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1.
Plant Cell ; 35(11): 4002-4019, 2023 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-37648256

RESUMEN

Heading date (flowering time), which greatly influences regional and seasonal adaptability in rice (Oryza sativa), is regulated by many genes in different photoperiod pathways. Here, we characterized a heading date gene, Early heading date 5 (Ehd5), using a modified bulked segregant analysis method. The ehd5 mutant showed late flowering under both short-day and long-day conditions, as well as reduced yield, compared to the wild type. Ehd5, which encodes a WD40 domain-containing protein, is induced by light and follows a circadian rhythm expression pattern. Transcriptome analysis revealed that Ehd5 acts upstream of the flowering genes Early heading date 1 (Ehd1), RICE FLOWERING LOCUS T 1 (RFT1), and Heading date 3a (Hd3a). Functional analysis showed that Ehd5 directly interacts with Rice outermost cell-specific gene 4 (Roc4) and Grain number, plant height, and heading date 8 (Ghd8), which might affect the formation of Ghd7-Ghd8 complexes, resulting in increased expression of Ehd1, Hd3a, and RFT1. In a nutshell, these results demonstrate that Ehd5 functions as a positive regulator of rice flowering and provide insight into the molecular mechanisms underlying heading date.


Asunto(s)
Flores , Oryza , Ritmo Circadiano , Flores/genética , Flores/metabolismo , Regulación de la Expresión Génica de las Plantas/genética , Oryza/genética , Oryza/metabolismo , Fotoperiodo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Repeticiones WD40/genética
2.
Genes Chromosomes Cancer ; 62(6): 353-360, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36704911

RESUMEN

Transcription factor EB (TFEB)-rearranged renal cell carcinoma (RCC) exhibits diverse gene fusion patterns and heterogeneous clinicopathologic features. Rare TFEB-amplified RCCs have been described recently and are associated with a more aggressive clinical course. Herein, we report a case of an 86-year-old man with a solid 9.2-cm kidney tumor that showed a diffuse high-grade sarcomatoid morphology. The tumor demonstrated a novel BYSL::TFEB fusion containing exons 1-2 of the BYSL gene fused to exons 3-10 of TFEB via next-generation sequencing by using NextSeq sequencer. Fluorescence in situ hybridization (FISH) studies displayed concurrent high-copy number TFEB amplification in two distinct patterns, a balanced increase of 5' and 3' copies, and solely increased 5' copies, and mouse double minute 2 (MDM2) gene amplification by using TFEB (6p21.1) dual-color break-apart probe and MDM2 FISH probe. Notably, the tumor showed a distinctive immunoprofile with overexpressions of TFEB, epithelial membrane antigen, Cathepsin K, and PDL-1 (SP263). FISH test for transcription factor binding to IGHM enhancer 3 (TFE3) was negative for rearrangement and corresponding immunonegativity of TFE3. These findings not only expand the repertoire of known TFEB fusion partners implicated in tumorigenesis, but also may provide novel information for target therapy.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Sarcoma , Neoplasias de los Tejidos Blandos , Humanos , Animales , Ratones , Hibridación Fluorescente in Situ , Neoplasias Renales/patología , Carcinoma de Células Renales/patología , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Exones , Sarcoma/genética , Neoplasias de los Tejidos Blandos/genética , Biomarcadores de Tumor/genética , Translocación Genética , Moléculas de Adhesión Celular/genética
3.
Angew Chem Int Ed Engl ; 63(22): e202403957, 2024 May 27.
Artículo en Inglés | MEDLINE | ID: mdl-38482736

RESUMEN

Cyclic ß,ß-difluoro-carbonyl compounds have a venerable history as drug discovery leads, but limitations in the synthesis arsenal continue to impede chemical space exploration. This challenge is particularly acute in the arena of fluorinated medium rings where installing the difluoromethylene unit subtly alters the ring conformation by expanding the internal angle (∠C-CF2-C>∠C-CH2-C): this provides a handle to modulate physicochemistry (e.g. pKa). To reconcile this disparity, a highly modular ring expansion has been devised that leverages simple α,ß-unsaturated esters and amides, and processes them to one-carbon homologated rings with concomitant geminal difluorination (6 to 10 membered rings, up to 95 % yield). This process is a rare example of the formal difluorination of an internal alkene and is enabled by sequential I(III)-enabled O-activation. Validation of enantioselective catalysis in the generation of unprecedented medium ring scaffolds is reported (up to 93 : 7 e.r.) together with X-ray structural analyses and product derivatization.

4.
Analyst ; 148(3): 683-689, 2023 Jan 31.
Artículo en Inglés | MEDLINE | ID: mdl-36629898

RESUMEN

Fluorescent lateral flow immunoassay (FLFIA) is widely used mainly because of its low cost and instant detection. Its limit of detection (LOD) is closely related to fluorescence signals, and the development of fluorescence signals with fine performance remains a challenge. In this work, dendritic mesoporous silica nanoparticles (DMSNs) were used as fine carriers due to their large pore size and stable performance. We successfully synthesized carbon dots (CDs) with a 560 nm maximum emission wavelength (CD560) by the hydrothermal method. A new type of fluorescence signal for FLFIA was observed by loading CD560 on DMSNs through the Si-O bond which is denoted as DMSNs@CD560. Applying DMSNs@CD560 to the FLFIA can eliminate the influence of interfacial background blue fluorescence thus improving its detection sensitivity. The formed DMSNs@CD560-FLFIA achieved high sensitivity detection of ovarian cancer biomarkers carbohydrate antigen 125 (CA125) and human epididymal protein 4 (HE4). The LOD of CA125 is 0.5 U mL-1 and the correlation coefficient R2 = 0.985, and the LOD of HE4 reaches 0.05 ng mL-1 and the correlation coefficient R2 = 0.981. The DMSNs@CD560-FLFIA is sensitive and efficient providing a new method for the early diagnosis of ovarian cancer.


Asunto(s)
Nanopartículas , Neoplasias Ováricas , Femenino , Humanos , Biomarcadores de Tumor , Antígeno Ca-125 , Carbono/química , Inmunoensayo/métodos , Neoplasias Ováricas/diagnóstico , Sensibilidad y Especificidad
5.
J Nat Prod ; 86(8): 1910-1918, 2023 08 25.
Artículo en Inglés | MEDLINE | ID: mdl-37530709

RESUMEN

Four new δ- and γ-lactone derivatives, hyperelatolides A-D (1-4, respectively), were discovered from the aerial portions of Hypericum elatoides R. Keller. Their structures were elucidated by analysis of NMR spectra, HRESIMS, quantum chemical calculations of NMR and ECD spectra, and X-ray crystallographic data. Hyperelatolides A (1) and B (2) represent the first examples of δ-lactone derivatives characterized by a (Z)-(5,5-dimethyl-2-(2-oxopropyl)cyclohexylidene)methyl moiety and a benzoyloxy group attached to the ß- and γ-positions of the δ-lactone core, respectively, while hyperelatolides C (3) and D (4) are unprecedented γ-lactone derivatives featuring substituents similar to those of 1 and 2. All compounds were tested for their inhibitory effects on NO production in LPS-activated BV-2 cells. Lactones 1 and 2 exhibited considerable antineuroinflammatory activity, with IC50 values of 5.74 ± 0.27 and 7.35 ± 0.26 µM, respectively. Moreover, the mechanistic study revealed that lactone 1 significantly suppressed nuclear factor kappa B signaling and downregulated the expression of inducible nitric oxide synthase and cyclooxygenase-2 in LPS-induced cells, which may contribute to its antineuroinflammatory activity.


Asunto(s)
Hypericum , Hypericum/química , Lipopolisacáridos/farmacología , Espectroscopía de Resonancia Magnética , Lactonas/farmacología , Lactonas/química , Transducción de Señal , Estructura Molecular , Óxido Nítrico
6.
J Nat Prod ; 86(1): 119-130, 2023 01 27.
Artículo en Inglés | MEDLINE | ID: mdl-36579935

RESUMEN

Nine new sesquiterpenes, hyperhubeins A-I (1-9), and 14 known analogues (10-23) were isolated from the aerial portions of Hypericum hubeiense. Their structures and absolute configurations were determined unambiguously via spectroscopic analysis, single-crystal X-ray diffraction, and electronic circular dichroism calculations. Compounds 1-3 possess an unprecedented sesquiterpene carbon skeleton. Further, a plausible biosynthetic pathway from farnesyl diphosphate (FPP) is proposed. The isolated phytochemicals were evaluated for neuroprotective and anti-neuroinflammatory properties in vitro. Compounds 1, 2, 5-8, 14, and 21 displayed notable neuroprotective activity against hydrogen peroxide (H2O2)-induced lesions in PC-12 cells at 10 µM. Additionally, compounds 1, 2, 12, and 13 exhibited inhibition of lipopolysaccharide (LPS)-induced nitric oxide (NO) production in BV-2 microglial cells, with their IC50 values ranging from 4.92 to 6.81 µM. Possible interactions between these bioactive compounds and inducible nitric oxide synthase (iNOS) were predicted via molecular docking. Moreover, Western blotting indicated that compound 12 exerted anti-neuroinflammatory activity by suppressing LPS-stimulated expression of toll-like receptor-4 (TLR-4) and inhibiting consequent activation of nuclear factor-kappa-B (NF-κB) signaling.


Asunto(s)
Hypericum , Sesquiterpenos , Antiinflamatorios/química , Lipopolisacáridos/farmacología , Lipopolisacáridos/metabolismo , Peróxido de Hidrógeno , Simulación del Acoplamiento Molecular , FN-kappa B/metabolismo , Microglía/metabolismo , Dicroismo Circular , Óxido Nítrico , Óxido Nítrico Sintasa de Tipo II/metabolismo
7.
Neuropathology ; 43(5): 391-395, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-36786200

RESUMEN

Pilocytic astrocytoma (PA), a central nervous system (CNS) World Health Organization grade 1 tumor, is mainly seen in children or young adults aged 5-19. Surgical resection often provides excellent outcomes, but residual tumors may still remain. This low-grade tumor is well recognized for its classic radiological and morphological features; however, some unique molecular findings have been unveiled by the application of next-generation sequencing (NGS). Among the genetic abnormalities identified in this low-grade tumor, increasing evidence indicates that BRAF alterations, especially BRAF fusions, play an essential role in PA tumorigenesis. Among the several fusion partner genes identified in PAs, KIAA1549-BRAF fusion is notably the most common detectable genetic alteration, especially in the cerebellar PAs. Here, we report a case of a young adult patient with a large, right-sided posterior fossa cerebellar and cerebellopontine angle region mass consistent with a PA. Of note, NGS detected a novel GNAI3-BRAF fusion, which results in an in-frame fusion protein containing the kinase domain of BRAF. This finding expands the knowledge of BRAF fusions in the tumorigenesis of PAs, provides an additional molecular signature for diagnosis, and a target for future therapy.


Asunto(s)
Astrocitoma , Neoplasias Encefálicas , Neoplasias del Sistema Nervioso Central , Niño , Adulto Joven , Humanos , Proteínas Proto-Oncogénicas B-raf/genética , Astrocitoma/diagnóstico por imagen , Astrocitoma/genética , Astrocitoma/metabolismo , Neoplasias del Sistema Nervioso Central/genética , Mutación , Carcinogénesis , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/genética , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/genética , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/metabolismo
8.
Am J Dermatopathol ; 45(9): e74-e82, 2023 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-37625813

RESUMEN

ABSTRACT: We report a 48-year-old man with CD30+ large cell transformation of mycosis fungoides (tMF) with distinctive anaplastic morphology. The patient initially presented with folliculotropic and syringotropic mycosis fungoides (MF) manifested as occipital scalp plaque and trunk and extremities patches. Six years later, he progressed to the tumor stage from his scalp lesion and developed cervical lymphadenopathy. Lymph node and scalp biopsies showed diffuse infiltration of CD30+ anaplastic cells with multinucleated, hallmark-like, Hodgkin-Reed-Sternberg-like, histiocytoid forms, indistinguishable from anaplastic large cell lymphoma (ALCL). T-cell receptor gamma gene (TCRg) rearrangement studies revealed identical clones in the initial MF scalp lesion and nodal anaplastic lesion, confirming the transformation. Ancillary studies showed absence of IRF4/DUSP22 and ALK rearrangements and positive RB1, SMARCA4, SOCS1, and TP53 mutations. The patient achieved partial response with systemic chemotherapy. Our case is an example of tMF presenting as the morphology and phenotype of ALCL. Because clinical behavior and therapeutic options of tMF and primary cutaneous ALCL may be different, it is clinically relevant to differentiate these 2 entities. The proof of clonal relationship may be useful in diagnostically challenging cases with features overlapping between tMF and primary cutaneous ALCL.


Asunto(s)
Micosis Fungoide , Neoplasias Cutáneas , Masculino , Humanos , Micosis Fungoide/genética , Biopsia , Células Clonales , Extremidades , Neoplasias Cutáneas/genética , ADN Helicasas , Proteínas Nucleares , Factores de Transcripción
9.
Acta Radiol ; 64(6): 2132-2136, 2023 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-37046386

RESUMEN

BACKGROUND: Ultrasound (US)-guided-only insertion at the bedside is safe and improves the success rates of peripherally inserted central catheter (PICC). However, PICC insertion procedures remain challenging for special cases. PURPOSE: To show that fluoroscopically guided tip repositioning, for failed US-guided PICC placement, safely led to satisfactory positioning in difficult cases and, importantly, improved success rates of PICC placements. MATERIAL AND METHODS: A retrospective study of 1560 patients who underwent US-guided PICC placement were performed. Patients who failed US-guided PICC placement were transferred to the interventional radiology department for fluoroscopically guided tip repositioning. Baseline characteristics as well as insertion-related factors were collected. All data were analyzed using SPSS software. RESULTS: In total, 37 (2.4%) patients who failed US-guided PICC placement accepted fluoroscopically guided adjustment or re-insertion. Of these 37 patients, 32 were enrolled. We observed no significant differences between right and left arm PICC access (P > 0.05), even though a higher percentage of PICCs were inserted into left arms (56.3%). The basilic vein (65.6%) was the most common insertion site. Only four patients experienced slight angiospasm (3.1%) and venous thrombosis (9.4%). US-guided PICC insertion failures were primarily due to line tip malposition (84.4%). All patients successfully underwent fluoroscopically guided tip repositioning, which resulted in optimal catheter tip positioning. PICC lines were adjusted in most patients (n=28, 87.5%). CONCLUSION: Malposition was the primary issue causing US-guided PICC insertion failure. Fluoroscopically guided tip repositioning safely and efficaciously led to satisfactory positioning in difficult cases; thus, we recommend this method for patients failing US-guided PICC placement.


Asunto(s)
Cateterismo Venoso Central , Cateterismo Periférico , Catéteres Venosos Centrales , Humanos , Cateterismo Venoso Central/métodos , Estudios Retrospectivos , Reposicionamiento de Medicamentos , Cateterismo Periférico/métodos , Catéteres , Ultrasonografía Intervencional
10.
Angew Chem Int Ed Engl ; 62(38): e202309789, 2023 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-37531257

RESUMEN

A main-group catalysis-based strategy to access 8-membered carbocycles via the direct carbofunctionalization of 2-phenethyl-substituted 1,3-dienes is disclosed. Through the intervention of an I(I)/I(III) catalysis cycle, the synthesis of densely functionalized, fluorinated benzocyclooctenes can be achieved in an operationally simple manner. Modulating the oxidation/activation regime, and the external nucleophile, the process has been extended to unify the challenging cyclization with formation of allylic C-O, C-N, and C-C bonds (>30 examples). Derivatization of the product benzocyclooctenes is demonstrated together with X-ray conformational analysis, preliminary validation of enantioselective catalysis and a scalable resolution protocol.

11.
Neurol Sci ; 43(2): 899-905, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-34973075

RESUMEN

BACKGROUND: Nocebo effect is prevalent among neurological diseases, resulting in low adherence and treatment outcome. We sought to examine the nocebo effect in randomized controlled trials (RCTs) in multiple system atrophy (MSA). METHODS: We searched RCTs in MSA from Medline since September, 2021. RCTs for drug treatment conducted in adult MSA patients with more than 5 cases in each treatment arm were included. We assessed the number of dropout due to placebo intolerance. We also did a symptomatic/disease-modifying subgroup analysis based on two different treatment purposes. The STATA software was used for statistical analysis. Overall heterogeneity was assessed using the Cochran Q and I2. RESULTS: Data were extracted from 11 RCTs fulfilling our search criteria. Of 540 placebo-treated patients, 64.2% reported at least one adverse event (AE) and 7.5% reported dropout because of AEs. The chance of dropping out because of an AE and experiencing at least one AE did not differ between placebo and active drug treatment arms. Besides, the pooled nocebo dropout rate in the symptomatic subgroup was similar to that of the disease-modifying subgroup. CONCLUSION: In MSA RCTs, nocebo dropout rate was not at a low level among neurological disorders. Nocebo effect was an important reason of dropout because of AE in placebo and active drug treatment arms. Different treatment purposes may not influence nocebo effect.


Asunto(s)
Atrofia de Múltiples Sistemas , Efecto Nocebo , Humanos , MEDLINE , Atrofia de Múltiples Sistemas/tratamiento farmacológico , Resultado del Tratamiento
12.
Angew Chem Int Ed Engl ; 61(18): e202201099, 2022 04 25.
Artículo en Inglés | MEDLINE | ID: mdl-35178846

RESUMEN

Catalytic enantioselective functionalization of unactivated 1,1-disubstituted alkenes is challenging due to the difficulty to discriminate the enantiotopic faces. Enantioselective hydrofunctionalization of unactivated 1,1-disubstituted alkenes with tunable Markovnikov and anti-Markovnikov selectivity remains elusive. We report here an amide-directed, regiodivergent and enantioselective hydroalkynylation of unactivated alkenes. The regioselectivity can be readily tuned by the choice of a proper ligand. Catalytic alkynylations occurred with tunable Markovnikov and anti-Markovnikov selectivity to afford products containing acyclic tertiary or quaternary stereocenters ß to an amide. Combining a sequence of alkene isomerization and regioselective hydroalkynylation, we further realized an iridium-catalyzed formal asymmetric conjugated alkynylation of ß,ß-disubstituted α,ß-unsaturated amides. Computational studies suggest that the regioselectivity is dictated by the ligand structures.


Asunto(s)
Alquenos , Iridio , Alquenos/química , Amidas/química , Catálisis , Iridio/química , Ligandos , Estereoisomerismo
13.
Angew Chem Int Ed Engl ; 61(26): e202200075, 2022 06 27.
Artículo en Inglés | MEDLINE | ID: mdl-35460133

RESUMEN

Preparation of skipped dienes with a quaternary carbon center at the C-3 position remains a synthetic challenge. We report here an iridium-catalyzed formal addition of tertiary sp3 C-H bond to alkyne for the facile preparation of skipped dienes. The tertiary allylic C-H bond is cleaved regioselectively, at the site of which a new C-C bond is formed. Enantioselective construction of acyclic quaternary carbon stereocenters is also demonstrated.


Asunto(s)
Alquinos , Iridio , Carbono/química , Catálisis , Iridio/química , Estructura Molecular , Polienos , Estereoisomerismo
14.
Clin Infect Dis ; 73(9): e3027-e3032, 2021 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-32910817

RESUMEN

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19), can be detected in respiratory samples by real-time reverse transcriptase polymerase chain reaction (RT-PCR) or other molecular methods. Accessibility of diagnostic testing for COVID-19 has been limited by intermittent shortages of supplies required for testing, including flocked nasopharyngeal (FLNP) swabs. METHODS: We developed a 3-dimensional printed nasopharyngeal (3DP) swab as a replacement of the FLNP swab. The performance of 3DP and FLNP swabs were compared in a clinical trial of symptomatic patients at 3 clinical sites (n = 291) using 3 SARS-CoV-2 emergency use authorization tests: a modified version of the Centers for Disease Control and Prevention (CDC) RT-PCR Diagnostic Panel and 2 commercial automated formats, Roche Cobas and NeuMoDx. RESULTS: The cycle threshold-C(t)-values from the gene targets and the RNase P gene control in the CDC assay showed no significant differences between swabs for both gene targets (P = .152 and P = .092), with the RNase P target performing significantly better in the 3DP swabs (P < .001). The C(t) values showed no significant differences between swabs for both viral gene targets in the Roche cobas assay (P = .05 and P = .05) as well as the NeuMoDx assay (P = .401 and P = .484). The overall clinical correlation of COVID-19 diagnosis between all methods was 95.88% (Kappa 0.901). CONCLUSIONS: The 3DP swabs were equivalent to standard FLNP in 3 testing platforms for SARS-CoV-2. Given the need for widespread testing, 3DP swabs printed onsite are an alternate to FLNP that can rapidly scale in response to acute needs when supply chain disruptions affect availability of collection kits.


Asunto(s)
Prueba de COVID-19 , COVID-19 , Humanos , Nasofaringe , Impresión Tridimensional , SARS-CoV-2 , Manejo de Especímenes
15.
J Clin Microbiol ; 59(2)2021 01 21.
Artículo en Inglés | MEDLINE | ID: mdl-33239382

RESUMEN

Highly accurate testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the point of care (POC) is an unmet diagnostic need in emergency care and time-sensitive outpatient care settings. Reverse transcription-PCR (RT-PCR) technology is the gold standard for SARS-CoV-2 diagnostics. We performed a multisite U.S. study comparing the clinical performance of the first U.S. Food and Drug Administration (FDA)-authorized POC RT-PCR for detection of SARS-CoV-2 in 20 min, the cobas Liat SARS-CoV-2 and influenza A/B nucleic acid test, to the most widely used RT-PCR laboratory test, the cobas 68/8800 SARS-CoV-2 test. Clinical nasopharyngeal swab specimens from 444 patients with 357 evaluable specimens at five U.S. clinical laboratories were enrolled from 21 September 2020 to 23 October 2020. The overall agreement between the Liat and 68/8800 systems for SARS-CoV-2 diagnostics was 98.6% (352/357). Using Liat, positive percent agreement for SARS-CoV-2 was 100% (162/162) and the negative percent agreement was 97.4% (190/195). The Liat is an RT-PCR POC test that provides highly accurate SARS-CoV-2 results in 20 min with performance equivalent to that of high-throughput laboratory molecular testing. Rapid RT-PCR testing at the POC can enable more timely infection control and individual care decisions for coronavirus disease 2019.


Asunto(s)
Prueba de Ácido Nucleico para COVID-19/métodos , COVID-19/diagnóstico , Sistemas de Atención de Punto , SARS-CoV-2/aislamiento & purificación , Prueba de Ácido Nucleico para COVID-19/instrumentación , Humanos , Nasofaringe/virología , SARS-CoV-2/genética , Factores de Tiempo , Estados Unidos
16.
Acta Pharmacol Sin ; 42(2): 301-310, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32699265

RESUMEN

Sorafenib is the first-line medication for advanced hepatocellular carcinoma (HCC), but it can only extend limited survival. It is imperative to find a combination strategy to increase sorafenib efficacy. Artesunate is such a preferred candidate, because artesunate is clinically well-tolerated and more importantly both drugs can induce ferroptosis through different mechanisms. In this study we investigated the combined effect of sorafenib and artesunate in inducing ferroptosis of HCC and elucidated the involved molecular mechanisms. We showed that artesunate greatly enhanced the anticancer effects of low dose of sorafenib against Huh7, SNU-449, and SNU-182 HCC cell lines in vitro and against Huh7 cell xenograft model in Balb/c nude mice. The combination index method confirmed that the combined effect of sorafenib and artesunate was synergistic. Compared with the treatment with artesunate or sorafenib alone, combined treatment induced significantly exacerbated lipid peroxidation and ferroptosis, which was blocked by N-acetyl cysteine and ferroptosis inhibitors liproxstatin-1 and deferoxamine mesylate, but not by inhibitors of other types of cell death (z-VAD, necrostatin-1 and belnacasan). In Huh7 cells, we demonstrated that the combined treatment induced oxidative stress and lysosome-mediated ferritinophagy, two essential aspects of ferroptosis. Sorafenib at low dose mainly caused oxidative stress through mitochondrial impairments and SLC7A11-invovled glutathione depletion. Artesunate-induced lysosome activation synergized with sorafenib-mediated pro-oxidative effects by promoting sequential reactions including lysosomal cathepsin B/L activation, ferritin degradation, lipid peroxidation, and consequent ferroptosis. Taken together, artesunate could be repurposed to sensitize sorafenib in HCC treatment. The combined treatment can be easily translated into clinical applications.


Asunto(s)
Artesunato/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Sorafenib/farmacología , Animales , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Artesunato/administración & dosificación , Carcinoma Hepatocelular/patología , Línea Celular Tumoral , Sinergismo Farmacológico , Ferroptosis/efectos de los fármacos , Humanos , Peroxidación de Lípido/efectos de los fármacos , Neoplasias Hepáticas/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Estrés Oxidativo/efectos de los fármacos , Sorafenib/administración & dosificación , Ensayos Antitumor por Modelo de Xenoinjerto
17.
Proc Natl Acad Sci U S A ; 115(47): E11091-E11100, 2018 11 20.
Artículo en Inglés | MEDLINE | ID: mdl-30397150

RESUMEN

Prostate cancer is a leading cause of cancer death in men over 50 years of age, and there is a characteristic marked decrease in Zn content in the malignant prostate cells. The cause and consequences of this loss have thus far been unknown. We found that in middle-aged rats a Zn-deficient diet reduces prostatic Zn levels (P = 0.025), increases cellular proliferation, and induces an inflammatory phenotype with COX-2 overexpression. This hyperplastic/inflammatory prostate has a human prostate cancer-like microRNA profile, with up-regulation of the Zn-homeostasis-regulating miR-183-96-182 cluster (fold change = 1.41-2.38; P = 0.029-0.0003) and down-regulation of the Zn importer ZIP1 (target of miR-182), leading to a reduction of prostatic Zn. This inverse relationship between miR-182 and ZIP1 also occurs in human prostate cancer tissue, which is known for Zn loss. The discovery that the Zn-depleted middle-aged rat prostate has a metabolic phenotype resembling that of human prostate cancer, with a 10-fold down-regulation of citric acid (P = 0.0003), links citrate reduction directly to prostatic Zn loss, providing the underlying mechanism linking dietary Zn deficiency with miR-183-96-182 overexpression, ZIP1 down-regulation, prostatic Zn loss, and the resultant citrate down-regulation, changes mimicking features of human prostate cancer. Thus, dietary Zn deficiency during rat middle age produces changes that mimic those of human prostate carcinoma and may increase the risk for prostate cancer, supporting the need for assessment of Zn supplementation in its prevention.


Asunto(s)
Adenocarcinoma/patología , Proteínas de Transporte de Catión/metabolismo , Próstata/patología , Hiperplasia Prostática/patología , Neoplasias de la Próstata/patología , Zinc/deficiencia , Adenocarcinoma/genética , Animales , Proliferación Celular , Ácido Cítrico/metabolismo , Dieta , Modelos Animales de Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , MicroARNs/biosíntesis , Hiperplasia Prostática/genética , Neoplasias de la Próstata/genética , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Transducción de Señal/genética , Transcripción Genética/genética , Células Tumorales Cultivadas , Zinc/metabolismo
18.
J Exp Bot ; 71(1): 90-104, 2020 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-31587070

RESUMEN

An increased concentration of cytosolic Ca2+ is an early response of plant cells to heat shock. Arabidopsis cyclic nucleotide-gated ion channel 6 (CNGC6) mediates heat-induced Ca2+ influx and is activated by cAMP. However, it remains unclear how the Ca2+ conductivity of CNGC6 is negatively regulated under the elevated cytosolic Ca2+ concentration. In this study, Arabidopsis calmodulin isoforms CaM1/4, CaM2/3/5, CaM6, and CaM7 were found to bind to CNGC6 to varying degrees, and this binding was dependent on the presence of Ca2+ and IQ6, an atypical isoleucine-glutamine motif in CNGC6. Knockout of CaM2, CaM3, CaM5, and CaM7 genes led to a marked increase in plasma membrane inward Ca2+ current under heat shock conditions; however, knockout of CaM1, CaM4, and CaM6 genes had no significant effect on plasma membrane Ca2+ current. Moreover, the deletion of IQ6 from CNGC6 led to a marked increase in plasma membrane Ca2+ current under heat shock conditions. Taken together, the data suggest that CNGC6-mediated Ca2+ influx is likely to be negatively regulated by CaM2/3/5 and CaM7 isoforms under heat shock conditions, and that IQ6 plays an important role in CaM binding and the feedback regulation of the channel.


Asunto(s)
Proteínas de Arabidopsis/genética , Arabidopsis/fisiología , Calmodulina/metabolismo , Canales Catiónicos Regulados por Nucleótidos Cíclicos/genética , Regulación de la Expresión Génica de las Plantas/genética , Respuesta al Choque Térmico/genética , Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Canales Catiónicos Regulados por Nucleótidos Cíclicos/metabolismo , Isoformas de Proteínas/metabolismo
19.
J Neurol Neurosurg Psychiatry ; 91(8): 846-848, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32354770

RESUMEN

BACKGROUND: Emergence of the novel corona virus (severe acute respiratory syndrome (SARS)-CoV-2) in December 2019 has led to the COVID-19 pandemic. The extent of COVID-19 involvement in the central nervous system is not well established, and the presence or the absence of SARS-CoV-2 particles in the cerebrospinal fluid (CSF) is a topic of debate. CASE DESCRIPTION: We present two patients with COVID-19 and concurrent neurological symptoms. Our first patient is a 31-year-old man who had flu-like symptoms due to COVID-19 and later developed an acute-onset severe headache and loss of consciousness and was diagnosed with a Hunt and Hess grade 3 subarachnoid haemorrhage from a ruptured aneurysm. Our second patient is a 62-year-old woman who had an ischaemic stroke with massive haemorrhagic conversion requiring a decompressive hemicraniectomy. Both patients' CSF was repeatedly negative on real-time PCR analysis despite concurrent neurological disease. CONCLUSION: Our report shows that patients' CSF may be devoid of viral particles even when they test positive for COVID-19 on a nasal swab. Whether SARS-CoV-2 is present in CSF may depend on the systemic disease severity and the degree of the virus' nervous tissue tropism and should be examined in future studies.


Asunto(s)
Betacoronavirus/aislamiento & purificación , Infecciones por Coronavirus/líquido cefalorraquídeo , Infecciones por Coronavirus/complicaciones , Neumonía Viral/líquido cefalorraquídeo , Neumonía Viral/complicaciones , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/virología , Adulto , COVID-19 , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pandemias , SARS-CoV-2 , Accidente Cerebrovascular/líquido cefalorraquídeo
20.
Pain Med ; 21(10): 2111-2116, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32951055

RESUMEN

OBJECTIVES: To explore the features of high-intensity zone (HIZ) in anterior annulus fibrosus and assess the association of anterior HIZ with low back pain (LBP). DESIGN, SETTING, AND SUBJECTS: A retrospective study of 5,940 discs in 1,188 individuals was conducted. METHODS: Subjects' information and LBP symptoms confirmed by an orthopedic surgeon were acquired from the medical record. Magnetic resonance (MR) image reading and analysis were performed by two experienced blinded radiologists. RESULTS: Two hundred eighty individuals exhibited 355 anterior HIZs in 355 discs. The prevalence was 23.57%; 88.45% were located in the inferior part of the annulus fibrosus. It frequently occurred in the middle and upper segments of lumbar spine, especially at L3/4 (45.63%). Of the 355 anterior HIZs, only 79 (22.25%) were consecutive-slides HIZ. Round type (63.38%) was the most common shape of anterior HIZs. The highest prevalence was found in individuals aged 60-69 years. LBP was confirmed in 141 anterior-HIZ individuals. The incidence of LBP in anterior-HIZ individuals was significantly higher than in non-HIZ subjects (50.36% vs 35.24%, χ2 = 18.314, P < 0.001). CONCLUSIONS: Anterior HIZ is a lower-prevalence, age-related sign on lumbar MR images. The spatial distribution of anterior HIZ can be distinguished from posterior HIZ. The number of consecutive anterior HIZ slides might suggest fewer Dallas grade 4 anterior annular disruptions in this sample. Anterior HIZ was correlated with LBP.


Asunto(s)
Disco Intervertebral , Dolor de la Región Lumbar , Anciano , Humanos , Disco Intervertebral/diagnóstico por imagen , Dolor de la Región Lumbar/diagnóstico por imagen , Dolor de la Región Lumbar/epidemiología , Vértebras Lumbares/diagnóstico por imagen , Región Lumbosacra/diagnóstico por imagen , Imagen por Resonancia Magnética , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos
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