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Neuropeptides are the most ubiquitous neurotransmitters in the immune system, regulating various biological processes. Neuropeptides play a significant role for the discovery of new drugs and targets for nervous system disorders. Traditional experimental methods for identifying neuropeptides are time-consuming and costly. Although several computational methods have been developed to predict the neuropeptides, the accuracy is still not satisfactory due to the representability of the extracted features. In this work, we propose an efficient and interpretable model, NeuroPpred-SHE, for predicting neuropeptides by selecting the optimal feature subset from both hand-crafted features and embeddings of a protein language model. Specially, we first employed a pre-trained T5 protein language model to extract embedding features and twelve other encoding methods to extract hand-crafted features from peptide sequences, respectively. Secondly, we fused both embedding features and hand-crafted features to enhance the feature representability. Thirdly, we utilized random forest (RF), Max-Relevance and Min-Redundancy (mRMR) and eXtreme Gradient Boosting (XGBoost) methods to select the optimal feature subset from the fused features. Finally, we employed five machine learning methods (GBDT, XGBoost, SVM, MLP, and LightGBM) to build the models. Our results show that the model based on GBDT achieves the best performance. Furthermore, our final model was compared with other state-of-the-art methods on an independent test set, the results indicate that our model achieves an AUROC of 97.8 % which is higher than all the other state-of-the-art predictors. Our model is available at: https://github.com/wenjean/NeuroPpred-SHE.
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Background: Adjuvant chemotherapy (ACT) is a well-recognized and well-established treatment for surgically resected non-small cell lung cancer (NSCLC), but its suitability for elderly patients remains controversial. Further investigation is warranted to guide ACT decisions in this demographic. Methods: We extracted data from the Surveillance, Epidemiology, and End Results (SEER) database, focusing on patients aged 70 years or older who underwent surgical resection for stage IB, II, or III NSCLC as per the 7th edition of the American Joint Committee on Cancer staging system (AJCC 7th edition). Propensity score matching (PSM), Kaplan-Meier analysis, and Cox regression were employed for statistical analyses. Results: There were 503 participants received ACT in this study of 2,000 patients aged 70 or older with stage IB-IIIB NSCLC who underwent surgical resection without preoperative chemotherapy. Overall, ACT did not significantly correlate with extended overall survival (OS) (P=0.07) compared to non-ACT. After 2:1 PSM, the matched cohort comprised 317 non-ACT and 206 ACT recipients. Post-PSM, the ACT group exhibited improved OS (P=0.044) compared to the non-ACT group. Cox regression analysis identified gender, primary tumor site, histologic grade, N stage, and ACT as independent predictors of OS (P<0.05). Subgroup analysis indicated amplified ACT benefits in individuals aged 70-79 years, male, with N1 stage, or those without radiotherapy. Conclusions: ACT may confer benefits to elderly stage IB-IIIB NSCLC patients, particularly those aged 70-79 years, male, and with N1 stage.
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RAS mutations occur in approximately 30% of tumors worldwide and have a poor prognosis due to limited therapies. Covalent targeting of KRAS G12C has achieved significant success in recent years, but there is still a lack of efficient therapeutic approaches for tumors with non-G12C KRAS mutations. A highly promising approach is to target the MAPK pathway downstream of RAS, with a particular focus on RAF kinases. First-generation RAF inhibitors have been authorized to treat BRAF mutant tumors for over a decade. However, their use in RAS-mutated tumors is not recommended due to the paradoxical ERK activation mainly caused by RAF dimerization. To address the issue of RAF dimerization, type II RAF inhibitors have emerged as leading candidates. Recent clinical studies have shown the initial effectiveness of these agents against RAS mutant tumors. Promisingly, type II RAF inhibitors in combination with MEK or ERK inhibitors have demonstrated impressive efficacy in RAS mutant tumors. This review aims to clarify the importance of RAF dimerization in cellular signaling and resistance to treatment in tumors with RAS mutations, as well as recent progress in therapeutic approaches to address the problem of RAF dimerization in RAS mutant tumors.
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A high-fat diet (HFD) may be linked to an increased colorectal cancer (CRC) risk. Stem cell proliferation and adipokine release under inflammatory and obese conditions are the main factors regulating CRC progression. Furthermore, alterations in intestinal flora have been linked to tumorigenesis and tumour progression. However, whether a HFD can promote CRC occurrence by altering intestinal flora remains unclear. The objective of this study was to identify bacterial strains enriched by a HFD and investigate the association and mechanism by which a HFD and bacterial enrichment promote CRC occurrence and development. In this study, the intestinal microbiota of mice was assessed using 16S rRNA and metagenomic sequencing. Serum metabolites of HFD-fed mice were assessed using tandem liquid chromatography-mass spectrometry. CRC cell lines and organoids were co-cultured with Coriobacteriaceae to evaluate the effect of these bacteria on the CPT1A-ERK signalling pathway. We found that Coriobacteriaceae were enriched in the colons of HFD-fed mice. An endogenous Coriobacteriaceae strain, designated as Cori.ST1911, was successfully isolated and cultured from the stools of HFD-fed mice, and the tumorigenic potential of Cori.ST1911 in CRC was validated in several CRC mouse models. Furthermore, Cori.ST1911 increased acylcarnitine levels by activating CPT1A, demonstrating the involvement of the CPT1A-ERK axis. We also found that the endogenous Lactobacillus strain La.mu730 can interfere with Cori.ST1911 colonisation and restore gut barrier function. In conclusion, we identified a novel endogenous intestinal Coriobacteriaceae, Cori.ST1911, which might lead to a new gut microbiota intervention strategy for the prevention and treatment of CRC.
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Neoplasias Colorrectales , Microbioma Gastrointestinal , Ratones , Animales , Dieta Alta en Grasa/efectos adversos , ARN Ribosómico 16S/genética , Carcinogénesis , Microbioma Gastrointestinal/fisiología , Neoplasias Colorrectales/etiologíaRESUMEN
The biological significance of self-assembled protein filament networks and their unique mechanical properties have sparked interest in the development of synthetic filament networks that mimic these attributes. Building on the recent advancement of autoaccelerated ring-opening polymerization of amino acid N-carboxyanhydrides (NCAs), this study strategically explores a series of random copolymers comprising multiple amino acids, aiming to elucidate the core principles governing gelation pathways of these purpose-designed copolypeptides. Utilizing glutamate (Glu) as the primary component of copolypeptides, two targeted pathways were pursued: first, achieving a fast fibrillation rate with lower interaction potential using serine (Ser) as a comonomer, facilitating the creation of homogeneous fibril networks; and second, creating more rigid networks of fibril clusters by incorporating alanine (Ala) and valine (Val) as comonomers. The selection of amino acids played a pivotal role in steering both the morphology of fibril superstructures and their assembly kinetics, subsequently determining their potential to form sample-spanning networks. Importantly, the viscoelastic properties of the resulting supramolecular hydrogels can be tailored according to the specific copolypeptide composition through modulations in filament densities and lengths. The findings enhance our understanding of directed self-assembly in high molecular weight synthetic copolypeptides, offering valuable insights for the development of synthetic fibrous networks and biomimetic supramolecular materials with custom-designed properties.
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Hidrogeles , Péptidos , Hidrogeles/química , Péptidos/química , Aminoácidos , Ácido Glutámico/química , Alanina/químicaRESUMEN
Background: There is variability in the prognosis of stage III-N2 lung adenocarcinoma (LUAD) patients. The current tumor-node-metastasis (TNM) staging is not sufficient to precisely estimate the prognosis of stage III-N2 LUAD patients. The Surveillance, Epidemiology, and End Results (SEER) database collected first-hand information from a large number of LUAD patients. Based on the SEER database, this study aimed to determine the prognostic factors that affect overall survival (OS) in stage III-N2 LUAD patients and then establish a nomogram for predicting OS in this type of cancer to identify the high-risk population that may require more frequent surveillance or intensive care. Methods: Data for 1,844 stage III-N2 primary LUAD patients who were registered between 2010 and 2015 were obtained from the SEER database. These patients were randomly assigned to either training (n=1,290) or validation (n=554) cohorts at a 7:3 ratio. The univariate and multivariate Cox regression (UCR and MCR) analyses were performed to find the relevant independent prognostic factors. To predict the OS based on these prognostic factors, a nomogram was then developed. The performance of the nomogram was examined based on the calibration curves, and receiver operating characteristic (ROC) curves. The ability of nomogram to stratify patient risk was validated by Kaplan-Meier survival analysis. Results: Age, gender, tumor location, T-stage and treatment modality (chemotherapy, radiation therapy, surgery and scope of lymph node dissection) of stage III-N2 LUAD patients were significantly associated with prognosis. The area under the curve (AUC) values of OS predicted by the nomogram constructed with these factors at 12-, 36- and 60-month were 0.784, 0.762 and 0.763 in the training cohort, whereas 0.707, 0.685 and 0.705 in the validation cohort, respectively. Additionally, calibration curves demonstrated concordance between predicted and observed outcomes. Nomogram risk stratification provides a meaningful distinction between patients with various survival risks. Conclusions: A survival prediction model that may be useful for risk stratification and decision-making is developed and validated for stage III-N2 LUAD patients. A high-risk patient predicted by the prediction model may require more frequent surveillance or intensive care.
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OBJECTIVE: This trial was to evaluate the efficacy of subxiphoid approach thoracoscopic thymectomy for postoperative pain control and length of hospital stay compared with a lateral intercostal approach thoracoscopic thymectomy. METHODS: This multicenter, open-label, randomized clinical superiority trial enrolled 101 eligible participants clinically diagnosed with Masaoka-Koga I-II thymoma between August 15, 2021, and February 15, 2022. Each enrolled participant was randomized and underwent subxiphoid approach thoracoscopic thymectomy or lateral intercostal approach thoracoscopic thymectomy. A per-protocol analysis for each coprimary outcome was performed in addition to the main intention-to-treat analysis. RESULTS: In the analysis for the coprimary outcomes, the pain Visual Analog Scale score area under the curve at 0 to 7 days was lower in the subxiphoid approach thoracoscopic thymectomy group than in the lateral intercostal approach thoracoscopic thymectomy group (difference, -4.82; 98.3% CI, -8.84 to -0.80). However, there was no significant difference between the 2 groups in the length of hospital stay (difference, 0.318; 98.3% CI, -0.190 to 0.825) or cumulative opioid consumption after surgery (difference, -4.630; 98.3% CI, -9.530 to 0.272). All patients underwent complete resection, and there was no significant difference (7.84% vs 8.00%, P = 1.000) in the rate of complications between the 2 groups. No recurrence or death occurred in the postoperative 6 months. CONCLUSIONS: This study found improved pain and similar length of hospital stay associated with the subxiphoid approach compared with the lateral intercostal approach in patients with suspected Masaoka-Koga I-II thymoma.
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The fractional-order (FO) nonlinear differential system with state-dependent (SD) delayed impulses (DI) is considered in this brief. The considered impulses are related to the delayed state of the system and the delays are SD. A novel lemma for the monotonicity of the solution of Caputo's FO derivative equation is given. By means of linear matrix inequality (LMI) and several comparative arguments, criteria of uniform stability, uniform asymptotical stability, and Mittag-Leffler stability are obtained. Compared with other works on integer-order (IO) impulsive delayed systems with SD delays or fixed delays, how to impose constraints on parameters and impulses is explored, without imposing the boundedness on the state delays. Two examples are implemented to examine the practicality and sharpness of our theoretical analysis.
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In this article, the finite-time observer-based sliding-mode control (SMC) problem is considered for stochastic Markovian jump systems (MJSs) with a deterministic switching chain (DSC) subject to time-varying delay and packet losses (PLs). First, the stochastic MJSs with DSC are appropriately modeled and the PLs case is characterized by using some Bernoulli random variables. Then, a nonfragile finite-time bounded sliding-mode observer is designed. Our objective is to propose a finite-time observer-based SMC approach such that for the above addressed system, the finite-time boundedness in a certain time interval can be guaranteed by giving sufficient criteria via the stochastic analysis skills and average dwell time (ADT) method. Moreover, a new robust finite-time sliding-mode controller can be designed to ensure reachability of the common sliding surface in the estimation space. Finally, a numerical example is provided to illustrate our theoretical results.
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Subsequently to the publication of the above article, an interested reader drew to the authors' attention that the miR200c and SiRhoE data panels in Fig. 5B on p. 1739 appeared to contain an overlap of the data, such that the data would have been derived from the same original source where the different panels were intended to show the results from differently performed experiments. The authors have reexamined their data, and realize that these data panels were inadvertently selected incorrectly; specifically, the data panel showing the results of the migration activities of A549 following transfection with SiRhoE in Fig. 5B was incorporated incorrectly during the process of assembling this figure, and this panel contained the overlap with the miR200c group. The revised version of Fig. 5, showing all the correct data for Fig. 5B, is presented on the next page. The authors confirm that the errors made in the presentation of Fig. 5 did not adversely affect the conclusions reported in this paper, and they are grateful to the Editor of International Journal of Oncology for granting them this opportunity to publish a Corrigendum. All the authors agree to the publication of this Corrigendum, and they also apologize to the readership for any inconvenience caused. [International Journal of Oncology 53: 17321742, 2018; DOI: 10.3892/ijo.2018.4493].
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Chronic stress has been reported to be associated with tumor initiation and progression. But the underlying mechanism and the specific role of tumor immunity in this process are still unknown. Herein, we applied the repeated restrain stress model in C57BL/6J mice and found that the tumor growth in stressed mice was accelerated compared with that in control mice. In addition, serotonin, also called 5-hydroxytryptamine (5-HT), in the serum of stressed mice was also elevated. Sertraline, a selective serotonin reuptake inhibitor used in the clinic, can restore the serum 5-HT level in stressed mice and restrain tumor growth. We further explored the distribution of major immune cells, including B lymphocytes cells, T lymphocytes, natural killer cells, dendritic cells, tumor-associated macrophages (TAM) and regulatory T cells (Treg). We found that the infiltration of CD8 + T cells in the tumor microenvironment (TME) decreased significantly in stressed mice. And the extra 5-HT treatment could further decrease the infiltration of CD8 + T cells in the TME. The expression of IFN-γ and Granular enzyme B (GzmB) in CD8 + T cells were also dropped in the stressed mice group, whereas the expression of programmed cell death protein 1 (PD-1) on CD8 + T cells was increased. The T cell deficiency induced by stress can be reversed by sertraline, indicating its promising role in strengthening the efficacy of anti-PDL1/PD-1 immunotherapy. The present study provides new mechanistic insights into the impact of chronic stress on antitumor immunity and implicates a novel combined immunotherapy strategy for cancer patients with chronic stress.
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Receptor de Muerte Celular Programada 1 , Serotonina , Animales , Linfocitos T CD8-positivos , Línea Celular Tumoral , Ratones , Ratones Endogámicos C57BL , Inhibidores Selectivos de la Recaptación de Serotonina , Sertralina/farmacología , Microambiente TumoralRESUMEN
Introducing engineered nanoparticles (NPs) into a biofluid such as blood plasma leads to the formation of a selective and reproducible protein corona at the particle-protein interface, driven by the relationship between protein-NP affinity and protein abundance. This enables scalable systems that leverage protein-nano interactions to overcome current limitations of deep plasma proteomics in large cohorts. Here the importance of the protein to NP-surface ratio (P/NP) is demonstrated and protein corona formation dynamics are modeled, which determine the competition between proteins for binding. Tuning the P/NP ratio significantly modulates the protein corona composition, enhancing depth and precision of a fully automated NP-based deep proteomic workflow (Proteograph). By increasing the binding competition on engineered NPs, 1.2-1.7× more proteins with 1% false discovery rate are identified on the surface of each NP, and up to 3× more proteins compared to a standard plasma proteomics workflow. Moreover, the data suggest P/NP plays a significant role in determining the in vivo fate of nanomaterials in biomedical applications. Together, the study showcases the importance of P/NP as a key design element for biomaterials and nanomedicine in vivo and as a powerful tuning strategy for accurate, large-scale NP-based deep proteomic studies.
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Nanopartículas , Corona de Proteínas , Corona de Proteínas/química , Proteoma , Proteómica , Nanopartículas/química , NanomedicinaRESUMEN
Aggresome formation is a protective cellular response to counteract proteasome dysfunction by sequestering misfolded proteins and reducing proteotoxic stress. Autophagic degradation of the protein aggregates is considered to be a key compensating mechanism for balancing proteostasis. However, the precise role of autophagy in proteasome inhibition-induced aggresome biogenesis remains unclear. Herein, we demonstrate that in the early stage of proteasome inhibition, the maturation of the autophagosome is suppressed, which facilitates aggresome formation of misfolded proteins. Proteasome inhibition-induced phosphorylation of SQSTM1 T269/S272 inhibits its autophagic receptor activity and promotes aggresome formation of misfolded proteins. Inhibiting SQSTM1 T269/S272 phosphorylation using Doramapimod aggravates proteasome inhibitor-mediated cell damage and tumor suppression. Taken together, our data reveal a negative effect of autophagy on aggresome biogenesis and cell damage upon proteasome inhibition. Our study suggests a novel therapeutic intervention for proteasome inhibitor-mediated tumor treatment.
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Complejo de la Endopetidasa Proteasomal , Proteínas Ubiquitinadas , Autofagia , Complejo de la Endopetidasa Proteasomal/metabolismo , Inhibidores de Proteasoma/farmacología , Proteína Sequestosoma-1/genética , Proteína Sequestosoma-1/metabolismo , Proteínas Ubiquitinadas/metabolismoRESUMEN
SignificanceDeep profiling of the plasma proteome at scale has been a challenge for traditional approaches. We achieve superior performance across the dimensions of precision, depth, and throughput using a panel of surface-functionalized superparamagnetic nanoparticles in comparison to conventional workflows for deep proteomics interrogation. Our automated workflow leverages competitive nanoparticle-protein binding equilibria that quantitatively compress the large dynamic range of proteomes to an accessible scale. Using machine learning, we dissect the contribution of individual physicochemical properties of nanoparticles to the composition of protein coronas. Our results suggest that nanoparticle functionalization can be tailored to protein sets. This work demonstrates the feasibility of deep, precise, unbiased plasma proteomics at a scale compatible with large-scale genomics enabling multiomic studies.
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Proteínas Sanguíneas , Aprendizaje Profundo , Nanopartículas , Proteómica , Proteínas Sanguíneas/química , Nanopartículas/química , Corona de Proteínas/química , Proteoma , Proteómica/métodosRESUMEN
p38δ is a member of p38 mitogen-activated protein kinases (MAPKs) family that displays cell- and tissue-specific expression patterns. Recent studies demonstrate that p38δ is centrally involved in several pathologic events, such as diabetes, neurodegeneration diseases, inflammatory diseases, and cancer, and suggest that it may be a potential target for diagnosis and therapy of specific diseases. A nanobody is a new type of antibody that exhibits high antigen-binding activity, solubility, stability, and easy production. This study utilized phage display to isolate nanobodies specifically against p38δ from a fully synthetic nanobody library. Two of them, nanobodies Nb13-6 and Nb13-1, display high binding activity to p38δ, less cross-reactivity with other p38 MAPKs, and high thermal and pH stabilities. Modeling and docking analysis indicated that Nb13-6 is mostly linked to the activation loop of p38δ. Furthermore, detailed studies revealed that Nb13-6 inhibited the protein kinase activity of p38δ and the growth of cancer cells. Therefore, this study provides p38δ-specific nanobodies that are promisingly exploited for diagnosing and treating p38δ-associated diseases.
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Proteína Quinasa 14 Activada por Mitógenos , Anticuerpos de Dominio Único , Proteína Quinasa 13 Activada por Mitógenos , Fosforilación , Anticuerpos de Dominio Único/farmacología , Proteínas Quinasas p38 Activadas por MitógenosRESUMEN
Protein aggregation and degradation via autophagy (aggrephagy) are major strategies adopted by cells to remove misfolded polypeptides when there is proteasome dysfunction. The functional protein complex consisting of heat shock protein 70 (Hsp70), cochaperone ubiquitin ligase carboxyl-terminal of Hsp70/Hsp90 interacting protein (CHIP), and co-chaperone Bcl-2-associated athanogene 3 (BAG3) has been associated with the activation of protein aggregation. However, data on the mechanisms of action of the complex in the protein degradation remains scant. Here, we report that upon proteasome stress, the M2 isoform of pyruvate kinase (PKM2) promotes the aggregation of ubiquitinated proteins and its knockout or knockdown aggravates the sensitivity of cells to proteasome inhibitors. Besides, following proteasome inhibition, PKM2 promotes the interaction of BAG3 with CHIP and HSP70. Interestingly, re-expression of loss-of-function mutants in PKM2-knockout cells showed that the regulatory function of PKM2 in this progress does not depend on the activity of glycolytic enzymes or protein kinases. Taken together, these findings demonstrate that PKM2 mediates the formation of the CHIP-HSP70-BAG3 protein complex and promotes the aggregation of ubiquitinated misfolded proteins, thus compensating for proteasome stress in cells.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas HSP70 de Choque Térmico/metabolismo , Complejos Multiproteicos/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Agregado de Proteínas , Piruvato Quinasa/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas Ubiquitinadas/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Reguladoras de la Apoptosis/genética , Células HEK293 , Proteínas HSP70 de Choque Térmico/genética , Células Hep G2 , Humanos , Complejos Multiproteicos/genética , Complejo de la Endopetidasa Proteasomal/genética , Piruvato Quinasa/genética , Ubiquitina-Proteína Ligasas/genética , Proteínas Ubiquitinadas/genéticaRESUMEN
In cells, actin and tubulin polymerization is regulated by nucleation factors, which promote the nucleation and subsequent growth of protein filaments in a controlled manner. Mimicking this natural mechanism to control the supramolecular polymerization of macromolecular monomers by artificially created nucleation factors remains a largely unmet challenge. Biological nucleation factors act as molecular scaffolds to boost the local concentrations of protein monomers and facilitate the required conformational changes to accelerate the nucleation and subsequent polymerization. An accelerated assembly of synthetic poly(l-glutamic acid) into amyloid fibrils catalyzed by cationic silica nanoparticle clusters (NPCs) as artificial nucleation factors is demonstrated here and modeled as supramolecular polymerization with a surface-induced heterogeneous nucleation pathway. Kinetic studies of fibril growth coupled with mechanistic analysis demonstrate that the artificial nucleators predictably accelerate the supramolecular polymerization process by orders of magnitude (e.g., shortening the assembly time by more than 10 times) when compared to the uncatalyzed reaction, under otherwise identical conditions. Amyloid-like fibrillation was supported by a variety of standard characterization methods. Nucleation followed a Michaelis-Menten-like scheme for the cationic silica NPCs, while the corresponding anionic or neutral nanoparticles had no effect on fibrillation. This approach shows the effectiveness of charge-charge interactions and surface functionalities in facilitating the conformational change of macromolecular monomers and controlling the rates of nucleation for fibril growth. Molecular design approaches like these inspire the development of novel materials via biomimetic supramolecular polymerizations.
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Amiloide , Péptidos , Amiloide/química , Proteínas Amiloidogénicas , Cinética , Péptidos/química , PolimerizacionRESUMEN
Colorectal cancer (CRC) is a heterogeneous disease at the cellular and molecular levels. Kirsten rat sarcoma (KRAS) is a commonly mutated oncogene in CRC, with mutations in approximately 40% of all CRC cases; its mutations result in constitutive activation of the KRAS protein, which acts as a molecular switch to persistently stimulate downstream signaling pathways, including cell proliferation and survival, thereby leading to tumorigenesis. Patients whose CRC harbors KRAS mutations have a dismal prognosis. Currently, KRAS mutation testing is a routine clinical practice before treating metastatic cases, and the approaches developed to detect KRAS mutations have exhibited favorable sensitivity and accuracy. Due to the presence of KRAS mutations, this group of CRC patients requires more precise therapies. However, KRAS was historically thought to be an undruggable target until the development of KRASG12C allele-specific inhibitors. These promising inhibitors may provide novel strategies to treat KRAS-mutant CRC. Here, we provide an overview of the role of KRAS in the prognosis, diagnosis and treatment of CRC.
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Biomarcadores de Tumor , Neoplasias Colorrectales/diagnóstico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/terapia , Oncogenes , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias Colorrectales/metabolismo , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Desarrollo de Medicamentos , Regulación Neoplásica de la Expresión Génica , Humanos , Biopsia Líquida/métodos , Biopsia Líquida/normas , Técnicas de Diagnóstico Molecular , Terapia Molecular Dirigida , Mutación , Pronóstico , Proteínas Proto-Oncogénicas p21(ras)/química , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Sensibilidad y Especificidad , Transducción de Señal , Relación Estructura-Actividad , Resultado del TratamientoRESUMEN
Evidence for the role of osteocalcin in glucose metabolism is increasing. The aim of this study was to examine the associations between osteocalcin and gestational diabetes mellitus. Thirteen discovery study subjects and 76 reduplication study subjects were recruited from the Maternal and Child Health Hospital Guangxi Zhuang Autonomous Region from May 2018 to August 2018. Total osteocalcin and biochemical indices of maternal serum and umbilical vein serum were analyzed. Placental tissue samples were used for transcriptome sequencing. For the discovery study subjects, the total osteocalcin concentration in umbilical vein serum was significantly higher than that in maternal serum and umbilical artery serum (55.32 ng/mL ± 17.37 vs. 12.06 ng/mL ± 5.42 [P < 0.001] vs. 38.31 ng/mL ± 11.52 [P < 0.01]), suggesting that trophoblasts may synthesize osteocalcin. In a reduplication subject study, the gestational diabetes mellitus group had lower umbilical vein serum total osteocalcin (51.46 ng/mL ± 24.29 vs. 67.00 ng/mL ± 25.33, P = 0.008), lower adiponectin (1099.72 µg/L ± 102.65 vs. 1235.85 µg/L ± 94.63, P < 0.001). Spearman's correlation analysis showed that umbilical vein serum total osteocalcin levels were closely correlated with leptin (r = -0.456, P = 0.007). A coexpression model of the placental RNA sequence was constructed. Two modules were correlated with osteocalcin, and the Gene ontology pathways of these modules were rich in glucose and lipid metabolism. In conclusion, the placenta may synthesize osteocalcin by itself, and a lower osteocalcin level in umbilical vein serum is associated with gestational diabetes mellitus.
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Diabetes Gestacional/metabolismo , Osteocalcina/metabolismo , Placenta/metabolismo , Adulto , Glucemia , Proliferación Celular , Femenino , Humanos , Osteocalcina/sangre , Osteocalcina/genética , Embarazo , ARN Mensajero/genética , ARN Mensajero/metabolismo , TrofoblastosRESUMEN
Serotonin (5-hydroxytryptamine, 5-HT) metabolism has long been linked to tumorigenesis and tumor progression. Numerous studies have shown the functions of 5-HT and its metabolites in the regulation of tumor biological processes like cell proliferation, invasion, metastasis, tumor angiogenesis and immunomodulatory through multi-step complex mechanisms. Reprogramming of 5-HT metabolism has been revealed in various tumors paving way for development of drugs that target enzymes, metabolites or receptors involved in 5-HT metabolic pathway. However, information on the role of 5-HT metabolism in cancer is scanty. This review briefly describes the main metabolic routes of 5-HT, the role of 5-HT metabolism in cancer and systematically summarizes the most recent advances in 5-HT metabolism-targeted cancer therapy.