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Proteolysis-targeting chimeras (PROTACs) technology has garnered significant attention over the last 10 years, representing a burgeoning therapeutic approach with the potential to address pathogenic proteins that have historically posed challenges for traditional small-molecule inhibitors. PROTACs exploit the endogenous E3 ubiquitin ligases to facilitate degradation of the proteins of interest (POIs) through the ubiquitin-proteasome system (UPS) in a cyclic catalytic manner. Despite recent endeavors to advance the utilization of PROTACs in clinical settings, the majority of PROTACs fail to progress beyond the preclinical phase of drug development. There are multiple factors impeding the market entry of PROTACs, with the insufficiently precise degradation of favorable POIs standing out as one of the most formidable obstacles. Recently, there has been exploration of new-generation advanced PROTACs, including small-molecule PROTAC prodrugs, biomacromolecule-PROTAC conjugates, and nano-PROTACs, to improve the in vivo efficacy of PROTACs. These improved PROTACs possess the capability to mitigate undesirable physicochemical characteristics inherent in traditional PROTACs, thereby enhancing their targetability and reducing off-target side effects. The new-generation of advanced PROTACs will mark a pivotal turning point in the realm of targeted protein degradation. In this comprehensive review, we have meticulously summarized the state-of-the-art advancements achieved by these cutting-edge PROTACs, elucidated their underlying design principles, deliberated upon the prevailing challenges encountered, and provided an insightful outlook on future prospects within this burgeoning field.
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Antineoplásicos , Neoplasias , Quimera Dirigida a la Proteólisis , Animales , Humanos , Antineoplásicos/farmacología , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Complejo de la Endopetidasa Proteasomal/metabolismo , Quimera Dirigida a la Proteólisis/farmacología , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
Atherosclerosis is one of the leading causes of death worldwide. miR-26 is a potential biomarker of atherosclerosis. Standardized diagnostic tests for miR-26 (MIR26-DX) have been developed, but the fastest progress has been in predicting the efficacy of IFN-α therapy for hepatocellular carcinoma (HCC, phase 3). MiR-26 slows atherosclerosis development by suppressing ACC1/2, ACLY, ACSL3/4, ALDH3A2, ALPL, BMP2, CD36, COL1A1, CPT1A, CTGF, DGAT2, EHHADH, FAS, FBP1, GATA4, GSK3ß, G6PC, Gys2, HMGA1, HMGB1, LDLR, LIPC, IL-1ß, IL-6, JAG2, KCNJ2, MALT1, ß-MHC, NF-κB, PCK1, PLCß1, PYGL, RUNX2, SCD1, SMAD1/4/5/7, SREBF1, TAB3, TAK1, TCF7L2, and TNF-α expression. Many agents targeting these genes, such as the ACC1/2 inhibitors GS-0976, PF-05221304, and MK-4074; the DGAT2 inhibitors IONIS-DGAT2Rx, PF-06427878, PF-0685571, and PF-07202954; the COL1A1 inhibitor HT-100; the stimulants 68Ga-CBP8 and RCT-01; the CPT1A inhibitors etomoxir, perhexiline, and teglicar; the FBP1 inhibitors CS-917 and MB07803; and the SMAD7 inhibitor mongersen, have been investigated in clinical trials. Interestingly, miR-26 better reduced intima-media thickness (IMT) than PCSK9 or CT-1 knockout. Many PCSK9 inhibitors, including alirocumab, evolocumab, inclisiran, AZD8233, Civi-007, MK-0616, and LIB003, have been investigated in clinical trials. Recombinant CT-1 was also investigated in clinical trials. Therefore, miR-26 is a promising target for agent development. miR-26 promotes foam cell formation by reducing ABCA1 and ARL4C expression. Multiple materials can be used to deliver miR-26, but it is unclear which material is most suitable for mass production and clinical applications. This review focuses on the potential use of miR-26 in treating atherosclerosis to support the development of agents targeting it.
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Aterosclerosis , MicroARNs , Humanos , Factores de Ribosilacion-ADP , Grosor Intima-Media Carotídeo , Diacilglicerol O-Acetiltransferasa , MicroARNs/genética , Proproteína Convertasa 9 , Proteína smad7 , Aterosclerosis/genéticaRESUMEN
The human living environment serves as a habitat for microorganisms and the presence of ubiquitous airborne microbes significantly impacts the natural material cycle. Through ongoing experimentation with beneficial microorganisms, humans have greatly benefited from airborne microbes. However, airborne pathogens endanger human health and have the potential to induce fatal diseases. Tracking airborne microbes is a critical prerequisite for a better understanding of bioaerosols, harnessing their potential advantages, and mitigating associated risks. Although technological breakthroughs have enabled significant advancements in accurately monitoring airborne pathogens, many puzzles about these microbes remain unanswered due to their high variability and environmental diffusibility. Consequently, advanced techniques and strategies for special identification, early warning, and efficient eradication of microbial contamination are continuously being sought. This review presents a comprehensive overview of the research status of airborne microbes, concentrating on the recent advances and challenges in sampling, detection, and inactivation. Particularly, the fundamental design principles for the collection and timely detection of airborne pathogens are described in detail, as well as critical factors for eliminating microbial contamination and enhancing indoor air quality. In addition, future research directions and perspectives for controlling airborne microbes are also suggested to promote the translation of basic research into real products.
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Myocardial infarction (MI) is a cardiovascular disease and troubles patients all over the world. Exosomes produced after long-term exercise training were discovered to mediate intercellular communication and alleviate MI-induced heart injury. However, the detailed roles of long-term exercise-derived exosomal long noncoding RNAs (LncRNAs) in MI remain uncovered. In this study, we collected and identified long-term exercise-derived exosomes, and established MI or hypoxia/reoxygenation (H/R) model after LncRNA colorectal neoplasia differentially expressed (CRNDE) depletion. This work proved that LncRNA CRNDE was highly expressed in long-term exercise-derived exosomes (p = 0.0078). CRNDE knockdown increased cardiomyocytes apoptosis and oxidative stress (p = 0.0036), and suppressed MI progress (p = 0.0005). CRNDE served as the sponge of miR-489-3p to affect Nrf2 expression (p = 0.0001). MiR-489-3p inhibition effectively reversed the effects of CRNDE depletion on hypoxia cardiomyocytes (p = 0.0002). These findings offered a promising therapeutic option for the treatment of MI.
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Ejercicio Físico , MicroARNs , Infarto del Miocardio , ARN Largo no Codificante , Humanos , Apoptosis/genética , Hipoxia , MicroARNs/metabolismo , Infarto del Miocardio/genética , Infarto del Miocardio/metabolismo , Factor 2 Relacionado con NF-E2/genética , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
A 27-year-old female patient presented with chronic spontaneous cerebrospinal fluid (CSF) rhinorrhea. She had deformity and weakness on the left side since childhood. Imaging examinations demonstrated hemi-hydranencephaly with a nearly complete absence of the right cerebral hemisphere, which was replaced with a membranous sac filled with CSF. She was accompanied with a frontal midline tumor containing lipids. After ventriculoperitoneal shunt, the CSF rhinorrhea completely ceased and no direct repair of the CSF fistula was necessary. The ventriculoperitoneal shunt procedure changes the CSF flow dynamics and releases the intracranial pressure, which may be a simple and effective procedure for CSF rhinorrhea in hemi-hydranencephaly.
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Rinorrea de Líquido Cefalorraquídeo , Implantes Dentales , Hidranencefalia , Femenino , Humanos , Niño , Adulto , Rinorrea de Líquido Cefalorraquídeo/cirugía , Derivación Ventriculoperitoneal , Hidranencefalia/complicaciones , Presión IntracranealRESUMEN
AIMS: To develop more potent drugs that eradicate persister bacteria and cure persistent urinary tract infections (rUTIs). METHODS AND RESULTS: We synthesized eight novel clinifloxacin analogs and measured minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), the time-kill curves in uropathogenic Escherichia coli (UPEC) UTI89, and applied the candidate drugs and combinations against biofilm bacteria in vitro and in mice. Transcriptomic analysis was performed for UPEC after candidate drug treatment to shed light on potential mechanism of action. We identified Compound 2, named Qingdafloxacin (QDF), which was more potent than clinafloxacin and clinically used levofloxacin and moxifloxacin, with an MIC of < 0.04 µg ml-1 and an MBC of 0.08â¼0.16 µg ml-1. In drug combination studies, QDF + gentamicin + nitrofuran combination but not single drugs completely eradicated all stationary phase bacteria containing persisters and biofilm bacteria, and all bacteria in a persistent UTI mouse model. Transcriptome analysis revealed that the unique antipersister activity of QDF was associated with downregulation of genes involved in bacterial stress response, DNA repair, protein misfolding repair, pyrimidine metabolism, glutamate, and glutathione metabolism, and efflux. CONCLUSIONS: QDF has high antipersister activity and its drug combinations proved highly effective against biofilm bacteria in vitro and persistent UTIs in mice, which may have implications for treating rUTIs.
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Quinolonas , Escherichia coli Uropatógena , Animales , Ratones , Escherichia coli Uropatógena/genética , Infección Persistente , Levofloxacino , BiopelículasRESUMEN
BACKGROUND: Ilicis chinensis folium extract (ICFE) is a powder extracted and processed with Ilex chinensis Sims (ICS) which has numerous bioactivities and is conventionally used in traditional Chinese medicine. Nonetheless, there has been no definitive study evaluating ICFE's application as a feed supplement for broilers. This research sought to determine the chemical composition and evaluate how dietary ICFE supplementation affects the growth performance, serum metrics, intestinal structure, and antioxidant capacity of broilers. METHODS: A total of 360 one-day-old broiler chicks were assigned to four treatments (with 9 replicates of 10 chicks, each) of dietary supplementation with ICFE at 0, 250, 500, and 1,000 mg /kg for 42 days. RESULTS: Ten polyphenolic compounds and two triterpenoid glycosides were detected by HPLC. In the grower stage and overall, broilers supplemented with 500 and 1,000 mg/kg ICFE exhibited a higher ADFI (P < 0.05) than the controls. Additionally, compared to the controls, broilers receiving low, medium, or high dosages of ICFE exhibited higher average daily gains (P < 0.05) throughout the starter stage and overall. Organ indices showed no significant variation, suggesting that ICFE was non-toxic. ICFE supplementation increased the height of villi in the duodenum and jejunum, reduced crypt depth, and increased the villus/crypt ratio in the duodenum (P < 0.05). Serum concentrations of IL-4 and IgA were increased in ICFE-supplemented broilers. The serum malondialdehyde concentration was reduced, whereas superoxide dismutase activity and total antioxidant capacity increased through supplementation with ICFE. CONCLUSION: ICFE supplementation can improve intestinal morphology, antioxidant capacity, and growth performance of broilers. Hence, ICFE is a promising and safe alternative to antibiotics in broilers, and 500 mg/kg appears to be the optimal dose.
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Antioxidantes , Pollos , Animales , Antioxidantes/farmacología , Dieta/veterinaria , Intestinos , Suplementos Dietéticos , Alimentación Animal/análisisRESUMEN
BRDs proteins that recognise chromatin acetylation regulate gene expression, are epigenetic readers and master transcription coactivators. BRDs proteins are now emerging as targets for new therapeutic development. Blocking the function of any of BRDs proteins can be a control agent for diseases, such as cancer. Traditional drugs like enzyme inhibitors and protein-protein inhibitors have many limitations. The therapeutic efficacy of them remains to be proven. Recently, Proteolysis-Targeting Chimaeras (PROTACs) have become an advanced tool in therapeutic intervention as they remove disease-causing proteins. Extremely potent and efficacious small-molecule PROTACs of the BRDs proteins, based on available, potent, and selective BRDs inhibitors, have been reported. This review presents a comprehensive overview of the development of PROTACs for BRDs proteins regulation in cancer, and the chances and challenges associated with this area are also highlighted.
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Descubrimiento de Drogas , Neoplasias , Humanos , Péptidos y Proteínas de Señalización Intercelular , Neoplasias/tratamiento farmacológico , Proteolisis , Factores de TranscripciónRESUMEN
Age-related cardiovascular disease is the leading cause of death in elderly populations. Coxibs, including celecoxib, valdecoxib, etoricoxib, parecoxib, lumiracoxib, and rofecoxib, are selective cyclooxygenase-2 (COX-2) inhibitors used to treat osteoarthritis and rheumatoid arthritis. However, many coxibs have been discontinued due to adverse cardiovascular events. COX-2 contains cyclooxygenase (COX) and peroxidase (POX) sites. COX-2 inhibitors block COX activity without affecting POX activity. Recently, quercetin-like flavonoid compounds with OH groups in their B-rings have been found to serve as activators of COX-2 by binding the POX site. Galangin-like flavonol compounds serve as inhibitors of COX-2. Interestingly, nabumetone, flurbiprofen axetil, piketoprofen-amide, and nepafenac are ester prodrugs that inhibit COX-2. The combination of galangin-like flavonol compounds with these prodrug metabolites may lead to the development of novel COX-2 inhibitors. This review focuses on the most compelling evidence regarding the role and mechanism of COX-2 in cardiovascular diseases and demonstrates that quercetin-like compounds exert potential cardioprotective effects by serving as cofactors of COX-2.
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Enfermedades Cardiovasculares/prevención & control , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Ciclooxigenasa 2/metabolismo , Quercetina/uso terapéutico , Animales , Antioxidantes/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Cardiotónicos/uso terapéutico , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/enzimología , Inhibidores de la Ciclooxigenasa 2/efectos adversos , Humanos , Osteoartritis/tratamiento farmacológico , Medición de Riesgo , Factores de RiesgoRESUMEN
Atherosclerosis, characterized by the formation of fat-laden plaques, is a chronic inflammatory disease. ABCA1 promotes cholesterol efflux, reduces cellular cholesterol accumulation, and regulates anti-inflammatory activities in an apoA-I- or ANXA1-dependent manner. The latter activity occurs by mediating the efflux of ANXA1, which plays a critical role in anti-inflammatory effects, cholesterol transport, exosome and microparticle secretion, and apoptotic cell clearance. ApoA-I increases ANXA1 expression via the ERK, p38MAPK, AKT, and PKC pathways. ApoA-I regulates the signaling pathways by binding to ABCA1, suggesting that apoA-I increases ANXA1 expression by binding to ABCA1. Furthermore, ANXA1 may increase ABCA1 expression. ANXA1 increases PPARγ expression by modulating STAT6 phosphorylation. PPARγ also increases ANXA1 expression by binding to the promoter of ANXA1. Therefore, ABCA1, PPARγ, and ANXA1 may form a feedback loop and regulate each other. Interestingly, the ANXA1 needs to be externalized to the cell membrane or secreted into the extracellular fluids to exert its anti-inflammatory properties. ABCA1 transports ANXA1 from the cytoplasm to the cell membrane by regulating lipidization and serine phosphorylation, thereby mediating ANXA1 efflux, likely by promoting microparticle and exosome release. The direct role of ABCA1 expression and ANXA1 release in atherosclerosis has been unclear. In this review, we focus on the role of ANXA1 in atheroprogression and its novel interaction with ABCA1, which may be useful for providing basic knowledge for the development of novel therapeutic targets for atherosclerosis and cardiovascular disease.
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Transportador 1 de Casete de Unión a ATP/metabolismo , Anexina A1/metabolismo , Aterosclerosis/etiología , Aterosclerosis/metabolismo , Susceptibilidad a Enfermedades , Transducción de Señal , Transportador 1 de Casete de Unión a ATP/genética , Animales , Anexina A1/genética , Apoptosis/genética , Aterosclerosis/patología , Transporte Biológico , Biomarcadores , Colesterol/metabolismo , Regulación de la Expresión Génica , Humanos , Macrófagos/inmunología , Macrófagos/metabolismo , Unión ProteicaRESUMEN
For years, intratumor injection of bacteria have been purported to be capable of an anticancer effect. However, these bacteria are mostly pathogenic including attenuated and genetically engineered bacteria. The gut microbiota has been discovered to play a key role in immunotherapy. Many remarkable advances have been made in characterizing the immune responses to gut microbiota. Interestingly, accumulating evidence has demonstrated that immunogenic cell death (ICD) plays a key role in the anticancer effect of chemotherapy, radiotherapy, photodynamic therapy and oncolytic virotherapy. Most interestingly, the gut microbiota may impact the ICD process. Given the importance of the gut microbiota in immune responses, cancer progression and the anticancer efficacy of drugs with immune effects. We propose a mechanism in which ICD may be the possible key link between gut microbiota and the anticancer efficacy of drugs with immune effects. However, the study of the relationship between the gut microbiota and ICD is limited, and it is still not clear how gut microbiota affect the ICD pathway. In this review, we discuss the mechanism by which the gut microbiota affects ICD, and suggest that ICD may be a possible key link between gut microbiota and the anticancer efficacy of drugs with immune effects.
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Muerte Celular Inmunogénica , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Terapia Combinada , Microbioma Gastrointestinal , Humanos , Inmunomodulación , Neoplasias/inmunología , Neoplasias/microbiología , Neoplasias/terapia , Transducción de Señal , Resultado del TratamientoRESUMEN
OBJECTIVE: Gastric cancer is one of the most common malignant tumors worldwide, and for resectable tumors, the most effective treatment is surgery with chemotherapy in neoadjuvant or adjuvant setting. However, the majority of patients fail to achieve the ideal initial response and/or develop resistance to chemotherapy. It was reported that long noncoding RNA regulator of reprogramming (ROR) is highly associated with the progression of gastric cancer. However, the role ROR in multidrug resistance (MDR) remains unclear. METHODS: The messenger RNA levels of 63 specimens of patients with gastric cancer were determined by real-time polymerase chain reaction analysis and were correlated with drug resistance and survival of patients. To determine the cellular functions of ROR, we generated gastric cancer MDR cells. The effect of ROR depletion on multidrug resistance-associated protein 1 (MRP1) expression and cell apoptosis were examined by immunoblotting analyses, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and flow cytometry. RESULTS: We found that ROR expression levels are positively associated with increased MDR and poor prognosis of patients with gastric cancer. Regulator of reprogramming expression is increased in gastric cancer cells resistant to adriamycin (ADR) and vincristine (VCR). Depletion of ROR reduced MRP1 expression and increased apoptosis of drug-resistant gastric cancer cells in response to ADR and VCR treatment. CONCLUSIONS: We demonstrated that ROR expression promotes MRP1 expression and MDR of gastric cancer cells and is correlated with increased MDR and poor prognosis of patients with gastric cancer. Our finding highlighted the potential of targeting ROR to improve the efficacy of chemotherapy.
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ARN Largo no Codificante/metabolismo , Neoplasias Gástricas/genética , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Resistencia a Antineoplásicos , Humanos , Persona de Mediana Edad , Neoplasias Gástricas/patologíaRESUMEN
Alkaline phosphatase (ALP) is a zinc-containing metalloprotein that shows very great significance in clinical diagnosis, which can catalyze the hydrolysis of phosphorylated species. ALP has the potential to serve as a valuable biomarker for detecting liver dysfunction and bone diseases. On the other hand, ALP is an efficient biocatalyst to amplify detection signals in the enzyme-linked assay. It has always been a major research focus to develop novel biosensors that can detect ALP activity with high selectivity and sensitivity. There have been numerous reports on the development of biosensors to determine ALP activity using a phosphorylated DNA probe. Among them, various beneficial strategies, such as λ exonuclease-mediated cleavage reaction, terminal deoxynucleotidyl transferase-triggered DNA polymerization, and Klenow fragment polymerase-catalyzed elongation, are employed to generate amplified and more intuitive signal. This review discusses and summarizes the development and advances of biosensors for ALP activity detection that use a well-designed phosphorylated DNA probe, aiming to provide some guidelines for the design of more sophisticated sensing strategies that exhibit improved sensitivity, selectivity, and adaptability in detecting ALP activity.
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Fosfatasa Alcalina , Técnicas Biosensibles , Sondas de ADN/genética , Hidrólisis , ADN , Límite de DetecciónRESUMEN
miR-135 is a highly conserved miRNA in mammals and includes miR-135a and miR-135b. Recent studies have shown that miR-135b is a key regulatory factor in cardio-cerebrovascular diseases. It is involved in regulating the pathological process of myocardial infarction, myocardial ischemia/reperfusion injury, cardiac hypertrophy, atrial fibrillation, diabetic cardiomyopathy, atherosclerosis, pulmonary hypertension, cerebral ischemia/reperfusion injury, Parkinson's disease, and Alzheimer's disease. Obviously, miR-135b is an emerging player in cardio-cerebrovascular diseases and is expected to be an important target for the treatment of cardio-cerebrovascular diseases. However, the crucial role of miR-135b in cardio-cerebrovascular diseases and its underlying mechanism of action has not been reviewed. Therefore, in this review, we aimed to comprehensively summarize the role of miR-135b and the signaling pathway mediated by miR-135b in cardio-cerebrovascular diseases. Drugs targeting miR-135b for the treatment of diseases and related patents, highlighting the importance of this target and its utility as a therapeutic target for cardio-cerebrovascular diseases, have been discussed.
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Lymph nodes (LNs) occupy a critical position in initiating and augmenting immune responses, both spatially and functionally. In cancer immunotherapy, tumor-specific vaccines are blooming as a powerful tool to suppress the growth of existing tumors, as well as provide preventative efficacy against tumorigenesis. Delivering these vaccines more efficiently to LNs, where antigen-presenting cells (APCs) and T cells abundantly reside, is under extensive exploration. Formulating vaccines into nanomedicines, optimizing their physiochemical properties, and surface modification to specifically bind molecules expressed on LNs or APCs, are common routes and have brought encouraging outcomes. Alternatively, porous scaffolds can be engineered to attract APCs and provide an environment for them to mature, proliferate and migrate to LNs. A relatively new research direction is inducing the formation of LN-like organoids, which have shown positive relevance to tumor prognosis. Cutting-edge advances in these directions and discussions from a future perspective are given here, from which the up-to-date pattern of cancer vaccination will be drawn to hopefully provide basic guidance to future studies.
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Tenascin C (TNC), a glycoprotein that is abundant in the tumor extracellular matrix (ECM), is strongly overexpressed in tumor tissues but virtually undetectable in most normal tissues. Many TNC antibodies, peptides, aptamers, and nanobodies have been investigated as delivery vectors, including 20A1, α-A2, α-A3, α-IIIB, α-D, BC-2, BC-4 BC-8, 81C6, ch81C6, F16, FHK, Ft, Ft-NP, G11, G11-iRGD, GBI-10, 19H12, J1/TN1, J1/TN2, J1/TN3, J1/TN4, J1/TN5, NJT3, NJT4, NJT6, P12, PL1, PL3, R6N, SMART, ST2146, ST2485, TN11, TN12, TNFnA1A2-Fc, TNfnA1D-Fc, TNfnBD-Fc, TNFnCD-Fc, TNfnD6-Fc, TNfn78-Fc, TTA1, TTA1.1, and TTA1.2. In particular, BC-2, BC-4, 81C6, ch81C6, F16, FHK, G11, PL1, PL3, R6N, ST2146, TN11, and TN12 have been tested in human tissues. G11-iRGD and simultaneous multiple aptamers and arginine-glycine-aspartic acid (RGD) targeting (SMART) may be assessed in clinical trials because G11, iRGD and AS1411 (SMART components) are already in clinical trials. Many TNC-conjugate agents, including antibody-drug conjugates (ADCs), antibody fragment-drug conjugates (FDCs), immune-stimulating antibody conjugates (ISACs), and radionuclide-drug conjugates (RDCs), have been investigated in preclinical and clinical trials. RDCs investigated in clinical trials include 111In-DTPA-BC-2, 131I-BC-2, 131I-BC-4, 90Y-BC4, 131I81C6, 131I-ch81C6, 211At-ch81C6, F16124I, 131I-tenatumomab, ST2146biot, FDC 131I-F16S1PF(ab')2, and ISAC F16IL2. ADCs (including FHK-SSL-Nav, FHK-NB-DOX, Ft-NP-PTX, and F16*-MMAE) and ISACs (IL12-R6N and 125I-G11-IL2) may enter clinical trials because they contain components of marketed treatments or agents that were investigated in previous clinical studies. This comprehensive review presents historical perspectives on clinical advances in TNC-conjugate agents to provide timely information to facilitate tumor-targeting drug development using TNC.
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Inmunoconjugados , Tenascina , Humanos , Matriz Extracelular , Péptidos , Inmunoconjugados/uso terapéutico , Línea Celular TumoralRESUMEN
Tenascin C (TNC), a rich glycoprotein of the extracellular matrix, exhibits a pro-atherosclerosis or anti-atherosclerosis effect depending on its location. TNC, especially its C domain/isoform (TNC-C), is strongly overexpressed in atherosclerotic plaque active areas but virtually undetectable in most normal adult tissues, suggesting that TNC is a promising delivery vector target for atherosclerosis-targeted drugs. Many delivery vectors were investigated by recognizing TNC-C, including G11, G11-iRGD, TN11, PL1, and PL3. F16 and FNLM were also investigated by recognizing TNC-A1 and TNC, respectively. Notably, iRGD was undergoing clinical trials. PL1 not only recognizes TNC-C but also the extra domain-B (EDB) of fibronectin (FN), which is also a promising delivery vector for atherosclerosis-targeted drugs, and several conjugate agents are undergoing clinical trials. The F16-conjugate agent F16IL2 is undergoing clinical trials. Therefore, G11-iRGD, PL1, and F16 have great development value. Furthermore, ATN-RNA and IMA950 were investigated in clinical trials as therapeutic drugs and vaccines by targeting TNC, respectively. Therefore, targeting TNC could greatly improve the success rate of atherosclerosis-targeted drugs and/or specific drug development. This review discussed the role of TNC in atherosclerosis, atherosclerosis-targeted drug delivery vectors, and agent development to provide knowledge for drug development targeting TNC.
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Aterosclerosis , Placa Aterosclerótica , Adulto , Humanos , Tenascina/genética , Aterosclerosis/tratamiento farmacológico , Matriz Extracelular , Placa Aterosclerótica/tratamiento farmacológico , Isoformas de ProteínasRESUMEN
BACKGROUND: Tert-butylhydroquinone (tBHQ), a synthetic phenolic antioxidant, is commonly used as a food preservative because of its potent antilipid peroxidation activity. Several lines of evidence have demonstrated that dietary supplementation with antioxidants has an antiatherogenic function through reducing cholesterol uptake or promoting reverse cholesterol transport. In this study, we investigated whether tBHQ affects expression of ATP-binding cassette transporter A1 (ABCA1) and the potential subsequent effect on cellular cholesterol homeostasis. METHODS AND RESULTS: tBHQ increased ABCA1 protein levels and markedly enhanced cholesterol efflux from THP-1 macrophage-derived foam cells. Furthermore, tBHQ reduced calpain-mediated ABCA1 proteolysis via activation of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1). Inhibition of HO-1 with a pharmacological inhibitor or siRNA and knockdown of Nrf2 suppressed the stimulatory effects of tBHQ on ABCA1 expression and calpain activity. CONCLUSIONS: Nrf2/HO-1 signaling is required for the regulation by tBHQ of ABCA1 expression and cholesterol efflux in macrophage-derived foam cells and an antiatherogenic role of tBHQ is suggested.
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Transportador 1 de Casete de Unión a ATP/biosíntesis , Antioxidantes/farmacología , Células Espumosas/metabolismo , Hemo-Oxigenasa 1/metabolismo , Hidroquinonas/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación hacia Arriba/efectos de los fármacos , Calpaína , Línea Celular Tumoral , Células Espumosas/patología , HumanosRESUMEN
Nanomaterials with intrinsic enzyme activity, referred to as nanozymes, have attracted substantial attention in recent years. Among them, phosphatase-mimicking nanozymes have become an increasingly important focus for future research, considering that phosphatase is not only one of key enzymes for phosphorous metabolism, which is essential for many biological processes (e.g., cellular regulation and signaling), but also one of extensively used biocatalytic labels in the enzyme-linked assays as well as a powerful tool enzyme in molecular biology laboratories. Nevertheless, compared with extensive oxidoreductase-mimicking nanozymes, there are a very limited number of nanozymes with phosphatase-like activity have been explored at present. The increasing demand of complex and individualized phosphatase-involved catalytic behaviors is pushing the development of more advanced phosphatase-mimicking nanozymes. Thus, we present an overview on recently reported phosphatase-like nanozymes, providing guidelines and new insights for designing more advanced phosphatase-mimicking nanozyme with superior properties.
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Técnicas Biosensibles , Nanoestructuras , Monoéster Fosfórico Hidrolasas , Catálisis , BiocatálisisRESUMEN
On December 22, 2021, the United States Food and Drug Administration approved the first main protease inhibitor, i.e., oral antiviral nirmatrelvir (PF-07321332)/ritonavir (Paxlovid), for the treatment of early severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Nirmatrelvir inhibits SARS-CoV-2 infection, but high doses or long-term treatment may cause embryonic developmental toxicity and changes in host gene expression. The chiral structure of nirmatrelvir plays a key role in its antiviral activity. Ritonavir boosts the efficacy of nirmatrelvir by inactivating cytochrome P450 3A4 expression and occupying the plasma protein binding sites. Multidrug resistance protein 1 inhibitors may increase the efficacy of nirmatrelvir. However, Paxlovid has many contraindications. Some patients treated with Paxlovid experience a second round of coronavirus disease 2019 (COVID-19) symptoms soon after recovery. Interestingly, the antiviral activity of nirmatrelvir metabolites, such as compounds 12-18, is similar to or higher than that of nirmatrelvir. Herein, we review the advances and challenges in using nirmatrelvir and its derivatives with the aim of providing knowledge for drug developers and physicians in the fight against COVID-19.