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1.
Eur J Med Chem ; 277: 116773, 2024 Nov 05.
Artículo en Inglés | MEDLINE | ID: mdl-39163779

RESUMEN

Due to the emerging global epidemic of obesity, developing safe and effective agents for anti-obesity is urgently needed. Our previous study found that 2-pyrimidinylindole derivative Wd3d exhibited potential anti-obesity activity. Herein, to further optimize the potential moiety, structural modifications were proceeded for two rounds in this study. Firstly, we designed, synthesized, and evaluated 36 new derivatives of 2-pyrimidinylindole scaffold with different substituents on the indole ring and pyrimidine ring to investigate their structure-activity relationship (SAR). Then, analogs with potent activity had the aldehyde group replaced with the acylhydrazone group to reduce cytotoxicity and improve metabolic stability. Detailed SAR studies and animal evaluation experiments led to the discovery of the compound 9ga, which significantly reduced TG accumulation with an EC50 value of 0.07 µM and showed relatively low cytotoxicity with an IC50 value of around 24 µM. Oral administration of 9ga effectively prevented the excessive growth of body weight and lessened fat mass as well as liver mass, decreased lipid accumulation in the liver and blood, and improved the heart injury parameter in the diet-induced obesity mouse model significantly better than Wd3d. A mechanism study showed that 9ga regulated the lipid metabolism during early adipogenesis by inhibiting PPARγ pathway. In conclusion, our study further highlights the anti-obesity potential of 2-pyrimidinylindole derivatives in diet-induced obesity.


Asunto(s)
Fármacos Antiobesidad , Diseño de Fármacos , Indoles , Obesidad , Relación Estructura-Actividad , Animales , Fármacos Antiobesidad/farmacología , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/química , Ratones , Indoles/química , Indoles/farmacología , Indoles/síntesis química , Obesidad/tratamiento farmacológico , Administración Oral , Estructura Molecular , Masculino , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinas/síntesis química , Relación Dosis-Respuesta a Droga , Ratones Endogámicos C57BL , Humanos , Células 3T3-L1
2.
Phytopathology ; 114(8): 1917-1925, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39135297

RESUMEN

The rice blast fungus Magnaporthe oryzae poses a significant challenge to maintaining rice production. Developing rice varieties with resistance to this disease is crucial for its effective control. To understand the genetic variability of blast isolates collected between 2015 and 2017, the 27 monogenic rice lines that carry specific resistance genes were used to evaluate blast disease reactions. Based on criteria such as viability, virulence, and reactions to resistance genes, 20 blast isolates were selected as representative strains. To identify novel resistance genes, a quantitative trait locus analysis was carried out utilizing a mixture of the 20 representative rice blast isolates and a rice population derived from crossing the blast-resistant cultivar 'Cheongcheong' with the blast-susceptible cultivar 'Nagdong'. This analysis revealed a significant locus, RM1227-RM1261 on chromosome 12, that is associated with rice blast resistance. Within this locus, 12 disease resistance-associated protein genes were identified. Among them, OsDRq12, a member of the nucleotide-binding, leucine-rich repeat disease resistance family, was chosen as the target gene for additional computational investigation. The findings of this study have significant implications for enhancing rice production and ensuring food security by controlling rice blast and developing resistant rice cultivars.


Asunto(s)
Resistencia a la Enfermedad , Variación Genética , Oryza , Enfermedades de las Plantas , Oryza/microbiología , Oryza/inmunología , Oryza/genética , Enfermedades de las Plantas/microbiología , Enfermedades de las Plantas/inmunología , Resistencia a la Enfermedad/genética , Sitios de Carácter Cuantitativo/genética , Genes de Plantas/genética , Ascomicetos/genética , Ascomicetos/patogenicidad , Ascomicetos/fisiología , Proteínas de Plantas/genética , Magnaporthe/genética , Magnaporthe/patogenicidad , Magnaporthe/fisiología
3.
J Med Chem ; 67(14): 12439-12458, 2024 Jul 25.
Artículo en Inglés | MEDLINE | ID: mdl-38996004

RESUMEN

The discovery of effective and safe antiobesity agents remains a challenging yet promising field. Our previous studies identified Bouchardatine derivatives as potential antiobesity agents. However, the 8a-aldehyde moiety rendered them unsuitable for drug development. In this study, we designed two series of novel derivatives to modify this structural feature. Through a structure-activity relationship study, we elucidated the role of the 8a-aldehyde group in toxicity induction. We identified compound 14d, featuring an 8a-N-acylhydrazone moiety, which exhibited significant lipid-lowering activity and reduced toxicity. Compound 14d shares a similar lipid-lowering mechanism with our lead compound 3, but demonstrates improved pharmacokinetic properties and safety profile. Both oral and injectable administration of 14d significantly reduced body weight gain and ameliorated metabolic syndrome in diet-induced obese mice. Our findings identify 14d as a promising antiobesity agent and highlight the potential of substituting the aldehyde group with an N-acylhydrazone to enhance drug-like properties.


Asunto(s)
Aldehídos , Fármacos Antiobesidad , Hidrazonas , Obesidad , Animales , Fármacos Antiobesidad/farmacología , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/farmacocinética , Fármacos Antiobesidad/uso terapéutico , Fármacos Antiobesidad/química , Hidrazonas/farmacología , Hidrazonas/química , Hidrazonas/síntesis química , Hidrazonas/farmacocinética , Hidrazonas/uso terapéutico , Ratones , Relación Estructura-Actividad , Aldehídos/química , Masculino , Obesidad/tratamiento farmacológico , Ratones Endogámicos C57BL , Dieta Alta en Grasa/efectos adversos , Humanos , Ratones Obesos , Estructura Molecular
4.
Plant Physiol Biochem ; 214: 108941, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39029307

RESUMEN

Arsenic, a hazardous heavy metal with potent carcinogenic properties, significantly affects key rice-producing regions worldwide. In this study, we present a quantitative trait locus (QTL) mapping investigation designed to identify candidate genes responsible for conferring tolerance to arsenic toxicity in rice (Oryza sativa L.) during the seedling stage. This study identified 17 QTLs on different chromosomes, including qCHC-1 and qCHC-3 on chromosome 1 and 3 related to chlorophyll content and qRFW-12 on chromosome 12 related to root fresh weight. Gene expression analysis revealed eight candidate genes exhibited significant upregulation in the resistant lines, OsGRL1, OsDjB1, OsZIP2, OsMATE12, OsTRX29, OsMADS33, OsABCG29, and OsENODL24. These genes display sequence alignment and phylogenetic tree similarities with other species and engaging in protein-protein interactions with significant proteins. Advanced gene-editing techniques such as CRISPR-Cas9 to precisely target and modify the candidate genes responsible for arsenic tolerance will be explore. This approach may expedite the development of arsenic-resistant rice cultivars, which are essential for ensuring food security in regions affected by arsenic-contaminated soil and water.


Asunto(s)
Arsénico , Oryza , Sitios de Carácter Cuantitativo , Estrés Fisiológico , Oryza/genética , Oryza/efectos de los fármacos , Oryza/metabolismo , Arsénico/toxicidad , Sitios de Carácter Cuantitativo/genética , Estrés Fisiológico/genética , Estrés Fisiológico/efectos de los fármacos , Haploidia , Mapeo Cromosómico , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Genes de Plantas , Regulación de la Expresión Génica de las Plantas/efectos de los fármacos , Cromosomas de las Plantas/genética
5.
PhytoKeys ; 241: 229-239, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38737294

RESUMEN

Chimonobambusapleiacantha, a newly-identified species of the genus Chimonobambusa Makino from southeast Sichuan, China, is meticulously described and illustrated herein. It is morphologically similar to Ch.tuberculata, but differs in having 4-angled internodes, thicker wall to 4.5-8.5 mm, more reclinate and elongated root thorns to 5-8 mm long, culm internodes with three grooves and two longitudinal ridges on the branch-bearing side, persistent culm leaves, densely brown-purple setose at the bottom of culm leaf sheaths together with sheath scar, developed foliage leaf fimbriae, 6-8 on each shoulder, ca. 3-8 mm long, abaxially white pubescent foliage leaf blades. Phenologically, new shoots usually appear in September to October. In the light of these key morphological and phenological characteristics, Ch.pleiacantha was identified as a new species of the genus Ch. Makino which is different from published species of this genus.

6.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 32(2): 458-465, 2024 Apr.
Artículo en Chino | MEDLINE | ID: mdl-38660852

RESUMEN

OBJECTIVE: To explore the correlation between peripheral blood B cell count and clinical features and prognosis of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). METHODS: The relationship of peripheral blood B cell count with clinical features, laboratory indexes and prognosis in 67 patients with newly diagnosed DLBCL was retrospectively analyzed. RESULTS: Patients were divided into low B-cell count group (B cell<0.1×109/L, n=34) and high B-cell count group (B cell≥0.1×109/L, n=33) according to the median B cell count values. Compared with the high B cell count group, the low B cell count group had a higher proportion of patients with Lugano stage III-IV, elevated LDH, elevated ß2-MG and IPI score 3-5 and increased CRP (P =0.033, 0.000, 0.023, 0.001, 0.033). The peripheral CD3+ and CD4+ cell counts of patients in the low B cell count group were significantly lower than those in the high B cell count group (P =0.010, 0.017). After initial treatment, overall response rate (ORR) and complete remission (CR) rate in high B cell count group were significantly higher than those in low B cell count group (P =0.032, 0.013). The median follow-up time of patients was 23(2-77) months, progression-free survival (PFS) and overall survival (OS) of patients in the high B cell count group were significantly better than those in the low B cell count group (P =0.001, 0.002). Univariate analysis showed that pretreatment low B cell count in the peripheral blood was associated with shortened PFS and OS (HR=4.108, P =0.002; HR=8.218, P =0.006). Multivariate analysis showed that low B cell count was an independent prognostic factor for shortened PFS (HR=3.116, P =0.037). CONCLUSION: Decreased peripheral blood B cell count in newly diagnosed DLBCL patients is associated with high-risk clinical features and may affect the efficacy of immunochemotherapy, which is associated with poor clinical prognosis.


Asunto(s)
Linfocitos B , Linfoma de Células B Grandes Difuso , Humanos , Linfoma de Células B Grandes Difuso/sangre , Linfoma de Células B Grandes Difuso/diagnóstico , Pronóstico , Estudios Retrospectivos , Recuento de Linfocitos , Masculino , Femenino , Persona de Mediana Edad
7.
Eur J Med Chem ; 260: 115729, 2023 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-37607439

RESUMEN

Obesity, a global pandemic posing a growing threat to human health, necessitates the development of effective and safe anti-obesity agents. Our previous studies highlighted the lipid-lowering effects of indolylquinazoline Bouchardatine and its derivatives. In this study, we employed scaffold hopping and simplification strategies to design and synthesize two new series derivatives by modifying the D ring. Extensive discussions have been conducted regarding the structure-activity relationship between lipid-lowering activity and the new compounds. These discussions have resulted in the discovery of 2-pyrimidinylindole derivatives as a promising scaffold for anti-obesity treatment. The new 2-pyrimidinylindole derivatives exhibited comparable lipid-lowering activity to the previously reported indolylquinazoline derivatives, including SYSU-3d and R17, with reduced toxicity. The most potent compound, 5a, demonstrated a larger therapeutic index, improved aqueous solubility and oral bioavailability compared to the previous lead compounds. In vivo evaluation indicated that 5a effectively reduced lipid accumulation in adipose tissue, improved glucose tolerance, and mitigated insulin resistance and liver function damage caused by a high-fat and high-cholesterol diet. Mechanism studies indicated that 5a may regulate lipid metabolism through the modulation of the PPARγ signaling pathway. Overall, our study has identified a highly active compound 5a, and provided the basis for further development of 2-pyrimidinylindole as a promising scaffold for obesity treatment.


Asunto(s)
Fármacos Antiobesidad , Hipercolesterolemia , Humanos , Metabolismo de los Lípidos , Fármacos Antiobesidad/farmacología , Disponibilidad Biológica , Obesidad/tratamiento farmacológico , Lípidos
8.
Mol Breed ; 43(5): 39, 2023 May.
Artículo en Inglés | MEDLINE | ID: mdl-37312747

RESUMEN

The gelatinization temperature of rice is an important factor in determining the eating and cooking quality, and it affects consumer preference. The alkali digestion value (ADV) is one of the main methods used to test the quality of rice and has a high correlation with the gelatinization temperature. For the development of high-quality rice, it is important to understand the genetic basis of palatability-related traits, and QTL analysis is a statistical method linking phenotypic data and genotype data and is an effective method to explain the genetic basis of variation in complex traits. QTL mapping related to the ADV of brown and milled rice was performed using the 120 Cheongcheong/Nagdong double haploid (CNDH) line. As a result, 12 QTLs related to ADV were detected, and 20 candidate genes were selected from the RM588-RM1163 region of chromosome 6 through screening by gene function analysis. The comparison of the relative expression level of candidate genes showed that OsSS1q6 is highly expressed in CNDH lines with high ADV in both brown rice and milled rice. In addition, OsSS1q6 has high homology with the starch synthase 1 protein and interacts with various starch biosynthesis-related proteins, such as GBSSII, SBE, and APL. Therefore, we suggest that OsSS1q6 identified through QTL mapping could be one of the various genes involved in the gelatinization temperature of rice by regulating starch biosynthesis. This study can be used as basic data for breeding high-quality rice and provides a new genetic resource that can increase the palatability of rice. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-023-01392-2.

9.
J Med Chem ; 66(11): 7387-7404, 2023 06 08.
Artículo en Inglés | MEDLINE | ID: mdl-37253101

RESUMEN

Metabolic reprogramming is a crucial hallmark of tumorigenesis. Modulating the reprogrammed energy metabolism is an attractive anticancer therapeutic strategy. We previously found a natural product, bouchardatine, modulated aerobic metabolism and inhibited proliferation in the colorectal cancer cell (CRC). Herein, we designed and synthesized a new series of bouchardatine derivatives to discover more potential modulators. We applied the dual-parametric high-content screening (HCS) to evaluate their AMP-activated protein kinase (AMPK) modulation and CRC proliferation inhibition effect simultaneously. And we found their antiproliferation activities were highly correlated to AMPK activation. Among them, 18a was identified with nanomole-level antiproliferation activities against several CRCs. Interestingly, the evaluation found that 18a selectively upregulated oxidative phosphorylation (OXPHOS) and inhibited proliferation by modulating energy metabolism. Additionally, this compound effectively inhibited the RKO xenograft growth along with AMPK activation. In conclusion, our study identified 18a as a promising candidate for CRC treatment and suggested a novel anti-CRC strategy by AMPK activating and OXPHOS upregulating.


Asunto(s)
Proteínas Quinasas Activadas por AMP , Neoplasias Colorrectales , Humanos , Proteínas Quinasas Activadas por AMP/metabolismo , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Alcaloides Indólicos/farmacología , Metabolismo Energético , Proliferación Celular , Línea Celular Tumoral
10.
Plants (Basel) ; 12(6)2023 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-36987002

RESUMEN

Amino acids are building blocks of proteins that are essential components of a wide range of metabolic pathways in plant species, including rice species. Previous studies only considered changes in the amino acid content of rice under NaCl stress. Here, we evaluated profiles of essential and non-essential amino acids in four rice genotype seedlings in the presence of three types of salts, namely NaCl, CaCl2, and MgCl2. Amino acid profiles in 14-day-old rice seedlings were determined. The total essential and non-essential amino acid contents in cultivar Cheongcheong were considerably increased upon NaCl and MgCl2 application, whereas total amino acids were increased upon NaCl, CaCl2, and MgCl2 application in the cultivar Nagdong. The total amino acid content was significantly lower in the salt-sensitive cultivar IR28 and salt-tolerant Pokkali under different salt stress conditions. Glycine was not detected in any of the rice genotypes. We observed that cultivars with the same origin respond similarly to each other under salinity stress conditions: cultivars Cheongcheong and Nagdong were found to show increased total amino acid content, whereas the content in foreign cultivars IR28 and Pokkali was found to decrease. Thus, our findings showed that the amino acid profile of each rice cultivar might depend on the origin, immune level, and genetic makeup of the respective cultivar.

11.
Plants (Basel) ; 12(3)2023 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-36771534

RESUMEN

We detected a new target quantitative trait locus (QTL) for lodging resistance in rice by analyzing lodging resistance to typhoons (Maysak and Haishen) using a scale from 0 (no prostrating) to 1 (little prostrating or prostrating) to record the resistance score in a Cheongcheong/Nagdong double haploid rice population. Five quantitative trait loci for lodging resistance to typhoons were detected. Among them, qTyM6 and qTyH6 exhibited crucial effects of locus RM3343-RM20318 on chromosome 6, which overlaps with our previous rice lodging studies for the loci qPSLSA6-2, qPSLSB6-5, and qLTI6-2. Within the target locus RM3343-RM20318, 12 related genes belonging to the cytochrome P450 protein family were screened through annotation. Os06g0599200 (OsTyM/Hq6) was selected for further analysis. We observed that the culm and panicle lengths were positively correlated with lodging resistance to typhoons. However, the yield was negatively correlated with lodging resistance to typhoons. The findings of this study improve an understanding of rice breeding, particularly the culm length, early maturing, and heavy panicle varieties, and the mechanisms by which the plant's architecture can resist natural disasters such as typhoons to ensure food safety. These results also provide the insight that lodging resistance in rice may be associated with major traits such as panicle length, culm length, tiller number, and heading date, and thereby improvements in these traits can increase lodging resistance to typhoons. Moreover, rice breeding should focus on maintaining suitable varieties that can withstand the adverse effects of climate change in the future and provide better food security.

12.
Artículo en Inglés | MEDLINE | ID: mdl-36691597

RESUMEN

Background: Diet acts on the human body through digestion in the stomach and absorption in the intestines. Thus, the emptying of the stomach should be the focus of the research mechanism of the combined medicine and food treatment of diabetes. The emptying function of the stomach and the secretion of related hormones may be the key points of traditional Chinese medicine. In the clinic, Yunvjian is a famous traditional Chinese formula for preventing and curing diabetes. However, the pharmacological action and mechanism of Yunvjian are also need to be probe. Objective: To assess the effect of Yunvjian on glucose, insulin level and gastric emptying function and related hormones on high-fat diet combined with STZ-induced diabetic rats. Methods: High-fat diet combined with STZ was used to construct type 2 diabetes mellitus (T2DM) rats model and received a 4-week Yunvjian administration. The animals were divided into 6 groups, respectively, as the Control group, the DM group, the DM + Acarbose group, the DM + YNH group, and the DM + YNL group. Radionuclide single-photon emission computed tomography (SPECT) technology was used to observe the gastric emptying rate and half-empty time; blood was took to test fasting insulin, and then the insulin resistance index (HOMA-IR) was calculated; HE staining was performed to detect islets and gastric antrum, immunohistochemical staining was performed to detect the number and morphology of pancreatic ß cells and gastric antrum Cajal cells, and the average optical density was calculated; the expression of ghrelin hormone in gastric antrum and serum was detected by ELISA and immunofluorescence; the expression of GHRS mRNA in gastric antrum was detected by RT-PCR method. Results: Yunvjian could significantly improve the glucose level and insulin function of rats. Compared with the DM group, Yunvjian was beneficial to low fasting blood glucose (FBG) (P < 0.01), increased glucose tolerance, and improved islet function at the same time (P < 0.05). At the same time, compared with the DM group (25.02 ± 0.05, 44 ± 12.33), the emptying rate of the DM + YNH group was significantly faster (64.98 ± 0.12), and the half row time was shortened (26 ± 8.29, P < 0.05). The gastric ghrelin levels in each group of Yunvjian increased with different degrees compared with the DM group (616.2 ± 26.23), especially in the DM + YNH group (863.51 ± 23.76, P < 0.01). Correspondingly, the expression of gastric GHSR mRNA in the DM + YNH and DM + YNL groups increased significantly compared with the DM group (P < 0.01). Conclusions: Yunvjian can effectively control glucose and improve islet function, which may be closely related to its influence on gastric emptying function and related hormone secretion regulation.

13.
Ying Yong Sheng Tai Xue Bao ; 33(10): 2628-2634, 2022 Oct.
Artículo en Chino | MEDLINE | ID: mdl-36384596

RESUMEN

Understanding the changes and influencing factors of soil organic carbon density (SOCD) during the conversion of uncultivated natural soil to croplands is of great significance for the assessment of carbon sequestration in arid areas. In this study, we compared SOCD in the uncultivated soil and that in croplands with different cultivation years (2-5, 12-15, 25-30, 40-50 years) in the Northeastern Ulan Buh Desert. The change of SOCD and its influencing factors at 0-2 m soil depth during the conversion of uncultivated natural soil to croplands were explored by the method of replacing time with space. The results showed that SOCD at the shallow soil depth (0-0.4 m) in croplands increased continuously with cultivation years, but basically at low levels (0.990-1.983 kg·m-2). The SOCD at deep soil (1.2-2 m) increased in the croplands with longer cultivation years (25-30 and 40-50 years), whereas no obvious change trends in both the croplands with shorter cultivation years (2-5 and 12-15 years) and the uncultivated natural soil. The SOCD at deep soil (1.2-2 m) were relatively large (28.9%-38.6%) of the 0-2 m soil depth of uncultivated natural soil and croplands with different cultivation years. The vertical distribution of SOCD in croplands with different cultivation years were well fitted by quadratic functions (with R2 ranging from 0.757 to 0.972). It was noteworthy that soil clay and silt contents had dominant influences on SOCD at all the soil profile (0-2 m), and that cultivation years mainly contributed to the accumulation of SOC at the shallow soil (0-0.4 m).


Asunto(s)
Carbono , Suelo , Carbono/análisis , Agricultura , China , Productos Agrícolas
14.
Front Plant Sci ; 13: 1041181, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36388489

RESUMEN

The overall effects of gibberellic acid (GA3) with NaCl on different rice genotypes are inadequately understood. The present study determines the effect of different GA3 (50 and 100 µM) concentrations on the morphophysiological, molecular and biochemical effects of 120 mM NaCl salt stress in rice seedlings. Salt stress reduced germination percentages and seedling growth and decreased bioactive GA content. It also downregulated the relative expression of α-amylase-related genes - OsAmy1A, OsAmy1C, and OsAmy3C in the salt-sensitive IR28 cultivar. Salt stress differentially regulated the expression of GA biosynthetic genes. Salt stress increased antioxidant activity in all rice genotypes tested, except in IR28. GA3 mitigates the effect of salt stress, rescuing seed germination and growth attributes. GA3 significantly increased bioactive GA content in Nagdong and pokkali (50 µM) and Cheongcheong and IR28 (100 µM) cultivars. The α-amylase genes were also significantly upregulated by GA3. Similarly, GA3 upregulated OsGA2ox1 and OsGA2ox9 expression in the Cheongcheong and salt-sensitive IR28 cultivars. The present study demonstrated that salt stress inactivates bioactive GA - inhibiting germination and seedlings growth - and decreases bioactive GA content and GSH activity in IR28 and Pokkali cultivars. Further, GA3 significantly reversed the effects of 120 mM NaCl salt stress in different rice genotypes. The current study suggested that the known coastal area salinity concentration can be significantly recovered with the application of exogenous GA3. Thus, it could be possible to grow eco-friendly rice close to the coastal zone in order to reduce the damage caused by salinity.

15.
World J Gastrointest Oncol ; 14(8): 1528-1539, 2022 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-36160735

RESUMEN

BACKGROUND: Approximately half of all new cases of gastric cancer (GC) and related deaths occur in China. More than 80% of patients with GC are diagnosed at an advanced stage, which results in poor prognosis. Although HER2-directed therapy and immune checkpoint inhibitors have been somewhat successful, new drugs are still needed for the treatment of GC. Notably, several gene fusion-targeted drugs have been approved by the United States Food and Drug Administration for solid tumors, including GC, such as larotrectinib for NTRK fusion-positive cancers and zenocutuzumab for NRG1 fusion-positive cancers. However, gene fusions involving targetable genes have not been well characterized in Chinese patients with GC. AIM: To identify the profile of fusions involving targetable genes in Chinese patients with GC using clinical specimens and determine the distribution of patients with gene fusion variants among the molecular subtypes of GC. METHODS: We retrospectively analyzed gene fusion events in tumor tissue samples from 954 Chinese patients with GC. Clinicopathological characteristics were obtained from their medical records. Genetic alterations, such as single nucleotide variants, indels, amplifications, and gene fusions, were identified using a targeted sequencing panel containing 825 genes. Fusions were validated by fluorescence in situ hybridization (FISH) using break-apart probes. The microsatellite instability (MSI) status was evaluated using MSIsensor from the targeted sequencing panel data. Tumor mutational burden (TMB) was calculated using the total number of nonsynonymous mutations divided by the total genomic targeted region. Chi-square analysis was used to determine the enrichment of gene fusions associated with the molecular subtypes of GC. RESULTS: We found that 1.68% (16/954) of patients harbored 20 fusion events involving targetable genes. RARA fusions (n = 5) were the most common, followed by FGFR2, BRAF, MET, FGFR3, RET, ALK, EGFR, NTRK2, and NRG1 fusions. Two of the RARA fusions, EML4-ALK (E6:E20) and EGFR-SEPTIN14 (E7:E10), have been identified in other tumors but not in GC. Surprisingly, 18 gene fusion events were previously not reported in any cancer types. Twelve of the eighteen novel gene fusions included complete exons encoding functional domains of targetable genes, such as the tyrosine kinase domain of receptor tyrosine kinases and the DNA- and ligand-binding domains of RARA. Consistent with the results of detection using the targeted sequencing fusion panel, the results of FISH (fluorescence in situ hybridization) confirmed the rearrangement of FGFR2 and BRAF in tumors from patients 04 and 09, respectively. Genetic analysis indicated that the fusion genes were significantly enriched in patients with ERBB2 amplification (P = 0.02); however, there were no significant differences between fusion-positive and fusion-negative patients in age, sex, MSI status, and TMB. CONCLUSION: We characterized the landscape of fusions involving targetable genes in a Chinese GC cohort and found that 1.68% of patients with GC harbor potential targetable gene fusions, which were enriched in patients with ERBB2 amplification. Gene fusion detection may provide a potential treatment strategy for patients with GC with disease progression following standard therapy.

16.
Int J Mol Sci ; 23(13)2022 Jul 02.
Artículo en Inglés | MEDLINE | ID: mdl-35806382

RESUMEN

Low temperature is a serious threat to the seed emergence of rice, which has become one of the main limiting factors affecting rice production in the world. It is of great significance to find the candidate genes controlling low-temperature tolerance during seed germination and study their functions for breeding new rice cultivars with immense low-temperature tolerance during seed germination. In the current experiment, 120 lines of the Cheongcheong Nagdong Double Haploid (CNDH) population were used for quantitative trait locus (QTL) analysis of low-temperature germinability. The results showed a significant difference in germination under low different temperature (LDT) (15 °C, 20 °C) conditions. In total, four QTLs were detected on chromosome 3, 6, and 8. A total of 41 genes were identified from all the four QTLs, among them, 25 genes were selected by gene function annotation and further screened through quantitative real-time polymerase chain reaction (qRT-PCR). Based on gene function annotation and level of expression under low-temperature, our study suggested the OsGPq3 gene as a candidate gene controlling viviparous germination, ABA and GA signaling under low-temperature. This study will provide a theoretical basis for marker-assisted breeding and lay the basis for further mining molecular mechanisms of low-temperature germination tolerance in rice.


Asunto(s)
Oryza , Estudios de Asociación Genética , Germinación/genética , Oryza/genética , Fitomejoramiento , Semillas/genética , Temperatura
17.
Front Plant Sci ; 13: 895282, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35783927

RESUMEN

Climate change leads to soil salinization, and the dynamic scarcity of freshwater has negatively affected crop production worldwide, especially Oryza sativa. The association among ion uptake, gene expression, antioxidant, biomass, and root and shoot development under different salt stress are not fully understood. Many studies are related to the effect of NaCl only. This study used two salts (CaCl2 and MgCl2) along with NaCl and analyzed their effects on mineral uptake (macronutrients and micronutrients), gene expression, seed germination, antioxidants, plant growth, and biomass in different rice genotypes. CaCl2 (up to 200 mM) slightly increased the germination percentage and seedling growth, whereas, 150 mM MgCl2 in the soil increased the root, shoot length, and fresh and dry weight in cultivars IR 28 and Cheongcheong. All agronomic traits among rice genotypes were drastically reduced by NaCl stress compared to other salts. Different salt stress differentially regulated ion uptake in the roots and shoots among different rice genotypes. Under different salt stress, a consistent decrease in Ca2+, Mn2+, and Fe2+ ions was observed in the roots of Cheongcheong, Nagdong, and IR 28. Similarly, under different salts, the stress in the shoots of Cheongcheong (Ca2+, Na+, and Zn2+) and Nagdong (Ca2+, Mg2+, Na+, and Zn2+) and the shoots of IR 28 (Ca2+ and Mg2+) consistently increased. Under different salts, a salt stress-related gene was expressed differentially in the roots of rice genotypes. However, after 6 and 12 h, there was consistent OsHKT1, OsNHX1, and OsSOS1 gene upregulation in the shoots of Nagdong and roots and shoots of the salt-tolerant cultivar Pokkali. Under different salt stress, glutathione (GSH) content increased in the shoot of IR 28 and Nagdong by NaCl, and MgCl2 salt, whereas, POD activity increased significantly by CaCl2 and MgCl2 in cultivar Cheongcheong and IR 28 shoot. Therefore, this study suggested that Pokkali responded well to NaCl stress only, whereas, the plant molecular breeding lab cultivar Nagdong showed more salt tolerance to different salts (NaCl, CaCl2, and MgCl2). This can potentially be used by agriculturists to develop the new salt-tolerant cultivar "Nagdong"-like Pokkali.

18.
Int J Mol Sci ; 23(9)2022 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-35563584

RESUMEN

An ideal plant architecture is an important condition to achieve high crop yields. The tiller angle is an important and complex polygenic trait of rice (Oryza sativa L.) plant architecture. Therefore, the discovery and identification of tiller angle-related genes can aid in the improvement of crop architecture and yield. In the present study, 222 SSR markers were used to establish a high-density genetic map of rice doubled haploid population, and a total of 8 quantitative trait loci (QTLs) were detected based on the phenotypic data of the tiller angle and tiller crown width over 2 years. Among them, four QTLs (qTA9, qCW9, qTA9-1, and qCW9-1) were overlapped at marker interval RM6235-RM24288 on chromosome 9 with a large effect value regarded as a stable major QTL. The selected promising related genes were further identified by relative gene expression analysis, which gives us a basis for the future cloning of these genes. Finally, OsSAURq9, which belongs to the SMALL AUXIN UP RNA (SAUR), an auxin-responsive protein family, was selected as a target gene. Overall, this work will help broaden our knowledge of the genetic control of tiller angle and tiller crown width, and this study provides both a good theoretical basis and a new genetic resource for the breeding of ideal-type rice.


Asunto(s)
Oryza , Sitios de Carácter Cuantitativo , Mapeo Cromosómico , Ácidos Indolacéticos , Oryza/genética , Fenotipo , Fitomejoramiento
19.
Plants (Basel) ; 11(4)2022 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-35214873

RESUMEN

Rice tillers are one of the most important traits for the yield and development of rice, although little is known about its mode of inheritance. Tiller numbers were recorded every 7 days a total of nine times, starting 30 days after transplantation. Quantitative trait locus (QTL) based analysis on a set of double haploid population derivatives of a cross between the Cheongcheong and Nagdong varieties identified a major effect of locus RM18130-RM3381 on chromosome 5, which was expressed in eight different growth stages. Within the target region RM18130-RM3381 (physical distance: 2.08 Mb), 61 candidate genes were screened by annotation. Among the candidate genes, Os05g0230700 (named OsIAA17q5), which belongs to the family of auxin-responsive genes, was selected as a target. Auxin promotes cell division and meristem maintenance and is an effective plant regulator which influences plant growth and development by altering the expression of various genes. OsIAA17q5 is expected to control the number of tillers. The present study provides further understanding of the basic genetic mechanisms that selectively express the control of tiller numbers in different growth stages, as well as provides valuable information for future research aimed at cloning the target gene. These results may contribute to developing a comprehensive understanding of the basic genetic processes regulating the developmental behavior of tiller numbers in rice.

20.
Zhongguo Zhong Yao Za Zhi ; 47(23): 6485-6493, 2022 Dec.
Artículo en Chino | MEDLINE | ID: mdl-36604895

RESUMEN

This paper aims to explore the neuroprotective effect of cinnamaldehyde(CA) in mice with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-induced subacute Parkinson's disease(PD) and the mechanism. To be specific, male C57 BL/6 mice(n=72, SPF) were randomized into control group, model group, positive control(madopar 0.1 mg·g~(-1)) group, and low-dose, me-dium-dose, and high-dose CA groups(0.15, 0.30, 0.60 mg·g~(-1)). MPTP(intraperitoneal injection, 0.03 mg·g~(-1), once a day for 5 days) was used to induce subacute PD in mice except for the control group. The administration began from the day of modeling and lasted 19 days. On the 0 th, 12 th, and 19 th day, the open field test, pole test, and rotarod test were carried out. After the tests, the mice were killed and brains were separated. In addition, the organ index was measured. The number of cells in substantia nigra(SN) in the midbrain of MPTP-induced PD model mice was detected based on hematoxylin and eosin(HE) staining. The levels of tyrosine hydroxylase(TH)-and α-synuclein(α-Syn)-positive cells in SN were determined by immunohistochemical staining, and the protein levels of TH and α-Syn in SN by Western blot. The results showed that the MPTP-stimulated mice had abnormal behaviors such as erect hair, arched back, rigidity of the tail, slow movement, and tremor, decreased number of crossings and rearing, increased frequency of urination and defecation, longer time of pole climbing, and shorter time of staying on the rotating rod. In addition, the mice showed obvious damage of neurons in the SN and reduced neuron cells in irregular arrangement with some shrinking. In addition, the average optical density of TH in SN decreased and that of α-Syn increased. All these suggested the successful modeling. CA displayed obvious therapeutic effect on the PD mice, as manifested by the increased number of crossings and rearing, decreased frequency of urination and defecation, shorter time of climbing pole, longer time of staying on the rotating rod, and more neuron cells in the SN with a few pykno-tic cells. Moreover, CA significantly alleviated the decrease of TH and the overexpression of α-Syn in SN. As a result, the MPTP-induced injury of dopaminergic neurons was alleviated. The performance of 0.3 mg·g~(-1) CA was the best. This study is expected to lay a scientific basis for the development of CA products.


Asunto(s)
Fármacos Neuroprotectores , Enfermedad de Parkinson , Masculino , Ratones , Animales , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/etiología , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Neuronas Dopaminérgicas , Sustancia Negra/metabolismo , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Tirosina 3-Monooxigenasa/metabolismo
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