A matching-adjusted indirect comparison of the efficacy of elranatamab versus teclistamab in patients with triple-class exposed/refractory multiple myeloma.

For patients with triple-class exposed/refractory multiple myeloma (TCE/RMM), where effective treatments options are limited, B-cell maturation antigen and CD3-directed bispecific antibodies offer a promising new approach. Teclistamab gained conditional approval in Europe and accelerated Food and Drug Administration (FDA) approval based on the MajesTEC-1 trial (NCT03145181). Elranatamab, approved by the FDA demonstrated its safety and efficacy in the MagnetisMM-3 trial (NCT04649359). Given the absence of head-to-head trials, an unanchored matching-adjusted indirect comparison (MAIC) was conducted to assess their relative efficacy. Key baseline characteristics were adjusted to be comparable between the two trials. In the MAIC, elranatamab demonstrated significantly better objective response rate and progression-free survival (PFS) than teclistamab, and numerically better complete response, duration of response, and overall survival (OS). These results suggest that elranatamab is an efficacious option for treating patients with TCE/R MM.

Preliminary Technical Validation of LittleBeats™: A Multimodal Sensing Platform to Capture Cardiac Physiology, Motion, and Vocalizations.

Across five studies, we present the preliminary technical validation of an infant-wearable platform, LittleBeats™, that integrates electrocardiogram (ECG), inertial measurement unit (IMU), and audio sensors. Each sensor modality is validated against data from gold-standard equipment using established algorithms and laboratory tasks. Interbeat interval (IBI) data obtained from the LittleBeats™ ECG sensor indicate acceptable mean absolute percent error rates for both adults (Study 1, N = 16) and infants (Study 2, N = 5) across low- and high-challenge sessions and expected patterns of change in respiratory sinus arrythmia (RSA). For automated activity recognition (upright vs. walk vs. glide vs. squat) using accelerometer data from the LittleBeats™ IMU (Study 3, N = 12 adults), performance was good to excellent, with smartphone (industry standard) data outperforming LittleBeats™ by less than 4 percentage points. Speech emotion recognition (Study 4, N = 8 adults) applied to LittleBeats™ versus smartphone audio data indicated a comparable performance, with no significant difference in error rates. On an automatic speech recognition task (Study 5, N = 12 adults), the best performing algorithm yielded relatively low word error rates, although LittleBeats™ (4.16%) versus smartphone (2.73%) error rates were somewhat higher. Together, these validation studies indicate that LittleBeats™ sensors yield a data quality that is largely comparable to those obtained from gold-standard devices and established protocols used in prior research.

A matching-adjusted indirect comparison of the efficacy of elranatamab versus physician's choice of treatment in patients with triple-class exposed/refractory multiple myeloma.

INTRODUCTION: For patients with triple-class exposed/refractory multiple myeloma (TCE/R MM), prognosis is poor and effective treatment options are limited. Elranatamab is a novel B-cell maturation antigen (BCMA)- and CD3-directed bispecific antibody which was approved by the US Food and Drug Administration in August 2023 and demonstrated safety and efficacy in patients with TCE/R MM in the phase 2, single-arm MagnetisMM-3 trial (NCT04649359). To compare the effectiveness of elranatamab vs physician's choice of treatment (PCT) in the absence of head-to-head comparative data, a matching-adjusted indirect comparison (MAIC) was conducted. METHODS: Individual patient data from MagnetisMM-3 (Cohort A [BCMA-naïve] N = 123, 14.7 months of follow-up) were reweighted to match published summary data from two real-world studies of PCT in patients with TCE/R MM (LocoMMotion and MAMMOTH) using a propensity score-type logistic regression. Unanchored MAIC analyses were conducted according to National Institute for Health and Care Excellence (NICE) Decision Support Unit (DSU) 18 guidance. RESULTS: Compared with PCT in LocoMMotion, elranatamab was associated with a significantly higher objective response rate (ORR rate difference: 37.52; 95% CI 26.20-48.83; odds ratio: 4.85; 95% CI 2.85-8.23) and complete or stringent complete response rate (≥CR rate difference: 42.29; 95% CI 31.84-52.74; odds ratio: 184.01; 95% CI 24.66-1372.86), longer progression-free survival (PFS HR 0.32; 95% CI 0.20-0.49), and overall survival (OS HR 0.62; 95% CI 0.40-0.94). Compared with PCT in MAMMOTH, elranatamab was associated with significantly higher ORR (rate difference: 28.14; 95% CI 16.77-39.52; odds ratio: 3.24; 95% CI 1.98-5.32) and ≥ CR (rate difference: 26.22; 95% CI 16.40-36.05; odds ratio: 5.48; 95% CI 2.88-10.44), as well as longer PFS (HR 0.25; 95% CI 0.17-0.37) and OS (HR 0.49; 95% CI 0.33-0.71). Sensitivity analysis results were consistent with the base case. CONCLUSION: In the MAIC, elranatamab was consistently associated with improved rates and depth of response and significantly longer PFS and OS versus PCT in LocoMMotion and MAMMOTH.

Associations between infant amygdala functional connectivity and social engagement following a stressor: A preliminary investigation.

Functional architecture of the infant brain, especially functional connectivity (FC) within the amygdala network and between the amygdala and other networks (i.e., default-mode [DMN] and salience [SAL] networks), provides a neural basis for infant socioemotional functioning. Yet, little is known about the extent to which early within- and between-network amygdala FC are related to infant stress recovery across the first year of life. In this study, we examined associations between amygdala FC (i.e., within-network amygdala connectivity, and between-network amygdala connectivity with the DMN and SAL) at 3 months and infant recovery from a mild social stressor at 3, 6 and 9 months. At 3 months, thirty-five infants (13 girls) underwent resting-state functional magnetic resonance imaging during natural sleep. Infants and their mothers completed the still-face paradigm at 3, 6, and 9 months, and infant stress recovery was assessed at each time point as the proportion of infant social engagement during the reunion episode. Bivariate correlations indicated that greater positive within-network amygdala FC and greater positive amygdala-SAL FC, but not amygdala-DMN FC, at 3 months predicted lower levels of stress recovery at 3 and 6 months, but were nonsignificant at 9 months. These findings provide preliminary evidence that early functional synchronization within the amygdala network, as well as segregation between the amygdala and the SAL, may contribute to infant stress recovery in the context of infant-mother interaction.

Recognition new energy vehicles based on improved YOLOv5.

In the field of Intelligent Traffic Systems (ITS), vehicle recognition is a hot research topic. Although different types of vehicles can already be recognized, further identification and statistics of new energy and fuel vehicles in unknown and complex environments remain a challenging task. In this paper, we propose a New Energy Vehicle Recognition and Traffic Flow Statistics (NEVTS) approach. Specifically, we first utilized the You Only Look Once v5 (YOLOv5) algorithm to detect vehicles in the target area, in which we applied Task-Specific Context Decoupling (TSCODE) to decouple the prediction and classification tasks of YOLOv5. This approach significantly enhanced the performance of vehicle detection. Then, track them upon detection. Finally, we use the YOLOv5 algorithm to locate and classify the color of license plates. Green license plates indicate new energy vehicles, while non-green license plates indicate fuel vehicles, which can accurately and efficiently calculate the number of new energy vehicles. The effectiveness of the proposed NEVTS in recognizing new energy vehicles and traffic flow statistics is demonstrated by experimental results. Not only can NEVTS be applied to the recognition of new energy vehicles and traffic flow statistics, but it can also be further employed for traffic timing pattern extraction and traffic situation monitoring and management.

Genome-wide analysis of the SMXL gene family in common bean and identification of karrikin-responsive PvSMXL2 as a negative regulator of PEG-induced drought stress.

Common bean (Phaseolus vulgaris L.) is a major legume crop worldwide, but its growth and development frequently face challenges due to abiotic stresses, particularly drought. Proper supplement of copper could mitigate the adverse effects of drought, but excessive accumulation of this metal in plants can be harmful. The suppressor of MAX2 1-like (SMXL) gene family, which plays important roles in various plant processes, including stress responses, remains poorly understood in common bean. In this study, we identified nine orthologues of SMXL genes in common bean, which are located on six chromosomes and classified into four subgroups. Basic molecular properties, including theoretical isoelectric point (PI), molecular weight (MW), grand average of hydropathicity (GVIO), gene structure, and conserved motifs were characterized, and numerous cis-elements in promoters were predicted. The expression patterns of PvSMXL genes were found to be distinct under 10% polyethylene glycol (PEG)-induced drought stress and 200 µM Cu treatments. Most PvSMXLs showed reduced expression in response to Cu treatment, whereas nearly half PvSMXLs exhibited inducible expression under drought stress. PvSMXL2, which exhibited a rapid response to karrikin 1 (KAR1), an active form of the plant growth regulators newly found in the smoke of burning plant material, was down-regulated by both PEG-induced drought and Cu stresses. Transient silencing of PvSMXL2 resulted in enhanced drought stress tolerance without conferring Cu tolerance. These findings provide valuable insights into the functions of SMXL genes in common bean under abiotic stress conditions.

Upregulation of LPGAT1 Enhances Lung Adenocarcinoma Proliferation.

BACKGROUND: Lung adenocarcinoma (LUAD) is one of the leading causes of cancer-related mortality. Lysophosphatidylglycerol acyltransferase (LPGAT1) regulates the biosynthesis of triacylglycerol, which is essential for maintaining phospholipid homeostasis and modulating the structural integrity of mitochondrial membranes. LPGAT1 has been demonstrated to be differentially expressed in normal lung tissue and LUAD tissues, and can serve as a metabolically relevant gene with potential prognostic value. However, the potential role of LPGAT1 in LUAD is still unknown. This study sought to determine the role of LPGAT1 in LUAD progression. METHODS: LPGAT1 expression was examined in LUAD cells and tumor tissues from LUAD patients. The effect of LPGAT1 was then assessed in both cell and animal models after LPGAT1 was knocked down by RNA interference. RESULTS: LPGAT1 was upregulated in LUAD tissues. Overexpression of LPGAT1 was associated with an unfavorable prognosis in LUAD patients, as revealed by univariate and multivariate Cox analyses. Knockdown of LPGAT1 abrogated tumor growth and proliferation in both cell and animal models. CONCLUSIONS: This study demonstrates that LPGAT1 promotes proliferation and inhibits apoptosis in LUAD. Hence, LPGAT1 may provide new treatment strategies for LUAD.

Functional neural network connectivity at 3 months predicts infant-mother dyadic flexibility during play at 6 months.

Early functioning of neural networks likely underlies the flexible switching between internal and external orientation and may be key to the infant's ability to effectively engage in social interactions. To test this hypothesis, we examined the association between infants' neural networks at 3 months and infant-mother dyadic flexibility (denoting the structural variability of their interaction dynamics) at 3, 6, and 9 months. Participants included thirty-five infants (37% girls) and their mothers (87% White). At 3 months, infants participated in a resting-state functional magnetic resonance imaging session, and functional connectivity (FC) within the default mode (DMN) and salience (SN) networks, as well as DMN-SN internetwork FC, were derived using a seed-based approach. When infants were 3, 6, and 9 months, infant-mother dyads completed the Still-Face Paradigm where their individual engagement behaviors were observed and used to quantify dyadic flexibility using state space analysis. Results revealed that greater within-DMN FC, within-SN FC, and DMN-SN anticorrelation at 3 months predicted greater dyadic flexibility at 6 months, but not at 3 and 9 months. Findings suggest that early synchronization and interaction between neural networks underlying introspection and salience detection may support infants' flexible social interactions as they become increasingly active and engaged social partners.

Understanding water conservation vs. profligation traits in vegetable legumes through a physio-transcriptomic-functional approach.

Vegetable soybean and cowpea are related warm-season legumes showing contrasting leaf water use behaviors under similar root drought stresses, whose mechanisms are not well understood. Here we conducted an integrative phenomic-transcriptomic study on the two crops grown in a feedback irrigation system that enabled precise control of soil water contents. Continuous transpiration rate monitoring demonstrated that cowpea used water more conservatively under earlier soil drought stages, but tended to maintain higher transpiration under prolonged drought. Interestingly, we observed a soybean-specific transpiration rate increase accompanied by phase shift under moderate soil drought. Time-series transcriptomic analysis suggested a dehydration avoidance mechanism of cowpea at early soil drought stage, in which the VuHAI3 and VuTIP2;3 genes were suggested to be involved. Multifactorial gene clustering analysis revealed different responsiveness of genes to drought, time of day and their interactions between the two crops, which involved species-dependent regulation of the circadian clock genes. Gene network analysis identified two co-expression modules each associated with transpiration rate in cowpea and soybean, including a pair of negatively correlated modules between species. Module hub genes, including the ABA-degrading gene GmCYP707A4 and the trehalose-phosphatase/synthase gene VuTPS9 were identified. Inter-modular network analysis revealed putative co-players of the hub genes. Transgenic analyses verified the role of VuTPS9 in regulating transpiration rate under osmotic stresses. These findings propose that species-specific transcriptomic reprograming in leaves of the two crops suffering similar soil drought was not only a result of the different drought resistance level, but a cause of it.

Transcriptome Dynamics of Common Bean Roots Exposed to Various Heavy Metals Reveal Valuable Target Genes and Promoters for Genetic Engineering.

Understanding the gene regulatory basis of plant response to heavy metals (HMs) is fundamental for the management of food safety and security. However, a comprehensive and comparative view of the plant responses to different HMs is still lacking. Here, we compared root transcriptomes in common bean under 9 HM treatments at 50 µM for three time points each. Cd, Cr, Co, Ni, and Pb caused most severe morphological and/or biochemical retardations. A total of 448 genes were found to be responsive to all nine HMs, which were mostly involved in photosynthesis, oxidization-reduction, and ion binding. Cd and Cu triggered the greatest number of unique differentially expressed genes (DEG)s, which were predominantly related to cellular transport/localization in the former and RNA binding in the latter. Short-term and prolonged HM treatments shaped very different DEG patterns. Weighted gene co-expression network analysis identified six co-expression modules showing exceptionally high transcripts abundance in specific HM × time scenarios. We experimentally verified the promoter activity of the gene GIP1 and the novel function of XTH23 under Cu/Cd stress. Collectively, the transcriptomic atlas provides valuable resources for better understanding the common and unique mechanisms of plant response to different HMs and offers a mass of candidate target genes/promoters for genetic engineering.

[Excretion of three alkaloids from Simiao Pills in urine, feces, and bile between normal and type 2 diabetic rats].

This study investigated the differences in excretion kinetics of three alkaloids and their four metabolites from Simiao Pills in normal and type 2 diabetic rats. The diabetes model was established in rats by injection of streptozotocin, and the alkaloids in urine, feces, and bile of normal and diabetic rats were detected by LC-MS/MS to explore the effect of diabetes on alkaloid excretion of Simiao Pills. The results showed that 72 h after intragastric administration of the extract of Simiao Pills, feces were the main excretion route of alkaloids from Simiao Pills. The total excretion rates of magnoflorine and berberine in normal rats were 4.87% and 56.54%, which decreased to 2.35% and 35.53% in diabetic rats, which had statistical significance(P<0.05). The total excretion rates of phellodendrine, magnoflorine, and berberine in the urine of diabetic rats decreased significantly, which were 53.57%, 60.84%, and 52.78% of those in normal rats, respectively. After 12 h of intragastric administration, the excretion rate of berberine in the bile of diabetic rats increased significantly, which was 253.33% of that of normal rats. In the condition of diabetes, the excretion rate of berberine metabolite, thalifendine significantly decreased in urine and feces, but significantly increased in bile. The total excretion rates of jateorrhizine and palmatine in the urine increased significantly, and t_(1/2) and K_e changed significantly. The results showed that diabetes affected the in vivo process of alkaloids from Simiao Pills, reducing their excretion in the form of prototype drug, affecting the biotransformation of berberine, and ultimately increasing the exposure of alkaloids in vivo, which would be conducive to the hypoglycemic effect of alkaloids. This study provides references for the clinical application and drug development of Simiao Pills in diabetes.

Network Pharmacology Integrated with Transcriptomics Analysis Reveals Ermiao Wan Alleviates Atopic Dermatitis via Suppressing MAPK and Activating the EGFR/AKT Signaling.

Background: Ermiao Wan (EMW) is commonly used to treat atopic dermatitis (AD) in China. However, the pharmacological mechanisms underlying the action of EMW against AD remain unclear. Purpose: We aimed to determine the mechanisms underlying the effectiveness of EMW in the treatment of AD. Methods: We evaluated the effect of EMW on AD induced by dinitrochlorobenzene (DNCB) in BALB/C mice. To clarify the key components of EMW in AD treatment, the main components of EMW were identified using HPLC. Serum pharmacochemistry was used to analyze the absorbed ingredients from blood. Based on the phytochemical results, network pharmacology and molecular docking were used to predict the action of EMW. Skin transcriptomic analysis was used to validate the network pharmacology results. RT-qPCR,ELISA, and immunohistochemical were performed to validate the results of skin transcriptomics. Results: EMW improved the symptoms of AD, with less rashes, less spontaneous scratching, less inflammatory cell infiltration, and fewer allergic reactions. The established HPLC method is simple and reliable. Chlorogenic acid, phellodendrine, magnoflorine, jatrorrhizine, palmatine, berberine, and atractylodin were the key effective ingredients with a high blood concentration. Fifty-seven primary causal targets of EMW against AD were identified. These targets are mainly involved in ErbB signaling pathways including EGFR, AKT1, MAPK8, JUN, MAPK1. Molecular docking showed that EGFR, AKT1, MAPK8, JUN, MAPK1 had good binding force with EMW. In AD mice, EMW regulated the EGFR/AKT signaling through upregulation of Grb2, GAB1, Raf-1, EGFR, and AKT, and downregulation of MAPK1 and JUN, compared to that in the MD group. Conclusion: EMW could alleviate AD through activating EGFR/AKT signaling and suppressing MAPK. This study provides a theoretical basis for the clinical use of EMW.

Gegen Qinlian decoction restores the intestinal barrier in bacterial diarrhea piglets by promoting Lactobacillus growth and inhibiting the TLR2/MyD88/NF-κB pathway.

Acute bacterial diarrhea is a severe global problem with a particularly high incidence rate in children. The microecology inhabiting the intestinal mucosa is the key factor leading to diarrhea. Gegen Qinlian decoction (GQD) is used to treat bacterial diarrhea, however, its underlying mechanism remains unclear. Thus, this study aimed to clarify the restorative effect of GQD on the intestinal barrier from the perspective of gut microbiota. A Tibetan piglet model with bacterial diarrhea was established through orally administered Escherichia coli, and diarrheal piglets were treated with GQD for three days. After treatment, GQD significantly ameliorated the diarrheal symptoms. GQD decreased the levels of IL-6, LPS, and DAO, and increased SIgA, ZO-1, and occludin levels in intestinal mucosa, indicating the restoration of intestinal barrier. GQD modulated the microbial compositions inhabited on the intestinal mucosa, especially an increase of the Lactobacillus. Spearman analysis showed that Lactobacillus was the key genus of intestinal barrier-related bacteria. Bacterial culture in vitro validated that GQD directly promoted Lactobacillus growth and inhibited E. coli proliferation. Moreover, the expressions of TLR2, MyD88, and NF-κB in the colon decreased after GQD treatment. In conclusion, GQD may treat diarrhea and restore the intestinal mucosal barrier by facilitating Lactobacillus growth and inhibiting the TLR2/MyD88/NF-κB signaling pathway.

Anomalous surface O3 changes in North China Plain during the northwestward movement of a landing typhoon.

As high impact weather in a large scale, typhoon movement from the northwest Pacific into inland regions influencing ambient O3 changes is unclear, especially in North China Plain (NCP). A landing Typhoon Ampil during July 17-24, 2018 was studied herein to characterize the surface O3 anomalies during its movement over NCP. Landing typhoons present large negative O3 anomalies at the center of the typhoon and positive O3 anomalies 600-1700 km away from the center. During the northwest movement of Typhoon Ampil to the NCP, the area and magnitude of both positive and negative O3 anomalies shrank, particularly in the western and northern periphery, where the typical diurnal change of O3 dissipated with nocturnal O3 enhancement in the NCP. The spatiotemporal patterns of surface O3 anomalies in the NCP were induced significantly during various stages of typhoon movement with a stable structure in the atmospheric boundary layer, strong solar radiation on sunny days, and stratosphere-to-troposphere transport (STT) in the typhoon periphery, depending on the changing intensity, distance, and orientation of the typhoon center. Among them, the STT played a considerable role and contributed 32% to the positive anomalies of surface O3 in the NCP. Under the influence of westerly jets and high pressure at mid-latitudes on the typhoon movement, strong wind convergences in the upper troposphere were formed intensifying the downdraft of O3-rich stratospheric air to the boundary layer in the NCP with an asymmetrical distribution of surface positive O3 anomalies over the periphery of typhoon. This study could improve our understanding of regional ozone changes with meteorological influences.

Stem-cell therapy via gastroscopy improves the outcome of esophageal anastomotic leakage.

Background: Esophageal anastomotic leakage (EAL) is a severe complication usually occurring after esophagectomy. Although there are various therapeutic methods for EAL treatment, they have not achieved satisfactory results. A previous study showed that the combination of mesenchymal stem cells (MSCs) and fibrin scaffold (FS) can treat EAL. This study aimed to evaluate the efficacy of the injection of MSCs and FS through a new engraftment gastroscope for EAL treatment. Methods: Twelve adult pigs were randomly divided into the MSCs group (n = 6) and control group (n = 6). A stomach tube was then inserted through the leakage to construct the EAL model, which was removed after one week. The combination of MSCs and FS was autografted at the EAL site for pigs in the MSCs group using the tailor-made gastroscope while only FS was autografted for the pigs in the control group. Local status of EAL was evaluated using gastroscopy. Histological analyses and western blot (WB) were used to assess the gross specimens of esophagi around EALs. Results: Gastroscopy showed a higher closure rate and a lower infection rate in the MSCs group than in the control group. However, the mortality was not significantly different between the two groups. HE staining showed a severe inflammatory response with dispersive infiltration of inflammatory cells and unhealed leakage in the control group. However, the infiltration of inflammatory cells was not altered in the MSCs group, and the leakage was completely healed. WB analyses showed that Myogenin and α-SMA expressions were significantly higher in the MSCs group than in the control group. Conclusion: A porcine model of EAL was successfully developed by accessing the transplantation site through the esophagus. Further data revealed that the implantation of MSCs in FS via the novel engraftment gastroscope can promote the repair and occlusion of EAL. Therefore, the proposed method is a promising strategy for EAL treatment.

Comparative pharmacokinetics, intestinal absorption and urinary excretion of six alkaloids from herb pair Phellodendri Chinensis cortex-Atractylodis Rhizoma.

Phellodendri Chinensis Cortex (PCC) and Atractylodis Rhizoma (AR) are frequently used as herb pair to treat eczema and gout owing to their synergistic effects. Alkaloids are the major ingredients from PCC and the effect of their combination on the in vivo processing of alkaloids remains unclear. In this study, a simple and reliable UPLC-MS/MS method for simultaneous determination of six alkaloids in rat plasma was developed. This method was applied to a comparative pharmacokinetic study between PCC and PCC-AR in rats. Effect of AR on absorption of alkaloids was investigated by a single-pass intestinal perfusion study. The effect of AR on urinary excretion of alkaloids was studied. Pharmacokinetic studies showed that the values of rea under the concentration-time curve of phellodendrine, magnoflorine and palmatine were greater in the PCC-AR group than in the PCC group. The intestinal absorptive parameters absorption rate constant and effective permeability of phellodendrine and jatrorrhizine in PCC-AR groups were higher than those in the PCC group. Urinary excretion studies revealed that the excreted amount of alkaloids in the PCC-AR group was lower than that in the PCC group. The results revealed that the combination of PCC and AR improves intestinal absorption of alkaloids and reduces their urinary excretion, which enhances their systemic exposure. This study may explain the synergetic effects of PCC and AR in clinical applications.

A tissue atlas of cadmium accumulation and the correlation with thiol-containing chelates in zucchini provide insights into cadmium partitioning and food safety.

Widespread heavy metal pollution in soils has posed serious threat to vegetable production and food security, yet little is still known about heavy metal accumulation and distribution in the majority of vegetable crops. Here, we report the generation of a tissue atlas of cadmium accumulation in zucchini (Cucurbita pepo var. Giromontial), a globally important cucurbit crop, based on two-season experiment with six genotypes grown under cadmium contaminated soils. Plant growth and development as manifested by biomass, flowering time and plant architecture were unaffected by 10 mg/kg cadmium treatment, but high level of cadmium enrichment was detected in all genotypes. Roots accumulated the largest amount of cadmium, whereas the cadmium concentrations in fruits was also considerable. The exocarps of fruits possessed nearly half of the total cadmium in fruits, rendering it a "hotspot" of safety risk. Measurement of the thiol-containing chelates revealed that concentration of GSH but not PCs was correlated with the cadmium concentration in subdivided fruit tissues, suggesting a mechanism of phloem-specific transportation of cadmium in the form of Cd-GSH. Based on the collective data, a tentative model describing the relationship between long-distance phloem transport and cadmium distribution in sink organs is proposed. The implications for food safety are discussed.

Simiao Wan and its ingredients alleviate type 2 diabetes mellitus via IRS1/AKT2/FOXO1/GLUT2 signaling.

Background: Type 2 diabetes mellitus (T2DM) is a metabolic disease. Simiao Wan (SMW) is a commonly used clinical drug for hyperuricemia treatment. SMW has been confirmed to improve insulin resistance and is expected to be a novel hypoglycemic agent. However, the hypoglycemic bioactive ingredients and mechanisms of action of SMW are unclear. Objective: To explore the hypoglycemic effects and reveal the mechanisms of SMW and bioactive ingredients (SMW-BI). Study design and methods: The hypoglycemic effects of SMW and SMW-BI were verified in a mouse model of T2DM induced by streptozotocin (STZ) and a high-fat and high-sugar diet (HFSD). Network pharmacology was used to predict the mechanisms of SMW and SMW-BI. Histological analysis and real-time quantitative polymerase chain reaction (RT-qPCR) verified network pharmacology results. RT-qPCR results were further verified by immunofluorescence (IFC) and molecular docking. The correlation between proteins and biochemical indicators was analyzed by Spearman's correlation. Results: Chlorogenic acid, phellodendrine, magnoflorine, jateorhizine, palmatine, berberine, and atractydin were identified as SMW-BI. After 8 weeks of treatment, SMW and SMW-BI decreased the levels of fasting blood glucose (FBG), total cholesterol (TC), triacylglycerols (TG) and low-density lipoprotein cholesterol (LDL-C), increased the level of high-density lipoprotein cholesterol (HDL-C), alleviated weight loss, and increased serum insulin levels in T2DM mice. In addition, SMW and SMW-BI improved hepatocyte morphology in T2DM mice, decreased the number of adipocytes, and increased liver glycogen. Network pharmacological analysis indicated that SMW and SMW-BI may exert hypoglycemic by regulating insulin receptor substrate 1 (IRS1)/RAC-beta serine/threonine-protein kinase (AKT2)/forkhead box protein O1 (FOXO1)/glucose transporter type 2 (GLUT2) signaling. Moreover, correlation analysis showed that SMW and SMW-BI were associated with activation of IRS1, AKT2, and GLUT2, and inhibiting FOXO1. RT-qPCR revealed that SMW and SMW-BI could increase levels of IRS1, AKT2, and GLUT2 in the livers of T2DM mice and lower the level of FOXO1. Furthermore, immunofluorescence analysis showed that FOXO1 expression in the livers of T2DM mice decreased after oral administration of SMW and SMW-BI. Furthermore, molecular docking showed that SMW-BI could bind directly to IRS1 and AKT2. Conclusion: SMW and SMW-BI are potential hypoglycemic drugs that alleviate T2DM by regulating IRS1/AKT2/FOXO1 signaling. Our study provides a research idea for screening the bioactive ingredients in traditional Chinese medicine (TCM).

Effects of steroid hormones on lipid metabolism in sexual dimorphism: A Mendelian randomization study.

Background: Although the role of steroid hormones in lipid levels has been partly discussed in the context of separate sexes, the causal relationship between steroid hormones and lipid metabolism according to sex has not been elucidated because of the limitations of observational studies. We assessed the relationship between steroid hormones and lipid metabolism in separate sexes using a two-sample Mendelian randomization (MR) study. Methods: Instrumental variables for dehydroepiandrosterone sulfate (DHEAS), progesterone, estradiol, and androstenedione were selected. MR analysis was performed using inverse-variance weighted, MR-Egger, weighted median, and MR pleiotropy residual sum and outlier tests. Cochran's Q test, the MR-Egger intercept test, and leave-one-out analysis were used for sensitivity analyses. Results: The results showed that the three steroid hormones affected lipid metabolism and exhibited sex differences. In males, DHEAS was negatively correlated with total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein B (P = 0.007; P = 0.006; P = 0.041, respectively), and progesterone was negatively correlated with TC and LDL-C (P = 0.019; P = 0.038, respectively). In females, DHEAS was negatively correlated with TC (P = 0.026) and androstenedione was negatively correlated with triglycerides and apolipoprotein A (P = 0.022; P = 0.009, respectively). No statistically significant association was observed between the estradiol levels and lipid metabolism in male or female participants. Conclusions: Our findings identified sex-specific causal networks between steroid hormones and lipid metabolism. Steroid hormones, including DHEAS, progesterone, and androstenedione, exhibited beneficial effects on lipid metabolism in both sexes; however, the specific lipid profiles affected by steroid hormones differed between the sexes.

[Comparative analysis of pharmacokinetics and intestinal absorption of six alkaloids between Sanmiao Pills and Simiao Pills in rats].

The present study investigated the differences in pharmacokinetics and intestinal absorption of six alkaloids in Sanmiao Pills and Simiao Pills in rats and explored the different efficacies of the two formulae. After oral administration of Sanmiao Pills and Simiao Pills in rats, blood samples were collected at different time points. Samples were prepared for the determination of six alkaloids in plasma by UPLC-MS/MS. The chromatography was performed on an ACE Excel 3 C_(18 )column with acetonitrile-0.1% formic acid in water as the mobile phase for gradient elution. Analytes were detected in the positive ion mode. Plasma concentrations and pharmacokinetic parameters were calculated. Intestinal absorption of alkaloids was investigated by single-pass intestinal perfusion and absorption parameters of ingredients were calculated. The results showed that the UPLC-MS/MS method for simultaneous determination of concentrations of six alkaloids in plasma was developed and validated by methodological investigations, such as specificity, calibration curves, precision, accuracy, recovery, matrix effect, and stability. The results of the pharmacokinetic assay revealed that C_(max) and AUC values of phellodendrine, berberine, magnoflorine, berberrubine, and jatrorrhizine in Simiao Pills were significantly increased, and CL/F values were reduced as compared with those in Sanmiao Pills, which indicated the increase in plasma concentrations of alkaloids. The intestinal absorption parameters K_(a )and P_(eff) values of phellodendrine, berberine, and jatrorrhizine in Simiao Pills were higher than those in Sanmiao Pills. The intestinal absorption and plasma concentrations of alkaloids in Simiao Pills were significantly higher than those in Sanmiao Pills, suggesting that the composition of Simiao Pills was more conducive to the alkaloids into the blood to resist inflammation and lower uric acid.