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1.
Front Public Health ; 12: 1386495, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38827618

RESUMEN

Introduction: Mitigating the spread of infectious diseases is of paramount concern for societal safety, necessitating the development of effective intervention measures. Epidemic simulation is widely used to evaluate the efficacy of such measures, but realistic simulation environments are crucial for meaningful insights. Despite the common use of contact-tracing data to construct realistic networks, they have inherent limitations. This study explores reconstructing simulation networks using link prediction methods as an alternative approach. Methods: The primary objective of this study is to assess the effectiveness of intervention measures on the reconstructed network, focusing on the 2015 MERS-CoV outbreak in South Korea. Contact-tracing data were acquired, and simulation networks were reconstructed using the graph autoencoder (GAE)-based link prediction method. A scale-free (SF) network was employed for comparison purposes. Epidemic simulations were conducted to evaluate three intervention strategies: Mass Quarantine (MQ), Isolation, and Isolation combined with Acquaintance Quarantine (AQ + Isolation). Results: Simulation results showed that AQ + Isolation was the most effective intervention on the GAE network, resulting in consistent epidemic curves due to high clustering coefficients. Conversely, MQ and AQ + Isolation were highly effective on the SF network, attributed to its low clustering coefficient and intervention sensitivity. Isolation alone exhibited reduced effectiveness. These findings emphasize the significant impact of network structure on intervention outcomes and suggest a potential overestimation of effectiveness in SF networks. Additionally, they highlight the complementary use of link prediction methods. Discussion: This innovative methodology provides inspiration for enhancing simulation environments in future endeavors. It also offers valuable insights for informing public health decision-making processes, emphasizing the importance of realistic simulation environments and the potential of link prediction methods.


Asunto(s)
Trazado de Contacto , Infecciones por Coronavirus , Brotes de Enfermedades , Coronavirus del Síndrome Respiratorio de Oriente Medio , Humanos , República de Corea/epidemiología , Infecciones por Coronavirus/transmisión , Infecciones por Coronavirus/prevención & control , Infecciones por Coronavirus/epidemiología , Trazado de Contacto/métodos , Brotes de Enfermedades/prevención & control , Cuarentena , Simulación por Computador
2.
Br J Pharmacol ; 2024 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-38925168

RESUMEN

BACKGROUND AND PURPOSE: Mitochondrial dysfunction contributes to the pathogenesis and maintenance of chemotherapy-induced peripheral neuropathy (CIPN), a significant limitation of cancer chemotherapy. Recently, the stimulation of mitophagy, a pivotal process for mitochondrial homeostasis, has emerged as a promising treatment strategy for neurodegenerative diseases, but its therapeutic effect on CIPN has not been explored. Here, we assessed the mitophagy-inducing activity of 3,5-dibromo-2-(2',4'-dibromophenoxy)-phenol (PDE701), a diphenyl ether derivative isolated from the marine sponge Dysidea sp., and investigated its therapeutic effect on a CIPN model. EXPERIMENTAL APPROACH: Mitophagy activity was determined by a previously established mitophagy assay using mitochondrial Keima (mt-Keima). Mitophagy induction was further verified by western blotting, immunofluorescence, and electron microscopy. Mitochondrial dysfunction was analysed by measuring mitochondrial superoxide levels in SH-SY5Y cells and Drosophila larvae. A thermal nociception assay was used to evaluate the therapeutic effect of PDE701 on the paclitaxel-induced thermal hyperalgesia phenotype in Drosophila larvae. KEY RESULTS: PDE701 specifically induced mitophagy but was not toxic to mitochondria. PDE701 ameliorated paclitaxel-induced mitochondrial dysfunction in both SH-SY5Y cells and Drosophila larvae. Importantly, PDE701 also significantly ameliorated paclitaxel-induced thermal hyperalgesia in Drosophila larvae. Knockdown of ATG5 or ATG7 abolished the effect of PDE701 on thermal hyperalgesia, suggesting that PDE701 exerts its therapeutic effect through mitophagy induction. CONCLUSION AND IMPLICATIONS: This study identified PDE701 as a novel mitophagy inducer and a potential therapeutic compound for CIPN. Our results suggest that mitophagy stimulation is a promising strategy for the treatment of CIPN and that marine organisms are a potential source of mitophagy-inducing compounds.

3.
Mar Drugs ; 22(6)2024 Jun 10.
Artículo en Inglés | MEDLINE | ID: mdl-38921577

RESUMEN

Sortase A (SrtA) is a cysteine transpeptidase that binds to the periplasmic membrane and plays a crucial role in attaching surface proteins, including staphylococcal protein A (SpA), to the peptidoglycan cell wall. Six pentacyclic polyketides (1-6) were isolated from the marine sponge Xestospongia sp., and their structures were elucidated using spectroscopic techniques and by comparing them to previously reported data. Among them, halenaquinol (2) was found to be the most potent SrtA inhibitor, with an IC50 of 13.94 µM (4.66 µg/mL). Semi-quantitative reverse transcription PCR data suggest that halenaquinol does not inhibit the transcription of srtA and spA, while Western blot analysis and immunofluorescence microscopy images suggest that it blocks the cell wall surface anchoring of SpA by inhibiting the activity of SrtA. The onset and magnitude of the inhibition of SpA anchoring on the cell wall surface in S. aureus that has been treated with halenaquinol at a value 8× that of the IC50 of SrtA are comparable to those for an srtA-deletion mutant. These findings contribute to the understanding of the mechanism by which marine-derived pentacyclic polyketides inhibit SrtA, highlighting their potential as anti-infective agents targeting S. aureus virulence.


Asunto(s)
Aminoaciltransferasas , Antibacterianos , Proteínas Bacterianas , Pared Celular , Cisteína Endopeptidasas , Poríferos , Staphylococcus aureus , Aminoaciltransferasas/antagonistas & inhibidores , Aminoaciltransferasas/metabolismo , Cisteína Endopeptidasas/metabolismo , Staphylococcus aureus/efectos de los fármacos , Pared Celular/efectos de los fármacos , Pared Celular/metabolismo , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/antagonistas & inhibidores , Animales , Poríferos/microbiología , Antibacterianos/farmacología , Antibacterianos/química , Policétidos/farmacología , Policétidos/química
4.
Sci Rep ; 14(1): 9495, 2024 04 25.
Artículo en Inglés | MEDLINE | ID: mdl-38664570

RESUMEN

The biological mechanisms regulating tenocyte differentiation and morphological maturation have not been well-established, partly due to the lack of reliable in vitro systems that produce highly aligned collagenous tissues. In this study, we developed a scaffold-free, three-dimensional (3D) tendon culture system using mouse tendon cells in a differentially adherent growth channel. Transforming Growth Factor-ß (TGFß) signaling is involved in various biological processes in the tendon, regulating tendon cell fate, recruitment and maintenance of tenocytes, and matrix organization. This known function of TGFß signaling in tendon prompted us to utilize TGFß1 to induce tendon-like structures in 3D tendon constructs. TGFß1 treatment promoted a tendon-like structure in the peripheral layer of the constructs characterized by increased thickness with a gradual decrease in cell density and highly aligned collagen matrix. TGFß1 also enhanced cell proliferation, matrix production, and morphological maturation of cells in the peripheral layer compared to vehicle treatment. TGFß1 treatment also induced early tenogenic differentiation and resulted in sufficient mechanical integrity, allowing biomechanical testing. The current study suggests that this scaffold-free 3D tendon cell culture system could be an in vitro platform to investigate underlying biological mechanisms that regulate tenogenic cell differentiation and matrix organization.


Asunto(s)
Diferenciación Celular , Proliferación Celular , Tendones , Tenocitos , Factor de Crecimiento Transformador beta1 , Animales , Factor de Crecimiento Transformador beta1/farmacología , Factor de Crecimiento Transformador beta1/metabolismo , Tendones/citología , Tendones/metabolismo , Ratones , Diferenciación Celular/efectos de los fármacos , Tenocitos/metabolismo , Tenocitos/citología , Proliferación Celular/efectos de los fármacos , Técnicas de Cultivo Tridimensional de Células/métodos , Células Cultivadas , Técnicas de Cultivo de Célula/métodos , Matriz Extracelular/metabolismo , Colágeno/metabolismo , Ingeniería de Tejidos/métodos
5.
J Nat Prod ; 87(2): 358-364, 2024 02 23.
Artículo en Inglés | MEDLINE | ID: mdl-38320400

RESUMEN

Bioassay-guided isolation of the extract from the marine sponge Diacarnus spinipoculum showing inhibitory activity against human transient receptor potential ankyrin 1 (hTRPA1) resulted in the isolation of 12 norditerpene cyclic peroxides (1-12) and eight norsesterterpene cyclic peroxides (13-20). Among these, 10 (5-7, 11, 12, 16-20) are unprecedented analogs. Compounds with either a hydroxy (5, 11) or a methoxy (6, 12) group attached to the cyclohexanone moiety were obtained as epimeric mixtures at C-11, while compounds 4, 6, 10, and 12 are likely the artifacts of isolation. The absolute configurations of the new compounds were established based on an NMR-based empirical method and comparison of specific rotation values. Mosher ester analysis revealed the absolute configurations of compounds 17-20. The inhibitory activity of the isolated compounds against hTRPA1 varied significantly depending on their structures, with the norsesterterpenoid 19 displaying the most potent activity (IC50 2.0 µM).


Asunto(s)
Diterpenos , Poríferos , Animales , Humanos , Ancirinas/antagonistas & inhibidores , Estructura Molecular , Peróxidos/farmacología , Peróxidos/química , Poríferos/química , Terpenos/farmacología , Terpenos/química
6.
Brain Tumor Res Treat ; 11(4): 281-288, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37953453

RESUMEN

Ewing sarcoma and peripheral primitive neuroectodermal tumor (ES/pPNET) is an undifferentiated malignant tumor that is most prevalent in children and young adults and often radiologically mimics a meningioma. A 38-year-old female patient visited our hospital with complaints of right-sided tinnitus, right hemiparesis, and imbalance. She underwent preoperative imaging and was subsequently diagnosed as having a meningioma on the petrous ridge. After partial resection, EWSR1-FLI1 gene fusion was confirmed, and she was diagnosed with ES/pPNET. The tumor was successfully treated using a multidisciplinary approach of adjuvant chemo- and radiotherapy. This case is noteworthy because it is an extremely rare case of an intracranial ES/pPNET, and it is worth sharing our clinical experience that the tumor was successfully treated through a multidisciplinary therapeutic approach even though complete resection was not achieved.

7.
Front Endocrinol (Lausanne) ; 14: 1238654, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37795375

RESUMEN

Background: Osteoporotic vertebral compression fractures commonly involve the superior vertebral body; however, their associated causes have not yet been clearly established. This study aimed to determine the trabecular structural differences between the superior and inferior regions of the vertebral body using cadaveric and clinical studies. Materials and methods: First, five vertebrae were collected from three human cadavers. The trabecular structures of the superior and inferior regions of each vertebral body were analyzed using micro-computed tomography (micro-CT), finite element analysis (FEA), and biomechanical test. Based on the results of the ex vivo study, we conducted a clinical study. Second, spine CT images were retrospectively collected. Bone volume and Hounsfield unit were analyzed for 192 vertebral bodies. Finally, after sample size calculation based on the pilot study, prospectively, 200 participants underwent dual-energy X-ray absorptiometry (DXA) of the lateral spine. The bone mineral densities (BMDs) of the superior and inferior regions of each lumbar vertebral body were measured. The paired t-test and Wilcoxon signed-rank test were used for the statistical analyses, and p-value < 0.05 was considered significant. Results: Cadaver studies revealed differences between the superior and inferior trabecular bone structures. The bone volume ratio, BMD, and various other trabecular parameters advocated for decreased strength of the superior region. Throughout the biomechanical study, the limitations of the compression force were 3.44 and 4.63 N/m2 for the superior and inferior regions, respectively. In the FEA study, the inferior region had a lower average displacement and higher von Mises stress than the superior region. In the clinical spine CT-based bone volume and BMD study, the bone volume was significantly higher in the inferior region than in the superior region. In the lateral spine DXA, the mean BMD of the superior region of vertebral bodies was significantly lower compared with that of the inferior region. Conclusion: The superior trabecular structure of the lumbar vertebral bodies possesses more biomechanical susceptibility compared with the inferior trabecular structure, confirming its dominant role in causing osteoporotic vertebral fractures. Physicians should also focus on the BMD values of the superior region of the vertebral body using lateral spine DXA to evaluate osteoporosis.


Asunto(s)
Fracturas por Compresión , Fracturas Osteoporóticas , Fracturas de la Columna Vertebral , Humanos , Cuerpo Vertebral , Microtomografía por Rayos X , Fracturas de la Columna Vertebral/diagnóstico por imagen , Fracturas de la Columna Vertebral/etiología , Estudios Retrospectivos , Fracturas por Compresión/complicaciones , Proyectos Piloto , Vértebras Lumbares/diagnóstico por imagen , Cadáver
8.
J Nat Prod ; 86(9): 2145-2150, 2023 09 22.
Artículo en Inglés | MEDLINE | ID: mdl-37610630

RESUMEN

Ten new norterpene alkaloids, coscinoderines A-J (1-10), were isolated from the marine sponge Coscinoderma bakusi. Each coscinoderine contains a 1,2,5-trisubstituted pyridinium moiety bearing a terpene unit at the C-2 position. Their structures were elucidated by analysis of NMR and HRMS data, and the absolute stereochemistry of 4 with a 2-methylbutyl group attached to the nitrogen was determined from a comparison of the calculated and measured ECD spectra. The isolation of coscinoderines expands the repertoire of pyridinium alkaloids isolated from marine sponges.


Asunto(s)
Alcaloides , Poríferos , Animales , Poríferos/química , Alcaloides/farmacología , Alcaloides/química , Espectroscopía de Resonancia Magnética , Terpenos , Estructura Molecular
9.
Int J Biol Macromol ; 252: 126520, 2023 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-37625744

RESUMEN

Despite the therapeutic potential of recombinant proteins, their cell permeabilities and stabilities remain significant challenges. Here we demonstrate that cyclized recombinant proteins can be used as universal cargos for permeable and stable delivery into cells and polydiacetylene liposomes. Utilizing a split intein-mediated process, cyclized model fluorescent proteins containing short tetraarginine (R4) and hexahistidine (H6) tags were generated without compromising their native protein functions. Strikingly, as compared to linear R4/H6-tagged proteins, the cyclized counterparts have substantially increased permeabilities in both cancer cells and synthetic liposomes, as well as higher resistances to enzymatic degradation in cancer cells. These properties are likely a consequence of structural constraints imposed on the proteins in the presence of short functional peptides. Additionally, photodynamic therapy by cyclized photoprotein-loaded liposomes in cancer cells was significantly improved in comparison to that by their non-cyclized counterparts. These findings suggest that our strategy will be universally applicable to intercellular delivery of proteins and therapeutics.


Asunto(s)
Liposomas , Péptidos , Péptidos/metabolismo , Proteínas Recombinantes , Proteínas Luminiscentes
10.
Angew Chem Int Ed Engl ; 62(35): e202305737, 2023 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-37335764

RESUMEN

The incorporation of nanopores into graphene nanostructures has been demonstrated as an efficient tool in tuning their band gaps and electronic structures. However, precisely embedding the uniform nanopores into graphene nanoribbons (GNRs) at the atomic level remains underdeveloped especially for in-solution synthesis due to the lack of efficient synthetic strategies. Herein we report the first case of solution-synthesized porous GNR (pGNR) with a fully conjugated backbone via the efficient Scholl reaction of tailor-made polyphenylene precursor (P1) bearing pre-installed hexagonal nanopores. The resultant pGNR features periodic subnanometer pores with a uniform diameter of 0.6 nm and an adjacent-pores-distance of 1.7 nm. To solidify our design strategy, two porous model compounds (1 a, 1 b) containing the same pore size as the shortcuts of pGNR, are successfully synthesized. The chemical structure and photophysical properties of pGNR are investigated by various spectroscopic analyses. Notably, the embedded periodic nanopores largely reduce the π-conjugation degree and alleviate the inter-ribbon π-π interactions, compared to the nonporous GNRs with similar widths, affording pGNR with a notably enlarged band gap and enhanced liquid-phase processability.

11.
Nat Commun ; 14(1): 2755, 2023 05 13.
Artículo en Inglés | MEDLINE | ID: mdl-37179387

RESUMEN

Owing to the strong absorption of water in the near-infrared (NIR) region near 1.0 µm, this wavelength is considered unsuitable as an imaging and analytical signal in biological environments. However, 1.0 µm NIR can be converted into heat and used as a local water-molecular heating strategy for the photothermal therapy of biological tissues. Herein, we describe a Nd-Yb co-doped nanomaterial (water-heating nanoparticles (NPs)) as strong 1.0 µm emissive NPs to target the absorption band of water. Furthermore, introducing Tm ions into the water-heating NPs improve the NIR lifetime, enabling the development of a NIR imaging-guided water-heating probe (water-heating NIR NPs). In the glioblastoma multiforme male mouse model, tumor-targeted water-heating NIR NPs reduce the tumor volume by 78.9% in the presence of high-resolution intracranial NIR long-lifetime imaging. Hence, water-heating NIR NPs can be used as a promising nanomaterial for imaging and photothermal ablation in deep-tissue-bearing tumor therapy.


Asunto(s)
Glioblastoma , Nanopartículas , Animales , Ratones , Masculino , Glioblastoma/diagnóstico por imagen , Glioblastoma/terapia , Terapia Fototérmica , Calefacción , Diagnóstico por Imagen , Fototerapia , Línea Celular Tumoral
12.
EJHaem ; 4(2): 370-380, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-37206279

RESUMEN

Signal regulatory protein alpha (SIRPα) is the receptor for cluster of differentiation (CD)47, a potent "don't eat me" signal for macrophages. Disruption of CD47-SIRPα signaling in the presence of prophagocytic signals can lead to enhanced phagocytosis of tumor cells, resulting in a direct antitumor effect; agents targeting this pathway have shown efficacy in non-Hodgkin lymphoma (NHL) and other tumor types. GS-0189 is a novel anti-SIRPα humanized monoclonal antibody. Here we report: (1) clinical safety, preliminary activity, and pharmacokinetics of GS-0189 as monotherapy and in combination with rituximab from a phase 1 clinical trial in patients with relapsed/refractory NHL (NCT04502706, SRP001); (2) in vitro characterization of GS-0189 binding to SIRPα; and (3) in vitro phagocytic activity. Clinically, GS-0189 was well tolerated in patients with relapsed/refractory NHL with evidence of clinical activity in combination with rituximab. Receptor occupancy (RO) of GS-0189 was highly variable in NHL patients; binding affinity studies showed significantly higher affinity for SIRPα variant 1 than variant 2, consistent with RO in patient and healthy donor samples. In vitro phagocytosis induced by GS-0189 was also SIRPα variant-dependent. Although clinical development of GS-0189 was discontinued, the CD47-SIRPα signaling pathway remains a promising therapeutic target and should continue to be explored.

13.
Anticancer Res ; 43(5): 1959-1965, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-37097656

RESUMEN

BACKGROUND/AIM: Unique cartilage matrix-associated protein (UCMA), a recently discovered vitamin K-dependent protein (VKDP) with a large number of γ-carboxyglutamic acid (Gla) residues, is associated with ectopic calcifications. Although the function of VKDPs is related to their γ-carboxylation status, the carboxylation status of UCMA in breast cancer is still unknown. Here, we investigated the inhibitory effect of UCMA with differing γ-carboxylation status on breast cancer cell lines, such as MDA-MB-231, 4T1, and E0771 cells. MATERIALS AND METHODS: Undercarboxylated UCMA (ucUCMA) was generated by mutating the γ-glutamyl carboxylase (GGCX) recognition sites. The ucUCMA and carboxylated UCMA (cUCMA) proteins were collected from culture media of HEK293-FT cells that had been transfected with mutated GGCX and wild-type UCMA expression plasmids, respectively. Boyden Transwell and colony formation assays were performed to evaluate cancer cell migration, invasion, and proliferation. RESULTS: Culture medium containing cUCMA protein inhibited the migration, invasion, and colony formation of MDA-MB-231 and 4T1 cells to a greater degree than medium containing ucUCMA protein. Significant reductions in the migration, invasion, and colony formation were also observed in cUCMA-treated E0771 cells compared to those in ucUCMA-treated cells. CONCLUSION: The inhibitory role of UCMA in breast cancer is closely related to its γ-carboxylation status. The results of this study may be a basis for the development of UCMA-based anti-cancer drugs.


Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Proteínas Matrilinas , Células HEK293 , Proteínas/metabolismo , Vitamina K/metabolismo , Cartílago
14.
FASEB J ; 37(2): e22763, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36625326

RESUMEN

Diabetic retinopathy (DR) is caused by retinal vascular dysfunction and neurodegeneration. Intraocular delivery of C-peptide has been shown to be beneficial against hyperglycemia-induced microvascular leakage in the retina of diabetes; however, the effect of C-peptide on diabetes-induced retinal neurodegeneration remains unknown. Moreover, extraocular C-peptide replacement therapy against DR to avoid various adverse effects caused by intravitreal injections has not been studied. Here, we demonstrate that systemic C-peptide supplementation using osmotic pumps or biopolymer-conjugated C-peptide hydrogels ameliorates neurodegeneration by inhibiting vascular endothelial growth factor-induced pathological events, but not hyperglycemia-induced vascular endothelial growth factor expression, in the retinas of diabetic mice. C-peptide inhibited hyperglycemia-induced activation of macroglial and microglial cells, downregulation of glutamate aspartate transporter 1 expression, neuronal apoptosis, and histopathological changes by a mechanism involving reactive oxygen species generation in the retinas of diabetic mice, but transglutaminase 2, which is involved in retinal vascular leakage, is not associated with these pathological events. Overall, our findings suggest that systemic C-peptide supplementation alleviates hyperglycemia-induced retinal neurodegeneration by inhibiting a pathological mechanism, involving reactive oxygen species, but not transglutaminase 2, in diabetes.


Asunto(s)
Diabetes Mellitus Experimental , Retinopatía Diabética , Hiperglucemia , Animales , Ratones , Factor A de Crecimiento Endotelial Vascular/metabolismo , Péptido C/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Retina/metabolismo , Factores de Crecimiento Endotelial Vascular , Retinopatía Diabética/metabolismo , Hiperglucemia/metabolismo , Suplementos Dietéticos
15.
Adv Mater ; 35(43): e2205520, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-36539122

RESUMEN

With advances in flexible electronics, innovative foldable, rollable, and stretchable displays have been developed to maintain their performance under various deformations. These flexible devices can develop more innovative designs than conventional devices due to their light weight, high space efficiency, and practical convenience. However, developing flexible devices requires material innovation because the devices must be flexible and exhibit desirable electrical insulating/semiconducting/metallic properties. Recently, emerging 2D materials such as graphene, hexagonal boron nitride, and transition metal dichalcogenides have attracted considerable research attention because of their outstanding electrical, optical, and mechanical properties, which are ideal for flexible electronics. The recent progress and challenges of 2D material growth and display applications are reviewed and perspectives for exploring 2D materials for display applications are discussed.

16.
FASEB J ; 36(12): e22643, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36331561

RESUMEN

Dopamine is a neurotransmitter that mediates visual function in the retina and diabetic retinopathy (DR) is the most common microvascular complication of diabetes and the leading cause of blindness; however, the role of dopamine in retinal vascular dysfunction in DR remains unclear. Here, we report a mechanism of hyperglycemic memory (HGM)-induced retinal microvascular dysfunction and the protective effect of dopamine against the HGM-induced retinal microvascular leakage and abnormalities. We found that HGM induced persistent oxidative stress, mitochondrial membrane potential collapse and fission, and adherens junction disassembly and subsequent vascular leakage after blood glucose normalization in the mouse retinas. These persistent hyperglycemic stresses were inhibited by dopamine treatment in human retinal endothelial cells and by intravitreal injection of levodopa in the retinas of HGM mice. Moreover, levodopa supplementation ameliorated HGM-induced pericyte degeneration, acellular capillary and pericyte ghost generation, and endothelial apoptosis in the mouse retinas. Our findings suggest that dopamine alleviates HGM-induced retinal microvascular leakage and abnormalities by inhibiting persistent oxidative stress and mitochondrial dysfunction.


Asunto(s)
Diabetes Mellitus , Retinopatía Diabética , Ratones , Animales , Humanos , Retinopatía Diabética/tratamiento farmacológico , Dopamina , Vasos Retinianos , Células Endoteliales , Levodopa/farmacología , Retina
17.
Mar Drugs ; 20(10)2022 Sep 25.
Artículo en Inglés | MEDLINE | ID: mdl-36286427

RESUMEN

Eighteen scalarane sesterterpenoids (1-18), including eight new derivatives (1-8), were isolated from the sponge Hyrtios erectus (family Thorectidae), the extract of which showed cytotoxicity against the HeLa and MCF-7 cell lines. Of the new derivatives, six compounds (1-6) were found to contain a γ-hydroxybutenolide moiety capable of reversible stereoinversion at the hydroxylated carbon center. Under the influence of other adjacent functional groups, each derivative exhibited a different stereochemical behavior, which was fully deduced by ROESY experiments. All the isolated compounds were examined for their cytotoxicity by MTS assay using staurosporine as a positive control (IC50 0.18 and 0.13 µΜ against HeLa and MCF-7 cells, respectively), and they were found to show weak growth inhibitory activities against HeLa and MCF-7 cells, with a minimal IC50 value of 20.0 µΜ. The compounds containing a γ-hydroxybutenolide moiety (1-3, 10, 12) showed cytotoxicity, with IC50 values ranging from 24.3 to 29.9 µΜ, and the most potent derivative was heteronemin (16). Although the cytotoxicities of isolated compounds were insufficient to discuss the structure-activity relationship, this research could contribute to expanding the structural diversity of scalaranes and understanding the stereochemical behavior of γ-hydroxybutenolides.


Asunto(s)
Antineoplásicos , Poríferos , Animales , Humanos , Estaurosporina , Poríferos/química , Células MCF-7 , Relación Estructura-Actividad , Carbono , Estructura Molecular , Sesterterpenos/farmacología , Sesterterpenos/química , Antineoplásicos/farmacología , Antineoplásicos/química , Ensayos de Selección de Medicamentos Antitumorales
18.
Chemosphere ; 309(Pt 1): 136464, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36122751

RESUMEN

Saxitoxin (STX) is a highly toxic marine neurotoxin produced by phytoplankton and a growing threat to ecosystems worldwide due to the spread of toxic algae. Although STX is an established sodium channel blocker, the overall profile of transcriptional levels in STX-exposed organisms has yet to be described. Here, we describe a toxicity assay and transcriptome analysis of the copepod Tigriopus japonicus exposed to STX. The half-maximal lethal concentration of STX was 12.35 µM, and a rapid mortality slope was evident at concentrations between 12 and 13 µM. STX induced changes in swimming behavior among the copepods after 10 min of exposure. In transcriptome analysis, gene ontology revealed that the genes involved in nervous system and gene expression were highly enriched. In addition, the congenital neurological disorder and nuclear factor erythroid 2-related factor 2-mediated oxidative stress pathways were identified to be the most significant in network analysis and toxicity pathway analysis, respectively. This study provides valuable information about the effects of STX and related transcriptional responses in T. japonicus.


Asunto(s)
Copépodos , Saxitoxina , Animales , Saxitoxina/toxicidad , Copépodos/genética , Ecosistema , Neurotoxinas/farmacología , Bloqueadores de los Canales de Sodio/farmacología
19.
Artículo en Inglés | MEDLINE | ID: mdl-35886467

RESUMEN

The purpose of this study is to determine the effect of cancer survivorship stage and health-related behaviors on the risk of developing mental health problems (depressive and anxiety disorders) in women who have experienced cancers that affect women (breast cancer, cervical cancer, ovarian cancer, endometrial cancer). Using the healthcare utilization and medical checkup data from 2010 to 2020 provided by the National Health Insurance Service, the occurrence of mental health problems since 2020 was tracked for 36,801 women diagnosed with cancer. The occurrence of mental health problems was defined as the cases in which the disease code was assigned to anxiety disorders (F40~F44, F48) and depressive disorders (F32~34, F41.2, F92) as presented in ICD-10. To evaluate the effect of cancer survivorship stage and health-related behaviors on the development of mental health problems, the hazard ratio (HR) and 95% confidence intervals (CI) were calculated using the Cox proportional hazard model. During the follow-up period of 5.6 years, anxiety disorder occurred in 14,698 (39.9%), and by cancer type, breast cancer survivors accounted for the most at 1.02 per 1000 person-years. The risk of anxiety disorders increased in those who experienced cervical cancer (AHR, 1.08, 95% CI, 1.03-1.13) and those in the acute survivorship stage (AHR, 1.38, 95% CI, 1.22-1.55). In terms of health-related behaviors, the risk of developing anxiety disorder was shown to be reduced in drinkers (AHR, 0.91, 95% CI, 0.87-0.96), former smokers (AHR, 0.86, 95% CI, 0.77-0.97), and current smokers (AHR, 0.80, 95% CI, 0.71-0.90). During the follow-up period of 5.6 years, depressive disorder occurred in 6168(16.8%), and by cancer type, ovarian cancer survivors accounted for the most at 1.30 per 1000 person-years. The risk of developing depressive disorders was highest in those who experienced ovarian cancer (AHR, 1.40, 95% CI, 1.27-1.53) and those in the acute survivorship stage (AHR, 2.99, 95% CI, 2.60-3.42). For health-related behaviors, the risk of developing depressive disorders was increased in former smokers (AHR, 1.32, 95% CI, 1.14-1.54), current smokers (AHR, 1.21, 95% CI, 1.04-1.41), and those with insufficient physical activity (AHR, 1.09, 95% CI, 1.02-1.15). It has been confirmed that cancer type, cancer survivorship stage, and health-related behaviors, such as smoking, drinking, and physical activity, are significantly related to the risk of mental health problems. Thus, it is necessary to develop strategies to cope with mental health problems at the individual and national levels and to develop interventions to promote a more active lifestyle.


Asunto(s)
Neoplasias de la Mama , Supervivientes de Cáncer , Neoplasias Ováricas , Neoplasias del Cuello Uterino , Neoplasias de la Mama/epidemiología , Estudios de Cohortes , Femenino , Humanos , Salud Mental , Neoplasias Ováricas/epidemiología , Modelos de Riesgos Proporcionales , Factores de Riesgo
20.
Anat Cell Biol ; 55(2): 142-147, 2022 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-35773217

RESUMEN

The frontal sinus is one of the four paranasal sinuses in humans, and knowledge of its anatomy is important when performing surgery involving the frontal bone or sinus. Although many studies have measured the frontal sinus using radiography and computed tomography (CT), few studies have evaluated by using three-dimensional (3D) analysis. The purpose of this study was to analyze the frontal sinus using 3D reconstruction analysis and determine the differences in linear and volumetric measurements between sexes, sides, and ages. The sample comprised 281 facial CT scans: 173 and 108 from males and females, respectively. The width, height, and length of each frontal sinus and total volume were all larger in males than in females. Almost all linear and volumetric measurements were larger in young adults than in older for both sexes, but not all of the differences were statistically significant. Linear and volumetric measurements were larger for males than females regardless of age group. There were no statistically significant differences between the right and left sides except the width in males. The size of the frontal sinus was strongly influenced by sex and age. The measurements reported here might be useful for improving surgical procedures involving the frontal sinus.

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