Silver-Catalyzed Dearomative Skeletal Editing of Indazoles by Donor Carbene Insertion.

Given the prevalence of heterocyclic scaffolds in drug-related molecules, converting these highly modular heterocyclic scaffolds into structural diversified and dearomatized analogs is an ideal strategy for improving their physicochemical and pharmacokinetic properties. Here, we described an efficient method for silver carbene-mediated dearomative N-N bond cleavage leading to skeletal hopping between indazole and 1,2-dihydroquinazoline via a highly selective single-carbon insertion procedure. Using this methodology, a series of dihydroquinazoline analogues with diarylmethylene-substituted quaternary carbon centers were constructed with excellent yields and good functional group compatibility, which was further illustrated by the late-stage diversification of important pharmaceutically active ingredients. DFT calculations indicated that the silver catalyst not only induces the formation of the silver carbene, but also activates the diazahexatriene intermediate, which plays a crucial role in the formation of the C-N bond.

Rhodium-Catalyzed One-Carbon Ring Expansion of Aziridines with Vinyl-N-triftosylhydrazones for the Synthesis of 2-Vinyl Azetidines.

Azetidines, being four-membered N-heterocycles, possess significant potential in contemporary medicinal chemistry owing to their favorable pharmacokinetic properties. Regrettably, the incorporation of functionalized azetidines into pharmaceutical lead structures has been impeded by the absence of efficient synthetic methods for their synthesis. In this study, a Rh-catalyzed one-carbon ring expansion of aziridines with vinyl-N-triftosylhydrazones is presented, which facilitates the synthesis of high value-added 2-alkenyl azetidine products. This research represents the first example of ring expansion of aziridines enabled by vinyl carbenes. Additionally, a one-pot two-step protocol, initiated from cinnamaldehyde, was successfully achieved, offering a step-economical and facile approach for the synthesis of these compounds. The pivotal aspect of this successful transformation lies in the in situ formation of an alkenyl aziridinium ylide intermediate. Experimental investigations, coupled with computational studies, suggest that a diradical pathway is involved in the reaction mechanism.

Dearomative Insertion of Fluoroalkyl Carbenes into Azoles Leading to Fluoroalkyl Heterocycles with a Quaternary Center.

The skeletal ring expansion of heteroarenes through carbene insertion is gaining popularity in synthetic chemistry. Efficient strategies for heterocyclic ring expansion to access heterocycles containing a fluoroalkyl quaternary carbon center through fluoroalkyl carbene insertion are highly desirable because of their broad applications in medicinal chemistry. Herein, we report a general strategy for the dearomative one-carbon insertion of azoles using fluoroalkyl N-triftosylhydrazones as fluoroalkyl carbene precursors, resulting in ring-expanded heterocycles in excellent yields with good functional-group compatibility. The broad generality of this methodology in the late-stage diversification of pharmaceutically interesting bioactive molecules and versatile transformations of the products has been demonstrated.

Bi-allelic variants in CEP295 cause Seckel-like syndrome presenting with primary microcephaly, developmental delay, intellectual disability, short stature, craniofacial and digital abnormalities.

BACKGROUND: Pathogenic variants in the centrosome protein (CEP) family have been implicated in primary microcephaly, Seckel syndrome, and classical ciliopathies. However, most CEP genes remain unlinked to specific Mendelian genetic diseases in humans. We sought to explore the roles of CEP295 in human pathology. METHODS: Whole-exome sequencing was performed to screen for pathogenic variants in patients with severe microcephaly. Patient-derived fibroblasts and CEP295-depleted U2OS and RPE1 cells were used to clarify the underlying pathomechanisms, including centriole/centrosome development, cell cycle and proliferation changes, and ciliogenesis. Complementary experiments using CEP295 mRNA were performed to determine the pathogenicity of the identified missense variant. FINDINGS: Here, we report bi-allelic variants of CEP295 in four children from two unrelated families, characterized by severe primary microcephaly, short stature, developmental delay, intellectual disability, facial deformities, and abnormalities of fingers and toes, suggesting a Seckel-like syndrome. Mechanistically, depletion of CEP295 resulted in a decrease in the numbers of centrioles and centrosomes and triggered p53-dependent G1 cell cycle arrest. Moreover, loss of CEP295 causes extensive primary ciliary defects in both patient-derived fibroblasts and RPE1 cells. The results from complementary experiments revealed that the wild-type CEP295, but not the mutant protein, can correct the developmental defects of the centrosome/centriole and cilia in the patient-derived skin fibroblasts. INTERPRETATION: This study reports CEP295 as a causative gene of the syndromic microcephaly phenotype in humans. Our study also demonstrates that defects in CEP295 result in primary ciliary defects. FUNDING: A full list of funding bodies that contributed to this study can be found under "Acknowledgments."

An optimized 3D-printed capsule scaffold utilizing artificial neural network for the targeted delivery of chlorogenic acid to the colon.

Chlorogenic acid (CGA) is an important bioactive polyphenol with extensive biological properties. This study aimed to fabricate an optimized three-dimensional (3D)-printed capsule scaffold and CGA capsules for targeted delivery of hydrophobic CGA to the colon. The optimized printing parameters identified using the neural network model were a temperature of 170 °C, a printing speed of 20 mm/s, and a nozzle diameter of 0.3 mm. The capsules exhibited slow releasing properties of CGA, and the releasing rates of Eudragit®FS 30D-sealed capsules (due to more cracks and voids) were faster than those of Eudragit®S100-sealed capsules. The Ritger-peppas model was the best fitting model to describe the releasing process of CGA from 8 CGA capsules (R2 ≥ 0.98). All CGA capsules exhibited shear-thinning properties with stable sol-gel viscosity at low shear rates. FTIR spectra confirmed the formation of non-covalent bonds between CGA and the sol. Overall, the obtained 3D-printed capsules provided a promising carrier for the targeted delivery of CGA in the development of personalized dietary supplements.

Research on cultural and creative design method of 2022 World Cup lamps based on AHP-FCE.

AIMS: Through an in-depth study of Qatari culture, to explore the application of the essence of the unique national culture to World Cup creative design, and to provide new ideas and reference design framework and ideas for the integration of culture and World Cup creative design. METHOD: Carry out design practice with Qatari culture, and discuss in detail the specific strategy of integrating national culture into the cultural and creative design of the World Cup. First, conduct user interviews based on grounded theory to collect and evaluate demand indicators and establish a hierarchical model, and then use the Analytic Hierarchy Process (AHP) to analyze user needs, construct design elements for the World Cup cultural and creative design, and calculate the weight of each design element to determine the design Ordering among elements. Finally, the optimal scheme is selected by scoring the scheme through fuzzy comprehensive evaluation method (FCE), so as to determine the final design scheme of the product. CONCLUSION: The article explores the specific practice method of integrating culture and design, and provides a solution reference for how to integrate excellent national culture into the World Cup cultural and creative design, which not only improves the cultural and spiritual connotation of the product, but also effectively realises the heritage and innovation of culture.

NEIL3 contributes to the Fanconi anemia/BRCA pathway by promoting the downstream double-strand break repair step.

Interstrand crosslinks (ICLs) repair by the canonical Fanconi anemia (FA) pathway generates double-strand breaks (DSBs), which are subsequently repaired by the homologous recombination (HR) pathway. Recent studies show that the NEIL3 DNA glycosylase repairs psoralen-ICLs by direct unhooking. However, whether and how NEIL3 regulates MMC and cisplatin-ICL repair remains unclear. Here we show that NEIL3 participates in DSB repair step of ICL repair by promoting HR pathway. Mechanistically, NEIL3 is recruited to the DSB sites through its GRF zinc finger motifs. NEIL3 interacts with the DSB resection machinery, including CtIP, the MRE11-RAD50-NBS1 (MRN) complex, and DNA2, which is mediated by the GRF zinc finger motifs. In addition, NEIL3 is necessary for the chromatin recruitment of the resection machinery, and depletion of NEIL3 decreases end resection and compromises HR. Taken together, our results show that NEIL3 plays an important role in MMC/cisplatin-ICL repair by promoting the HR step in FA/BRCA pathway.

Diagnosis of patients with mucopolysaccharidosis type II via RNA sequencing.

BACKGROUND: Mucopolysaccharidosis type II (MPS II) is an X-linked recessive lysosomal storage disorder caused by various variants in the IDS gene. It is known that genomic recombinants between IDS and its homologous pseudogene IDSP1 account for a small number of patients, for whom genetic diagnosis usually relies on restriction enzyme digestion at specific loci. Nevertheless, such approach cannot reveal the impact of rearrangements on IDS transcription, which is crucial for the interpretation of the pathogenicity of rearrangement variants. METHODS: RNA sequencing (RNA-seq) was explored to analyze transcriptional alterations in four male MPS II patients who were negative for Sanger sequencing of the IDS gene. Reverse transcription-polymerase chain reaction and TA clone sequencing were used to validate RNA-seq analysis results. The IDS-IDSP1 recombinant was determined by sequencing the indicated loci in genome. RESULTS: Differential expression analysis showed the expression levels of IDS gene in patients were largely reduced compared to the healthy individuals. Differential splicing analysis revealed skipping of exons 8 and 9 of IDS, without any splice-junction defects at the genomic level. In addition, two types of fusion transcripts, IDS_EOLA1 and IDS_EOLA1-DT_EOLA1 were identified by gene fusion analysis. Sequencing of the known rearrangement alleles showed these four patients have the same type of IDS-IDSP1 recombinant. CONCLUSION: We establish an RNA-seq workflow to analyze transcriptional characteristics of IDS gene from multiple perspectives. Our study validates the diagnostic value of RNA-seq in MPS II, including the discovery of transcriptional alterations and the potential to suggest genome-level rearrangements in IDS.

Sacubitril/valsartan protects against arsenic trioxide induced cardiotoxicity in vivo and in vitro.

The cardiotoxicity induced by arsenic trioxide (ATO) limits its clinical application in acute promyelocytic leukemia treatment. Sacubitril/valsartan (LCZ696) is an effective drug for the treatment of heart failure. In this study, we aimed to investigate the protective effect and mechanisms of LCZ696 against the ATO-induced cardiotoxicity in mice and H9c2 cells. We found that LCZ696 could alleviate the decrease of ejection fraction and fractional shortening induced by ATO, thereby improving mouse cardiac contractile function. LCZ696 could also reduce the myocardial enzyme, resist oxidative stress, mitigate myocardial fibrosis, and ameliorate myocardial structure, thereby alleviating myocardial damage caused by ATO. In addition, LCZ696 could significantly increase the cell viability and reduce the accumulation of reactive oxygen species in ATO-treated H9c2 cells. Besides, in vivo and in vitro studies have been found that LCZ696 could restore the expression of Bcl-2 and reduce Bax and Caspase-3 levels, inhibiting ATO-induced apoptosis. Meanwhile, LCZ696 decreased the levels of IL-1, IL-6, and TNF-α, alleviating the inflammatory injury caused by ATO. Furthermore, LCZ696 prevented NF-κB upregulation induced by ATO. Our findings revealed that LCZ696 has a considerable effect on preventing cardiotoxicity induced by ATO, which attributes to its capability to suppress oxidative stress, inflammation, and apoptosis.

DNA damage and repair in the hematopoietic system.

Although hematopoietic stem cells (HSCs) in the bone marrow are in a state of quiescence, they harbor the self-renewal capacity and the pluripotency to differentiate into mature blood cells when needed, which is key to maintain hematopoietic homeostasis. Importantly, HSCs are characterized by their long lifespan ( e. g., up to 60 months for mice), display characteristics of aging, and are vulnerable to various endogenous and exogenous genotoxic stresses. Generally, DNA damage in HSCs is endogenous, which is typically induced by reactive oxygen species (ROS), aldehydes, and replication stress. Mammalian cells have evolved a complex and efficient DNA repair system to cope with various DNA lesions to maintain genomic stability. The repair machinery for DNA damage in HSCs has its own characteristics. For instance, the Fanconi anemia (FA)/BRCA pathway is particularly important for the hematopoietic system, as it can limit the damage caused by DNA inter-strand crosslinks, oxidative stress, and replication stress to HSCs to prevent FA occurrence. In addition, HSCs prefer to utilize the classical non-homologous end-joining pathway, which is essential for the V(D)J rearrangement in developing lymphocytes and is involved in double-strand break repair to maintain genomic stability in the long-term quiescent state. In contrast, the base excision repair pathway is less involved in the hematopoietic system. In this review, we summarize the impact of various types of DNA damage on HSC function and review our knowledge of the corresponding repair mechanisms and related human genetic diseases.

Supplementation of Bacillus sp. DU-106 Alleviates Antibiotic-Associated Diarrhea in Association with the Regulation of Intestinal Microbiota in Mice.

Bacillus sp. DU-106, a potential probiotic, has been proved to activate innate immunity, reduce hypercholesterolemia, and regulate the gut microbiota of mice. In the present study, we investigated the therapeutic effect of strain DU-106 in antibiotic-associated diarrhea (AAD) via analyzing the changes in gut microbial composition in mice. The results indicated that supplementation of strain DU-106 alleviated gastrointestinal symptoms, improved gut barrier integrity and immunoglobulin-A level of mice with AAD. A 16S rRNA sequencing showed that antibiotics decreased bacterial diversity and the abundances of Alistipes, Roseburia, Hungatella, Eubacterium-xylanophilum, Lachnospiraceae-UCG-001, Intestinimonas, and Lachnospiraceae-NK4A136, but increased the abundance of Klebsiella, Bacteroidota, and Verrucomicrobiota. However, strain DU-106 treatment reversed these alternations in mice with AAD. In conclusion, strain DU-106 could alleviate AAD in association with the regulation of intestinal microbiota and could be used as an alternative treatment for AAD.

Novel compound heterozygous variant of TOE1 results in a mild type of pontocerebellar hypoplasia type 7: an expansion of the clinical phenotype.

The target of EGR1 protein 1 (TOE1) is a 3-exonuclease belonging to the Asp-Glu-Asp-Asp deadenylase family that plays a vital role in the maturation of a variety of small nuclear RNAs (snRNAs). Bi-allelic variants in TOE1 have been reported to cause a rare and severe neurodegenerative syndrome, pontocerebellar hypoplasia type 7 (PCH7) (OMIM # 614,969), which is characterized by progressive neurodegeneration, developmental delay, and ambiguous genitalia. Here, we describe the case of a 5-year-6-month-old female Chinese patient who presented with cerebral dysplasia, moderate intellectual disability, developmental delay, and dystonia. Trio whole-exome sequencing revealed two previously unreported heterozygous variants of TOE1 in the patient, including a maternal inherited splicing variant c.237-2A > G and a de novo missense variant c.551G > T, p.Arg184Leu. TA clone sequencing showed trans status of the two variants, indicating the missense variant occurred on the paternal strand in the patient. Clinical features of the patient were mostly concordant with previous reports but brain deformities (enlarged lateral ventricle and deepened cerebellum sulcus without microcephaly and reduced cerebellar volume) were less severe than in typical PCH7 patients. Moreover, the patient had no gonadal malformation, which is common and variable in patients with PCH7. In summary, we report the case of a Chinese patient with atypical PCH7 caused by a novel TOE1 compound variant. Our work suggests that variations in the TOE1 gene can lead to highly variable clinical phenotypes.

Structural characterization and immunoregulatory activity of polysaccharides from Dendrobium officinale leaves.

In this study, two kinds of polysaccharides from leaves of Dendrobium officinale, namely DLP-1 and DLP-2, were obtained by hot water extraction, ethanol sedimentation, and chromatographic separation using DEAE-52 cellulose and Sephadex G-100 columns. They were composed of different monosaccharides and the content of monosaccharides varied significantly while DLP-1 (Mw 1.38 × 106  Da) was mainly composed of mannose (71.69%) and glucose (22.89%), and DLP-2 (Mw 1.93 × 106  Da) was constituted by rhamnose (35.05%), arabinose (24.12%), and galactose (25.65%). A triple-helical conformation was exhibited by both of them. The scanning electron microscope image of DLP-1 showed an irregular and large lamellar shape, as well as a smooth surface and a porous interior, illustrating they had an amorphous structure. In contrast, DLP-2 revealed a rough, loose, and uneven surface consisting of large sponge-like particles. Nuclear magnetic resonance analysis showed that (1→4)-ß-D-Manp, (1→4)-ß-D-Glcp, and (1→4)-2-O-acetyl-ß-D-Manp were the main linkage types of DLP-1, whereas DLP-2 was constituted by a large amount of (1→4)-ß-D-Manp, (1→4)-ß-D-Glcp, and other residues. Besides, DLP-1 and DLP-2 stimulated the proliferation and phagocytic capacities of RAW 264.7 cells and improved the production of nitric oxide, interleukin-6, TNF-α, and IL-1ß. These results proved that both DLP-1 and DLP-2 possessed excellent immunoregulatory bioactivities and could be functional food or adjuvant drug. PRACTICAL APPLICATIONS: The leaf of Dendrobium officinale is a by-product with huge biomass. The lack of systematic research on its chemical composition and pharmacologic effect, leading to a great waste of resources. In order to maximize the value of D. officinale, this study aimed to investigate the structural characteristics and immunologic effects of two polysaccharide fractions (DLP-1 and DLP-2) from D. officinale leaves, showing that DLP-1 and DLP-2 in D. officinale leaves could be used as anti-inflammatory agents to avoid wasting.

Pharmacokinetic Characteristics, Tissue Bioaccumulation and Toxicity Profiles of Oral Arsenic Trioxide in Rats: Implications for the Treatment and Risk Assessment of Acute Promyelocytic Leukemia.

Oral arsenic trioxide (ATO) has demonstrated a favorable clinical efficiency in the treatment of acute promyelocytic leukemia (APL). However, the pharmacokinetic characteristics, tissue bioaccumulation, and toxicity profiles of arsenic metabolites in vivo following oral administration of ATO have not yet been characterized. The present study uses high performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS) to assess the pharmacokinetics of arsenic metabolites in rat plasma after oral and intravenous administration of 1 mg kg-1 ATO. In addition, the bioaccumulation of arsenic metabolites in blood and selected tissues were evaluated after 28 days oral administration of ATO in rats at a dose of 0, 2, 8, and 20 mg kg-1 d-1. The HPLC-HG-AFS analysis was complemented by a biochemical, hematological, and histopathological evaluation conducted upon completion of ATO treatment. Pharmacokinetic results showed that arsenite (AsIII) reached a maximum plasma concentration rapidly after initial dosing, and the absolute bioavailability of AsIII was 81.03%. Toxicological results showed that the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and white blood cells (WBC) in the 20 mg kg-1 d-1 ATO group were significantly increased compared to the control group (p < 0.05). The distribution trend of total arsenic in the rat was as follows: whole blood > kidney > liver > heart. Dimethylated arsenic (DMA) was the predominant bioaccumulative metabolite in the whole blood, liver, and heart, while monomethylated arsenic (MMA) was the predominant one in the kidney. Collectively, these results revealed that oral ATO was rapidly absorbed, well-tolerated, and showed organ-specific and dose-specific bioaccumulation of arsenic metabolites. The present study provides preliminary evidence for clinical applications and the long-term safety evaluation of oral ATO in the treatment of APL.

Evaluation of arsenic species in leukocytes and granulocytes of acute promyelocytic leukemia patients treated with arsenic trioxide.

Concentrations of arsenic metabolites were important to clarify the sensitivity and resistance of APL (acute promyelocytic leukemia) patients to arsenic trioxide (As2O3). Our purpose was to evaluate levels and distributions of arsenic species in leukocytes and granulocytes of APL patients. Inorganic arsenic (iAs), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA) were measured by high performance liquid chromatography coupled inductively coupled plasma mass spectrometry (HPLC-ICP-MS). Leukocytes were collected from 21 patients treated with As2O3 during induction, consolidation, and drug-withdrawal period. The upregulation of granulocytes in induction period was closely related to the differentiation of promyelocytes. Therefore, granulocytes were collected during induction period from 4 APL patients and purified by flow cytometry sorting using a panel of monoclonal antibodies specific for CD45, CD3, CD14, and CD19. The developed HPLC-ICP-MS method was precise and accurate with the limit of quantification of 0.5 ng/mL. During induction, consolidation, and drug-withdrawal period, the general trend of arsenic species was iAs > MMA > DMA (P < 0.05) in leukocytes. iAs was predominant arsenic species with median concentration of 10.84 (6.03-14.62) ng/mL. MMA was major methylated metabolite with median concentration of 0.94 (0.60-2.50) ng/mL. Moreover, arsenicals were detected in leukocytes during drug-withdrawal. In granulocytes, iAs was found during induction period with median concentration of 1.08 ng/mL, while MMA and DMA were not detected. These results showed that iAs was the primary arsenic species in leukocytes and granulocytes from APL patients treated with As2O3. This study suggested that iAs might play a dominant therapeutic role during the whole treatment process of APL.

Effect of renal impairment on arsenic accumulation, methylation capacity, and safety in acute promyelocytic leukemia (APL) patients treated with arsenic trioxide.

Background: Arsenic trioxide (ATO) was successfully applied to treat acute promyelocytic leukemia (APL).Methods: Inorganic arsenic (iAs), monomethylarsonic acid (MMAV) and dimethyarsinic acid (DMAV) in plasma of 143 APL patients with different renal function were determined. Arsenic methylation capacity was evaluated by iAs%, MMAV%, DMAV%, primary methylation index (PMI, MMAV/iAs), and secondary methylated index (SMI, DMAV/MMAV). Arsenic accumulation with administration frequency were explored. Moreover, safety assessments were performed.Results: Compared with normal renal function, MMAV and DMAV concentrations increased 1.5-4 fold in moderate and severe renal impairment groups, iAs increased 1.3-1.7 fold. APL patients with renal impairment showed lower iAs%, but higher DMAV% and PMI in plasma than those with normal renal function (P < 0.05). MMAV, DMAV, and tAs apparently accumulated with administration frequency in moderate and severe renal dysfunction groups. The incidence of QTc interval prolongation and liver injury increased with the increasing severity of renal impairment.Conclusion: Renal dysfunction may increase exposure to arsenic and arsenic accumulation and affect methylation capacity, then the clinical safety in APL patients treated with ATO. Arsenic-level monitoring and dosing regimen adjustment should be considered in APL patients with moderate and severe renal dysfunction.

Monomethylated arsenic was the Major methylated arsenic in Red blood cells of acute promyelocytic leukemia patients treated with arsenic trioxide.

BACKGROUND: Arsenic trioxide (ATO) has been successfully applied in the treatment of acute promyelocytic leukemia (APL). Arsenic metabolites including inorganic arsenic and methylated arsenic could lead to different toxicity and curative effect. This study aims to establish a method to determine arsenic species in red blood cells (RBCs), clarify the distribution characteristics of arsenic species in RBCs. METHODS: Steady state blood samples were collected from 97 APL patients. H2O2 and HClO4 were used to release the hemoglobin bounding arsenic and precipitate protein. Arsenite (iAsIII), arsenate (iAsV), monomethylarsonic acid (MMAV) and dimethylarsinic acid (DMAV) in plasma and RBCs were detected by HPLC-HG-AFS. Free and bound arsenic species in RBCs were separated by 30 kDa molecular mass cutoff filters and determined to evaluate hemoglobin binding capacity of different arsenic species. RESULTS: The method was validated with accuracy ranged from 84.75% to 104.13%. Arsenic species in RBCs followed the trend iAs > MMA > DMA (p < 0.01), while the concentration of DMA was significantly higher than iAs and MMA in plasma (p < 0.01). The correlation between iAs concentration in plasma and corresponding RBCs arsenic level was weak. And the concentrations of DMA and MMA in plasma were moderately positive correlated with those in RBCs. Hemoglobin-binding ratios of iAs, MMA and DMA were all over 70 %. CONCLUSIONS: In this study, we provided a reliable method to determine arsenic species in RBCs of APL patients treated with ATO by HPLC-HG-AFS. It was confirmed that the concentration of DMA is the highest in plasma, while MMA is the most predominant methylated arsenic in RBCs. High affinity of MMA with human Hb was responsible for the accumulation of arsenic in RBCs of APL patients.

Characteristics and clinical influence factors of arsenic species in plasma and their role of arsenic species as predictors for clinical efficacy in acute promyelocytic leukemia (APL) patients treated with arsenic trioxide.

Background: Arsenic trioxide (ATO) is successfully applied to treat acute promyelocytic leukemia (APL). Arsenic species levels in blood are critical to reveal metabolic mechanism and relationship between arsenic species and clinical response. Characteristics and influence factors of arsenic species in APL patients have not been studied.Methods: 305 plasma samples from APL patients treated with ATO were analyzed using HPLC-HG-AFS. Trough concentration (Ctrough), distribution, methylation levels of arsenic species were evaluated. The influence factors on arsenic species levels of plasma and association between arsenic concentrations and clinical efficacy were explored.Results: Ctrough of arsenic in effective treatment groups provide basis for defining the target range of arsenic plasma concentrations in APL patients treated with ATO. Distribution trends: DMAV > AsIII, MMAV> AsV (p < 0.0001) for continuous slow-rate (CS) infusion and DMAV > MMAV > AsIII > AsV (p < 0.0001) for conventional infusion. Infusion methods and combined medication may affect arsenic metabolism. There was a weak correlation between ATO dose and plasma Ctrough of arsenic species. Ctrough of plasma arsenic species had predictive value for treatment efficacy.Conclusion: Arsenic concentration monitoring in APL patients treated with ATO is required. These findings are critical to optimize treatment outcomes of ATO therapy.

Potato resistant starch inhibits diet-induced obesity by modifying the composition of intestinal microbiota and their metabolites in obese mice.

Potato resistant starch type 3 (PRS) is helpful for weight-loss. To investigate the regulatory effects of PRS on high-fat diet (HFD)-induced obesity, different doses of PRS (5%, 15% and 25%) were fed to mice for 12 weeks. Metabolic syndrome related to obesity, intestinal microbiota composition and its metabolites as well as the relationship among them were studied. Results showed that PRS could regulate HFD-induced metabolic syndrome in a dose dependent manner; promote the proliferation of intestinal cells and expression of tight junction proteins, such as Occludin and zonula occludens (ZO)-1; reduce the Firmicutes/Bacteroidetes (F/B) rate; regulate the relative abundance of intestinal microbiota, such as Bifidobacterium, Ruminococcus, Bacteroides and Coprococcus; and promote the production of microbial metabolites, such as propionic acid and acetic acid. Besides, the alteration in the intestinal microbiota composition and metabolites were significantly correlated. It could be concluded that propionic acid and acetic acid were the two dominant metabolites of Bifidobacterium, Ruminococcus, Bacteroides, and Coprococcus, which contributed to the anti-obesity potential of PRS, metabolic syndrome alleviation, and intestinal barrier dysfunction.

Characteristics of arsenic species in cerebrospinal fluid (CSF) of acute promyelocytic leukaemia (APL) patients treated with arsenic trioxide plus mannitol.

Arsenic speciation in cerebrospinal fluid (CSF) is critical for treatment/prevention of central nervous system (CNS) relapse in acute promyelocytic leukaemia (APL) patients treated with arsenic trioxide (ATO). Previous study showed low total arsenic level in CSF of APL patients. Mannitol infusion was applied to improve blood-brain barrier (BBB) permeability for arsenic. Arsenite (AsIII ), monomethylarsonic acid (MMAV ), dimethylarsinic acid (DMAV ), and arsenate (AsV ) in CSF and plasma were analysed by high performance liquid chromatography-hydride generation-atomic fluorescence spectrometry (HPLC-HG-AFS). The profile and concentration of arsenic species in CSF from APL patients administered ATO alone and in combination with mannitol were compared. The overall distribution trend of arsenic species in CSF was AsIII , DMAV > MMAV > AsV . Arsenicals accumulated in CSF with administration frequency. The permeability of BBB for AsIII was higher than that for MMAV and DMAV . Arsenic concentration in CSF was much lower than that in plasma. There were significantly higher arsenic species concentrations in CSF of APL patients treated with mannitol than that without mannitol. Mannitol infusion significantly increased AsIII penetration into CSF, which was beneficial to optimize efficacy in APL patients with CNS relapse.