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Inhibition of SIRT3 exhibited potency in triggering leukemic cell differentiation. In discovery of potent SIRT3 inhibitors for cancer differentiation therapy, structural modification was performed on the previously developed lead compound P6. A total of 33 compounds were designed and synthesized. In the enzyme inhibitory assay, several molecules S18, S26, S27 and T5 showed potent SIRT3 inhibitory activity with IC50 value of 0.53, 1.86, 5.06, and 2.88 µM, respectively. Moreover, the tested compounds exhibited SIRT3 inhibitory selectivity over SIRT1 and SIRT2. Compounds S27 and T5 were potent in inhibition the growth of MM1.S and RPMI-8226 cells in the in vitro antiproliferative test. Significantly, representative compounds, especially S27 and T5, promoted differentiation of tested MM cells in the cellular morphological evaluation, accompanied by increasing the expression of differentiation antigen CD49e and human immunoglobulin light chain lambda and kappa. Additionally, molecule S18 without antiproliferative potency itself, showed significant inhibitory activity against growth factor IL-6 induced RPMI-8226 cell proliferation. Collectively, potent SIRT3 selective inhibitors with MM cell differentiation potency were developed for further discovery of anticancer drugs.
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Antineoplásicos , Diferenciación Celular , Proliferación Celular , Sirtuina 3 , Humanos , Sirtuina 3/metabolismo , Sirtuina 3/antagonistas & inhibidores , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Relación Estructura-Actividad , Quinolinas/química , Quinolinas/farmacología , Simulación del Acoplamiento MolecularRESUMEN
Cinnamoyl-containing nonribosomal peptides (CCNPs) constitute a unique family of natural products. The enzyme mechanism for the biaryl phenol coupling reaction of the bicyclic CCNPs remains unclear. Herein, we report the discovery of two new arabinofuranosylated bicyclic CCNPs cihanmycins (CHMs) A (1) and B (2) from Amycolatopsis cihanbeyliensis DSM 45679 and the identification of the CHM biosynthetic gene cluster (cih BGC) by heterologous expression in Streptomyces lividans SBT18 to afford CHMs C (3) and D (4). The structure of 1 was confirmed by X-ray diffraction analysis. Three cytochrome P450 enzyme (CYP)-encoding genes cih26, cih32, and cih33 were individually inactivated in the heterologous host to produce CHMs E (5), F (6), and G (7), respectively. The structures of 5 and 6 indicated that Cih26 was responsible for the hydroxylation and epoxidation of the cinnamoyl moiety, and Cih32 should catalyze the ß-hydroxylation of three amino acid residues. Cih33 and its homologues DmlH and EpcH were biochemically verified to convert CHM G (7) with a monocyclic structure to a bicyclic skeleton of CHM C (3) through an intramolecular C-O phenol coupling reaction. The substrate 7-bound crystal structure of DmlH not only established the structure of 7, which was difficult for NMR analysis for displaying anomalous splitting signals, but also provided the binding mode of macrocyclic peptides recognized by these intramolecular C-O coupling CYPs. In addition, computational studies revealed a water-mediated diradical mechanism for the C-O phenol coupling reaction. These findings have shed important mechanistic insights into the CYP-catalyzed phenol coupling reactions.
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Proline Rich 12 (PRR12) protein is primarily expressed in the brain and localized in the nucleus. The variants in the PRR12 gene were reported to be related to neuroocular syndrome. Patients with PRR12 gene presented with intellectual disability (ID), neuropsychiatric disorders, some congenital anomalies, and with or without eye abnormalities. Here, we report an 11-year-old boy with a novel PRR12 variant c.1549_1568del, p.(Pro517Alafs*35). He was the first PRR12 deficiency patient in China and presented with ID, short stature, and mild scoliosis. He could not concentrate on his studies and was diagnosed with attention deficit hyperactivity disorder (ADHD). The insulin-like growth factor 1 (IGH-1) was low in our patient, which may be the cause of his short stature. Patients with neuroocular syndrome are rare, and further exploration is needed to understand the reason for neurodevelopmental abnormalities caused by PRR12 variants. Our study further expands on the PRR12 variants and presents a new case involving PPR12 variants.
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In this study, metabolomics and proteomics were performed to investigate the fluctuations of non-volatile compounds and proteins in tea leaves from three tea cultivars with varying colours during withering. A total of 2798 compounds were detected, exhibiting considerable variations in amino acids, phenylpropanoids, and flavonoids. The ZH1 cultivar displayed increased levels of amino acids but decreased levels of polyphenols, which might be associated with the up-regulation of enzymes responsible for protein degradation and subsequent amino acid production, as well as the down-regulation of enzymes involved in phenylpropanoid and flavonoid biosynthesis. The FUD and ZH1 cultivars had elevated levels of flavanols and flavanol-O-glycosides, which were regulated by the upregulation of FLS. The ZJ and ZH1 cultivars displayed elevated levels of theaflavin and peroxidase. This work presents a novel investigation into the alterations of metabolites and proteins between tea cultivars during withering, and helps with the tea cultivar selection and manufacturing development.
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Camellia sinensis , Metabolómica , Hojas de la Planta , Proteínas de Plantas , Camellia sinensis/química , Camellia sinensis/metabolismo , Camellia sinensis/genética , Camellia sinensis/crecimiento & desarrollo , Color , Flavonoides/análisis , Flavonoides/metabolismo , Flavonoides/química , Multiómica , Hojas de la Planta/química , Hojas de la Planta/metabolismo , Hojas de la Planta/crecimiento & desarrollo , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Polifenoles/metabolismo , Polifenoles/química , Polifenoles/análisis , Proteómica , Té/químicaRESUMEN
AIMS: Sodium tanshinone IIA sulfonate (STS) injection has been widely used as adjunctive therapy for pulmonary heart disease (PHD) in China. Nevertheless, the efficacy of STS injection has not been systematically evaluated so far. Hence, the efficacy of STS injection as adjunctive therapy for PHD was explored in this study. METHODS: Randomized controlled trials (RCTs) were screened from China Science and Technology Journal Database, China National Knowledge Infrastructure, Wanfang Database, PubMed, Sino-Med, Google Scholar, Medline, Chinese Biomedical Literature Database, Cochrane Library, Embase and Chinese Science Citation Database until 20 January 2024. Literature searching, data collection and quality assessment were independently performed by two investigators. The extracted data was analyzed with RevMan 5.4 and STATA 14.0. Basing on the methodological quality, dosage of STS injection, control group measures and intervention time, sensitivity analysis and subgroup analysis were performed. RESULTS: 19 RCTs with 1739 patients were included in this study. Results showed that as adjunctive therapy, STS injection combined with Western medicine showed better therapeutic efficacy than Western medicine alone for PHD by increasing the clinical effective rate (RR = 1.22; 95% CI, 1.17 to 1.27; p < 0.001), partial pressure of oxygen (MD = 10.16; 95% CI, 5.07 to 15.24; p < 0.001), left ventricular ejection fraction (MD = 8.66; 95% CI, 6.14 to 11.18; p < 0.001) and stroke volume (MD = 13.10; 95% CI, 11.83 to 14.38; p < 0.001), meanwhile decreasing the low shear blood viscosity (MD = -1.16; 95% CI, -1.57 to -0.74; p < 0.001), high shear blood viscosity (MD = -0.64; 95% CI, -0.86 to -0.42; p < 0.001), plasma viscosity (MD = -0.23; 95% CI, -0.30 to -0.17; p < 0.001), hematokrit (MD = -8.52; 95% CI, -11.06 to -5.98; p < 0.001), fibrinogen (MD = -0.62; 95% CI, -0.87 to -0.37; p < 0.001) and partial pressure of carbon dioxide (MD = -8.56; 95% CI, -12.09 to -5.02; p < 0.001). CONCLUSION: STS injection as adjunctive therapy seemed to be more effective than Western medicine alone for PHD. However, due to low quality of the included RCTs, more well-designed RCTs were necessary to verify the efficacy of STS injection.
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Medicamentos Herbarios Chinos , Fenantrenos , Enfermedad Cardiopulmonar , Humanos , Enfermedad Cardiopulmonar/tratamiento farmacológico , Inyecciones , Fenantrenos/uso terapéutico , Medicamentos Herbarios Chinos/uso terapéuticoRESUMEN
Cancer, a complex and heterogeneous disease, arises from genomic instability. Currently, DNA damage-based cancer treatments, including radiotherapy and chemotherapy, are employed in clinical practice. However, the efficacy and safety of these therapies are constrained by various factors, limiting their ability to meet current clinical demands. Metal nanoparticles present promising avenues for enhancing each critical aspect of DNA damage-based cancer therapy. Their customizable physicochemical properties enable the development of targeted and personalized treatment platforms. In this review, we delve into the design principles and optimization strategies of metal nanoparticles. We shed light on the limitations of DNA damage-based therapy while highlighting the diverse strategies made possible by metal nanoparticles. These encompass targeted drug delivery, inhibition of DNA repair mechanisms, induction of cell death, and the cascading immune response. Moreover, we explore the pivotal role of physicochemical factors such as nanoparticle size, stimuli-responsiveness, and surface modification in shaping metal nanoparticle platforms. Finally, we present insights into the challenges and future directions of metal nanoparticles in advancing DNA damage-based cancer therapy, paving the way for novel treatment paradigms.
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SCOPE: l-Theanine (l-Thea) is an amino acid which is naturally present in tea leaves. It has been associated with possible health advantages, including obesity prevention, but the underlying molecular mechanisms have not been elucidated. METHODS AND RESULTS: A multiomics approach is utilized to examine the mechanism by which l-Thea exerts its antiobesity effects. This study reveals that l-Thea administration significantly ameliorates high-fat diet (HFD)-induced obesity in rats by improving body weight and hyperlipidemia. l-Thea mitigates HFD-induced inflammation and reverses hepatic and colonic damage, and intestinal barrier. This research verifies that the preventive effect of l-Thea on obesity in rats induced by an HFD with colitis is accomplished by suppressing the phosphorylation of important proteins in the NF-κB/mitogen-activated protein kinase (MAPK) pathways. Metabolome analysis reveals that l-Thea regulates HFD-induced metabolic disorders, specifically through modulation of steroid hormone biosynthesis. Microbiome analysis reveals that l-Thea mitigates HFD-induced dysbiosis by increasing the relative abundance of obesity-associated probiotic bacteria, including Blautia coccoides and Lactobacillus murinus, while simultaneously suppressing the abundance of pathogenic bacteria. CONCLUSIONS: l-Thea alleviates colitis generated by an HFD by restoring the integrity of the intestinal barrier, suppressing inflammation through regulation of MAPK/NF-κB signaling pathways, and enhancing microbial metabolism in colon.
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Colon , Dieta Alta en Grasa , Obesidad , Animales , Masculino , Ratas , Colitis/inducido químicamente , Colitis/tratamiento farmacológico , Colon/efectos de los fármacos , Colon/metabolismo , Dieta Alta en Grasa/efectos adversos , Disbiosis , Microbioma Gastrointestinal/efectos de los fármacos , Glutamatos/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , FN-kappa B/metabolismo , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacosRESUMEN
Targeted assembly of nanoparticles in biological systems holds great promise for disease-specific imaging and therapy. However, the current manipulation of nanoparticle dynamics is primarily limited to organic pericyclic reactions, which necessitate the introduction of synthetic functional groups as bioorthogonal handles on the nanoparticles, leading to complex and laborious design processes. Here, we report the synthesis of tyrosine (Tyr)-modified peptides-capped iodine (I) doped CuS nanoparticles (CuS-I@P1 NPs) as self-catalytic building blocks that undergo self-propelled assembly inside tumour cells via Tyr-Tyr condensation reactions catalyzed by the nanoparticles themselves. Upon cellular internalization, the CuS-I@P1 NPs undergo furin-guided condensation reactions, leading to the formation of CuS-I nanoparticle assemblies through dityrosine bond. The tumour-specific furin-instructed intracellular assembly of CuS-I NPs exhibits activatable dual-modal imaging capability and enhanced photothermal effect, enabling highly efficient imaging and therapy of tumours. The robust nanoparticle self-catalysis-regulated in situ assembly, facilitated by natural handles, offers the advantages of convenient fabrication, high reaction specificity, and biocompatibility, representing a generalizable strategy for target-specific activatable biomedical imaging and therapy.
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Nanopartículas , Neoplasias , Humanos , Furina , Fototerapia , Neoplasias/diagnóstico por imagen , Neoplasias/terapia , Nanopartículas/química , Catálisis , Cobre/químicaRESUMEN
Bisphenol A (BPA) is a prevalent endocrine disruptor found in natural environments. Exposure to BPA has been associated with male infertility. The natural phytochemical icariin (ICA) has demonstrated significant promise for the treatment of male infertility. However, its effectiveness is limited due to its low bioavailability, poor water solubility, and insufficient targeting abilities. Herein, novel nanoparticles are generated from the natural silk fibroin, which are used to load ICA. The efficient drug delivery system (ICA-SNPs) result in significantly focused drug distribution to spermatogonium, enhancing the anti-infertility properties of ICA, and can effectively mitigate spermatogenesis dysfunction induced by BPA, control serum sex hormone levels, and enhance testicular ultrastructure. Additionally, the ICA-SNPs restore spermatogenesis dysfunction primarily via the hormone biosynthesis, spermatogonium meiosis process, and glycerophospholipid metabolism.
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Compuestos de Bencidrilo , Fibroínas , Flavonoides , Infertilidad Masculina , Nanopartículas , Fenoles , Masculino , Humanos , Espermatogénesis , Infertilidad Masculina/inducido químicamente , Infertilidad Masculina/tratamiento farmacológicoRESUMEN
Replication stress (RS) induced by DNA damage plays a significant role in conferring the anticancer effects of radiotherapy and is tightly associated with radioresistance of cancer cells. Amplification of RS represents an effective approach to improving the efficacy of radiotherapy, although the development of selective RS amplifiers remains an unexplored frontier. We herein present an RS nano amplifier (RSNA) consisting of a catalytic FePt nanoparticle loaded with the chemotherapeutic doxorubicin (DOX), which selectively exacerbates RS in cancer cells by promoting replication fork (RF) catastrophe. RSNA converts the excessive reactive oxygen species (ROS) in cancer cells into oxygen, enhancing the DNA-damaging effects of radiotherapy to create more template lesions that impede RF progression in coalition with DOX. After radiation, ROS scavenging by RSNA accelerates RF progression through damaged template strands, increasing the frequency of RF collapse into double-strand breaks. Moreover, pretreatment with RSNA accumulates cancer cells in the S phase, exposing more RFs to radiation-induced RS. These effects of RSNA convergently maximize RS in cancer cells, effectively overcoming the radioresistance of cancer cells without affecting normal cells. Our study demonstrates the feasibility of selectively amplifying RS to boost radiotherapy.
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Neoplasias , Humanos , Especies Reactivas de Oxígeno , División Celular , Neoplasias/tratamiento farmacológico , Neoplasias/radioterapia , Catálisis , Daño del ADN , Doxorrubicina/farmacologíaRESUMEN
BACKGROUND: BICRA, a transcript regulator, was identified as the genetic factor of Coffin-Siris syndrome 12 (CSS12) recently, which was characterized by diverse neurodevelopmental delays. Up to now, limited studies of BICRA in neurodevelopmental delay have been reported. METHODS: Clinical data such as EEGs, MRIs, routine blood, and physical examination were collected. Trio whole exome sequencing (WES) of the family was performed, and all variants with a minor allele frequency (<0.01) in exon and canonical splicing sites were selected for further pathogenic evaluation. Candidate variants were validated by Sanger sequencing. The BICRA-related literature was reviewed and the clinical characteristics were summarized. RESULTS: We reported a CSS12 proband with a narrow and slightly clinical phenotype who only exhibited language developmental delay, hypotonia, and slight gastrointestinal features. WES revealed a de novo variant in exon 6 of BICRA [NM_015711.3: c.1666C>T, p.Gln556*]. This variant resulted in an early translation termination at 556th of BICRA, not collected in the public population database (gnomAD), and classified as pathogenic according to the ACMG guideline. CONCLUSION: Our results expanded the pathogenic genetic and clinical spectrum of BICRA-related diseases.
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Anomalías Múltiples , Discapacidad Intelectual , Micrognatismo , Humanos , Factores de Transcripción/genética , Discapacidad Intelectual/genética , Anomalías Múltiples/genética , Anomalías Múltiples/diagnóstico , Micrognatismo/genéticaRESUMEN
l-Theanine is the most abundant free amino acid present in tea. Several tea components have been studied for their impact on male fertility, but little is known about the effects of l-theanine. Cyclophosphamide (CP) is an antineoplastic and immunosuppressive agent that reduces fertility in males. In the present study, we evaluated the effect of l-theanine on CP-induced testicular toxicity in male mice. A single dosage of 50 mg/kg saline or CP was administered intraperitoneally over the course of 5 days. Mice were administered l-theanine (80 mg/kg) or saline by gavage for 30 days. Animals were euthanized 24 h after the last l-theanine administration, and the testes were removed for histopathological and transmission electron microscopy analysis. Histological evaluation and transmission electron microscopy showed that administration of l-theanine alleviated CP-induced damage to the testicles, including spermatogonial cells, epithelial cells, seminiferous tubules, and basement membrane. An integrated proteomics and metabolomics investigation of testes revealed that l-theanine therapy substantially affected the quantity of 719 proteins (395 upregulated and 324 downregulated) and 196 metabolites (75 upregulated and 111 downregulated). The top three enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for these proteins and metabolites were purine metabolism, choline metabolism in cancer, and arachidonic acid metabolism. This is the first study to reveal the protective effect of l-theanine on CP-induced testicular toxicity. l-Theanine could be a potential natural active substance for resistance to the testis toxicity induced by CP.
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Glutamatos , Testículo , Ratones , Masculino , Animales , Glutamatos/metabolismo , Ciclofosfamida/toxicidad , Té/metabolismoRESUMEN
BACKGROUND: Given that seizures may be triggered by vaccination, this study aimed to evaluate the risk and correlative factors of seizures in patients with epilepsy (PWE) after being vaccinated against coronavirus disease 2019 (COVID-19). METHODS: This study retrospectively enrolled PWE who were vaccinated against COVID-19 in the epilepsy centers of 11 hospitals in China. We divided the PWE into two groups as follows: (1) patients who developed seizures within 14 days of vaccination were assigned to the SAV (with seizures after vaccination) group; (2) patients who were seizure-free within 14 days of vaccination were assigned to the SFAV (seizure-free after vaccination) group. To identify potential risk factors for seizure reccurence, the binary logistic regression analysis was performed. Besides, 67 PWE who had not been vaccinated were also included for elucidating the effects of vaccination on seizures recurrence, and binary logistic regression analysis was performed to determine whether vaccination would affect the recurrence rate of PWE who had drug reduction or withdrawal. RESULTS: The study included a total of 407 patients; of which, 48 (11.8%) developed seizures within 14 days after vaccination (SAV group), whereas 359 (88.2%) remained seizure-free (SFAV group). The binary logistic regression analysis revealed that duration of seizure freedom ( P â<â0.001) and withdrawal from anti-seizure medications (ASMs) or reduction in their dosage during the peri-vaccination period were significantly associated with the recurrence of seizures (odds ratioâ=â7.384, 95% confidence intervalâ=â1.732-31.488, P â=â0.007). In addition, 32 of 33 patients (97.0%) who were seizure-free for more than three months before vaccination and had a normal electroencephalogram before vaccination did not have any seizures within 14 days of vaccination. A total of 92 (22.6%) patients experienced non-epileptic adverse reactions after vaccination. Binary logistic regression analysis results showed that vaccine did not significantly affect the recurrence rate of PWE who had the behavior of ASMs dose reduction or withdrawal ( P â=â0.143). CONCLUSIONS: PWE need protection from the COVID-19 vaccine. PWE who are seizure-free for >3 months before vaccination should be vaccinated. Whether the remaining PWE should be vaccinated depends on the local prevalence of COVID-19. Finally, PWE should avoid discontinuing ASMs or reducing their dosage during the peri-vaccination period.
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COVID-19 , Epilepsia , Humanos , Estudios Retrospectivos , Vacunas contra la COVID-19/uso terapéutico , Anticonvulsivantes/uso terapéutico , Epilepsia/tratamiento farmacológico , VacunaciónRESUMEN
Acute kidney injury (AKI) caused by anti-tumor drugs, such as cisplatin, is a severe complication with no effective treatment currently, leading to the reduction or discontinuation of chemotherapy. Natural products or herbal medicines are gradually considered as promising agents against cisplatin-induced AKI with the advantages of multi-targeting, multi-effects, and less resistance. In this study, we investigated the effects of kaempferide, a natural flavonoid extracted from the rhizome of Kaempferia galanga, in experimental AKI models in vitro and in vivo. We first conducted pharmacokinetic study in mice and found a relative stable state of kaempferide with a small amount of conversion into kaempferol. We showed that both kaempferide (10 µM) and kaempferol (10 µM) significantly inhibited cisplatin-caused injuries in immortalized proximal tubule epithelial cell line HK-2. In AKI mice induced by injection of a single dose of cisplatin (15 mg/kg), oral administration of kaempferide (50 mg/kg) either before or after cisplatin injection markedly improved renal function, and ameliorated renal tissue damage. We demonstrated that kaempferide inhibited oxidative stress and induced autophagy in cisplatin-treated mice and HK-2 cells, thus increasing tubular cell viability and decreasing immune responses to attenuate the disease progression. In addition, treatment with kaempferide significantly ameliorated ischemia-reperfusion-induced renal injury in vitro and in vivo. We conclude that kaempferide is a promising natural product for treating various AKI. This study has great implications for promotion of its use in healthcare products, and help to break through the limited use of cisplatin in the clinic.
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Lesión Renal Aguda , Cisplatino , Ratones , Animales , Cisplatino/farmacología , Quempferoles/farmacología , Quempferoles/uso terapéutico , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/patología , Estrés Oxidativo , Autofagia , Apoptosis , Ratones Endogámicos C57BLRESUMEN
Objectives: Several COVID-19 vaccines list "uncontrolled epilepsy" as a contraindication for vaccination. This consequently restricts vaccination against COVID-19 in patients with epilepsy (PWE). However, there is no strong evidence that COVID-19 vaccination can exacerbate conditions in PWE. This study aims to determine the impact of COVID-19 vaccination on PWE. Methods: PWE were prospectively recruited from 25 epilepsy centers. We recorded the seizure frequency at three time periods (one month before the first vaccination and one month after the first and second vaccinations). A generalized linear mixed-effects model (GLMM) was used for analysis, and the adjusted incidence rate ratio (AIRR) with 95% CI was presented and interpreted accordingly. Results: Overall, 859 PWE were included in the analysis. Thirty-one (3.6%) and 35 (4.1%) patients were found to have increased seizure frequency after the two doses, respectively. Age had an interaction with time. The seizure frequency in adults decreased by 81% after the first dose (AIRR=0.19, 95% CI:0.11-0.34) and 85% after the second dose (AIRR=0.16, 95% CI:0.08-0.30). In juveniles (<18), it was 25% (AIRR=0.75, 95% CI:0.42-1.34) and 51% (AIRR=0.49, 95% CI:0.25-0.95), respectively. Interval between the last seizure before vaccination and the first dose of vaccination (ILSFV) had a significant effect on seizure frequency after vaccination. Seizure frequency in PWE with hereditary epilepsy after vaccination was significantly higher than that in PWE with unknown etiology (AIRR=1.95, 95% CI: 1.17-3.24). Two hundred and seventeen (25.3%) patients experienced non-epileptic but not serious adverse reactions. Discussion: The inactivated COVID-19 vaccine does not significantly increase seizure frequency in PWE. The limitations of vaccination in PWE should focus on aspects other than control status. Juvenile PWE should be of greater concern after vaccination because they have lower safety. Finally, PWE should not reduce the dosage of anti-seizure medication during the peri-vaccination period.
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COVID-19 , Epilepsia , Adulto , Humanos , Vacunas contra la COVID-19/efectos adversos , Estudios Prospectivos , COVID-19/prevención & control , COVID-19/complicaciones , Epilepsia/tratamiento farmacológico , Vacunación/efectos adversosRESUMEN
Platinum (Pt) resistance in cancer almost inevitably occurs during clinical Pt-based chemotherapy. The spontaneous nucleotide-excision repair of cancer cells is a representative process that leads to Pt resistance, which involves the local DNA bending to facilitate the recruitment of nucleotide-excision repair proteins and subsequent elimination of Pt-DNA adducts. By exploiting the structural vulnerability of this process, we herein report a nuclease-mimetic Pt nanozyme that can target cancer cell nuclei and induce concurrent DNA platination and oxidative cleavage to overcome Pt drug resistance. We show that the Pt nanozyme, unlike cisplatin and conventional Pt nanoparticles, specifically induces the nanozyme-catalyzed cleavage of the formed Pt-DNA adducts by generating in situ reactive oxygen species, which impairs the damage recognition factors-induced DNA bending prerequisite for nucleotide-excision repair. The recruitment of downstream effectors of nucleotide-excision repair to DNA lesion sites, including xeroderma pigmentosum groups A and F, is disrupted by the Pt nanozyme in cisplatin-resistant cancer cells, allowing excessive accumulation of the Pt-DNA adducts for highly efficient cancer therapy. Our study highlights the potential benefits of applying enzymatic activities to the use of the Pt nanomedicines, providing a paradigm shift in DNA damaging chemotherapy.
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Neoplasias , Platino (Metal) , Platino (Metal)/farmacología , Aductos de ADN , Cisplatino/farmacología , Endonucleasas , Resistencia a Antineoplásicos , ADN , Estrés Oxidativo , Nucleótidos , Neoplasias/tratamiento farmacológicoRESUMEN
Four new efrotomycins, A1-A4 (1-4), were isolated from the salt mine-derived Amycolatopsis cihanbeyliensis DSM 45679 and structurally determined. Efrotomycins A3 (3) and A4 (4) feature a tetrahydrofuran ring configured distinctly from known elfamycins. Heterologous expression of the efrotomycin gene cluster (efr BGC) in Streptomyces lividans SBT18 led to efrotomycin B1 (5), the yield of which was improved several fold upon introduction of the transporter gene efrT, a putative self-resistance determinant outside of the efr BGC.
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Actinomycetales , Piridonas , Familia de MultigenesRESUMEN
The goal of this work was to develop a sensitive and accurate method based on high performance liquid chromatography with tandem mass spectrometry (LC-MS) detection for determining the concentration of the Sinomenine derivative SWX in plasma and tissue of rat. Chromatographic separation was achieved on an Agilent SB-C18 (2.1*50â¯mm, 2.7⯵m) column. The mobile phase consisted of acetonitrile (solvent A) and 0.2â¯% formic acid in water (solvent B) with gradient elution as follows: 0-3â¯min, 50-90â¯% A, 3â¯min-3.01â¯min, 90-50â¯% A, 90â¯% A in 3.01â¯min-10â¯min. The flow rate was set to 0.3â¯mL/min. The column temperature was 40⯰C, and the sample injection volume was 10⯵L. The calibration curve had good linearity in the range of 10â¯ng/mL to 600â¯ng/mL. Biological samples were prepared by protein precipitation with acetonitrile. The area under the curve (AUC) and the peak drug concentration (Cmax) were linearly related to SWX dose. After oral administration of 25, 50 and 100 mg/kg SWX and intravenous administration of 0.5â¯mg/kg SWX, respectively, the absolute bioavailability of SWX was estimated as 12.4â¯%, 12.2â¯% and 10.6â¯%. SWX was widely distributed in heart, liver, spleen, lung, kidney, brain, breast, and fat, especially in lung, liver, and spleen. Distribution of SWX in brain suggested that it can pass the blood-brain barrier. The method established in this study has the advantages of high recovery and good reproducibility, and was suitable for the determination of the content of Sinomenine derivatives, providing a reliable scientific tool for carrying out pharmacokinetics research, providing a reliable scientific resource.
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Espectrometría de Masas en Tándem , Ratas , Animales , Cromatografía Liquida/métodos , Espectrometría de Masas en Tándem/métodos , Reproducibilidad de los Resultados , Cromatografía Líquida de Alta Presión/métodos , Acetonitrilos , SolventesRESUMEN
Dysregulation or aberrant signaling transduction contributes to tumorigenesis. Targeting these abnormal signaling pathways becomes an effective anticancer strategy. However, feedback activation or crosstalk between signaling pathways drives adaptive drug resistance which causes failure of cancer therapy. In this review article, we summarized treatments that cause feedback activation of AKT, ERK, STAT3, EGFR, FGFR, and HER2/3 signaling pathways and the combination therapy to enhance anti-tumor effect or to overcome drug resistance, to explore the underlying mechanisms that define the protein molecules participated or regulated the feedback activation. In addition, we reviewed clinical trials that employ combination treatments to suppress feedback activation and improve therapeutic efficacy of cancer treatments.
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Neoplasias , Transducción de Señal , Humanos , Retroalimentación , Línea Celular Tumoral , Resistencia a Medicamentos , Resistencia a Antineoplásicos , Neoplasias/tratamiento farmacológico , Neoplasias/genéticaRESUMEN
Background: The diagnostic capabilities of exosomes in the field of reproductive biomedicine have attracted much attention. The aim of this scientometric study was to statistically and qualitatively assess the knowledge structure, hot issues, and research trends of papers about exosomes in the field of reproduction using visualization methods. Methods: The Web of Science Core Collection was searched for studies on exosomes in the field of reproduction. We performed bibliometric and visual analyses using VOSviewer, CiteSpace, and Microsoft Excel. Results: After database search, 1,011 articles were included, with number of studies being published every year continually increasing. These publications came from 61 nations or regions, with the US having the highest number. The University of Queensland was the main institution in which the research was conducted. The journal Placenta contained the highest number studies. There were 5,247 authors in total. Carlos Salomon had the highest number of papers with co-citations. Exosomes, extracellular vesicles, pregnancy, microRNAs, preeclampsia, placenta, microvesicles, gene expression, biomarkers, and first trimester were the most frequently used terms. Conclusion: Exosome research is booming in reproductive biomedicine. Future studies will likely focus on exosomes as biomarkers in gamete formation and fertilization, pregnancy, and cancers associated with reproduction. In addition to focusing on fundamental research, we should concentrate on the application of the results and the investigation of exosomes in infertile patients.