Acetylcholinesterase inhibitory phloroglucinols from tropic Rhodomyrtus tomentosa.

Four previously undescribed phloroglucinols, including three pairs of enantiomers, (±)-rhodotomentodimer F, (±)-rhodotomentodimer G, and (±)-rhodotomentomonomer E, and one phloroglucinol-sesquiterpene meroterpenoid, rhodotomentodione E, together with one previously reported congener, (±)-rhodomyrtosone A, were obtained from the leaves of Rhodomyrtus tomentosa. The structures including absolute configurations of previously undescribed isolates were elucidated by extensive spectroscopic analysis (HRESIMS and NMR), ECD calculations, and single-crystal X-ray diffraction. (±)-Rhodotomentodimer F is a rare phloroglucinol derivative conjugated by a ß-triketone moiety and an unprecedented resorcinol unit via the formation of a rare bis-furan ring system, whereas (±)-rhodotomentomonomer E shares a rearranged pentacyclic scaffold. Pharmacologically, (±)-rhodotomentomonomer E showed the strongest human acetylcholinesterase (hAChE) inhibitory effect with an IC50 value of 1.04 ± 0.05 µM. Molecular formula studies revealed that hydrogen bonds formed between hAChE residues Glu202, Ser203, Ala204, Gly121, Gly122, Tyr337, and His447 and (±)-rhodotomentomonomer E played crucial roles in its observed activity. These findings indicated that the leaves of Rhodomyrtus tomentosa can supply a rich source of hAChE inhibitors. These inhibitors might potentially be utilized in the therapeutic strategy for Alzheimer's disease, offering promising candidates for further research and development.

Phytocannabinoid-like meroterpenoids from twigs and leaves of Rhododendron spinuliferum.

Six pairs of previously undescribed enantiomeric phytocannabinoid-like meroterpenoids, (±)-spinulinoids A‒F, and two naturally occurring compounds, (+)-rhododaurichromanic acid A and (E)-4-((3,7-dimethylocta-2,6-dien-1-yl)oxy)benzoic acid, together with one known congener, (-)-rhododaurichromanic acid A, were obtained from the twigs and leaves of Rhododendron spinuliferum. Their structures were established by their extensive spectral data (NMR and HRESIMS), ECD calculations, and single-crystal X-ray diffraction data. Spinulinoids A and B are unprecedented phytocannabinoid-like meroterpenoids constructed by the resorcinol moiety and a ß-bisabolene unit, whereas spinulinoid C represents a rare adduct of quinone and ß-bisabolene with a tricyclic 6/6/6 ring system.

Validation of the IMPEDE VTE score for prediction of venous thromboembolism in Chinese patients with multiple myeloma: A single-center retrospective cohort study.

Multiple myeloma (MM) significantly increases the risk of venous thromboembolism (VTE) within 6 months of treatment initiation. The IMPEDE VTE score is a VTE risk prediction model which is recently incorporated into the National Comprehensive Cancer Network (NCCN) guidelines, but it lacks validation among Asians, including Chinese MM patients. We performed a retrospective chart review of 405 Chinese with newly diagnosed MM who started therapy at Beijing Jishuitan Hospital between April 2013 to October 2022. The 6-month cumulative incidence of VTE was 3.8 % (95 % CI:1.6-7.6), 8.6 % (95 % CI: 5.3-21.9) and 40.5 % (95 % CI: 24.9-55.7) in the low-, intermediate- and high-risk groups (P < 0.001), respectively. The C-statistic of the IMPEDE VTE scores for predicting VTE within 6 months of treatment initiation was 0.74 (95 % CI: 0.65-0.83). Of note, in this single-center cohort study, we propose that the anticoagulant LMWH may be more effective than the antiplatelet aspirin in potentially preventing VTE in newly diagnosed MM patients. Our findings suggest that the IMPEDE VTE score is a valid evidence-based risk stratification tool in Chinese patients with newly diagnosed MM.

Oligomeric phloroglucinols with hAChE inhibitory and antibacterial activities from tropic Rhodomyrtus tomentosa.

Alzheimer's diseases (AD) and other infectious diseases caused by drug-resistance bacteria have posed a serious threat to human lives and global health. With the aim to search for human acetylcholinesterase (hAChE) inhibitors and antibacterial agents from medicinal plants, 16 phloroglucinol oligomers, including two new phloroglucinol monomers (1a and 1b), four new phloroglucinol dimers (3a, 3b, 4b, and 5a), six new phloroglucinol trimers (6a, 6b, 7a, 7b, 8a, and 8b), and two naturally occurring phloroglucinol monomers (2a and 2b), along with two known congeners (4a and 5b), were purified from the leaves of tropic Rhodomyrtus tomentosa. The structures and absolute configurations of these new isolates were unequivocally established by comprehensive analyses of their spectroscopic data (NMR and HRESIMS), ECD calculation, and single crystal X-ray diffraction. Structurally, 3a/3b shared a rare C-5' formyl group, whereas 6a/6b possessed a unique C-7' aromatic ring. In addition, 7a/7b and 8a/8b were rare phloroglucinol trimers with a bis-furan and a C-6' hemiketal group. Pharmacologically, the mixture of 3a and 3b showed the most potent human acetylcholinesterase (hAChE) inhibitory activity with an IC50 value of 1.21 ± 0.16 µM. The molecular docking studies of 3a and 3b in the hAChE binding sites were performed, displaying good agreement with the in vitro inhibitory effects. In addition, the mixture of 3a and 3b displayed the most significant anti-MRSA (methicillin-resistant Staphylococcus aureus) with MIC and MBC values of both 0.50 µg/mL, and scanning electron microscope (SEM) studies revealed that they could destroy the biofilm structures of MRSA. The findings provide potential candidates for the further development of anti-AD and anti-bacterial agents.

[Soil Stoichiometry Characterization in the Oasis-desert Transition Zone of Linze, Zhangye].

To investigate the changes in C, N, P, and K contents and ecological stoichiometry of desert oasis soils and to elucidate their ecological responses to environmental factors, 10 sample plots were selected in the Zhangye Linze desert oasis in the middle part of the Hexi Corridor, and surface soil samples were collected to determine the C, N, P and K contents of soils and to reveal the distribution characteristics of soil nutrient contents and stoichiometric ratios in different habitats and the correlation with other environmental factors. The results showed that:① the distribution of soil carbon was uneven and heterogeneous across sites (R=0.761, P=0.06). The highest mean value was 12.85 g·kg-1 in the oasis, followed by 8.65 g·kg-1 in the transition zone and 4.1 g·kg-1 in the desert. ② The content of total soil potassium did not vary significantly and was high among deserts, transition zones, and oases and low in saline areas. ③ The mean soil C:N value was 12.92, the mean C:P value was 11.69, and the mean N:P value was 0.9, all of which were lower than the global average soil content (13.33, 72.0, and 5.9) and the Chinese soil average (12, 52.7, and 3.9). ④ Soil water content was the most influential factor affecting C, N, P, K, and ecological stoichiometry characteristics of desert oasis soils, with a contribution of 86.9%, followed by soil pH and soil porosity, with contributions of 9.2% and 3.9%, respectively. The results of this study provide basic information for the restoration and conservation of desert and oasis ecosystems and establish a basis for future study of the biodiversity maintenance mechanism in the region and its correlation with the environment.

High cholesterol intake remodels cholesterol turnover and energy homeostasis in Nile tilapia (Oreochromis niloticus).

The roles of dietary cholesterol in fish physiology are currently contradictory. The issue reflects the limited studies on the metabolic consequences of cholesterol intake in fish. The present study investigated the metabolic responses to high cholesterol intake in Nile tilapia (Oreochromis niloticus), which were fed with four cholesterol-contained diets (0.8, 1.6, 2.4 and 3.2%) and a control diet for eight weeks. All fish-fed cholesterol diets showed increased body weight, but accumulated cholesterol (the peak level was in the 1.6% cholesterol group). Then, we selected 1.6% cholesterol and control diets for further analysis. The high cholesterol diet impaired liver function and reduced mitochondria number in fish. Furthermore, high cholesterol intake triggered protective adaptation via (1) inhibiting endogenous cholesterol synthesis, (2) elevating the expression of genes related to cholesterol esterification and efflux, and (3) promoting chenodeoxycholic acid synthesis and efflux. Accordingly, high cholesterol intake reshaped the fish gut microbiome by increasing the abundance of Lactobacillus spp. and Mycobacterium spp., both of which are involved in cholesterol and/or bile acids catabolism. Moreover, high cholesterol intake inhibited lipid catabolic activities through mitochondrial ß-oxidation, and lysosome-mediated lipophagy, and depressed insulin signaling sensitivity. Protein catabolism was elevated as a compulsory response to maintain energy homeostasis. Therefore, although high cholesterol intake promoted growth, it led to metabolic disorders in fish. For the first time, this study provides evidence for the systemic metabolic response to high cholesterol intake in fish. This knowledge contributes to an understanding of the metabolic syndromes caused by high cholesterol intake or deposition in fish. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-022-00158-7.

Atorvastatin remodels lipid distribution between liver and adipose tissues through blocking lipoprotein efflux in fish.

The regulation of cholesterol metabolism in fish is still unclear. Statins play important roles in promoting cholesterol metabolism development in mammals. However, studies on the role of statins in cholesterol metabolism in fish are currently limited. The present study evaluated the effects of statins on cholesterol metabolism in fish. Nile tilapia (Oreochromis niloticus) were fed on control diets supplemented with three atorvastatin levels (0, 12, and 24 mg/kg diet, ATV0, ATV12, and ATV24, respectively) for 4 wk. Intriguingly, the results showed that both atorvastatin treatments increased hepatic cholesterol and triglyceride contents mainly through inhibiting bile acid synthesis and efflux, and compensatorily enhancing cholesterol synthesis in fish liver (P < 0.05). Moreover, atorvastatin treatment significantly inhibited hepatic very-low-density lipoprotein (VLDL) assembly and thus decreased serum VLDL content (P < 0.05). However, fish treated with atorvastatin significantly reduced cholesterol and triglycerides contents in adipose tissue (P < 0.05). Further molecular analysis showed that atorvastatin treatment promoted cholesterol synthesis and lipogenesis pathways, but inhibited lipid catabolism and low-density lipoprotein (LDL) uptake in the adipose tissue of fish (P < 0.05). In general, atorvastatin induced the remodeling of lipid distribution between liver and adipose tissues through blocking VLDL efflux from the liver to adipose tissue of fish. Our results provide a novel regulatory pattern of cholesterol metabolism response caused by atorvastatin in fish, which is distinct from mammals: cholesterol inhibition by atorvastatin activates hepatic cholesterol synthesis and inhibits its efflux to maintain cholesterol homeostasis, consequently reduces cholesterol storage in fish adipose tissue.

Microcella aerolata sp. nov., isolated from electronic waste-associated bioaerosols.

A Gram-positive, non-motile, non-spore-forming and short rod-shaped actinomycete strain, designated GA224T, was isolated from electronic waste-associated bioaerosols. The optimal growth conditions for this isolate, a facultatively anaerobic bacterium, were 37 °C and pH 8.0. The cell-wall peptidoglycan type was B2γ, with 2,4-diaminobutyric acid (DAB) as the diamino acids, while the major menaquinone was MK-12. The polar lipid profile was composed of diphosphatidylglycerol, phosphatidylglycerol, unidentified phospholipids, unidentified glycolipids and an unidentified lipid. The major cellular fatty acids were anteiso-C15:0 and iso-C16:0. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain GA224T fell within the genus Microcella. The draft genome of strain GA224T comprised 2,495,189 bp with a G + C content of 72.2 mol%. The average nucleotide identity and digital DNA-DNA hybridization values between strain GA224T and the type strain of the type species of Microcella species were lower than 95% and 70%, respectively. Based on the phenotypic, chemotaxonomic and genomic data, strain GA224T represents a novel species, for which the name Microcella aerolata sp. nov. is proposed, with GA224T as the type strain (= GDMCC 1.2165 T = JCM 34462 T).

Phylogenomic Analyses of Alismatales Shed Light into Adaptations to Aquatic Environments.

Land plants first evolved from freshwater algae, and flowering plants returned to water as early as the Cretaceous and multiple times subsequently. Alismatales is the largest clade of aquatic angiosperms including all marine angiosperms, as well as terrestrial plants. We used Alismatales to explore plant adaptations to aquatic environments by analyzing a data set that included 95 samples (89 Alismatales species) covering four genomes and 91 transcriptomes (59 generated in this study). To provide a basis for investigating adaptations, we assessed phylogenetic conflict and whole-genome duplication (WGD) events in Alismatales. We recovered a relationship for the three main clades in Alismatales as (Tofieldiaceae, Araceae) + core Alismatids. We also found phylogenetic conflict among the three main clades that was best explained by incomplete lineage sorting and introgression. Overall, we identified 18 putative WGD events across Alismatales. One of them occurred at the most recent common ancestor of core Alismatids, and three occurred at seagrass lineages. We also found that lineage and life-form were both important for different evolutionary patterns for the genes related to freshwater and marine adaptation. For example, several light- or ethylene-related genes were lost in the seagrass Zosteraceae, but are present in other seagrasses and freshwater species. Stomata-related genes were lost in both submersed freshwater species and seagrasses. Nicotianamine synthase genes, which are important in iron intake, expanded in both submersed freshwater species and seagrasses. Our results advance the understanding of the adaptation to aquatic environments and WGDs using phylogenomics.

Roseicella aerolata sp. nov., isolated from bioaerosols of electronic waste.

A novel Gram-stain-negative, non-motile, spherical-shaped and facultatively anaerobic bacterial strain, designated as GB24T was isolated from bioaerosols of an E-waste dismantling site in Guiyu, Guangdong Province, South PR China. Growth occurred at 15-40 °C (optimum 37 °C), pH 5.5-9.5 (optimum 7.0), and up to 0.5 % NaCl (w/v) under aerobic conditions, GB24T was characterized taxonomically and phylogenetically. The sole isoprenoid quinone detected was ubiquinone-10 (Q-10). The polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, three unidentified glycolipids, one unidentified phospholipid, and one unidentified aminolipid. Carotenoid pigments were produced. The major cellular fatty acids (> 10 % of total fatty acids) were C17 : 1ω6c (51.5 %) and summed feature 8 (13.5 %, comprising C18 : 1ω7c and/or C18 : 1ω6c). Phylogenetic analysis based on 16S rRNA gene sequence and draft genome grouped strain GB24T into the genus Roseicella. GB24T was most closely related to Roseicella frigidaeris DB1506T with 97.5 % 16S rRNA gene sequence similarity. The draft genome of GB24T comprised 6 153 170 bp with a DNA G+C content of 71.5 %. The average nucleotide identity (ANI) and in silico DNA-DNA hybridization (isDDH) values between GB24T and DB1506T were 83.2 % (Ortho ANI), 83.3 % [ANI by blast (ANIb)] and 27.0 %, respectively. Further genomic analysis of GB24T revealed the secondary metabolite clusters of terpene and phosphonate, which indicate the capacity for malleobactin (14 %) and phosphinothricin (6 %) tripeptide production. On the basis of the genotypic, chemotaxonomic and phenotypic results, GB24T represents a novel species, for which the name Roseicella aerolata sp. nov. is proposed. The type strain of Roseicella aerolata is GB24T (= GDMCC 1.2169T = JCM 34449T).

circ_0067934 promotes the progression of papillary thyroid carcinoma cells through miR-1301-3p/HMGB1 axis.

Papillary thyroid carcinoma (PTC) is the most prevalent form of thyroid cancer (TC). There is increasing evidence that circular RNAs play a role in the tumorigenesis of PTC. The aim of our study was to evaluate the potential function of circ_0067934 in PTC and the underlying molecular mechanism. In our study, cell viability assay, quantitative real-time PCR (qRT-PCR), colony formation assay, flow cytometry, wound-healing assay, Transwell invasion assay, western blot, soft agar assay, RNA immunoprecipitation (RIP), dual-luciferase reporter assay, immunohistochemical (IHC) staining, and tumor xenograft formation were conducted to evaluate the effects of circ_0067934 in PTC cells. We found that circ_0067934 was upregulated in PTC tissues and cell lines. Knockdown of circ_0067934 inhibited growth, colony formation, migration, invasion, EMT, and tumor xenograft growth, and induced apoptosis of PTC cells. Moreover, circ_0067934 acted as a molecular sponge for miR-1301-3p, and depletion of miR-1301-3p abrogated the effects of circ_0067934 knockdown in PTC cells. In addition, HMGB1 was a target of miR-1301-3p, and miR-1301-3p overexpression inhibited the malignant effects of PTC cells via suppressing HMGB1. Furthermore, knockdown of circ_0067934 suppressed HMGB1 expression, PI3K/Akt, and MAPK activation by sponging miR-1301-3p. In nude mice, circ_0067934 depletion repressed tumor xenograft growth of PTC cells. In conclusion, our results provided a novel insight into circ_0067934 in the tumorigenesis and progression of PTC. circ_0067934 might be a prognostic marker or therapeutic target for PTC treatment.

The Value of Serum Cell-Free DNA Levels in Patients With Schizophrenia.

Background: Schizophrenia is a severe mental disorder, which has a major impact on the quality of life and imposes a huge burden on the family. However, the pathogenesis of schizophrenia remains unclear and there are no specific biomarkers. Therefore, we intend to explore whether cf-DNA levels are related to the occurrence and development of schizophrenia. Methods: We analyzed and compared the concentration of cf-DNA in 174 SZ patients and 100 matched healthy controls by using quantitative real-time PCR by amplifying the Alu repeats. Results: We found that cf-DNA levels in peripheral blood reliably distinguished SZ patients from healthy controls (P < 0.05). The ROC analysis also supports the above conclusion. By tracking the absolute concentration of serum cf-DNA in primary cases, we found a distinct increase before treatment with antipsychotics, which decreased progressively after treatment. Conclusions: The present work indicates that cf-DNA may improve the efficiency of disease diagnosis, and the level of cf-DNA plays a predictive role in the development of schizophrenia. By evaluating the level of cf-DNA, we might play a certain role in a more reasonable and standardized clinical treatment of schizophrenia.

Systematics of Lobelioideae (Campanulaceae): review, phylogenetic and biogeographic analyses.

Lobelioideae, the largest subfamily within Campanulaceae, includes 33 genera and approximately1200 species. It is characterized by resupinate flowers with zygomorphic corollas and connate anthers and is widely distributed across the world. The systematics of Lobelioideae has been quite challenging over the years, with different scholars postulating varying theories. To outline major progress and highlight the existing systematic problems in Lobelioideae, we conducted a literature review on this subfamily. Additionally, we conducted phylogenetic and biogeographic analyses for Lobelioideae using plastids and internal transcribed spacer regions. We found that former studies have reached agreement on the southern African origin of Lobelioideae, herbaceous habit and Asian origin of giant lobelioids, the convergent evolution of giant rosette lobelioids, and lastly, the multiple cosmopolitan and independent radiation of lobelioids in Africa, Pacific Basin, and the Hawaiian Islands. Also, Apetahia Baill., Sclerotheca A.DC., and Cyanea Gaudich. are paraphyletic, while Lobelia L., Pratia Gaudich., Centropogon C.Presl, Siphocampylus Pohl, and Isotoma Lindl. are polyphyletic. The taxonomy of these genera, especially Lobelia, is particularly quite frustrating. This calls for further reappraisals using both morphological and molecular data.

Establishment of a Tear Ferning Test Protocol in the Mouse Model.

Purpose: Analysis of ferning formation after tear drop desiccation on a glass slide has been applied as a simple method to examine tear normality and is referred to as the tear ferning (TF) test. Despite use of the TF test in clinical settings and in some animals, thus far no TF test protocol has been developed for the mouse model. This study aimed to establish a mouse TF test protocol that can be used for dry eye research using the mouse as the study model. Methods: Tear samples were collected from 24 healthy mice after repeated flushes with 2, 5, 10, or 20 µL wash solutions, either 0.9% NaCl saline or sterile water, on the ocular surface. After sample collection, TF tests were performed at variable drop volumes (2-20 µL), at a relative humidity of either 46% ± 2% or 53% ± 2%, and with temperature fixed at 24°C ± 2°C for comparison. Moreover, the influence of osmolarity (between 280 and 360 mOsm/L) and pH values (6.5-8.0) and the effect of centrifugation (4000 rpm, 10 minutes) on ferning formation were examined. Reproducibility and ferning storage stability were also determined. Results: An optimized protocol was established with relative humidity at 46% ± 2% and drop aliquot at 2 µL, using 0.9% NaCl saline as the wash solution. Using sterilized water as the wash solution did not result in any crystalloid formation. Centrifugation did not aid ferning formation in any of the samples. Higher osmolarity increased ferning formation from grades between 0 to 1 to grades between 2 to 3, but pH values that varied between 6.5 and 8.0 did not affect ferning formation. The established mouse TF test protocol also displayed reproducibility and storage stability. Conclusions: A TF test protocol for the mouse model was established that could be used for comparative analyses under various ocular surface disease conditions. Translational Relevance: This mouse TF test protocol will facilitate the application of basic research into the mouse model to clinical care.

Simultaneous Determination of Five Components of Chaihu-Shugan-San in Beagle Plasma by HPLC-MS/MS and Its Application to a Pharmacokinetic Study after a Single Dose of Chaihu-Shugan-San.

Chaihu-shugan-san (CHSGS) has been widely used in China to treat depression and gastrointestinal diseases for thousands of years, but little is known about its pharmacokinetic properties. The purpose of our study is to develop a reliable and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method to detect five components in beagle plasma and study their pharmacokinetic after oral administration of CHSGS in beagles. An Agilent C18 column (2.1 × 150 mm, 3.5 µm) was used to separate the analytes, and the column temperature was maintained at 40°C. A gradient elution procedure was used with solvent A (acetonitrile) and solvent B (0.1% formic acid, aqueous) as mobile phases. The elution procedure was 60% B-10% B (0-3 min) and 10% B-60% B (3.1-4 min). The flow rate was 0.3 mL/min, and the total measurement time was 4 min. Within the determined range, the standard calibration curves of the five analytes had a satisfactory linear relationship (r 2 ≥ 0.9923). The recovery rate (n = 6) of the five analytes was between 85.42% and 90.85%, and the matrix effects (n = 6) were between 94.52% and 103.91%. These results show that the validated method could be successfully applied to study the pharmacokinetic in beagles after a single dose of CHSGS.

Distribution pattern and habitat preference for Lobelia species (Campanulaceae) in five countries of East Africa.

East Africa is one of the centres of distribution and diversity for Lobelia L. (Campanulaceae, sub-family Lobelioideae). Lobelia habitats in East Africa have been facing habitat fragmentation and loss, which are recognised as a major threat to biodiversity. However, previous plant conservation studies in East Africa only focused on protected areas and ignored unprotected areas. Future conservation strategies of plants, such as Lobelia, will depend on knowledge of their distribution patterns and habitat preference in East Africa. To understand the distribution pattern and the habitat preference of Lobelia in five countries (Kenya, Uganda, Tanzania, Rwanda and Burundi) of East Africa, we conducted a literature review in the seven major vegetation regions (afro-alpine, afro-montane forest, drier savannah, grasslands, wetter savannah, Zambezian woodland and semi-desert and desert). We also employed meander and patterned searches, which allowed greater opportunities for recording Lobelia species. Our results showed that the genus is distributed in all of the seven regions of the five countries with 54 taxa. The afro-montane forest region, with 41 taxa, is the richest in species diversity, followed by the Zambezian woodland region with 18 taxa. The semi-desert and desert region has the lowest number with only four taxa. The afro-alpine region has 15 taxa, although the region is the smallest by area. The herbaceous type was found in all regions, while the giant type has a clear preference for the afro-alpine and afro-montane forest regions. Future conservation for Lobelia should consider its habitat preference by, for example, focusing on the afro-alpine and afro-montane forest regions. This study will facilitate the setting of future conservation strategies for Lobelia.

[Research Advance of Venetoclax in Hematological Tumors--Review].

Venetoclax is a selective inhibitor of the anti-apoptotic protein B-cell lymphoma 2（BCL-2）and has great potential in treating a variety of hematological tumors. In recent years, domestic and foreign scholars have tried to use venetoclax singal or in combination with some drugs to treat the patients with hematological tumors, including elderly acute myeloid leukemia（AML）patients un suitable for intensive chemotherapy, relapsed or refractory chronic lymphocytic leukemia（CLL）, Non-Hodgkin's lymphoma（NHL）and multiple myeloma（MM）patients, these studies have achieved good results．At the same time，some scholars found that the secondary drug-resistance occurred in some patients who continuous treated with Venetoclax, and explored the Venetoclax-resistant mechanism. In this review, the research advance of Venetoclax in hematological tumors and the mechanisms of drug resistance are summarized and discussed briefly.

Simultaneous determination of six components of Danzhi Xiaoyao Pill in beagle plasma by HPLC-MS/MS and a study of pharmacokinetic of paeoniflorin and geniposide after single-dose administration.

This study was to develop a reliable and simple high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) to detect paeoniflorin, geniposide, saikosaponin b2, liquiritin, paeonol and atractylenolide Ⅲ in beagle plasma and to study pharmacokinetic of paeoniflorin and geniposide after single-dose administration of Danzhi Xiaoyao Pill (DZXY). Chromatographic separation was performed using an Agilent C18 column, and multiple reaction monitoring (MRM) mode was used. A gradient elution procedure was used with solvent A (acetonitrile) and solvent B (0.1 % formic acid-water) as mobile phases. The elution procedure was as follows: 85 % B-30 % B (0-7 min) and 30 % B-30 % B (7.1-8 min). The flow rate was 0.3 mL/min. The column temperature was 40 ℃, and the injection volume was 10 µL. The main analytical parameters of paeoniflorin, geniposide, saikosaponin b2, liquiritin, paeonol and atractylenolide Ⅲ were m/z 525→449, m/z 433→224, m/z 780→617, m/z 417→254, m/z 167→43 and m/z 249→231, respectively. Ethyl acetate was used to extract the analytes in the plasma. Standard calibration curves of six analytes showed satisfactory linearity (r2≥0.99 2) within the determined ranges. The lower limits of quantification were 0.5 ng/mL for paeoniflorin and liquiritin, 2.5 ng/mL for geniposide and saikosaponin b2 and 1.0 ng/mL for atractylenolide Ⅲ and paeonol, respectively. The intra-day and inter-day precision (RSD %) were all below 6.94 %, and the intra-day and inter-day accuracy (RE %) were within ± 6.10 %. The recovery and ME of six analytes were 85.99 %-98.10 % and 95.78%-108.06%, respectively. Additionally, the method we established in this experiment can be successfully used to study the pharmacokinetics of paeoniflorin and geniposide in beagle plasma.

The Occurrence and Longitudinal Changes of Cognitive Impairment After Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: More and more evidence suggests that cognitive impairment (CI) after stroke is closely related to the quality of life of stroke patients. The primary aim of this study is to investigate the occurrence and longitudinal changes of CI at different stages after acute ischemic stroke (AIS) in Chinese patients. METHODS: The data of this study come from the impairment of cognition and Sleep after acute ischemic stroke or transient ischemic attack in Chinese patients study (ICONS), a nationwide multicenter prospective registry that recruited consecutive AIS or transient ischemic attack in-hospital patients within 7 days after onset. Patients were followed for Montreal Cognitive Assessment (MoCA) scale at 2-week (2w), 3 months (3m) and 12 months (12m). CI was defined as MoCA score≦22. No cognitive impairment (NCI) was defined as MoCA score>22. RESULTS: A total of 2432 AIS patients were enrolled in this study. Overall, 72.94% of patients were male and the average age was 60.95 years. Median National Institutes of Health Stroke Scale score was 3. The occurrence rate of CI was 52.38%, 35.55% and 34.16% at 2w, 3m and 12m. Among patients with CI at 2w and 3m, 39.9% and 27.9% of patients returned to NCI at next follow-up point. At 3m and 12m follow-up, there were also 9.6% and 12.7% new CI patients. The two cognitive items with the highest abnormal rate were "Delayed recall" (89.35%, 83.33% and 82.80%) and "Visuospatial/executive" (78.91%, 73.42% and 70.08%). The cognitive item with the highest percentage of improved patients was "Orientation" (60.91-76.68%), and the cognitive item with the lowest percentage of improved patients was "Language" (35.85-44.50%). CONCLUSION: CI had a relatively high occurrence at 2w to 12m after AIS. CI at 3m and 12m was significantly lower than that at 2w after stroke. The occurrence of abnormalities and recovery probability for different cognitive items also differed greatly.