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We use computational design coupled with experimental characterization to systematically investigate the design principles for macrocycle membrane permeability and oral bioavailability. We designed 184 6-12 residue macrocycles with a wide range of predicted structures containing noncanonical backbone modifications and experimentally determined structures of 35; 29 are very close to the computational models. With such control, we show that membrane permeability can be systematically achieved by ensuring all amide (NH) groups are engaged in internal hydrogen bonding interactions. 84 designs over the 6-12 residue size range cross membranes with an apparent permeability greater than 1 × 10-6 cm/s. Designs with exposed NH groups can be made membrane permeable through the design of an alternative isoenergetic fully hydrogen-bonded state favored in the lipid membrane. The ability to robustly design membrane-permeable and orally bioavailable peptides with high structural accuracy should contribute to the next generation of designed macrocycle therapeutics.
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Amidas , Péptidos , Amidas/química , Hidrógeno , Enlace de Hidrógeno , Lípidos , Péptidos/químicaRESUMEN
Secretory proteins are cotranslationally or posttranslationally translocated across lipid membranes via a protein-conducting channel named SecY in prokaryotes and Sec61 in eukaryotes. The vast majority of secretory proteins in bacteria are driven through the channel posttranslationally by SecA, a highly conserved ATPase. How a polypeptide chain is moved by SecA through the SecY channel is poorly understood. Here, we report electron cryomicroscopy structures of the active SecA-SecY translocon with a polypeptide substrate. The substrate is captured in different translocation states when clamped by SecA with different nucleotides. Upon binding of an ATP analog, SecA undergoes global conformational changes to push the polypeptide substrate toward the channel in a way similar to how the RecA-like helicases translocate their nucleic acid substrates. The movements of the polypeptide substrates in the SecA-SecY translocon share a similar structural basis to those in the ribosome-SecY complex during cotranslational translocation.
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Proteínas Bacterianas , Proteínas de Escherichia coli , Proteína SecA/metabolismo , Proteínas Bacterianas/metabolismo , Canales de Translocación SEC/metabolismo , Modelos Moleculares , Transporte de Proteínas , Péptidos/metabolismo , Proteínas de Escherichia coli/metabolismoRESUMEN
BACKGROUND: C4d may be used as a marker to evaluate the condition and prognosis of adults with IgA nephropathy, but there have been few studies of children with IgA nephropathy. METHODS: C4d immunohistochemical staining was performed on samples from children with IgA nephropathy with C1q-negative immunofluorescence. The clinical and pathological treatment and prognostic characteristics of children in the C4d-positive and -negative groups were compared. RESULTS: A total of sixty-five children with IgA nephropathy were included in the study and were followed up for an average of 37 months. C4d was mainly deposited along the capillary loops. The urinary protein-to-creatinine ratio (UPCR) in the C4d-positive group was significantly higher than that in the C4d-negative group (3.97 vs. 0.81, P < 0.001), and the average integrated optical density value of each child was positively correlated with the UPCR (r = 0.441, P < 0.001). There was a significant difference in the proportions of children with mesangial hypercellularity (M1) (68.97% vs. 44.44%, P = 0.048) and segmental glomerulosclerosis (S1) (65.52% vs. 33.33%, P = 0.010) between the C4d-positive group and the C4d-negative group. The proportion of children who received immunosuppressants in the C4d-positive group was higher than that in the C4d-negative group (86.21% vs. 36.11%, P < 0.001). There was no significant difference in the proportion of children developing kidney failure between the two groups. CONCLUSION: C4d was found to be associated with proteinuria, segmental lesions, and immunosuppressant treatment. Activation of the lectin pathway may reflect the severity of clinical and pathological manifestations of IgA nephropathy in children. A higher resolution version of the Graphical abstract is available as Supplementary information.
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Glomerulonefritis por IGA , Adulto , Humanos , Niño , Glomerulonefritis por IGA/complicaciones , Glomerulonefritis por IGA/tratamiento farmacológico , Complemento C4b/análisis , Estudios Retrospectivos , Proteinuria/complicaciones , Gravedad del PacienteRESUMEN
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a check point protein expressed on the surface of T cells and plays a central role in regulating the immune response. In recent years, CTLA-4 has become a popular target for cancer immunotherapy in which blocking CTLA-4 can restore T-cell function and enhance the immune response against cancer. Currently, there are many CTLA-4 inhibitors in a variety of modalities, including cell therapies, which are being developed in both preclinical and clinical stages to further harness the potential of the target for the treatment of certain types of cancer. In drug discovery research, measuring the level of CTLA-4 in T cells is important for drug discovery and development because it provides key information for quantitative assessment of the pharmacodynamics, efficacy, and safety of the CTLA-4-based therapies. However, to our best knowledge, there is still no report of a sensitive, specific, accurate, and reliable assay for CTLA-4 measurement. In this work, an LC/MS-based method was developed to measure CTLA-4 in human T cells. The assay demonstrated high specificity with an LLOQ of 5 copies of CTLA-4 per cell when using 2.5 million T cells for analysis. As shown in the work, the assay was successfully used to measure CTLA-4 levels in subtype T-cell samples from individual healthy subjects. The assay could be applied in supporting the studies of CTLA-4-based cancer therapies.
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Neoplasias , Humanos , Antígeno CTLA-4/metabolismo , Neoplasias/tratamiento farmacológico , Inmunoterapia/métodos , Linfocitos T/metabolismoRESUMEN
The tight relationships between microbiome and traditional Chinese medicine(TCM)have been widely recognized. New technologies, results, and theories are emerging in the field of microbiomics in recent years with the advances in high-throughput sequencing and multi-omics technologies. Based on the previous research, the present study has proposed the concept of TCM microbiomics(TCMM), which is an interdisciplinary subject aiming at elucidating the functions and applications of microbiome in the areas of herb resources, herb processing, herb storage, and clinical effects by using modern technology of biology, ecology, and informatics. This subject essentially contains the structures, functions, interactions, molecular mechanisms, and application strategies of the microbiome associated with the quality, safety, and efficacy of TCM. Firstly, the development of the TCMM concept was summarized, with the profound understanding of TCMM on the complexity and entirety of microbiome being emphasized. Then, the research contents and applications of TCMM in promoting the sustainable development of herb resources, improving the standardization and diversification of herb fermentation, strengthening the safety of herb storage, and resolving the scientific connotation of theories and clinical efficacy of TCM are reviewed. Finally, the research strategies and methods of TCM microbiomics were elaborated from basic research, application research, and system research. TCMM is expected to promote the integrative development of TCM with frontier science and technology, thereby expanding the depth and scope of TCM study and facilitating TCM modernization.
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Medicina Tradicional China , Proyectos de Investigación , Ecología , Fermentación , Secuenciación de Nucleótidos de Alto RendimientoRESUMEN
Panax notoginseng contains triterpene saponins, flavonoids, amino acids, polysaccharides, volatile oil and other active components, which have the effects of promoting blood circulation, stopping bleeding, removing blood stasis, etc. This study summarized the herbal research, chemical constituents and main pharmacological activities of P. notoginseng, and based on the theory of Q-markers of traditional Chinese medicine, predicted and analyzed the Q-markers of P. notoginseng from the aspects of plant kinship, efficacy, drug properties, measurability of chemical components, etc. It was found that ginsenosides Rg_1, Re, and Rb_1 with specific content ratio, ginsenosides Rb_2, Rb_3, Rc, Rd, Rh_2, and Rg_3, notoginseng R_1, dencichine and quercetin could be used as potential Q-markers of P. notoginseng, which facilitated the formulation of quality standards reflecting the efficacy of P. notoginseng.
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Medicamentos Herbarios Chinos , Ginsenósidos , Panax notoginseng , Panax , Saponinas , Panax notoginseng/química , Ginsenósidos/farmacología , Ginsenósidos/análisis , Saponinas/análisis , Medicina Tradicional China , Medicamentos Herbarios Chinos/farmacología , Panax/químicaRESUMEN
The core rhizosphere microbiome is critical for plant fitness. However, its contribution to the belowground biomass and saponin contents of Panax notoginseng remains unclear. High-throughput sequencing of amplicon and metagenome was performed to obtain the microbiome profiles and functional traits in P. notoginseng rhizosphere across a large spatial scale. We obtained 639 bacterial and 310 fungal core OTUs, which were mainly affected by soil pH and organic matter (OM). The core taxa were grouped into four ecological clusters (i.e. high pH, low pH, high OM and low OM) for sharing similar habitat preferences. Furthermore, structural equation modelling (SEM) and correlation analyses revealed that the diversity and composition of core microbiomes, as well as the metagenome-derived microbial functions, were related to belowground biomass and saponin contents. Key microbial genera related to the two plant indicators were also identified. In short, this study explored the main driving environmental factors of core microbiomes in the P. notoginseng rhizosphere and revealed that the core microbiomes and microbial functions potentially contributed to the belowground biomass and saponin contents of the plant. This work may enhance our understanding of interactions between microbes and perennial plants and improve our ability to manage root microbiota for the sustainable production of herbal medicine.
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Microbiota , Panax notoginseng , Saponinas , Rizosfera , Panax notoginseng/microbiología , Microbiología del Suelo , Biomasa , Raíces de Plantas/microbiología , Microbiota/genéticaRESUMEN
In the immuno-oncology field, surrogate mouse monoclonal antibodies are often preferred in establishing proper PK/PD/efficacy correlations as well as supporting anticipated mouse to human translation. Thus, a highly sensitive and specific bioanalytical method is needed in quantifying those surrogate mouse antibodies after dosing in mice. Unfortunately, when specific reagents, such as recombinant target antigen and anti-idiotypic antibody, are not available, measuring mouse surrogate antibody drugs in mice is very challenging for ligand binding assay (LBA) due to the severe cross reactivity potential. Different from LBA, if at least one unique surrogate peptide can be identified from the surrogate antibody sequence, the immunoaffinity enrichment based LC/MS/MS assay may be able to differentiate the analyte response from the high endogenous immunoglobulin background and provide adequate sensitivity. Herein, a new automated multicycle immunoaffinity enrichment method was recently developed to extract a surrogate mouse IgG1 (mIgG1) antibody drug from mouse plasma using a commercially available antimouse IgG1 secondary antibody. In the assay, reuse of the capture antibody up to six times mostly resolved the binding capacity issue caused by the abundant endogenous mIgG1 and made the immunoaffinity enrichment step more cost-effective. Combined with a unique surrogate peptide identified from the antibody, the LC/MS/MS assay achieved a limit of quantitation of 5 ng/mL with satisfactory assay precision, accuracy, and dynamic range. The successful implementation of this novel approach in discovery pharmacokinetic (PK) studies eliminates the dependence on specially generated immunoaffinity capturing reagents.
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Preparaciones Farmacéuticas , Espectrometría de Masas en Tándem , Animales , Automatización , Cromatografía Liquida , Inmunoglobulina G , Ratones , Péptidos , Preparaciones Farmacéuticas/sangreRESUMEN
Hydroxypyridinones (HOPOs) have been used in the chelation therapy of iron and actinide metals. Their application in metal-based radiopharmaceuticals has also been increasing in recent years. This review article focuses on how multidentate HOPOs can be used in targeted radiometal-based diagnostic and therapeutic radiopharmaceuticals. The general structure of radiometal-based targeted radiopharmaceuticals, a brief description of siderophores, the basic structure and properties of bidentate HOPO, some representative HOPO multidentate chelating agents, radiopharmaceuticals based on HOPO multidentate bifunctional chelators for gallium-68, thorium-227 and zirconium-89, as well as the future prospects of HOPO multidentate bifunctional chelators in other metal-based radiopharmaceuticals are described and discussed in turn. The HOPO metal-based radiopharmaceuticals that have shown good prospects in clinical and preclinical studies are gallium-68, thorium-227 and zirconium-89 radiopharmaceuticals. We expect HOPO multidentate bifunctional chelators to be a very promising platform for building novel targeted radiometal-based diagnostic and therapeutic radiopharmaceuticals.
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Quelantes , Sistemas de Liberación de Medicamentos , Piridonas , Radiofármacos , Quelantes/química , Quelantes/uso terapéutico , Radioisótopos de Galio/química , Radioisótopos de Galio/uso terapéutico , Humanos , Piridonas/química , Piridonas/uso terapéutico , Radioisótopos/química , Radioisótopos/uso terapéutico , Radiofármacos/química , Radiofármacos/uso terapéutico , Torio/química , Torio/uso terapéutico , Circonio/química , Circonio/uso terapéuticoRESUMEN
The development of quality Chinese medicine is an important way to improve the quality of Chinese medicine, and ensure the safety and effectiveness of Chinese medicine. This article systematically elaborates the definition, classification, standard and mana-gement certification strategy of quality Chinese medicine. We present the quality Chinese medicine which is higher quality than that of eligible Chinese medicine based on quality control standards. Quality Chinese medicine is strictly in accordance with management procedures, likely GAP and GMP et al, during the productive process, which quality indicators is higher than that of the current relevant national quality standards, such as Chinese Pharmacopoeia(ChP) et al; its limited indicators such as exogenous pollutants and endogenous toxic substances are lower than that of the current relevant national quality standards, likely ChP et al; meanwhile these Chinese herbal medicine, medicinal pieces, patent medicines, and health products and foods with Chinese medicine raw materials are been certificated by quality Chinese medicine. At the same time, this article systematically expounds the five major management systems of quality Chinese medicine, including technical training management for practitioners, productive process management, standard mana-gement, quality inspection and certification management, and product traceability management. And we put forward strategies to improve the supervision and management system, and promote the standardization and development of quality Chinese medicine by improving the technical management system of quality Chinese medicine, strengthening the quality management system and six sigma(6σ) management in the company. These strategies will provide a reliable basis and effective way to improve the quality of Chinese medicine.
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Medicamentos Herbarios Chinos , Medicina Tradicional China , Alimentos , Control de Calidad , Estándares de ReferenciaRESUMEN
BACKGROUND: Propofol is a common sedative-hypnotic drug traditionally used for inducing and maintaining general anesthesia. Recent studies have drawn attention to the nonanesthetic effects of propofol, but the potential mechanism by which propofol suppresses non-small-cell lung cancer (NSCLC) progression has not been fully elucidated. METHODS: For the in vitro experiments, we used propofol (0, 2, 5, and 10 µg/mL) to treat A549 cells for 1, 4, and 12 hours and Cell Counting Kit-8 (CCK-8) to detect proliferation. Apoptosis was measured with flow cytometry. We also transfected A549 cells with an microribonucleic acid-21 (miR-21) mimic or negative control ribonucleic acid (RNA) duplex and phosphatase and tensin homolog, deleted on chromosome 10 (PTEN) small interfering ribonucleic acid (siRNA) or negative control. PTEN, phosphorylated protein kinase B (pAKT), and protein kinase B (AKT) expression were detected using Western blotting, whereas miR-21 expression was examined by real-time polymerase chain reaction (RT-PCR). In vivo, nude mice were given injections of A549 cells to grow xenograft tumors; 8 days later, the mice were intraperitoneally injected with propofol (35 mg/kg) or soybean oil. Tumors were then collected from mice and analyzed by immunohistochemistry and Western blotting. RESULTS: Propofol inhibited growth (1 hour, P = .001; 4 hours, P ≤ .0001; 12 hours, P = .0004) and miR-21 expression (P ≤ .0001) and induced apoptosis (1 hour, P = .0022; 4 hours, P = .0005; 12 hours, P ≤ .0001) in A549 cells in a time and concentration-dependent manner. MiR-21 mimic and PTEN siRNA transfection antagonized the suppressive effects of propofol on A549 cells by decreasing PTEN protein expression (mean differences [MD] [95% confidence interval {CI}], -0.51 [-0.86 to 0.16], P = .0058; MD [95% CI], 0.81 [0.07-1.55], P = .0349, respectively), resulting in an increase in pAKT levels (MD [95% CI] = -0.82 [-1.46 to -0.18], P = .0133) following propofol exposure. In vivo, propofol treatment reduced NSCLC tumor growth (MD [95% CI] = -109.47 [-167.03 to -51.91], P ≤ .0001) and promoted apoptosis (MD [95% CI] = 38.53 [11.69-65.36], P = .0093). CONCLUSIONS: Our study indicated that propofol inhibited A549 cell growth, accelerated apoptosis via the miR-21/PTEN/AKT pathway in vitro, suppressed NSCLC tumor cell growth, and promoted apoptosis in vivo. Our findings provide new implications for propofol in cancer therapy and indicate that propofol is extremely advantageous in surgical treatment.
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Anestésicos Intravenosos/farmacología , Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Propofol/farmacología , Transducción de Señal/efectos de los fármacos , Células A549 , Anestésicos Intravenosos/uso terapéutico , Animales , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/genética , Humanos , Neoplasias Pulmonares/genética , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , MicroARNs/efectos de los fármacos , Fosfohidrolasa PTEN/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
To breed new varieties of medicinal plants with high resistance is the premise to ensure the production of high-quality medicinal materials. Molecular breeding using modern molecular biology and genetic technology can save time and effort and realize rapid and accurate breeding. Here we are trying to summarize the difference of breeding characteristics between medicinal plants and crops such as genetic background and breeding purpose. The strategy of molecular breeding of medicinal plants was summarized, and the four-phases breeding based on high-throughput sequencing and target gene mining was emphasized. We put forward the current molecular breeding of medicinal plants in the condition of four phases breeding is the optimal technological way of breeding, and gene editing breeding is the direction of medicinal plants breeding.
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Plantas Medicinales/genética , Cruzamiento , Barajamiento de ADN , Edición Génica , FitomejoramientoRESUMEN
Appropriate producing areas can guarantee the quality of Tibetan medicine, but research on the suitable ecological factors and suitable producing areas of Tibetan medicinal plants is scarce. This paper used the Geographic Information System for Global Medicinal Plants(GMPGIS) to analyze the ecological suitability of Tibetan medicinal plants nationwide. For the first time, the range of ecological factors and main soil types of Tibetan medicinal plants were extracted, such as the average annual temperature-19.4-24.2 â, annual average precipitation 17-4 088 mm, annual average sunshine 124.2-171.6 W·m~(-2). The main soil types were black calcareous soil, thin layer soil, chestnut soil and so on. Based on 337 sampling points, the largest ecological similarity area of Tibetan medicine across the country was obtained through ecological similarity analysis. In addition to Tibet and Qinghai provinces and Tibetan Autonomous Prefectures in Sichuan, Gansu, and Yunnan provinces, Jiuquan city and Linxia county in Gansu province, Panzhihua and Ya'an in Sichuan province, and Xinjiang, Inner Mongolia, and Shanxi provinces also had larger suitable cultivation areas. In addition, by analyzing the current situation of Tibetan medicine industry, the research pointed out that there were some problems such as unreasonable development and utilization of resources, lack of standards and norms, weak basic research and imperfect industrial system, and made corresponding countermeasures for sustainable development of resources, formulation of standards and specifications, promotion of medicine through science and technology, expansion of domestic and foreign markets, etc. This study provided the basis for guiding the rational layout of production bases, introduction and breeding of plant Tibetan medicine nationwide, laying the foundation for the scientific and standardized production of high-quality Tibetan medicine, clarifying the development direction of Tibetan medicine industry, and providing ideas for the development strategy of Tibetan medicine and other national medicine industry.
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Desarrollo Industrial , Medicina Tradicional Tibetana , China , Suelo , TibetRESUMEN
BACKGROUND: The programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) pathway has been shown to be involved in trauma-induced immunosuppression and to influence CD4+ T cell differentiation. MicroRNA (miR)-21 is a critical player in immune responses. However, it remains largely unknown whether miR-21 is regulated by PD-1 and influences CD4+ T-cell lineage choice after gastric cancer resection. METHODS: In the present study, we analyzed the percentages of T-helper (Th)-17/regulatory T (Treg) cells and PD-1/PD-L1 expression on peripheral blood mononuclear cells (PBMCs) during the perioperative period. We also detected the secretion of interleukin (IL)-17 and transforming growth factor (TGF)-ß1 using enzyme-linked immunosorbent assays (ELISAs). Furthermore, PBMCs isolated from patients were transfected with or without adenovirus-short hairpin-PD-1 (Ad-sh-PD1), pre-miR-21 or adenovirus-green fluorescent protein (Ad-GFP), and the percentages of Th17/Treg cells and related transcription factors were measured. RESULTS: In patients who underwent gastric cancer resection, the number of Th17 cells decreased, whereas the number of Treg cells increased, accompanied by an increased expression of PD-1/PD-L1. In addition, the expression of RORγt and IL-17 decreased, whereas the expression of Foxp3 and TGF-ß1 increased. In vitro, silencing PD-1 via Ad-sh-PD1 promoted the expression of miR-21 and increased the percentage of Th17 cells, but decreased the percentage of Treg cells. The overexpression of miR-21 increased the percentage of Th17 cells but decreased the percentage of Treg cells. CONCLUSIONS: Our study demonstrated that gastric cancer resection altered the balance of Th17/Treg cells and increased PD-1/PD-L1 expression. In the in vitro experiments, the transfection of Ad-sh-PD1 ameliorated Th17/Treg cell imbalance partially by increasing the expression of miR-21.
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Antígeno B7-H1/metabolismo , Gastrectomía/mortalidad , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Receptor de Muerte Celular Programada 1/metabolismo , Neoplasias Gástricas/inmunología , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Biomarcadores de Tumor/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Interleucina-17/metabolismo , Masculino , Persona de Mediana Edad , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Pronóstico , Transducción de Señal , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patología , Neoplasias Gástricas/cirugía , Tasa de Supervivencia , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Highly potent DNA damaging agents have become a key class of toxins for antibody-drug conjugate (ADC) based targeted therapy. However, until recently, no quantitative bioanalytical method was available to measure the toxin in the form of DNA adducts. In this work, a novel microwave assisted organic solvent extraction and LC-MS/MS based bioanalytical method was developed to extract and quantify DNA-bound toxin IGN-P1 in tissue samples. Using ADC-1 as the model ADC, the method was orthogonally checked with a radioactive method for the recovery of free toxins from DNA adducts in biological matrices. It was found that the bioanalytical method can achieve a high recovery of the IGN-P1 toxin from DNA adducts. In further assessment, tumor and organ tissue samples collected at multiple time points from in vivo studies after dosing with two other ADCs, ADC-2 and ADC-3, were measured by the method. Given the generic nature of the established bioanalytical method without the need of radiolabels, the methodology could be broadly utilized to quantitatively assess the relationship between DNA adduct levels and pharmacological/toxicological effects.
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Benzodiazepinas/análisis , Aductos de ADN/análisis , Inmunoconjugados/análisis , Hígado/química , Bazo/química , Animales , Cromatografía Liquida , Humanos , Espectrometría de Masas , Ratones , Ratones SCID , Estructura Molecular , Neoplasias Experimentales/diagnósticoRESUMEN
Deteriorating lake water quality has become a serious environmental issue around the globe. Heavy metals dissolved in the overlying water of lakes are notably more toxic than those found in lake sediment. Given this, we sought to better understand the characteristics of particular major ion and dissolved heavy metal in Dongting Lake-the second largest freshwater lake in China. Overlying water samples were collected from Dongting Lake to investigate the major ion geochemistry and to examine the relationship between the major ions and dissolved heavy metals. Chemical analysis of the overlying water showed that the average cation concentration was the highest for Ca2+, followed by Mg2+, Na+, and K+. Similarly, the highest anion concentration was SO42-, followed by Cl-, NO3-, and HCO3-. Total dissolved solids in the overlying water of Dongting Lake ranged from 66.19 to 159.20 mg/L, with an average value of 93.13 mg/L. The predominant hydrochemical type was Ca-SO4. The mean concentrations of dissolved heavy metal in both surface and deep waters decreased in the following order: Zn > Cr > Ni > Cu > Pb > Cd. Importantly, all of the selected heavy metals tested in the overlying water were lower than the corresponding toxicity reference values. Co-occurrence network analyses were performed and compared the correlations between all measured major ions and heavy metals. Results of the subsequent principal component analyses revealed that heavy metal levels in the aquatic environment primarily originated from natural processes and were enhanced by anthropogenic activities.
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Lagos/química , Metales Pesados/análisis , Contaminantes Químicos del Agua/análisis , Sulfato de Calcio/análisis , China , Monitoreo del Ambiente , Sedimentos Geológicos/química , Iones , Lagos/análisis , Metales Pesados/química , Nitratos/análisis , Sulfatos/análisis , Calidad del AguaRESUMEN
The shortage of new cannabis varieties with low THC and high CBD content and irregular planting techniques have become the bottleneck for he development of non-psychoactive medicinal cannabis industry. Based on the cannabis germplasm resources,this paper proposes strategies for breeding high CBD content,seed-type and high-efficiency,dwarf non-psychoactive medicinal cannabis varieties through molecular marker development,assisted breeding,genetic engineering breeding and traditional breeding. According to the suitable ecological factors of non-psychoactive medicinal cannabis,the CBD content and grain yield of non-psychoactive medicinal cannabis can be improved by regulating the nutritional structure and illumination properties of non-psychoactive medicinal cannabis,scientific harvesting and storage. At the same time,in order to further accelerate the application of non-psychoactive medicinal cannabis,we can accelerate the selection of new varieties of non-psychoactive medicinal cannabis by mining genetic information of cannabis,and strengthen the application of information technology and automation of modern agriculture in the production of non-psychoactive medicinal cannabis. Provide basis for the cultivation and wide application of new non-psychoactive medicinal cannabis varieties with high quality and high yield.
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Cannabidiol/análisis , Cannabis , Marihuana Medicinal , AgriculturaRESUMEN
The excessive pesticide residues and heavy metals in traditional Chinese medicine seriously endanger human health and the sustainable development of Chinese medicine industry. In order to improve the quality of traditional Chinese medicine and establish a general standard for maximum residue limits(MRL) of pesticides in pollution-free traditional Chinese medicine and decoction pieces, and to ensure the safety of clinical medication from its origin, MRLs were calculated based on the formula(MRL=A×W/100M) from Chinese Pharmacopeia, comparing it with the current Chinese and international standards as well as literature review, the RAND/UCLA appropriateness method(RAM) was applied to determine the categories and MRLs of pesticides in pollution-free traditional Chinese medicine and decoction pieces. Two questionnaires were drafted for expert panel and appropriateness analysis was carried out with the 9-point Likert scale to determine the general standard for MRLs of pollution-free traditional Chinese medicine and decoction pieces. The results showed that a total of nine experts from different fields scored the necessity of standard-setting and 206 pesticide residue limits respectively. The appropriateness scores of 206 pesticides were greater than 7, and appropriateness rate was 100%, which signifies that the expert panel has reached consensus. In summary, based on the RAM, the general standard for maximum residue limits of pesticides in pollution-free Chinese medicines and decoction pieces has reached an expert consensus. Comparing with the MRLs of medicinal plants and plant-sourced food from CAC, Europe Union, the United States, South Korea, Japan, Australia, New Zealand and Canada, 206 MRLs from this general standard share 88.8% in common, 4.4% of which is higher and 6.8% lower than those international standards. This has provided a basis for standardizing the use of pesticides in pollution-free traditional Chinese medicine.
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Medicamentos Herbarios Chinos/normas , Residuos de Plaguicidas/análisis , Plaguicidas/análisis , Medicina Tradicional ChinaRESUMEN
Cultivated ginseng in the farmland would become the mainly planting mode of Panax ginseng. However,there are relatively few cultivation ginseng varieties for farmland in China. Correlative analysis of qualitity and agronomic traits of P. ginseng cultivation in the farmland could provide a reference for the selection of excellent germplasm and new variety breeding of P. ginseng. In this study,the main index of saponin and agronomic traits of 4-6 years' samples were analyzed by UPLC and measured. The results show that there was significant difference in agronomic indexes of Damaya. The coefficient of variation of the root length( CV = 41. 97%) and fresh weight( CV = 31. 81%) were maximum,and the coefficient of variation of the stems thickness( 16. 72%) and root thickness were minimum. There was a significant correlation between yield and root thickness( P<0. 05). There was significant difference in drug yield of different harvest years( P<0. 05),and the yield of 6-years was 31. 52%-39. 69% higher than 4-years. However,there wasn't significant difference in total ginsenosides between 4 and 6 years old P. ginseng,but there was significant difference in ginseng Rg2,Rc and Rb2( P<0. 05),and the ginsenoside contents of different harvesting years were accorded with the criterion standards of 2015 Chinese Pharmacopoeia. There was no significant correlation between the saponin and the agronomic trait,while there was positive correlation with root thickness( P < 0. 05). Therefore,the stem diameter was positive correlation with yield of P. ginseng. Selection of the stem thickness of seedlings is beneficial to the increase of the yield and breeding of P. ginseng.
Asunto(s)
Producción de Cultivos , Ginsenósidos/análisis , Panax/química , China , Fitomejoramiento , Raíces de Plantas/crecimiento & desarrollo , Tallos de la Planta/crecimiento & desarrolloRESUMEN
Plasma stability assessment under physiological temperature is an essential step for developing and optimizing antibody drug conjugate (ADC) molecules, especially those with cleavable linkers. The assessment of plasma stability often requires monitoring multiple analytes using a combination of bioanalytical assays for free payloads, conjugated payloads (or conjugated antibodies), total antibodies, and payloads that have migrated from antibodies to plasma constituent proteins. Bioanalytical assays are needed in early drug discovery to quickly screen diverse ADC candidates of different antibody constructs, linker variants, and antibody anchor sites. To improve the sensitivity and selectivity of LC/MS/MS-based assays for the assessment, immunocapture has been widely used for extracting ADCs and unconjugated antibodies from plasma samples. In this study, a novel two-step immunocapture LC/MS/MS assay was described to allow the quantification of conjugated payloads, total antibodies, and migrated payloads forming adducts with albumin in the plasma samples for stability assessment. A target antigen immobilized on magnetic beads was used to exhaustively extract the ADC and antibody-associated species. The remaining supernatant was then extracted further with anti-albumin beads for recovering the albumin-associated adducts for quantification. The method was optimized for higher efficiency and cost-effectiveness using microwave enhanced papain-based enzymatic cleavage for measuring conjugated payloads of ADCs and lysyl endopeptidase cleavage in the total antibody assay. A maleimide linker-based ADC with a proprietary payload, TAK-001, was used to demonstrate the streamlined workflow of the ADC stability assessment. The method could provide valuable evaluation of the stability of the ADC as well as the quantitative assessment of the albumin adducts formed from the linker-payload migration in mouse and human plasma. Furthermore, the method should be readily adaptable for other ADCs using thiol-maleimide conjugation chemistry.