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The topological physics has sparked intensive investigations into topological lattices in photonic, acoustic, and mechanical systems, powering counterintuitive effects otherwise inaccessible with usual settings. Following the success of these endeavors in classical wave dynamics, there has been a growing interest in establishing their topological counterparts in diffusion. Here, we propose an additional real-space dimension in diffusion, and the system eigenvalues are transformed from "imaginary" to "real." By judiciously tailoring the effective Hamiltonian with coupling networks, localized and delocalized topological modes are realized in heat transfer. Simulations and experiments in active thermal lattices validate the effectiveness of the proposed theoretical strategy. This approach can be applied to establish various topological lattices in diffusion systems, offering insights into engineering topologically protected edge states in dynamic diffusive scenarios.
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Multiple myeloma (MM) is the second most common hematological tumor in adults. Immunomodulatory drugs (IMiDs), such as thalidomide and lenalidomide (Len), are effective drugs for the treatment of multiple myeloma. Len can recruit IKZF1 and IKZF3 to cereblon (CRBN), a substrate receptor of the cullin 4-RING E3 ligase (CRL4), promote their ubiquitination and degradation, and finally inhibit the proliferation of myeloma cells. However, MM patients develop resistance to IMiDs over time, leading to disease recurrence and deterioration. To explore the possible approaches that may enhance the sensitivity of IMiDs to MM, in this study, we used the proximity labeling technique TurboID and quantitative proteomics to identify Lys-63-specific deubiquitinase BRCC36 as a CRBN-interacting protein. Biochemical experiments demonstrated that BRCC36 in the BRISC complex protects CRBN from lysosomal degradation by specifically cleaving the K63-linked polyubiquitin chain on CRBN. Further studies found that a small-molecule compound SHIN1, which binds to BRISC complex subunit SHMT2, can upregulate CRBN by elevating BRCC36. The combination of SHIN1 and Len can further increase the sensitivity of MM cells to IMiDs. Therefore, this study provides the basis for the exploration of a possible strategy for the SHIN1 and Len combination treatment for MM.
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Proteínas Adaptadoras de Transdução de Sinal , Lenalidomida , Lisossomos , Mieloma Múltiplo , Ubiquitina-Proteína Ligases , Humanos , Mieloma Múltiplo/patologia , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/metabolismo , Lenalidomida/farmacologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Lisossomos/metabolismo , Lisossomos/efeitos dos fármacos , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Linhagem Celular Tumoral , Ubiquitinação/efeitos dos fármacos , Proteólise/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Enzimas Desubiquitinantes/metabolismo , Enzimas Desubiquitinantes/antagonistas & inibidoresRESUMO
The follicle is the basic structural and functional unit of the ovary in female mammals. The excessive depletion of follicles will lead to diminished ovarian reserve or even premature ovarian failure, resulting in diminished ovarian oogenesis and endocrine function. Excessive follicular depletion is mainly due to loss of primordial follicles. Our analysis of published human ovarian single-cell sequencing results by others revealed a significant increase in rho-associated protein kinase 1 (ROCK1) expression during primordial follicle development. However, the role of ROCK1 in primordial follicle development and maintenance is not clear. This study revealed a gradual increase in ROCK1 expression during primordial follicle activation. Inhibition of ROCK1 resulted in reduced primordial follicle activation, decreased follicular reserve, and delayed development of growing follicles. This effect may be achieved through the HIPPO pathway. The present study indicates that ROCK1 is a key molecule for primordial follicular reserve and follicular development.NEW & NOTEWORTHY ROCK1, one of the Rho GTPases, plays an important role in primordial follicle reserve and follicular development. ROCK1 was primarily expressed in the cytoplasm of oocytes and granulosa cell in mice. Inhibition of ROCK1 significantly reduced the primordial follicle reserve and delayed growing follicle development. ROCK1 regulates primordial follicular reserve and follicle development through the HIPPO signaling pathway. These findings shed new lights on the physiology of sustaining female reproduction.
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Oócitos , Folículo Ovariano , Animais , Feminino , Humanos , Camundongos , Células da Granulosa/metabolismo , Mamíferos , Oogênese , Folículo Ovariano/metabolismo , Ovário/metabolismo , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismoRESUMO
Owing to its diverse activation processes including single-electron transfer (SET) and hydrogen-atom transfer (HAT), visible-light photocatalysis has emerged as a sustainable and efficient platform for organic synthesis. These processes provide a powerful avenue for the direct functionalization of C(sp3)-H bonds under mild conditions. Over the past decade, there have been remarkable advances in the enantioselective functionalization of the C(sp3)-H bond via photocatalysis combined with conventional asymmetric catalysis. Herein, we summarize the advances in asymmetric C(sp3)-H functionalization involving visible-light photocatalysis and discuss two main pathways in this emerging field: (a) SET-driven carbocation intermediates are followed by stereospecific nucleophile attacks; and (b) photodriven alkyl radical intermediates are further enantioselectively captured by (i) chiral π-SOMOphile reagents, (ii) stereoselective transition-metal complexes, and (iii) another distinct stereoscopic radical species. We aim to summarize key advances in reaction design, catalyst development, and mechanistic understanding, to provide new insights into this rapidly evolving area of research.
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Topological Anderson phases (TAPs) offer intriguing transitions from ordered to disordered systems in photonics and acoustics. However, achieving these transitions often involves cumbersome structural modifications to introduce disorders in parameters, leading to limitations in flexible tuning of topological properties and real-space control of TAPs. Here, we exploit disordered convective perturbations in a fixed heat transport system. Continuously tunable disorder-topology interactions are enabled in thermal dissipation through irregular convective lattices. In the presence of a weak convective disorder, the trivial diffusive system undergos TAP transition, characterized by the emergence of topologically protected corner modes. Further increasing the strength of convective perturbations, a second phase transition occurs converting from TAP to Anderson phase. Our work elucidates the pivotal role of disorders in topological heat transport and provides a novel recipe for manipulating thermal behaviors in diverse topological platforms.
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Previously, a novel Corynebacterium glutamicum strain for the de novo biosynthesis of tailored poly-γ-glutamic acid (γ-PGA) has been constructed by our group. The strain was based on the γ-PGA synthetase complex, PgsBCA, which is the only polyprotein complex responsible for γ-PGA synthesis in Bacillus spp. In the present study, PgsBCA was reconstituted and overexpressed in C. glutamicum to further enhance γ-PGA synthesis. First, we confirmed that all the components (PgsB, PgsC, and PgsA) of γ-PGA synthetase derived from B. licheniformis are necessary for γ-PGA synthesis, and γ-PGA was detected only when PgsB, PgsC, and PgsA were expressed in combination in C. glutamicum. Next, the expression level of each pgsB, pgsC, and pgsA was tuned in order to explore the effect of expression of each of the γ-PGA synthetase subunits on γ-PGA production. Results showed that increasing the transcription levels of pgsB or pgsC and maintaining a medium-level transcription level of pgsA led to 35.44% and 76.53% increase in γ-PGA yield (γ-PGA yield-to-biomass), respectively. Notably, the expression level of pgsC had the greatest influence (accounting for 68.24%) on γ-PGA synthesis, followed by pgsB. Next, genes encoding for PgsC from four different sources (Bacillus subtilis, Bacillus anthracis, Bacillus methylotrophicus, and Bacillus amyloliquefaciens) were tested in order to identify the influence of PgsC-encoding orthologues on γ-PGA production, but results showed that in all cases the synthesis of γ-PGA was significantly inhibited. Similarly, we also explored the influence of gene orthologues encoding for PgsB on γ-PGA production, and found that the titer increased to 17.14 ± 0.62 g/L from 8.24 ± 0.10 g/L when PgsB derived from B. methylotrophicus replaced PgsB alone in PgsBCA from B. licheniformis. The resulting strain was chosen for further optimization, and we achieved a γ-PGA titer of 38.26 g/L in a 5 L fermentor by optimizing dissolved oxygen level. Subsequently, by supplementing glucose, γ-PGA titer increased to 50.2 g/L at 48 h. To the best of our knowledge, this study achieved the highest titer for de novo production of γ-PGA from glucose, without addition of L-glutamic acid, resulting in a novel strategy for enhancing γ-PGA production.
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Corynebacterium glutamicum , Fermentação , Corynebacterium glutamicum/genética , Corynebacterium glutamicum/metabolismo , Ácido Glutâmico , Ácido Poliglutâmico/genética , Ligases/metabolismo , Glucose/metabolismoRESUMO
The chemical synthesis of homogeneously ubiquitylated histones is a powerful approach to decipher histone ubiquitylation-dependent epigenetic regulation. Among the various methods, α-halogen ketone-mediated conjugation chemistry has recently been an attractive strategy to generate single-monoubiquitylated histones for biochemical and structural studies. Herein, we report the use of this strategy to prepare not only dual- and even triple-monoubiquitylated histones but also diubiquitin-modified histones. We were surprised to find that the synthetic efficiencies of multi-monoubiquitylated histones were comparable to those of single-monoubiquitylated ones, suggesting that this strategy is highly tolerant to the number of ubiquitin monomers installed onto histones. The facile generation of a series of single-, dual-, and triple-monoubiquitylated H3 proteins enabled us to evaluate the influence of ubiquitylation patterns on the binding of DNA methyltransferase 1 (DNMT1) to nucleosomes. Our study highlights the potential of site-specific conjugation chemistry to generate chemically defined histones for epigenetic studies.
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Histonas , Cetonas , Ubiquitinação , Histonas/química , Histonas/metabolismo , Histonas/síntese química , Cetonas/química , Ubiquitina/química , Humanos , DNA (Citosina-5-)-Metiltransferase 1/metabolismo , DNA (Citosina-5-)-Metiltransferase 1/química , Nucleossomos/química , Nucleossomos/metabolismoRESUMO
Compared with conventional topological insulator that carries topological state at its boundaries, the higher-order topological insulator exhibits lower-dimensional gapless boundary states at its corners and hinges. Leveraging the form similarity between Schrödinger equation and diffusion equation, research on higher-order topological insulators has been extended from condensed matter physics to thermal diffusion. Unfortunately, all the corner states of thermal higher-order topological insulator reside within the band gap. Another kind of corner state, which is embedded in the bulk states, has not been realized in pure diffusion systems so far. Here, we construct higher-dimensional Su-Schrieffer-Heeger models based on sphere-rod structure to elucidate these corner states, which we term "in-bulk corner states." Because of the anti-Hermitian properties of diffusive Hamiltonian, we investigate the thermal behavior of these corner states through theoretical calculation, simulation, and experiment. Furthermore, we study the different thermal behaviors of in-bulk corner state and in-gap corner state. Our results would open a different gate for diffusive topological states and provide a distinct application for efficient heat dissipation.
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Pathogenic bacterial membrane proteins (MPs) are a class of vaccine and antibiotic development targets with widespread clinical application. However, the inherent hydrophobicity of MPs poses a challenge to fold correctly in living cells. Herein, we present a comprehensive method to improve the soluble form of MP antigen by rationally designing multi-epitope chimeric antigen (ChA) and screening two classes of protein-assisting folding element. The study uses a homologous protein antigen as a functional scaffold to generate a ChA possessing four epitopes from transferrin-binding protein A of Glaesserella parasuis. Our engineered strain, which co-expresses P17 tagged-ChA and endogenous chaperones groEL-ES, yields a 0.346 g/L highly soluble ChA with the property of HPS-positive serum reaction. Moreover, the protein titer of ChA reaches 4.27 g/L with >90% soluble proportion in 5-L bioreactor, which is the highest titer reported so far. The results highlight a timely approach to design and improve the soluble expression of MP antigen in industrially viable applications.
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Antígenos de Bactérias , Antígenos de Bactérias/genética , Antígenos de Bactérias/imunologia , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/química , Proteínas Recombinantes de Fusão/metabolismo , Reatores Biológicos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/química , Escherichia coli/genética , Escherichia coli/metabolismo , Clostridiales/genética , Clostridiales/metabolismo , SolubilidadeRESUMO
OBJECTIVES: Colitis is a global disease usually accompanied by intestinal epithelial damage and intestinal inflammation, and an increasing number of studies have found natural products to be highly effective in treating colitis. Anemoside B4 (AB4), an abundant saponin isolated from Pulsatilla chinensis (Bunge), which was found to have strong anti-inflammatory activity. However, the exact molecular mechanisms and direct targets of AB4 in the treatment of colitis remain to be discovered. METHODS: The anti-inflammatory activities of AB4 were verified in LPS-induced cell models and 2, 4, 6-trinitrobenzene sulfonic (TNBS) or dextran sulfate sodium (DSS)-induced colitis mice and rat models. The molecular target of AB4 was identified by affinity chromatography analysis using chemical probes derived from AB4. Experiments including proteomics, molecular docking, biotin pull-down, surface plasmon resonance (SPR), and cellular thermal shift assay (CETSA) were used to confirm the binding of AB4 to its molecular target. Overexpression of pyruvate carboxylase (PC) and PC agonist were used to study the effects of PC on the anti-inflammatory and metabolic regulation of AB4 in vitro and in vivo. RESULTS: AB4 not only significantly inhibited LPS-induced NF-κB activation and increased ROS levels in THP-1 cells, but also suppressed TNBS/DSS-induced colonic inflammation in mice and rats. The molecular target of AB4 was identified as PC, a key enzyme related to fatty acid, amino acid and tricarboxylic acid (TCA) cycle. We next demonstrated that AB4 specifically bound to the His879 site of PC and altered the protein's spatial conformation, thereby affecting the enzymatic activity of PC. LPS activated NF-κB pathway and increased PC activity, which caused metabolic reprogramming, while AB4 reversed this phenomenon by inhibiting the PC activity. In vivo studies showed that diisopropylamine dichloroacetate (DADA), a PC agonist, eliminated the therapeutic effects of AB4 by changing the metabolic rearrangement of intestinal tissues in colitis mice. CONCLUSION: We identified PC as a direct cellular target of AB4 in the modulation of inflammation, especially colitis. Moreover, PC/pyruvate metabolism/NF-κB is crucial for LPS-driven inflammation and oxidative stress. These findings shed more light on the possibilities of PC as a potential new target for treating colitis.
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Colite , Saponinas , Ratos , Camundongos , Animais , Piruvato Carboxilase/metabolismo , NF-kappa B/metabolismo , Lipopolissacarídeos/farmacologia , Simulação de Acoplamento Molecular , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/metabolismo , Inflamação/metabolismo , Saponinas/farmacologia , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Macrófagos/metabolismo , Sulfato de Dextrana/efeitos adversos , Sulfato de Dextrana/metabolismo , Camundongos Endogâmicos C57BL , Modelos Animais de DoençasRESUMO
BACKGROUND: This research explored the factors influencing early neurological outcomes (ENO) in patients who had vertebrobasilar artery occlusion (VBAO) and received endovascular treatment (EVT), as well as examining the causal influence of ENO on the prognosis of VBAO patients. METHODS: A retrospective review was carried out on patients from 65 Chinese stroke centers, all within 24 hours of the estimated occlusion time. ENO includes early neurological improvement (ENI) and early neurological deterioration (END), defined as a decrease or an increase of at least 4 points in NIHSS score between baseline and 24 hours after EVT. Death within 24 hours after EVT also consider as END. END was further divided into explainable END and unexplainable END (unEND). Independent predictors of ENO and the association between ENO and outcomes in patients with VBAO were determined using center-adjusted analyses. The study developed a multivariate logistic regression model to examine the comparative risk of unEND versus explainable END on the clinical outcomes in VBAO patients. RESULTS: A total of 2257 patients were included. Glasgow Coma Scale (GCS) (OR 1.16, 95% CI 1.03-1.30) and successful reperfusion (OR 1.15, 95% CI 1.02-1.30) were associated with ENI. Baseline NIHSS (OR 0.60, 95% CI 0.53-0.68), successful reperfusion (OR 0.79, 95% CI 0.71-0.89) and puncture to reperfusion time (OR 1.17, 95% CI 1.03-1.33) were associated with END. When examining three-month prognostic indexes, both END and ENI were found to be linked to the three-month outcomes, but in opposite directions. A subgroup analysis of END suggested that unexplained END typically demonstrated a more favorable prognosis compared to explained END, although the prognosis remained generally unfavorable. CONCLUSIONS: ENO, whether they manifested as early improvement or deterioration, were linked to the prognosis of VBAO patients undergoing EVT. The outcomes after unEND were more favorable than those following explained END.
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Cancer cells largely rely on aerobic glycolysis or the Warburg effect to generate essential biomolecules and energy for their rapid growth. The key modulators in glycolysis including glucose transporters and enzymes, e.g. hexokinase 2, enolase 1, pyruvate kinase M2, lactate dehydrogenase A, play indispensable roles in glucose uptake, glucose consumption, ATP generation, lactate production, etc. Transcriptional regulation and post-translational modifications (PTMs) of these critical modulators are important for signal transduction and metabolic reprogramming in the glycolytic pathway, which can provide energy advantages to cancer cell growth. In this review we recapitulate the recent advances in research on glycolytic modulators of cancer cells and analyze the strategies targeting these vital modulators including small-molecule inhibitors and microRNAs (miRNAs) for targeted cancer therapy. We focus on the regulation of the glycolytic pathway at the transcription level (e.g., hypoxia-inducible factor 1, c-MYC, p53, sine oculis homeobox homolog 1, N6-methyladenosine modification) and PTMs (including phosphorylation, methylation, acetylation, ubiquitination, etc.) of the key regulators in these processes. This review will provide a comprehensive understanding of the regulation of the key modulators in the glycolytic pathway and might shed light on the targeted cancer therapy at different molecular levels.
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Glicólise , Neoplasias , Processamento de Proteína Pós-Traducional , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/genética , Glicólise/efeitos dos fármacos , Animais , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Transcrição Gênica , Terapia de Alvo Molecular/métodos , Regulação Neoplásica da Expressão GênicaRESUMO
The circadian clock is the inner rhythm of life activities and is controlled by a self-sustained and endogenous molecular clock, which maintains a ~ 24 h internal oscillation. As the core element of the circadian clock, BMAL1 is susceptible to degradation through the ubiquitin-proteasome system (UPS). Nevertheless, scant information is available regarding the UPS enzymes that intricately modulate both the stability and transcriptional activity of BMAL1, affecting the cellular circadian rhythm. In this work, we identify and validate UBR5 as a new E3 ubiquitin ligase that interacts with BMAL1 by using affinity purification, mass spectrometry, and biochemical experiments. UBR5 overexpression induced BMAL1 ubiquitination, leading to diminished stability and reduced protein level of BMAL1, thereby attenuating its transcriptional activity. Consistent with this, UBR5 knockdown increases the BMAL1 protein. Domain mapping discloses that the C-terminus of BMAL1 interacts with the N-terminal domains of UBR5. Similarly, cell-line-based experiments discover that HYD, the UBR5 homolog in Drosophila, could interact with and downregulate CYCLE, the BMAL1 homolog in Drosophila. PER2-luciferase bioluminescence real-time reporting assay in a mammalian cell line and behavioral experiments in Drosophila reveal that UBR5 or hyd knockdown significantly reduces the period of the circadian clock. Therefore, our work discovers a new ubiquitin ligase UBR5 that regulates BMAL1 stability and circadian rhythm and elucidates the underlying molecular mechanism. This work provides an additional layer of complexity to the regulatory network of the circadian clock at the post-translational modification level, offering potential insights into the modulation of the dysregulated circadian rhythm.
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Fatores de Transcrição ARNTL , Ritmo Circadiano , Ubiquitina-Proteína Ligases , Ubiquitinação , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , Fatores de Transcrição ARNTL/metabolismo , Fatores de Transcrição ARNTL/genética , Animais , Humanos , Ritmo Circadiano/fisiologia , Células HEK293 , Proteólise , Relógios Circadianos/fisiologia , Proteínas Circadianas Period/metabolismo , Proteínas Circadianas Period/genéticaRESUMO
BACKGROUND: Colonoscopy is the most frequently used diagnostic and therapeutic tool for the treatment of colorectal diseases. Although the complication rate is low, it can be potentially serious. Intussusception is a rare and severe complication often associated with polypectomy. Only a handful of post-colonoscopy intussusception cases have been reported, making this study a valuable addition to the medical literature. CASE SUMMARY: Case 1: A 61-year-old man underwent colonoscopy with polypectomy for chronic abdominal pain. The patient experienced abdominal pain 11 hours later but was still discharged after pain management. He was readmitted due to recurring pain. Computed tomography (CT) showed colo-colonic intussusception. Initial conservative management and attempts at endoscopic reduction failed; therefore, laparoscopic right hemicolectomy was performed. Histopathological examination revealed tubular adenomas in the polyps and inflammation in the resected specimens. Case 2: A 59-year-old woman underwent colonoscopy with polypectomy for a polyp in the transverse colon. She experienced upper abdominal pain, fever, nausea, and vomiting 9 hours after the procedure. Emergency CT and blood tests revealed a colo-colonic intussusception near the hepatic flexure and an elevated white blood cell count. Initial attempts at endoscopic reduction failed and conservative treatment showed no improvement. She underwent successful laparoscopic reduction and recovered uneventfully. Histopathological examination of the resected polyp revealed hyperplasia. CONCLUSION: Post-colonoscopy intussusception in adults is rare, and polypectomy may contribute to its occurrence. Early diagnosis is crucial, with prompt CT examination serving as key. After excluding malignancies, conservative management and reduction of intussusception should be considered before surgical bowel resection.
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Industrial biotechnology is regarded as the most promising technology for sustainable industrial development. The advancement of synthetic biology creates new opportunities and infinite possibilities for the progress of industrial biotechnology. Fermentation engineering is the grab and foothold of the industrialization of all the biotechnologies. Our teaching team optimized the teaching content and innovated the teaching mode to establish a teaching system of synthetic biology matching fermentation engineering. We highlighted the teaching characteristics (telling fermentation story cultivated the craftsmanship spirit; bioeconomic education strengthened the engineering thinking; bioethics and safety education fostered a sense of responsibility), then we summarized and prospected the teaching reform of this course. We believe that the teaching reform of synthetic biology will improve the learning performance of postgraduates, provide a reference for the teaching of synthetic biology in related fields, and promote the development of industrial biotechnology (strengthening the innovation capability in biological manufacturing and cultivating new momentum for bioeconomy).
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Biotecnologia , Fermentação , Biologia Sintética , Educação de Pós-Graduação , Ensino , Engenharia MetabólicaRESUMO
Ubiquitin-fold modifier 1 (UFM1) is covalently conjugated to protein substrates via a cascade of enzymatic reactions, a process known as UFMylation. UFMylation orchestrates an array of vital biological functions, including maintaining endoplasmic reticulum (ER) homeostasis, facilitating protein biogenesis, promoting cellular differentiation, regulating DNA damage response, and participating in cancer-associated signaling pathways. UFMylation has rapidly evolved into one of the forefront research areas within the last few years, yet much remains to be uncovered. In this review, first, UFMylation and its cellular functions associated with diseases are briefly introduced. Then, we summarize the proteomic approaches for identifying UFMylation substrates and explore the impact of UFMylation on gene transcription, protein translation, and maintenance of ER homeostasis. Next, we highlight the intricate regulation between UFMylation and two protein degradation pathways, the ubiquitin-proteasome system and the autophagy-lysosome pathway, and explore the potential of UFMylation system as a drug target. Finally, we discuss emerging perspectives in the UFMylation field. This review may provide valuable insights for drug discovery targeting the UFMylation system.
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Processamento de Proteína Pós-Traducional , Proteostase , Humanos , Proteostase/fisiologia , Animais , Autofagia/fisiologia , Retículo Endoplasmático/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , ProteínasRESUMO
Colorectal cancer is one of the most common malignancies and ranks second in terms of cancer-related mortality worldwide due to its metastasis, drug resistance, and reoccurrence. High-mobility gene group A2 (HMGA2) is overexpressed in colorectal cancer, contributing to the aggressiveness of tumor malignance, and promotes drug resistance in many types of cancer. However, the underlying molecular mechanism of HMGA2 is yet to be elucidated. In this study, we showed that HMGA2 is overexpressed in colorectal cancer tissue, and knockdown of HMGA2 significantly inhibited colorectal cancer cell growth and migratory capability. HMGA2 regulates the cancer cell response to a widely used anti-cancer drug, paclitaxel (PTX). HMGA2 knockdown increased cell death, whereas HMGA2 overexpression decreased cell death after PTX treatment. Furthermore, lower reactive oxygen species (ROS) levels and mitochondrial potential were detected in HMGA2 overexpression cells after PTX treatment. However, HMGA2 knockdown produced the opposite effect. RNA sequencing showed a p53 signaling pathway-dependent regulation in HMGA2 knockdown cells. Combined with p53 inhibitors and HMGA2 knockdown, a synergetic effect of more cell death was observed in colorectal cancer cells after PTX treatment. Thus, we showed that HMGA2 can activate p53 signaling to regulate colorectal cancer cell death after PTX treatment. Altogether, our results reveal novel insights into the molecular mechanisms underlying HMGA2-mediated cancer cell resistance against PTX and highlight the potential of targeting HMGA2 and p53 signaling for the therapeutic investigation of colorectal cancer.
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The morbidity of oral squamous cell carcinoma (OSCC) has been rising year after year, making it a major global health issue. But the molecular pathogenesis of OSCC is currently unclear. To study the potential pathogenesis of OSCC, the differentially expressed genes (DEGs) were screened, and multiple databases were used to perform the tumor stage, expression, prognosis, protein-protein interaction (PPI) networks, modules, and the functional enrichment analysis. Moreover, we have identified SP110 as the key candidate gene and conducted various analyses on it using multiple databases. The research indicated that there were 211 common DEGs, and they were enriched in various GO terms and pathways. Meanwhile, one DEG is significantly related to short disease-free survival, four are associated with overall survival, and 12 DEGs have close ties with tumor staging. Additionally, the SP110 is significantly associated with methylation level, HPV status, tumor staging, gender, race, tumor grade, age, and overall/disease-free survival of oral cancer patients, as well as the immune process. The copy number variation of SP110 significantly affected the abundance of immune infiltration. Therefore, we speculate that SP110 could be used as the diagnostic and therapeutic biomarker for OSCC, and can help to further understand oral carcinogenesis.
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HER2 overexpression is associated with various tumor types and prompted the development of targeted therapies. Previously, iso-[211At]SGMAB-5F7 was developed as a HER2-targeted alpha therapy agent, demonstrating promising therapeutic efficacy in the preclinical stage. Aiming for an 18F-labeled tracer for companion diagnostics in clinical translation, we employed the Al18F-RESCA strategy in our current work and investigated whether [18F]AlF-RESCA-5F7 could visualize HER2 expression in vivo. [18F]AlF-RESCA-5F7 was attained with high radiochemical purity (> 99%) and molar activity in the range of 16.5 ± 8.8 GBq/µmol (n = 8). Compared to previously reported radiotracers that contained 5F7 as the HER2-targeting carrier and fluorine-18 as the positron-emitting isotope, the radiosynthesis was simplified to one single step within 30 min. The dissociation constant of [18F]AlF-RESCA-5F7 was determined as 3.3 nM via saturation binding assay using SKOV3 ovarian carcinoma cells. Tumor uptake of the novel tracer in Balb/c nude mice bearing SKOV3 xenografts was 4.69 ± 1.51, 3.34 ± 0.82 and 3.77 ± 0.99 %ID/g at 1, 2, and 4 h post-injection. Even though high retention of radioactivity was seen in the kidneys, micro-PET/CT imaging of [18F]AlF-RESCA-5F7 delineated the tumor up to 4 h post-injection with minimal activity in the gallbladder, intestines, and bone. This study suggests that [18F]AlF-RESCA-5F7 is a promising HER2 PET radiotracer with an eased radiolabeling method. Whether [18F]AlF-RESCA-5F7 could work as a companion diagnostic agent to assist in patient stratification and treatment monitoring of iso-[211At]SGMAB-5F7 warrants further investigation.