índice de Masa Corporal , Neoplasias Gástricas/diagnóstico por imagen , Neoplasias Gástricas/cirugía , Neoplasias Gástricas/patología , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/cirugía , Ganglios Linfáticos/patología , Colorantes , Gastrectomía/métodos , Estudios Retrospectivos
19.
Front Public Health ; 12: 1328089, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38444441

RESUMEN

Background: Ultraviolet B (UVB) from sunlight represents a major environmental factor that causes toxic effects resulting in structural and functional cutaneous abnormalities in most living organisms. Although numerous studies have indicated the biological mechanisms linking UVB exposure and cutaneous manifestations, they have typically originated from a single study performed under limited conditions. Methods: We accessed all publicly accessible expression data of various skin cell types exposed to UVB, including skin biopsies, keratinocytes, and fibroblasts. We performed biological network analysis to identify the molecular mechanisms and identify genetic biomarkers. Results: We interpreted the inflammatory response and carcinogenesis as major UVB-induced signaling alternations and identified three candidate biomarkers (IL1B, CCL2, and LIF). Moreover, we confirmed that these three biomarkers contribute to the survival probability of patients with cutaneous melanoma, the most aggressive and lethal form of skin cancer. Conclusion: Our findings will aid the understanding of UVB-induced cutaneous toxicity and the accompanying molecular mechanisms. In addition, the three candidate biomarkers that change molecular signals due to UVB exposure of skin might be related to the survival rate of patients with cutaneous melanoma.


Asunto(s)
Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/genética , Neoplasias Cutáneas/genética , Secuencia de Bases , Biomarcadores , ARN
20.
J Infect Public Health ; 17(5): 774-779, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38518683

RESUMEN

BACKGROUND: Acinetobacter baumannii, a common carbapenem-resistant gram-negative bacillus, usually causes nosocomial infections. Colistin has been used for carbapenem-resistant A. baumannii (CRAB) infections; however, only a few studies have evaluated colistin as a treatment option compared to appropriate controls. We investigated the effectiveness of colistin monotherapy in treating CRAB pneumonia compared to those treated without an active drug. METHODS: Adult patients (≥ 18 years) with CRAB isolated from respiratory specimens were screened from September 2017 to August 2022. Only patients with pneumonia treated with colistin monotherapy (colistin group) were included and compared to those without any active antibiotics (no active antibiotics [NAA] group). The primary and secondary outcomes were 30-day all-cause mortality and acute kidney injury within 30 days. The inverse probability of the treatment-weighted Cox proportional hazard model was used to compare mortality between groups. RESULTS: Among the 826 adult patients with CRAB in their respiratory specimens, 45 and 123 patients were included in the colistin and NAA groups, respectively. Most of the CRAB pneumonia (91.1%) cases were hospital-acquired pneumonia. The 30-day all-cause mortality rates in the colistin and NAA groups were 58.3% and 56.1%, respectively, and no difference was observed after adjustments (adjusted hazard ratio, 0.74; 95% CI, 0.47-1.17). The incidence of acute kidney injury was higher in the colistin group (65.3%) compared to the NAA group (39.0%) (P = 0.143). CONCLUSIONS: Colistin monotherapy did not significantly improve treatment outcomes for CRAB pneumonia. The development and evaluation of new antimicrobials for CRAB pneumonia should be advocated in clinical practice.


Asunto(s)
Infecciones por Acinetobacter , Acinetobacter baumannii , Lesión Renal Aguda , Neumonía , Adulto , Humanos , Colistina/uso terapéutico , Estudios de Cohortes , Estudios Retrospectivos , Infecciones por Acinetobacter/tratamiento farmacológico , Infecciones por Acinetobacter/epidemiología , Antibacterianos , Carbapenémicos/uso terapéutico , Neumonía/tratamiento farmacológico , Lesión Renal Aguda/inducido químicamente
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