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1.
Chem Commun (Camb) ; 2024 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-38847207

RESUMO

A new method to synthesise functionalised cycloheptatrienes was established using the anionic 8π-electrocyclic reaction of ß-ketoester-derived dienyne substrates. The cyclised products were converted to a variety of cycloheptatriene derivatives including tropones. Using this method, a concise, first total synthesis of (-)-orobanone, a natural sesquiterpenoid, was achieved.

2.
Cureus ; 16(5): e59868, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38854215

RESUMO

We present a case of rocuronium-induced hypertensive crises that occurred twice in a patient with paraganglioma. An 86-year-old woman was first scheduled for laminectomy for lumbar spinal stenosis. Five minutes after intravenous induction of anesthesia using fentanyl, propofol, rocuronium, and remifentanil, the patient's blood pressure (BP) and heart rate (HR) suddenly increased with no stimuli. Surgery was postponed because the patient was suspected of having pheochromocytoma. After that, paraganglioma was diagnosed, and surgery for removal of the paraganglioma was scheduled after the commencement of alpha-blocker therapy. The patient's hemodynamic parameters remained stable when anesthesia was induced with an infusion of remimazolam. Subsequently, immediately after rocuronium was administered as an intravenous bolus, the patient's arterial BP and HR increased, and plasma concentrations of noradrenaline and rocuronium had markedly increased. Ten minutes after the administration of rocuronium, the patient's BP and HR gradually and fully recovered without any intervention. The plasma concentrations of both noradrenaline and rocuronium also concurrently decreased. We conclude that simultaneous increases in BP, HR, and plasma concentration of noradrenaline revealed a direct correlation with rocuronium.

3.
Nutrients ; 16(10)2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38794690

RESUMO

BACKGROUND: The utility of using indirect calorimetry (IC) to estimate energy needs and methods for its application to this purpose remain unclear. This systematic review investigated whether using IC to estimate energy expenditure in critically ill patients is more meaningful for improving survival than other estimation methods. METHODS: Comprehensive searches were conducted in MEDLINE using PubMed, Cochrane Central Register of Controlled Trials, and Igaku-Chuo-Zasshi up to March 2023. RESULTS: Nine RCTs involving 1178 patients were included in the meta-analysis. The evidence obtained suggested that energy delivery by IC improved short-term mortality (risk ratio, 0.86; 95% confidence interval [CI], 0.70 to 1.06). However, the use of IC did not appear to affect the length of ICU stay (mean difference [MD], 0.86; 95% CI, -0.98 to 2.70) or the duration of mechanical ventilation (MD, 0.66; 95% CI, -0.39 to 1.72). Post hoc analyses using short-term mortality as the outcome found no significant difference by target calories in resting energy expenditure, whereas more frequent IC estimates were associated with lower short-term mortality and were more effective in mechanically ventilated patients. CONCLUSIONS: This updated meta-analysis revealed that the use of IC may improve short-term mortality in patients with critical illness and did not increase adverse events.


Assuntos
Calorimetria Indireta , Estado Terminal , Metabolismo Energético , Estado Terminal/terapia , Humanos , Respiração Artificial , Ingestão de Energia , Tempo de Internação , Unidades de Terapia Intensiva , Ensaios Clínicos Controlados Aleatórios como Assunto , Apoio Nutricional/métodos
4.
Cureus ; 16(4): e58721, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38779233

RESUMO

Introduction Food questionnaire surveys are often used to evaluate masticatory function. In daily clinical practice in Japan, a survey is performed using a list of food groups suitable for the Japanese diet. The foods on the list were categorized into five food groups based on their mastication index. The patient's masticatory function is determined by the food groups that can be eaten. The masticatory index, which indicates chewability, was defined based on the percentage of 110 denture wearers who responded that they could eat food normally. A survey with this list is useful because of its simplicity; however, there is a lack of objective data on the physical properties of food samples. Consequently, to make the results of the food questionnaire survey more objective indicators, we performed a texture analysis of the food samples on the list. Methods We performed a texture analysis of 93 samples from 77 food items on the list. Compression tests were performed using a texture analyzer, and hardness, cohesiveness, adhesiveness, viscosity, and gumminess were calculated by a texture profile analysis. Results Even with the same ingredients, the results differed depending on the presence or absence of food skin, the direction of pressing (vertical or horizontal), cooking methods, and temperature differences. However, the masticatory index was negatively correlated with hardness (-0.4157, p<0.001) and gumminess which is determined as the product of hardness×cohesiveness (-0.4980, p<0.001). Conclusion This study suggests that the masticatory index indicating chewability may be related to the hardness and cohesiveness of food samples. Even for foods with the same hardness, the degree of difficulty in forming a food mass is expected to vary depending on differences in cohesiveness. Moreover, the presence or absence of food skin, the direction of food fibers, cooking methods, and temperature differences change the physical properties of the food. Therefore, the composition and structure of the foods or eating habits of patients should be taken into consideration when conducting a food questionnaire survey.

5.
iScience ; 27(6): 109816, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38779480

RESUMO

Muscle fiber type composition (% slow-twitch and % fast-twitch fibers) is associated with metabolism, with increased slow-twitch fibers alleviating metabolic disorders. Previously, we reported that dietary fish oil intake induced a muscle fiber-type transition in a slower direction in rats. The aim of this study was to determine the functionality of eicosapentaenoic acid (EPA), a unique fatty acid in fish oil, to skeletal muscle fiber type and metabolism in rats. Here, we showed that dietary EPA promotes whole-body oxidative metabolism and improves muscle function by increasing proportion of slow-twitch type 1 fibers in rats. Transcriptomic and metabolomic analyses revealed that EPA supplementation activated the peroxisome proliferator-activated receptor δ (PPARδ) and AMP-activated protein kinase (AMPK) pathways in L6 myotube cultures, which potentially increasing slow-twitch fiber share. This highlights the role of EPA as an exercise-mimetic dietary component that improves metabolism and muscle function, with potential benefits for health and athletic performance.

6.
Int J Hematol ; 2024 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-38795248

RESUMO

Measurable residual disease (MRD)-guided pre-emptive therapies are now widely used to prevent post-transplant hematological relapse in patients with acute myeloid leukemia (AML). This single-center retrospective study aimed to clarify the significance of pre-emptive treatment based on Wilms' tumor gene-1 mRNA (WT1) monitoring for MRD in patients with AML who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients with AML who received chemotherapy for hematological relapse or WT1 increase after allo-HSCT were eligible for inclusion. From January 2017 to June 2022, 30 patients with a median age of 57 (16-70) years were included and stratified into two groups: 10 with WT1 increase and 20 with hematological relapse. The median times from HCT to WT1 increase or hematological relapse were 309 days (range: 48-985) or 242 days (range: 67-1116), respectively. Less intensive chemotherapy using azacitidine or cytarabine was selected for all patients with WT1 increase and 12 (60%) with hematological relapse. The 1-year overall survival and event-free survival rates for WT1 increase and hematological relapse were 70% vs. 44% (P = 0.024) and 70% vs. 29% (P = 0.029), respectively. These real-world data suggest that WT1-guided pre-emptive therapy may be superior to therapy after hematological relapse in patients with AML who have undergone allo-HSCT.

7.
Chemistry ; : e202401908, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38770667

RESUMO

We describe a method for the synthesis of various 2-silyloxy-2-norbornen-7-ones by exploiting the specific reactivity of the 1,4-bis(silyloxy)-1,3-cyclopentadiene framework, which is generated by the silylation of a 2,2-disubstituted-1,3-cyclopentanedione bearing a picolinoyloxy group at the 2' position of its C-2 side chain. The release of the acyloxy group during the reaction generates carbocations that are then attacked by silyloxy-substituted carbons in the 1,4-bis(silyloxy)-1,3-cyclopentadiene moiety skeleton, forming a 4,5-cis-fused ring skeleton. Skeletal rearrangement of the bicyclic core results in the formation of the corresponding 2-silyloxy-2-norbornen-7-one. This novel transformation of 1,3-cyclopentanedione moieties can be used to synthesise other cyclopentenone-fused bicyclic frameworks.

8.
EuroIntervention ; 20(9): 561-570, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38726719

RESUMO

BACKGROUND: Vessel-level physiological data derived from pressure wire measurements are one of the important determinant factors in the optimal revascularisation strategy for patients with multivessel disease (MVD). However, these may result in complications and a prolonged procedure time. AIMS: The feasibility of using the quantitative flow ratio (QFR), an angiography-derived fractional flow reserve (FFR), in Heart Team discussions to determine the optimal revascularisation strategy for patients with MVD was investigated. METHODS: Two Heart Teams were randomly assigned either QFR- or FFR-based data of the included patients. They then discussed the optimal revascularisation mode (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) for each patient and made treatment recommendations. The primary endpoint of the trial was the level of agreement between the treatment recommendations of both teams as assessed using Cohen's kappa. RESULTS: The trial included 248 patients with MVD from 10 study sites. Cohen's kappa in the recommended revascularisation modes between the QFR and FFR approaches was 0.73 [95% confidence interval {CI} : 0.62-0.83]. As for the revascularisation planning, agreements in the target vessels for PCI and CABG were substantial for both revascularisation modes (Cohen's kappa=0.72 [95% CI: 0.66-0.78] and 0.72 [95% CI: 0.66-0.78], respectively). The team assigned to the QFR approach provided consistent recommended revascularisation modes even after being made aware of the FFR data (Cohen's kappa=0.95 [95% CI:0.90-1.00]). CONCLUSIONS: QFR provided feasible physiological data in Heart Team discussions to determine the optimal revascularisation strategy for MVD. The QFR and FFR approaches agreed substantially in terms of treatment recommendations.


Assuntos
Angiografia Coronária , Doença da Artéria Coronariana , Reserva Fracionada de Fluxo Miocárdico , Intervenção Coronária Percutânea , Humanos , Reserva Fracionada de Fluxo Miocárdico/fisiologia , Feminino , Masculino , Doença da Artéria Coronariana/fisiopatologia , Doença da Artéria Coronariana/terapia , Doença da Artéria Coronariana/cirurgia , Doença da Artéria Coronariana/diagnóstico por imagem , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/métodos , Idoso , Ponte de Artéria Coronária/métodos , Tomada de Decisão Clínica , Cateterismo Cardíaco/métodos , Equipe de Assistência ao Paciente
9.
Org Biomol Chem ; 22(23): 4637-4640, 2024 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-38716558

RESUMO

Jamaicamide B was isolated from the cyanobacterium Moorea producens in Jamaica and shows neurotoxicity. This unique mixed peptide-polyketide structure contains a pyrrolinone ring, a ß-methoxy enone, an (E)-olefin, an undetermined stereocenter at C9, an (E)-chloroolefin, and a terminal alkyne. We report herein the first total synthesis and structural confirmation of the marine natural product (9R)-jamaicamide B.


Assuntos
Cianobactérias , Cianobactérias/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Estereoisomerismo , Estrutura Molecular
10.
Circ Rep ; 6(5): 178-182, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38736847

RESUMO

Background: Genetic testing for cardiovascular diseases (CVD) is vital, but is underutilized in Japan due to limited insurance coverage, accessibility, and public disinterest. This study explores demographic factors influencing the decision to undergo CVD genetic testing. Methods and Results: We compared the CVD history and baseline demographics of Japanese adults who underwent genetic testing with those who did not, using an Internet survey. The regression model indicated that men, the young, married individuals, parents, and those with CVD, higher score for rationality, and lower quality of life were more inclined to undergo testing. Conclusions: Targeting strategies for CVD genetic testing could focus on these demographics.

11.
Artigo em Inglês | MEDLINE | ID: mdl-38758432

RESUMO

Skeletal muscle tissue increases or decreases its volume by synthesizing or degrading myofibrillar proteins. The ubiquitin-proteasome system plays a pivotal role during muscle atrophy, where muscle ring finger proteins (Murf) function as E3 ubiquitin ligases responsible for identifying and targeting substrates for degradation. Our previous study demonstrated that overexpression of Ozz, an E3 specific to embryonic myosin heavy chain (Myh3), precisely reduced the Myh3 replacement rate in the thick filaments of myotubes (E. Ichimura et al., Physiol Rep. 9:e15003, 2021). These findings strongly suggest that E3 plays a critical role in regulating myosin replacement. Here, we hypothesized that the Murf isoforms, which recognize Myhs as substrates, reduced the myosin replacement rates through the enhanced Myh degradation by Murfs. First, fluorescence recovery after a photobleaching experiment was conducted to assess whether Murf isoforms affected the GFP-Myh3 replacement. In contrast to Murf2 or Murf3 overexpression, Murf1 overexpression selectively facilitated the GFP-Myh3 myosin replacement. Next, to examine the effects of Murf1 overexpression on the replacement of myosin isoforms, Cherry-Murf1 was coexpressed with GFP-Myh1, GFP-Myh4, or GFP-Myh7 in myotubes. Intriguingly, Murf1 overexpression enhanced the myosin replacement of GFP-Myh4 but did not affect those of GFP-Myh1 or GFP-Myh7. Surprisingly, overexpression of Murf1 did not enhance the ubiquitination of proteins. These results indicate that Murf1 selectively regulated myosin replacement in a Myh isoform-dependent fashion, independent of enhanced ubiquitination. This suggests that Murf1 may have a role beyond functioning as a ubiquitin ligase E3 in thick filament myosin replacement.

12.
J Autoimmun ; 145: 103217, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38581915

RESUMO

The autoimmunity-promoting cytokine, Interleukin-15 (IL-15), is often claimed to be a key pathogenic cytokine in alopecia areata (AA). Yet, rhIL-15 promotes human hair follicle (HF) growth ex vivo. We have asked whether the expression of IL-15 and its receptor (IL-15R) isoforms is altered in human AA and how IL-15 impacts on human HF immune privilege (HF-IP) in the presence/absence of interferon-γ (IFNγ), the well-documented key AA-pathogenic cytokine, as well as on hair regrowth after experimental AA induction in vivo. Quantitative immunohistomorphometry showed the number of perifollicular IL-15+ T cells in AA skin biopsies to be significantly increased compared to healthy control skin, while IL-15, IL-15Rα, and IL-15Rγ protein expression within the hair bulb were significantly down-regulated in AA HFs. In organ-cultured human scalp HFs, rhIL-15 significantly reduced hair bulb expression of MICA, the key "danger" signal in AA pathogenesis, and increased production of the HF-IP guardian, α-MSH. Crucially, ex vivo, rhIL-15 prevented IFNγ-induced HF-IP collapse, restored a collapsed HF-IP by IL-15Rα-dependent signaling (as documented by IL-15Rα-silencing), and protected AA-preventive immunoinhibitory iNKT10 cells from IFNγ-induced apoptosis. rhIL-15 even promoted hair regrowth after experimental AA induction in human scalp skin xenotransplants on SCID/beige mice in vivo. Our data introduce IL-15 as a novel, functionally important HF-IP guardian whose signaling is constitutively defective in scalp HFs of AA patients. Our data suggest that selective stimulation of intrafollicular IL-15Rα signaling could become a novel therapeutic approach in AA management, while blocking it pharmacologically may hinder both HF-IP restoration and hair re-growth and may thus make HFs more vulnerable to AA relapse.


Assuntos
Alopecia em Áreas , Folículo Piloso , Privilégio Imunológico , Interferon gama , Interleucina-15 , Interleucina-15/metabolismo , Interleucina-15/imunologia , Folículo Piloso/imunologia , Folículo Piloso/metabolismo , Humanos , Animais , Alopecia em Áreas/imunologia , Alopecia em Áreas/metabolismo , Camundongos , Interferon gama/metabolismo , Feminino , Receptores de Interleucina-15/metabolismo , Receptores de Interleucina-15/imunologia , Masculino , Adulto , Pessoa de Meia-Idade , Subunidade alfa de Receptor de Interleucina-15/metabolismo , Subunidade alfa de Receptor de Interleucina-15/imunologia , Pele/imunologia , Pele/metabolismo , Pele/patologia , Modelos Animais de Doenças
13.
World Neurosurg ; 186: e353-e359, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38570091

RESUMO

BACKGROUND: In the treatment of nonsmall cell lung cancer (NSCLC), a disease-free survival of 5 years is a criterion for cure. This study aimed to evaluate the characteristics and outcomes of patients with brain metastases of NSCLC after a disease-free survival of 5 years (late recurrent brain metastasis [LRBM]). METHODS: We reviewed 1281 consecutive patients with brain metastasis of lung cancer at a single institute between November 2014 and December 2022. Relevant articles were retrieved from PubMed. Only peer-reviewed journals published in English were included. RESULTS: Six patients (0.47%) showed LRBM. Three were male. The median age at lung cancer diagnosis was 45 years. The histological diagnosis of all patients was adenocarcinoma. Driver gene mutations were observed in five patients. The median latency period from lung cancer treatment to the development of brain metastasis was 13 years. All patients had no metastasis to any other organs and underwent craniotomies. The median follow-up duration after craniotomy was 3.5 years. No local intracranial recurrences were observed. Three patients had distant intracranial recurrences at 7, 2, and 0.6 years after craniotomy. Five patients survived for 8, 4, 3, 2, and 0.3 years after craniotomy. One patient experienced re-recurrence in the lung 4 years after craniotomy and died 3.7 years later. In our systematic review, only six studies described LRBM of NSCLC. CONCLUSIONS: LRBM is rare in patients with NSCLC. In our institution, many of these patients harbored driver gene mutations, and achieved long-term survival with aggressive local therapy. Multicenter analysis is mandatory.


Assuntos
Neoplasias Encefálicas , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/mortalidade , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Feminino , Intervalo Livre de Doença , Adulto , Idoso , Craniotomia , Mutação , Recidiva Local de Neoplasia/patologia
14.
Front Cell Infect Microbiol ; 14: 1360438, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38562961

RESUMO

Background: The Philippines bears health and economic burden caused by high dengue cases annually. Presently, the Philippines still lack an effective and sustainable vector management. The use of Wolbachia, a maternally transmitted bacterium, that mitigate arbovirus transmission has been recommended. Cytoplasmic incompatibility and viral blocking, two characteristics that make Wolbachia suitable for vector control, depend on infection prevalence and density. There are no current Wolbachia release programs in the Philippines, and studies regarding the safety of this intervention. Here, we screened for Wolbachia in Aedes aegypti collected from Metropolitan Manila, Philippines. We designed location-specific primers for qPCR to test whether this improved Wolbachia detection in Ae. aegypti. We explored if host sex and Wolbachia strain could be potential factors affecting Wolbachia density. Methods: Ae. aegypti mosquitoes (n=429) were screened for natural Wolbachia by taqman qPCR using location-specific Wolbachia surface protein primers (wspAAML) and known 16S rRNA primers. Samples positive for wspAAML (n=267) were processed for Sanger sequencing. We constructed a phylogenetic tree using IQ-TREE 2 to further characterize Wolbachia present in the Philippine Ae. aegypti. We then compared Wolbachia densities between Wolbachia groups and host sex. Statistical analyses were done using GraphPad Prism 9.0. Results: Wolbachia prevalence for 16S rRNA (40%) and wspAAML (62%) markers were high. Wolbachia relative densities for 16S rRNA ranged from -3.84 to 2.71 and wspAAML from -4.02 to 1.81. Densities were higher in male than female mosquitoes. Wolbachia strains detected in Ae. aegypti clustered into supergroup B. Some 54% (123/226) of these sequences clustered under a group referred to here as "wAegML," that belongs to the supergroup B, which had a significantly lower density than wAegB/wAlbB, and wAlbA strains. Conclusion: Location-specific primers improved detection of natural Wolbachia in Ae. aegypti and allowed for relative quantification. Wolbachia density is relatively low, and differed between host sexes and Wolbachia strains. An economical way of confirming sporadic or transient Wolbachia in Ae. aegypti is necessary while considering host sex and bacterial strain.


Assuntos
Aedes , Wolbachia , Animais , Humanos , Aedes/microbiologia , Wolbachia/genética , Filipinas , RNA Ribossômico 16S/genética , Mosquitos Vetores , Filogenia
15.
Discov Oncol ; 15(1): 95, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38564036

RESUMO

Metaplastic breast carcinoma (MBC), a category of breast cancer, includes different histological types, which are occasionally mixed and heterogeneous. Considering the heterogeneity of cancer cells in a tumour mass has become highly significant, not only from a biological aspect but also for clinical management of recurrence. This study aimed to analyse the immunohistochemical and molecular profiles of each MBC component of a tumour mass. Twenty-five MBC tumours were histologically evaluated, and the most frequent MBC component (c) was squamous cell carcinoma (SCC), followed by spindle cell carcinoma (SpCC). A total of 69 components of MBC and non-MBC in formalin-fixed paraffin-embedded sections were examined for 7 markers by immunohistochemistry. SCC(c) were significantly PTEN negative and CK14 positive, and SpCC(c) were significantly E-cadherin negative and vimentin positive. Multivariate analyses revealed that immunohistochemical profiles of normal/intraductal (IC)(c), no special type (NST)(c), and MBC(c) differed; moreover, SCC(c) and SpCC(c) were distinctly grouped. PTEN gene mutation was detected only in SCC(c) (2/7), but not in SpCC(c). Next-generation sequence analyses for 2 cases with tumours containing SCC(c) demonstrated that PTEN gene mutation increased progressively from IC(c) to NST(c) to SCC(c). In conclusion, the immunohistochemical and molecular profiles of the SCC(c) of MBC are distinct from those of the SpCC(c).

16.
Radiol Case Rep ; 19(6): 2100-2105, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38645548

RESUMO

A 74-year-old woman, who had been receiving olaparib for the treatment of ovarian cancer for more than a year, visited the emergency department complaining of a fever that had lasted for 1 month. She had been taking antipyretics and antibiotics for her fever, but without any effect. Although she had no symptoms other than fever, she had stopped taking olaparib for 1 week before her visit because she had developed anemia caused by myelosuppression from olaparib. After discontinuing olaparib, her maximum body temperature decreased. On admission, chest X-ray revealed no abnormalities, but chest CT showed diffuse ground-glass opacities. Chest CT taken 5 days later showed partial improvement; therefore, we diagnosed her with interstitial lung disease (ILD) associated with olaparib. After short-term steroid treatment, the ground-glass opacities disappeared, and the patient became afebrile. The CT scan taken for tumor evaluation 2 days before the onset of fever showed a few centrilobular nodular opacities and small patchy ground-glass opacities. These findings could indicate early lesions of ILD, but they seemed inconspicuous and nonspecific, and it might have been difficult to diagnose ILD then. To date, few cases of ILD associated with olaparib have been reported. However, based on previous reports, fever is often seen, and CT findings mainly comprise diffuse ground-glass opacities, and in some cases, centrilobular nodular shadows. Thus, in conjunction with the findings of the present case, these characteristics may be representative of olaparib-induced ILD.

17.
Proc Natl Acad Sci U S A ; 121(17): e2322363121, 2024 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-38640341

RESUMO

Anti-microbial resistance (AMR) is one of the greatest threats to global health. The continual battle between the emergence of AMR and the development of drugs will be extremely difficult to stop as long as traditional anti-biotic approaches are taken. In order to overcome this impasse, we here focused on the type III secretion system (T3SS), which is highly conserved in many Gram-negative pathogenic bacteria. The T3SS is known to be indispensable in establishing disease processes but not essential for pathogen survival. Therefore, T3SS inhibitors may be innovative anti-infective agents that could dramatically reduce the evolutionary selective pressure on strains resistant to treatment. Based on this concept, we previously identified a polyketide natural product, aurodox (AD), as a specific T3SS inhibitor using our original screening system. However, despite its promise as a unique anti-infective drug of AD, the molecular target of AD has remained unclear. In this paper, using an innovative chemistry and genetic biology-based approach, we show that AD binds to adenylosuccinate synthase (PurA), which suppresses the production of the secreted proteins from T3SS, resulting in the expression of bacterial virulence both in vitro and in vivo experiments. Our findings illuminate the potential of PurA as a target of anti-infective drugs and vaccination and could open a avenue for application of PurA in the regulation of T3SS.


Assuntos
Aurodox , Sistemas de Secreção Tipo III , Sistemas de Secreção Tipo III/metabolismo , Aurodox/farmacologia , Antibacterianos/farmacologia , Antibacterianos/química , Bactérias Gram-Negativas/metabolismo , Proteínas de Bactérias/metabolismo
18.
Cell Tissue Res ; 396(2): 231-243, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38438567

RESUMO

C-C motif chemokine ligand 2 (CCL2) has been reported to be expressed in the bovine endometrium during pregnancy. However, the details of its functions involved in the implantation mechanism are still not clear. The purpose of this study is to analyze the functional properties of CCL2 in the bovine endometrium and embryos. The expression of CCR2 was not different between the luteal phase and implantation phase of their endometrial tissues, but was significantly high in IFNa treated bovine endometrial stromal (BES) cells in vitro. The expressions of PGES1, PGES2, AKR1C4, and AKR1C4 were high at the implantation stage compared with the luteal stage. On the other hand, PGES2 and AKR1B1 in BEE and PGES3 and AKR1A1 in BES were significantly increased by CCL2 treatment, respectively. The expressions of PCNA and IFNt were found significantly high in the bovine trophoblastic cells (BT) treated with CCL2 compared to the control. CCL2 significantly increased the attachment rate of BT vesicles to BEE in in vitro co-culture system. The expression of OPN and ICAM-1 increased in BEE, and ICAM-1 increased in BT by CCL2 treatment, respectively. The present results indicate that CCL2 has the potential to regulate the synthesis of PGs in the endometrium and the embryo growth. In addition, CCL2 has the possibility to regulate the process of bovine embryo attachment to the endometrium by modulation of binding molecules expression.


Assuntos
Quimiocina CCL2 , Implantação do Embrião , Endométrio , Prostaglandinas , Animais , Bovinos , Feminino , Gravidez , Quimiocina CCL2/metabolismo , Implantação do Embrião/genética , Endométrio/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Interferon Tipo I , Proteínas da Gravidez , Prostaglandinas/metabolismo , Receptores CCR2/metabolismo , Células Estromais/metabolismo , Trofoblastos/metabolismo , Trofoblastos/citologia
19.
Life (Basel) ; 14(3)2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38541713

RESUMO

Remarkable advancements have been made in the treatment outcomes of multiple myeloma (MM) patients; however, for frail elderly patients, these treatment outcomes are still insufficient. Elderly MM patients are increasing, as are their treatment regimens. There is a heightened demand to assess these patients in order to provide optimized treatments. While continuous treatment is more common for MM patients when compared to fixed-duration treatment, due to the risk of treatment interruption causing reduced survival rates, effectiveness and safety are essential. Treatment goals vary for each patient, but must preserve their quality of life (QOL). When planning treatments for these patients, frailty evaluation is increasingly emphasized as a stratification factor which helps develop accurate screening tools. Daratumumab (DARA) therapy, used globally, is not only effective in frail elderly MM patients, but also has QOL benefits. Proficiency in utilizing DARA regimens is potentially advantageous for patients not included in clinical trials, and innovative usage can further broaden its scope. The development of tools to accurately assess frailty and the establishment of optimal treatments for frail elderly MM patients are imperative. This review is an overview, challenging the frailty assessments for MM patients, re-examining the evidence for DARA regimens in frail elderly MM patients, and discussing potential areas for improvement.

20.
Rev Esp Enferm Dig ; 2024 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-38450507

RESUMO

Ectopic pancreas (EP) is defined as pancreatic tissue that lacks anatomical or vascular connections to the normal pancreas. EP is generally asymptomatic and is detected incidentally during endoscopy. However, due to pseudocyst formation, inflammation, or malignant transformation, it may cause non-specific gastrointestinal symptoms, such as abdominal pain, abdominal discomfort, nausea, vomiting, and bleeding. Pseudocyst formation in EP may result from the retention of exocrine secretions in the absence of connections between the glandular epithelium and gastric lumen. We herein report a case of EP with a pseudocyst associated with epigastric pain. EP with a pseudocyst, although rare, needs to be considered in a differential diagnosis of cystic lesions of the stomach.

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