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Proteolysis targeting chimeras (PROTAC) are bifunctional chimeric molecules capable of directly degrading binding proteins through the ubiquitin-proteasome pathway. PROTACs have demonstrated significant potential in overcoming drug resistance and targeting previously untreatable targets. However, several limitations still need to be addressed, including their high molecular weight resulting in poor membrane permeability and bioavailability. In this study, we proposed that cancer-targeted penetrating peptides could enhance the cell permeability of PROTACs. We developed 26 novel targeted penetrating peptides for leukemia and lymphoma cells, among which C9C-f(3Bta) and Cyclo-C9C-R exhibited superior membrane permeability, targetability, and stability. By combining C9C-f(3Bta) and Cyclo-C9C-R with IMA-PROTAC, we effectively enhanced the anti-proliferative activity of IMA-PROTAC, facilitated degradation of Bcr-Abl protein in K562 cells, and reduced downstream STAT5 phosphorylation. Furthermore, the combined application promoted cell apoptosis while blocking G1 phase progression. HPLC-MRM-MS revealed that the combination of C9C-f(3Bta) or Cyclo-C9C-R with IMA-PROTAC significantly enhanced intracellular IMA-PROTAC content. In summary, our proof-of-concept study validated the hypothesis that combining PROTACs with targeted penetrating peptides can improve protein degradation efficiency as well as anti-proliferative capabilities.
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The complex etiological factors associated with metabolic dysfunction-associated fatty liver disease (MAFLD), including perturbed iron homeostasis, and the unclear nature by which they contribute to disease progression have resulted in a limited number of effective therapeutic interventions. Here, we report that patients with metabolic dysfunction-associated steatohepatitis (MASH), a pathological subtype of MAFLD, exhibit excess hepatic iron and that it has a strong positive correlation with disease progression. FerroTerminator1 (FOT1) effectively reverses liver injury across multiple MASH models without notable toxic side effects compared with clinically approved iron chelators. Mechanistically, our multi-omics analyses reveal that FOT1 concurrently inhibits hepatic iron accumulation and c-Myc-Acsl4-triggered ferroptosis in various MASH models. Furthermore, MAFLD cohort studies suggest that serum ferritin levels might serve as a predictive biomarker for FOT1-based therapy in MASH. These findings provide compelling evidence to support FOT1 as a promising novel therapeutic option for all stages of MAFLD and for future clinical trials.
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Extracellular vesicles (EVs) are shown to be a novel viral transmission model capable of increasing a virus's tropism. According to our earlier research, cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or transfected with envelope protein plasmids generate a novel type of EVs that are micrometer-sized and able to encase virus particles. Here, we showed the capacity of these EVs to invade various animals both in vitro and in vivo independent of the angiotensin-converting enzyme 2 receptor. First, via macropinocytosis, intact EVs produced from Vero E6 (monkey) cells were able to enter cells from a variety of animals, including cats, dogs, bats, hamsters, and minks, and vice versa. Second, when given to zebrafish with cutaneous wounds, the EVs showed favorable stability in aqueous environments and entered the fish. Moreover, infection of wild-type (WT) mice with heterogeneous EVs carrying SARS-CoV-2 particles led to a strong cytokine response and a notable amount of lung damage. Conversely, free viral particles did not infect WT mice. These results highlight the variety of processes behind viral transmission and cross-species evolution by indicating that EVs may be possible vehicles for SARS-CoV-2 spillover and raising risk concerns over EVs' potential for viral gene transfer.
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COVID-19 , Vesículas Extracelulares , SARS-CoV-2 , Animales , Vesículas Extracelulares/virología , Vesículas Extracelulares/metabolismo , SARS-CoV-2/fisiología , SARS-CoV-2/patogenicidad , SARS-CoV-2/genética , COVID-19/transmisión , COVID-19/virología , Ratones , Chlorocebus aethiops , Células Vero , Humanos , Cricetinae , Proteínas de la Envoltura de Coronavirus/metabolismo , Proteínas de la Envoltura de Coronavirus/genética , Perros , Pez Cebra/virología , Gatos , Quirópteros/virología , Enzima Convertidora de Angiotensina 2/metabolismo , Enzima Convertidora de Angiotensina 2/genéticaRESUMEN
Highly pathogenic viruses from family Phenuiviridae, which are mainly transmitted by arthropods, have intermittently sparked epidemics worldwide. In particular, tick-borne bandaviruses, such as severe fever with thrombocytopenia syndrome virus (SFTSV), continue to spread in mountainous areas, resulting in an average mortality rate as high as 10.5%, highlighting the urgency and importance of vaccine development. Here, an mRNA vaccine developed based on the full-length SFTSV glycoprotein, containing both the receptor-binding domain and the fusion domain, was shown to confer complete protection against SFTSV at a very low dose by triggering a type 1 helper T cell-biased cellular immune response in rodents. Moreover, the vaccine candidate elicited long-term immunity and protection against SFTSV for at least 5 months. Notably, it provided complete cross-protection against other bandaviruses, such as the Heartland virus and Guertu virus, in lethal challenge models. Further research revealed that the conserved epitopes among bandaviruses within the full-length SFTSV glycoprotein may facilitate broad-spectrum protection mediated by the cellular immune response. Collectively, these findings demonstrate that the full-length SFTSV glycoprotein mRNA vaccine is a promising vaccine candidate for SFTSV and other bandaviruses, and provide guidance for the development of broad-spectrum vaccines from conserved antigens and epitopes. IMPORTANCE: Tick-borne bandaviruses, such as SFTSV and Heartland virus, sporadically trigger outbreaks in addition to influenza viruses and coronaviruses, yet there are no specific vaccines or therapeutics against them. mRNA vaccine technology has advantages in terms of enabling in situ expression and triggering cellular immunity, thus offering new solutions for vaccine development against intractable viruses, such as bandaviruses. In this study, we developed a novel vaccine candidate for SFTSV by employing mRNA vaccination technology and using a full-length glycoprotein as an antigen target. This candidate vaccine confers complete and durable protection against SFTSV at a notably low dose while also providing cross-protection against Heartland virus and Guertu virus. This study highlights the prospective value of full-length SFTSV-glycoprotein-based mRNA vaccines and suggests a potential strategy for broad-spectrum bandavirus vaccines.
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Glicoproteínas , Phlebovirus , Síndrome de Trombocitopenia Febril Grave , Vacunas Virales , Animales , Phlebovirus/inmunología , Phlebovirus/genética , Ratones , Síndrome de Trombocitopenia Febril Grave/prevención & control , Síndrome de Trombocitopenia Febril Grave/inmunología , Glicoproteínas/inmunología , Vacunas Virales/inmunología , Vacunas Virales/administración & dosificación , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/sangre , Vacunas de ARNm/inmunología , Protección Cruzada/inmunología , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/administración & dosificación , Femenino , Inmunidad Celular , Ratones Endogámicos BALB CRESUMEN
Human papillomavirus (HPV) is a prevalent sexually transmitted pathogen associated with cervical cancer. Detecting high-risk HPV (hr-HPV) infections is crucial for cervical cancer prevention, particularly in resource-limited settings. Here, we present a highly sensitive and specific sensor for HPV-16 detection based on CRISPR/Cas12a coupled with enhanced single nanoparticle dark-field microscopy (DFM) imaging techniques. Ag-Au satellites were assembled through the hybridization of AgNPs-based spherical nucleic acid (Ag-SNA) and AuNPs-based spherical nucleic acid (Au-SNA), and their disassembly upon target-mediated cleavage by the Cas12a protein was monitored using DFM for HPV-16 quantification. To enhance the cleavage efficiency and detection sensitivity, the composition of the ssDNA sequences on Ag-SNA and Au-SNA was optimized. Additionally, we explored using the SynSed technique (synergistic sedimentation of Brownian motion suppression and dehydration transfer) as an alternative particle transfer method in DFM imaging to traditional electrostatic deposition. This addresses the issue of inconsistent deposition efficiency of Ag-Au satellites and their disassembly due to their size and charge differences. The sensor achieved a remarkable limit of detection (LOD) of 10 fM, lowered by 9-fold compared to traditional electrostatic deposition methods. Clinical testing in DNA extractions from 10 human cervical swabs demonstrated significant response differences between the positive and negative samples. Our sensor offers a promising solution for sensitive and specific HPV-16 detection, with implications for cancer screening and management.
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Sistemas CRISPR-Cas , Oro , Papillomavirus Humano 16 , Nanopartículas del Metal , Papillomavirus Humano 16/genética , Humanos , Sistemas CRISPR-Cas/genética , Oro/química , Nanopartículas del Metal/química , Plata/química , Microscopía/métodos , Límite de Detección , Infecciones por Papillomavirus/diagnóstico , Infecciones por Papillomavirus/virología , ADN Viral/análisis , ADN Viral/genética , Proteínas Asociadas a CRISPR/metabolismo , Proteínas Asociadas a CRISPR/químicaRESUMEN
OBJECTIVE: To review the efficacy of exercise treatments on chronic obstructive pulmonary disease (COPD). DATA SOURCES: PubMed, Scopus, Science Direct, Ebscohost, SPORTDiscus, ProQuest, Web of Science. REVIEW METHODS: A systematic review was performed to identify the relevant studies published from 2011 to 2023. Studies were selected using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 5170 articles were retrieved and assessed using the Physiotherapy Evidence Database (PEDro) scale. The risk of bias in individual studies was assessed with the Cochrane risk of bias tool. RESULTS: A total of 38 eligible studies were included. Eight studies evaluated the effects of Tai Chi, followed by Liuzijue (five studies) and yoga (three studies). The duration of the exercise programmes ranged from 8 weeks to 3 years, and the frequency was between 2 and 7 times a week. Exercise sessions lasted between 20 and 90 min. Low-intensity exercise improved lung function after six months. Whole-body exercise improved dyspnea more than local exercise. Water-based exercise improved physical endurance more than land exercise, and quality of life was unaffected by long-term exercise. CONCLUSION: This systematic review highlights the benefit of exercise treatments as a potential adjunct treatment for COPD patients.
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Terapia por Ejercicio , Enfermedad Pulmonar Obstructiva Crónica , Calidad de Vida , Yoga , Humanos , Enfermedad Pulmonar Obstructiva Crónica/rehabilitación , Enfermedad Pulmonar Obstructiva Crónica/terapia , Terapia por Ejercicio/métodos , Taichi Chuan/métodos , Disnea/terapia , Disnea/rehabilitaciónRESUMEN
Conventional tumor diagnosis and treatment approaches have significant limitations in clinical application, whereas personalized theranostistic nanoplatforms can ensure advanced diagnosis, precise treatment, and even a good prognosis in cancer. Tumor microenvironment (TME)-targeted therapeutic strategies offer absolute advantages in all aspects compared to tumor cell-targeted therapeutic strategies. It is essential to create a TME-responsive all-in-one nanotheranostic platform to facilitate individualized tumor treatment. Based on the TME-responsive multifunctional nanotheranostic platform, we focus on the combined use of multimodal imaging and therapeutic protocols and summary and outlooks on the latest advanced nanomaterials and structures for creating the integrated nanotheranostic system based on material science, which provide insights and reflections on the development of innovative TME-targeting tools for cancer theranostics.
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Imagen Multimodal , Neoplasias , Nanomedicina Teranóstica , Microambiente Tumoral , Humanos , Imagen Multimodal/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/diagnóstico por imagen , Nanomedicina Teranóstica/métodos , Animales , Nanoestructuras , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Antineoplásicos/uso terapéuticoRESUMEN
INTRODUCTION: Non-healing wounds resulting from trauma, surgery, and chronic diseases annually affect millions of individuals globally, with limited therapeutic strategies available due to the incomplete understanding of the molecular processes governing tissue repair and regeneration. Salvianolic acid B (Sal B) has shown promising bioactivities in promoting angiogenesis and inhibiting inflammation. However, its regulatory mechanisms in tissue regeneration remain unclear. PURPOSE: This study aims to investigate the effects of Sal B on wound healing and regeneration processes, along with its underlying molecular mechanisms, by employing zebrafish as a model organism. METHODS: In this study, we employed a multifaceted approach to evaluate the impact of Sal B on zebrafish tail fin regeneration. We utilized whole-fish immunofluorescence, TUNEL staining, mitochondrial membrane potential (MMP), and Acridine Orange (AO) probes to analyze the tissue repair and regenerative under Sal B treatment. Additionally, we utilized transgenic zebrafish strains to investigate the migration of inflammatory cells during different phases of fin regeneration. To validate the importance of Caveolin-1 (Cav1) in tissue regeneration, we delved into its functional role using molecular docking and Morpholino-based gene knockdown techniques. Additionally, we quantified Cav1 expression levels through the application of in situ hybridization. RESULTS: Our findings demonstrated that Sal B expedites zebrafish tail fin regeneration through a multifaceted mechanism involving the promotion of cell proliferation, suppression of apoptosis, and enhancement of MMP. Furthermore, Sal B was found to exert regulatory control over the dynamic aggregation and subsequent regression of immune cells during tissue regenerative processes. Importantly, we observed that the knockdown of Cav1 significantly compromised tissue regeneration, leading to an excessive infiltration of immune cells and increased levels of apoptosis. Moreover, the knockdown of Cav1 also affects blastema formation, a critical process influenced by Cav1 in tissue regeneration. CONCLUSION: The results of this study showed that Sal B facilitated tissue repair and regeneration through regulating of immune cell migration and Cav1-mediated fibroblast activation, promoting blastema formation and development. This study highlighted the potential pharmacological effects of Sal B in promoting tissue regeneration. These findings contributed to the advancement of regenerative medicine research and the development of novel therapeutic approaches for trauma.
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Benzofuranos , Caveolina 1 , Cicatrización de Heridas , Pez Cebra , Animales , Aletas de Animales/efectos de los fármacos , Aletas de Animales/fisiología , Animales Modificados Genéticamente , Apoptosis/efectos de los fármacos , Benzofuranos/farmacología , Caveolina 1/metabolismo , Movimiento Celular/efectos de los fármacos , Depsidos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Simulación del Acoplamiento Molecular , Regeneración/efectos de los fármacos , Cicatrización de Heridas/efectos de los fármacos , Proteínas de Pez Cebra/metabolismoRESUMEN
AIM: To explore the effects of hepatocyte growth factor (HGF) on retinal pigment epithelium (RPE) cell behaviors. METHODS: The human adult retinal pigment epithelial cell line-19 (ARPE-19) were treated by HGF or mesenchymal-epithelial transition factor (MET) inhibitor SU11274 in vitro. Cell viability was detected by a Cell Counting Kit-8 assay. Cell proliferation and motility was detected by a bromodeoxyuridine incorporation assay and a wound healing assay, respectively. The expression levels of MET, phosphorylated MET, protein kinase B (AKT), and phosphorylated AKT proteins were determined by Western blot assay. The MET and phosphorylated MET proteins were also determined by immunofluorescence assay. RESULTS: HGF increased ARPE-19 cells' viability, proliferation and migration, and induced an increase of phosphorylated MET and phosphorylated AKT proteins. SU11274 significantly reduced cell viability, proliferation, and migration and decreased the expression of MET and AKT proteins. SU11274 suppressed HGF-induced increase of viability, proliferation, and migration in ARPE-19 cells. Additionally, SU11274 also blocked HGF-induced phosphorylation of MET and AKT proteins. CONCLUSION: HGF enhances cellular viability, proliferation, and migration in RPE cells through the MET/AKT signaling pathway, whereas this enhancement is suppressed by the MET inhibitor SU11274. HGF-induced MET/AKT signaling might be a vital contributor of RPE cells survival.
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Leukemia is a malignant clonal disease of hematopoietic stem cells, which accounts for about 3% of the total incidence of tumors and is particularly prevalent among children and adolescents. It mainly includes four types of leukemia, namely ALL, AML, CLL, and CML, which are often aggressive and challenging diseases to treat. Several signaling pathways are dysregulated in almost all types of leukemia, such as JAK, PI3K, and MAPK, and others are dysregulated in specific types of leukemia, like Wnt/ß-catenin, Hedgehog, FLT3, Bcr-Abl, and so on. Many efforts have been devoted to developing small molecule inhibitors targeting protein kinases involved in leukemia-related signaling pathways. In this review, we focus on the study of signaling pathways and protein kinases that developed as targets of anti-leukemia drug therapy and report the research progress of relevant small molecule kinase inhibitors over the last five years.
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We investigated the effect of melatonin on bisphenol A (BPA)-induced oxidative stress damage in testicular tissue and Leydig cells. Mice were gavaged with 50 mg/kg BPA for 30 days, and concurrently, were injected with melatonin (10 mg/kg and 20 mg/kg). Leydig cells were treated with 10 µmol/L of BPA and melatonin. The morphology and organ index of the testis and epididymis were observed and calculated. The sperm viability and density were determined. The expressions of melatonin receptor 1A and luteinizing hormone receptor, and the levels of malonaldehyde, antioxidant enzymes, glutathione, steroid hormone synthases, aromatase, luteinizing hormone, testosterone, and estradiol were measured. TUNEL assay was utilized to detect testicular cell apoptosis. The administration of melatonin at 20 mg/kg significantly improved the testicular index and epididymis index in mice treated with BPA. Additionally, melatonin promoted the development of seminiferous tubules in the testes. Furthermore, the treatment with 20 mg/kg melatonin significantly increased sperm viability and sperm density in mice, while also promoting the expressions of melatonin receptor 1A and luteinizing hormone receptor in Leydig cells of BPA-treated mice. Significantly, melatonin reduced the level of malonaldehyde in testicular tissue and increased the expression of antioxidant enzymes (superoxide dismutase 1, superoxide dismutase 2, and catalase) as well as the content of glutathione. Moreover, melatonin also reduced the number of apoptotic Leydig cells and spermatogonia, aromatase expression, and estradiol level, while increasing the expression of steroid hormone synthases (steroidogenic acute regulatory protein, cytochrome P450 family 17a1, cytochrome P450 17α-hydroxylase/20-lyase, and, 17ß-hydroxysteroid dehydrogenase) and the level of testosterone. Melatonin exhibited significant potential in alleviating testicular oxidative stress damage caused by BPA. These beneficial effects may be attributed to melatonin's ability to enhance the antioxidant capacity of testicular tissue, promote testosterone synthesis, and reduce testicular cell apoptosis.
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BACKGROUND: The impact of melatonin on bisphenol A (BPA)-induced testicular apoptosis and endoplasmic reticulum (ER) stress was explored. METHODS: The mice received BPA (50 mg/kg) by gavage for 30 days while being injected with 20 mg/kg melatonin. Protein expressions were detected with western blotting. The Terminal Deoxynucleotidyl Transferase dUTP Nick End Labeling (TUNEL) assay measured testicular cell apoptosis. Testosterone was quantified by employing enzyme-linked immunosorbent assay (ELISA). RESULTS: Melatonin promoted the development of seminiferous tubules, restored the orderly arrangement of the germ cells, and increased epithelial layers in the seminiferous tubules in BPA-treated mice. Moreover, in BPA-treated mouse testicular cells, melatonin markedly upregulated melatonin receptor 1A (MTNR1A) and melatonin Receptor 2 (MTNR2) expressions while downregulating ER molecular chaperones glucose-regulated protein 78 (GRP78) and glucose-regulated protein 94 (GRP94). Furthermore, it decreased p-PERK, p-IRE1, and ATF6α, as well as the apoptotic proteins cysteine-containing aspartate-specific proteases-12 (caspase-12) and cleaved cysteine-containing aspartate-specific proteases-3 (cleaved caspase-3), causing the suppression of testicular cell apoptosis. Additionally, melatonin increased the levels of cytochrome P450 17α-hydroxylase/20-lyase (CYP17A1), 17ß-hydroxysteroid dehydrogenase 3 (17ß-HSD3), and 3ß-hydroxysteroid dehydrogenase 4 (3ß-HSD4), in the ER, and elevated testosterone levels in testicular tissue. CONCLUSIONS: Melatonin can significantly alleviate testicular apoptosis and ER stress induced by BPA, which is because of the upregulation of melatonin receptor expression in testicular cells, inhibition of ER stress-related pathways, and enhancement of testosterone synthesis.
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Compuestos de Bencidrilo , Melatonina , Fenoles , Masculino , Ratones , Animales , Melatonina/farmacología , Receptores de Melatonina , Ácido Aspártico , Cisteína , Apoptosis , Estrés del Retículo Endoplásmico , Testosterona , Péptido HidrolasasRESUMEN
Amplification-free digital immunoassays (DIAs) typically utilize optical nanoparticles to enhance single immunocomplex molecule detection. The efficiency and uniformity of transferring the nanoparticles from a bulk solution to a solid surface determine the limit of detection (LOD) and the accuracy of DIAs. Previous methods suffer from issues like low efficiency, nonuniform distribution, and particle aggregation. Here, we present a novel technique named synergistic sedimentation of Brownian motion suppression and dehydration transfer (SynSed) for nanoparticles using water-soluble polymers. The efficiency of transferring quantum dots (QDs) was increased from 10.7 to 91.4%, and the variation in QD distribution was restricted to 8.8%. By incorporating SynSed into DIAs, we achieved a remarkable reduction in the LOD (down to 3.9 aM) for carcinoembryonic antigen and expanded the dynamic range to cover 3 orders of magnitude in concentration, ranging from 0.01 to 10 fM. DIAs enhanced with SynSed possess ultrahigh sensitivity, advanced accuracy, and specificity, offering a great premise in early disease diagnostics, risk stratification, and treatment response monitoring.
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RATIONALE: Ornidazole is a synthetic nitroimidazole derivative that is commonly prescribed for antiparasitic or anti-anaerobic infections. It is generally well tolerated, with known side effects including gastrointestinal tract, anaphylaxis, and central nervous system reactions. Ornidazole-induced binocular reactive keratitis and several mucocutaneous lesions have been rarely reported. PATIENT CONCERNS: A 52-year-old woman who suffered from vaginitis and received an ornidazole vaginal plug (0.5 g). Approximately 20 minutes after the suppository was inserted into the vagina, her lips were swollen and valva and labia were burning. Her eyes were red, sore, and watery. DIAGNOSIS: She was diagnosed as Steven-Johnson syndrome by the ophthalmologist. According to the Naranjo scale, the adverse drug reaction was evaluated to be probable and severe. INTERVENTIONS: Dexamethasone was intravenous administrated as anti-inflammatory therapy for 10 days. Eye drops were locally given to relieve edema and promote healing of the epithelium. The symptoms of her eyes, lips, vulva and crissum were soon relieved. OUTCOMES: The patient was discharge from hospital with improved symptoms. LESSONS: In order to avoid severe adverse effect, the patient should not use metronidazole ether orally or vaginally. The case emphasized the importance of rapid and accurate diagnosis of Steven-Johnson syndrome induced by ornidazole vaginal plug, especially when the eye symptoms were the chief complaint without body skin involved.
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Antiinfecciosos , Ornidazol , Síndrome de Stevens-Johnson , Humanos , Femenino , Persona de Mediana Edad , Síndrome de Stevens-Johnson/diagnóstico , Síndrome de Stevens-Johnson/tratamiento farmacológico , Síndrome de Stevens-Johnson/etiología , Ornidazol/efectos adversos , Piel/patología , Antiparasitarios , MetronidazolRESUMEN
Based on the crucial role of histone deacetylase (HDAC) and receptor tyrosine kinase in angiogenesis, in situ assembly, skeletal transition, molecular hybridization, and pharmacophore fusion were employed to yield seventy-six multi-target angiogenesis inhibitors. Biological evaluation indicated that most of the compounds exhibited potent proliferation inhibitory activity on MCF-7 cells, with the TH series having the highest inhibitory activity on MCF-7 cells. In addition, the IC50 values of TA11 and TH3 against HT-29 cellswere 0.078 µmol/L and 0.068 µmol/L, respectively. The cytotoxicity evaluation indicated that TC9, TA11, TM4, and TH3 displayed good safety against HEK293T cells. TH2 and TH3 could induce apoptosis of MCF-7 cells. Molecular modeling and ADMET prediction results indicated that most of target compounds showed promising medicinal properties, which was consistent with the experimental results. Our findings provided new lead compounds for the structural optimization of multi-target angiogenesis inhibitors.
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Inhibidores de la Angiogénesis , Antineoplásicos , Humanos , Relación Estructura-Actividad , Línea Celular Tumoral , Inhibidores de la Angiogénesis/farmacología , Angiogénesis , Células HEK293 , Inhibidores de Histona Desacetilasas/química , Ensayos de Selección de Medicamentos Antitumorales , Diseño de Fármacos , Simulación del Acoplamiento Molecular , Antineoplásicos/química , Proliferación CelularRESUMEN
In recent years, targeting tumor angiogenesis has emerged as a prominent research focus in the treatment and prevention of tumor expansion. A7R (ATWLPPR) exhibits high affinity and specificity for VEGFR-2, which is overexpressed in various tumors. To enhance the tumor tissue and cell penetration capabilities of A7R, we substituted its non-critical amino acid with Arginine (R) and Glutamic acid (E), cyclized the mutant peptide, and linked it to the membrane permeation sequence using coordination principles. We designed and synthesized fifteen novel penetrating peptides that target tumor blood vessels and cells, followed by conducting various biological evaluations and cell imaging experiments. The results demonstrated that Cyclo-A7R-RRR and A7R-RLLRLLR exhibited excellent permeability towards tumor cells, with Cyclo-A7R-RRR showing superior serum stability compared to A7R. Furthermore, the modified peptides showed no toxicity towards HeLa cells, U251 cells, HuH-7 cells, and HEK293 cells under 10 µmol/L. Utilizing Cyclo-A7R-RRR or A7R-RLLRLLR for transmembrane delivery of drug molecules could significantly improve their efficacy. Our findings broaden the potential application scenarios of A7R in targeted tumor angiogenesis.
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Sistemas de Liberación de Medicamentos , Glioma , Humanos , Glioma/tratamiento farmacológico , Células HeLa , Células HEK293 , Péptidos/farmacología , Péptidos/uso terapéutico , Línea Celular TumoralRESUMEN
Oocytes are the female germ cells, which are susceptible to stress stimuli. The development of oocytes in the ovary is affected by many environmental and metabolic factors, food toxins, aging, and pathological factors. Mitochondria are the main target organelles of these factors, and the damage to mitochondrial structure and function can affect the production of ATP, the regulation of redox reactions, and apoptosis in oocytes. Mitochondrial damage is closely related to the decrease in oocyte quality and is the main factor leading to female infertility. Antioxidant foods or drugs have been used to prevent mitochondrial damage from some stressors or to repair damaged mitochondria, thereby improving oocyte development and female reproductive outcomes. In this paper, the damage of mitochondria during oocyte development by the above factors has been reviewed, and the relevant measures to alleviate the damage of mitochondria in oocytes have been discussed. Our findings may provide a theoretical basis and experimental basis for improving female fertility.
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Infertilidad Femenina , Oocitos , Femenino , Humanos , Oocitos/metabolismo , Envejecimiento/metabolismo , Mitocondrias/metabolismo , OvarioRESUMEN
Rapid, simple and sensitive screening of foodborne pathogens is of great significance to ensure food safety. In this study, an aptamer-functionalized polydiacetylene (Apta-PDA) biosensor was developed for the detection of E. coli O157:H7, S. typhimurium or V. parahaemolyticus. First, aptamers responding to the target bacteria were modified on the surface of magnetic beads by covalent binding to form MBs-oligonucleotide conjugates for bacterial enrichment. Then, an Apta-PDA biosensor was obtained by connecting the aptamers to the PDA nanovesicles using the carbodiimide method. Molecular recognition occurred in the presence of the target bacteria, whereby the aptamer folded into a sequence-defined unique structure, resulting in an MBs-Apta/bacteria/Apta-PDA sandwich structure. Due to the optical properties of PDA, the blue-red transition of the detection system could be observed by the naked eye and quantified by the colorimetric response percentage (CR%). Under optimized conditions, the detection limits of E. coli O157:H7, S. typhimurium and V. parahaemolyticus were 39, 60 and 60 CFU/ml, respectively, with a selectivity of 100% and a reaction time of 30 min. Compared with the gold standard method, the accuracy of the three target bacteria detection reached 98%, 97.5% and 97%, respectively, and the sensitivity and specificity were both greater than 90%. The entire detection process was rapid and easy to execute without any special equipment, making this technology particularly suitable for resource-poor laboratories or regions.
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Aptámeros de Nucleótidos , Técnicas Biosensibles , Escherichia coli O157 , Técnicas Biosensibles/métodos , Polímero Poliacetilénico , Microbiología de Alimentos , Aptámeros de Nucleótidos/químicaRESUMEN
BACKGROUND: Scraping therapy is widely used in treating stage I and II essential hypertension in China. However, there has been no systematic evaluation of the efficacy of scraping therapy on blood pressure and sleep quality in stage I and II essential hypertension. SEARCH STRATEGY: Seven electronic databases (PubMed, Scopus, Cochrane Library, Web of Science, EBSCO, China National Knowledge Infrastructure and Wanfang Data electronic databases) were searched from inception to December 2022. Based on the principle of combining subject words with text words, the search strategy was constructed around search terms for "scraping therapy," "scraping," "Guasha," "Gua sha," "hypertension," and "high blood pressure" during the database searches. INCLUSION CRITERIA: Randomized controlled trials (RCTs) were included if they recruited patients with stage I and II essential hypertension and included a scraping therapy intervention. The intervention group received antihypertensive drugs and scraping therapy, while the control group only took antihypertensive drugs. DATA EXTRACTION AND ANALYSIS: Review Manager 5.4.0 and STATA 15.1 were used to enter all the relevant outcome variables to conduct the meta-analysis. The quality of the selected RCTs was assessed using the PEDro scale. The sensitivity analysis was carried out by iteratively excluding individual studies and repeating the analysis to determine the stability of the findings and identify any studies with greater influence on the outcome. Subgroup analysis was performed to find the source of heterogeneity. Funnel plots were used to evaluate the publication bias of included studies. RESULTS: Nine RCTs including 765 participants were selected. Meta-analysis showed that scraping therapy combined with medication had an advantage over the use of medication alone in lowering systolic blood pressure (mean difference [MD] = -5.09, 95% confidence interval [CI] = -6.50 to -3.67, P < 0.001) and diastolic blood pressure (MD = -2.66, 95% CI = -3.17 to -2.14, P < 0.001). Subgroup analysis showed that scraping therapy improved sleep quality in middle-aged patients with hypertension, but the efficacy was better in elderly patients (MD = -7.91, 95% CI = -8.65 to -7.16, P < 0.001) than in middle-aged patients (MD = -2.67, 95% CI = -4.12 to -1.21, P = 0.0003). CONCLUSION: The available evidence indicates that scraping therapy has significant effects on patients with stage I and II hypertension, and it improves sleep quality for elderly patients with hypertension better than for middle-aged ones. Scraping therapy can be an adjunctive treatment for stage I and II essential hypertension. However, further high-quality studies are needed to verify its effectiveness and the best therapeutic strategies. Please cite this article as: Zhu, Z, Wang J, Pan, X. Efficacy of scraping therapy on blood pressure and sleep quality in stage I and II essential hypertension: A systematic review and meta-analysis. J Integr Med. 2024; 22(1): 12-21.