A crucial role of adenosine deaminase in regulating gluconeogenesis in mice.

Adenosine deaminase (ADA) catalyzes the irreversible deamination of adenosine (ADO) to inosine and regulates ADO concentration. ADA ubiquitously expresses in various tissues to mediate ADO-receptor signaling. A significant increase in plasma ADA activity has been shown to be associated with the pathogenesis of type 2 diabetes mellitus. Here, we show that elevated plasma ADA activity is a compensated response to high level of ADO in type 2 diabetes mellitus and plays an essential role in the regulation of glucose homeostasis. Supplementing with more ADA, instead of inhibiting ADA, can reduce ADO levels and decrease hepatic gluconeogenesis. ADA restores a euglycemic state and recovers functional islets in db/db and high-fat streptozotocin diabetic mice. Mechanistically, ADA catabolizes ADO and increases Akt and FoxO1 phosphorylation independent of insulin action. ADA lowers blood glucose at a slower rate and longer duration compared to insulin, delaying or blocking the incidence of insulinogenic hypoglycemia shock. Finally, ADA suppresses gluconeogenesis in fasted mice and insulin-deficient diabetic mice, indicating the ADA regulating gluconeogenesis is a universal biological mechanism. Overall, these results suggest that ADA is expected to be a new therapeutic target for diabetes.

DEKR-SPrior: An Efficient Bottom-Up Keypoint Detection Model for Accurate Pod Phenotyping in Soybean.

The pod and seed counts are important yield-related traits in soybean. High-precision soybean breeders face the major challenge of accurately phenotyping the number of pods and seeds in a high-throughput manner. Recent advances in artificial intelligence, especially deep learning (DL) models, have provided new avenues for high-throughput phenotyping of crop traits with increased precision. However, the available DL models are less effective for phenotyping pods that are densely packed and overlap in in situ soybean plants; thus, accurate phenotyping of the number of pods and seeds in soybean plant is an important challenge. To address this challenge, the present study proposed a bottom-up model, DEKR-SPrior (disentangled keypoint regression with structural prior), for in situ soybean pod phenotyping, which considers soybean pods and seeds analogous to human people and joints, respectively. In particular, we designed a novel structural prior (SPrior) module that utilizes cosine similarity to improve feature discrimination, which is important for differentiating closely located seeds from highly similar seeds. To further enhance the accuracy of pod location, we cropped full-sized images into smaller and high-resolution subimages for analysis. The results on our image datasets revealed that DEKR-SPrior outperformed multiple bottom-up models, viz., Lightweight-OpenPose, OpenPose, HigherHRNet, and DEKR, reducing the mean absolute error from 25.81 (in the original DEKR) to 21.11 (in the DEKR-SPrior) in pod phenotyping. This paper demonstrated the great potential of DEKR-SPrior for plant phenotyping, and we hope that DEKR-SPrior will help future plant phenotyping.

Residual networks without pooling layers improve the accuracy of genomic predictions.

KEY MESSAGE: Residual neural network genomic selection is the first GS algorithm to reach 35 layers, and its prediction accuracy surpasses previous algorithms. With the decrease in DNA sequencing costs and the development of deep learning, phenotype prediction accuracy by genomic selection (GS) continues to improve. Residual networks, a widely validated deep learning technique, are introduced to deep learning for GS. Since each locus has a different weighted impact on the phenotype, strided convolutions are more suitable for GS problems than pooling layers. Through the above technological innovations, we propose a GS deep learning algorithm, residual neural network for genomic selection (ResGS). ResGS is the first neural network to reach 35 layers in GS. In 15 cases from four public data, the prediction accuracy of ResGS is higher than that of ridge-regression best linear unbiased prediction, support vector regression, random forest, gradient boosting regressor, and deep neural network genomic prediction in most cases. ResGS performs well in dealing with gene-environment interaction. Phenotypes from other environments are imported into ResGS along with genetic data. The prediction results are much better than just providing genetic data as input, which demonstrates the effectiveness of GS multi-modal learning. Standard deviation is recommended as an auxiliary GS evaluation metric, which could improve the distribution of predicted results. Deep learning for GS, such as ResGS, is becoming more accurate in phenotype prediction.

Epigenetic Insights Into Necrotizing Enterocolitis: Unraveling Methylation-Regulated Biomarkers.

Necrotizing enterocolitis (NEC) is a multifactorial gastrointestinal disease with high morbidity and mortality among premature infants. This study aimed to identify novel methylation-regulated biomarkers in NEC intestinal tissue through multiomics analysis. We analyzed DNA methylation and transcriptome datasets from ileum and colon tissues of patients with NEC. We identify methylation-related differential genes (MrDEGs) based on the rule that the degree of methylation in the promoter region is inversely proportional to RNA transcription. These MrDEGs included ADAP1, GUCA2A, BCL2L14, FUT3, MISP, USH1C, ITGA3, UNC93A and IL22RA1. Single-cell data revealed that MrDEGs were mainly located in the intestinal epithelial part of intestinal tissue. These MrDEGs were verified through Target gene bisulfite sequencing and RT-qPCR. We successfully identified and verified the ADAP1, GUCA2A, IL22RA1 and MISP, primarily expressed in intestinal epithelial villus cells through single-cell data. Through single-gene gene set enrichment analysis, we found that these genes participate mainly in the pathological process of T-cell differentiation and the suppression of intestinal inflammation in NEC. This study enhances our understanding of the pathogenesis of NEC and may promote the development of new precision medicine methods for NEC prediction and diagnosis.

Characterization of erm(B)-Carrying Integrative and Conjugative Elements Transferred from Streptococcus anginosus to Other Streptococci and Enterococci.

Integrative and conjugative elements (ICEs) are important vectors of lateral gene transfer and contribute to the evolution of bacterial pathogens. However, studies on the transfer among species and the physiological consequences of ICEs are rare. The objective of this study was to investigate the cross-species transferability of newly identified erm(B)-carried ICE in Streptococcus anginosus San95 and its physiological consequences after transfer. The erm(B)-carried ICE, characterized by a triple serine integrase module, integrated into hsdM genes, thus designated ICESan95_hsdM. Analysis of ICESan95_hsdM revealed 32 additional ICESan95-like ICEs in the available NCBI genome (n = 24) and sequence of clinical isolates (n = 8). Polymerase chain reaction (PCR) was used to evaluate the 467 clinical isolates, of which 84 were positive for core genes (integrase, relaxase, and T4SS genes) of ICESan95_hsdM. Cross-species transfer experiments demonstrated that ICESan95_hsdM could transfer from S. anginosus to different streptococcal and enterococcal recipients. Growth and competitive culture assays showed acquisition of ICESan95_hsdM incurred no fitness cost. Our work discovered a group of ICEs in Streptococci and Enterococci. For the first time, we demonstrated the broad cross-species transferability to different species or genera of ICEs with no fitness cost that enables commensal S. anginosus to deliver antimicrobial resistance genes to other streptococci and enterococci.

Microwave hyperthermia enhances radiosensitization by decreasing DNA repair efficiency and inducing oxidative stress in PC3 prostatic adenocarcinoma cells.

PURPOSE: Radiotherapy (RT) is the primary treatment for prostate cancer (PCa); however, the emergence of castration-resistant prostate cancer (CRPC) often leads to treatment failure and cancer-related deaths. In this study, we aimed to explore the use of microwave hyperthermia (MW-HT) to sensitize PCa to RT and investigate the underlying molecular mechanisms. METHODS: We developed a dedicated MW-HT heating setup, created an in vitro and in vivo MW-HT + RT treatment model for CRPC. We evaluated PC3 cell proliferation using CCK-8, colony experiments, DAPI staining, comet assay and ROS detection method. We also monitored nude mouse models of PCa during treatment, measured tumor weight, and calculated the tumor inhibition rate. Western blotting was used to detect DNA damage repair protein expression in PC3 cells and transplanted tumors. RESULTS: Compared to control, PC3 cell survival and clone formation rates decreased in RT + MW-HT group, demonstrating significant increase in apoptosis, ROS levels, and DNA damage. Lower tumor volumes and weights were observed in treatment groups. Ki-67 expression level was reduced in all treatment groups, with significant decrease in RT + MW-HT groups. The most significant apoptosis induction was confirmed in RT + MW-HT group by TUNEL staining. Protein expression levels of DNA-PKcs, ATM, ATR, and P53/P21 signaling pathways significantly decreased in RT + MW-HT groups. CONCLUSION: MW-HT + RT treatment significantly inhibited DNA damage repair by downregulating DNA-PKcs, ATM, ATR, and P53/P21 signaling pathways, leading to increased ROS levels, aggravate DNA damage, apoptosis, and necrosis in PC3 cells, a well-established model of CRPC.

Clinical characteristics and antimicrobial therapy of healthcare-associated carbapenem-non-susceptible gram-negative bacterial meningitis: a 16-year retrospective cohort study.

OBJECTIVE: Healthcare-associated Gram-negative bacterial meningitis is a substantial clinical issue with poor outcomes, especially for neurosurgical patients. Here, we aimed to study the characteristics and treatment options of patients with healthcare-associated carbapenem-non-susceptible (Carba-NS) Gram-negative bacterial meningitis. METHODS: This observational cohort study was conducted at a teaching hospital from 2004 to 2019. The clinical characteristics of patients with meningitis with Carba-NS and carbapenem-susceptible (Carba-S) bacilli were compared, and the antimicrobial chemotherapy regimens and outcomes for Carba-NS Gram-negative bacterial meningitis were analyzed. RESULTS: A total of 505 patients were included, of whom 83.8% were post-neurosurgical patients. The most common isolates were Acinetobacter spp. and Klebsiella spp., which had meropenem-resistance rates of 50.6% and 42.5%, respectively, and showed a markedly growing carbapenem-resistance trend. Kaplan-Meier curve analysis revealed that Carba-NS Gram-negative bacilli were associated with a significantly higher in-hospital mortality rate (18.8%, 35/186) compared to the Carba-S group (7.4%, 9/122; P = 0.001). For Carba-NS Enterobacterales meningitis, aminoglycoside-based and trimethoprim-sulfamethoxazole-based regimens yielded significantly higher clinical efficacy rates than non-aminoglycoside-based and non-trimethoprim-sulfamethoxazole-based regimens (69.0% vs. 38.7%, P = 0.019 and 81.8% vs. 46.9%, P = 0.036, respectively). For Carba-NS A. baumannii complex meningitis, tetracycline-based (including doxycycline, minocycline, or tigecycline) therapy achieved a significantly higher clinical efficacy rate (62.9%, 22/35) than the non-tetracycline-based therapy group (40.4%, 19/47; P = 0.044). CONCLUSIONS: Our findings revealed that Carba-NS Gram-negative bacilli are associated with higher in-hospital mortality in patients with healthcare-associated meningitis. The combination therapies involving particular old antibiotics may improve patients' outcome. TRIAL REGISTRATION: This study was registered on the Chinese Clinical Trial Register under ChiCTR2000036572 (08/2020).

Targeted drug delivery of engineered mesenchymal stem/stromal-cell-derived exosomes in cardiovascular disease: recent trends and future perspectives.

In recent years, stem cells and their secretomes, notably exosomes, have received considerable attention in biomedical applications. Exosomes are cellular secretomes used for intercellular communication. They perform the function of intercellular messengers by facilitating the transport of proteins, lipids, nucleic acids, and therapeutic substances. Their biocompatibility, minimal immunogenicity, targetability, stability, and engineerable characteristics have additionally led to their application as drug delivery vehicles. The therapeutic efficacy of exosomes can be improved through surface modification employing functional molecules, including aptamers, antibodies, and peptides. Given their potential as targeted delivery vehicles to enhance the efficiency of treatment while minimizing adverse effects, exosomes exhibit considerable promise. Stem cells are considered advantageous sources of exosomes due to their distinctive characteristics, including regenerative and self-renewal capabilities, which make them well-suited for transplantation into injured tissues, hence promoting tissue regeneration. However, there are notable obstacles that need to be addressed, including immune rejection and ethical problems. Exosomes produced from stem cells have been thoroughly studied as a cell-free strategy that avoids many of the difficulties involved with cell-based therapy for tissue regeneration and cancer treatment. This review provides an in-depth summary and analysis of the existing knowledge regarding exosomes, including their engineering and cardiovascular disease (CVD) treatment applications.

Time-Series Field Phenotyping of Soybean Growth Analysis by Combining Multimodal Deep Learning and Dynamic Modeling.

The rate of soybean canopy establishment largely determines photoperiodic sensitivity, subsequently influencing yield potential. However, assessing the rate of soybean canopy development in large-scale field breeding trials is both laborious and time-consuming. High-throughput phenotyping methods based on unmanned aerial vehicle (UAV) systems can be used to monitor and quantitatively describe the development of soybean canopies for different genotypes. In this study, high-resolution and time-series raw data from field soybean populations were collected using UAVs. The RGB (red, green, and blue) and infrared images are used as inputs to construct the multimodal image segmentation model-the RGB & Infrared Feature Fusion Segmentation Network (RIFSeg-Net). Subsequently, the segment anything model was employed to extract complete individual leaves from the segmentation results obtained from RIFSeg-Net. These leaf aspect ratios facilitated the accurate categorization of soybean populations into 2 distinct varieties: oval leaf type variety and lanceolate leaf type variety. Finally, dynamic modeling was conducted to identify 5 phenotypic traits associated with the canopy development rate that differed substantially among the classified soybean varieties. The results showed that the developed multimodal image segmentation model RIFSeg-Net for extracting soybean canopy cover from UAV images outperformed traditional deep learning image segmentation networks (precision = 0.94, recall = 0.93, F1-score = 0.93). The proposed method has high practical value in the field of germplasm resource identification. This approach could lead to the use of a practical tool for further genotypic differentiation analysis and the selection of target genes.

Effects of different traditional Chinese exercise in the treatment of essential hypertension: a systematic review and network meta-analysis.

Background: As a therapy to prevent and treat essential hypertension (EH), traditional Chinese exercises (TCEs) were widely used in clinical practice. However, there is a lack of strictly comparison of the antihypertensive efficacy of different TCEs, which not conducive to the selection of the best and most optimal treatment. This study aimed to perform a network meta-analysis to objectively evaluate which TCE has the best effects in assisting with lowering blood pressure. Methods: PubMed, Embase, the Cochrane Library, Chinese National Knowledge Infrastructure (CNKI), VIP, SinoMed and Wanfang Data were searched for all randomized controlled trials (RCTs) on TCEs for the treatment of EH published up to July 10, 2023. RoB2.0 tool was utilized to evaluate the quality of the RCTs. The network meta-analysis was performed by R 4.1.2 and Stata 17.0. Weighted mean difference (WMD) was calculated for continuous outcomes. Results: A total of 29 studies, including 2,268 patients were included to analyze 6 different interventions. The network meta-analysis results presented that in comparison with control group, Tai Chi + antihypertensive medication [WMD = -10.18, 95% CI, (-14.94, -5.44)] is the most effective intervention for lowering systolic blood pressure (SBP), and Wuqinxi + antihypertensive medication [WMD = -10.36, 95% CI (-18.98, -1.66)] is the most effective intervention for lowering diastolic blood pressure (DBP). Conclusion: TCEs combined with antihypertensive medication may be able to achieve more prominent antihypertensive effects with Tai Chi and Wuqinxi potentially being the higher-priority options. However, well-designed randomized studies are warranted to further verify currently conclusion.

Case Report: Robotic pylorus-preserving pancreatoduodenectomy for periampullary rhabdomyosarcoma in a 3-year-old patient.

Periampullary neoplasm is rare in pediatric patients and has constituted a strict indication for pancreatoduodenectomy (PD), which is a procedure sporadically reported in the literature among children. Robotic PD has been routinely performed for periampullary neoplasm in periampullary neoplasm, but only a few cases in pediatric patients have been reported. Here, we report the case of a 3-year-old patient with periampullary rhabdomyosarcoma treated with robotic pylorus-preserving PD and share our experience with this procedure in pediatric patients. A 3-year-old patient presented with obstructive jaundice and a mass in the pancreatic head revealed by imaging. A laparoscopic biopsy was performed. Jaundice progressed with abdominal pain and elevated alpha-amylase leading to urgent robotic exploration in which a periampullary neoplasm was revealed and pathologically diagnosed as rhabdomyosarcoma by frozen section examination. After pylorus-preserving PD, we performed a conventional jejunal loop following a child reconstruction, including an end-to-end pancreaticojejunostomy, followed by end-to-side hepaticojejunostomy and duodenojejunostomy. Delayed gastric emptying (DGE) presented with increasing drain from the nasogastric tube (NGT) a week after the surgery and improved spontaneously within 10 days. In a 13-month follow-up until the present, our case patient recovered well without potentially fatal complications, such as pancreatic fistula. Robotic PD in pediatric patients was safe and effective without intra- or postoperative complications.

Alterations of gut microbiota in infants with biliary atresia identified by 16S rRNA-sequencing.

BACKGROUND: Biliary atresia (BA) is a severe neonatal disease with progressive intra- and extra-hepatic bile ducts inflammation and hepatic fibrosis. Characterization of gut microbiome profiles in infants with biliary atresia can provide valuable information and potential disease biomarkers. Our study aims to explore the relationship between gut microbiota and biliary atresia. METHODS: 16 S ribosomal RNA (rRNA) gene sequencing was carried out to identify the differences in composition and diversity of gut microbiota between infants with BA and healthy subjects. A total of 31 infants with biliary atresia and 20 healthy subjects were recruited. RESULTS: The composition of gut microbiota in BA group was significantly different with the normal control group (P < 0.05) and the abundance ratio of Klebsiella/Bifidobacterium showed great potential for identification of BA (P < 0.01). In addition, the differential bacterial taxa were involved in lipid and vitamins metabolism. CONCLUSION: Our results could provide potential non-invasive biomarker for identification of biliary atresia and contribute to the treatment in terms of ameliorating microbiota dysbiosis.

Type I BREX system defends against antibiotic-resistant plasmids in Escherichia coli.

The Bacteriophage Exclusion (BREX) system is a novel antiphage defense system identified in Bacillus cereus in 2015. The purpose of this study was to investigate the presence of the BREX system defenses against antibiotic-resistant plasmids such as blaKPC and blaNDM invasion in Escherichia coli. The BREX system was present in 5.4% (23/424) of E. coli clinical isolates and 6.5% (84/1283) of E. coli strains with completely sequenced genomes in the GenBank database. All 23 BREX-positive E. coli clinical isolates were susceptible to carbapenems, while all five isolates carrying blaKPC and 11 carrying blaNDM were BREX-negative. For E. coli strains in the GenBank database, 37 of 38 strains carrying blaKPC and 109 of 111 strains carrying blaNDM were BREX negative. The recognition site sequence of methyltransferase PglX in a clinical E. coli 3756 was 5'-CANCATC-3' using PacBio single-molecular real-time sequencing. The transformation efficiency of plasmid psgRNA-ColAori-target with the PglX recognition site was reduced by 100% compared with the plasmid without the recognition site in E. coli DH5α-pHSG398-BREX. The BREX showed lower defense efficacy against plasmid psgRNA-15Aori-target which had the same plasmid backbone but different surrounding sequences of recognition sites with psgRNA-ColAori-target. The conjugation frequency of the KPC-2 plasmid and NDM-5 plasmid in E. coli 3756-ΔBREX was higher than that in E. coli 3756 clinical isolate (1.0 × 10-6 vs 1.3 × 10-7 and 5.5 × 10-7 vs 1.7 × 10-8, respectively). This study demonstrated that the type I BREX system defends against antibiotic-resistant plasmids in E. coli.

A transformer-based genomic prediction method fused with knowledge-guided module.

Genomic prediction (GP) uses single nucleotide polymorphisms (SNPs) to establish associations between markers and phenotypes. Selection of early individuals by genomic estimated breeding value shortens the generation interval and speeds up the breeding process. Recently, methods based on deep learning (DL) have gained great attention in the field of GP. In this study, we explore the application of Transformer-based structures to GP and develop a novel deep-learning model named GPformer. GPformer obtains a global view by gleaning beneficial information from all relevant SNPs regardless of the physical distance between SNPs. Comprehensive experimental results on five different crop datasets show that GPformer outperforms ridge regression-based linear unbiased prediction (RR-BLUP), support vector regression (SVR), light gradient boosting machine (LightGBM) and deep neural network genomic prediction (DNNGP) in terms of mean absolute error, Pearson's correlation coefficient and the proposed metric consistent index. Furthermore, we introduce a knowledge-guided module (KGM) to extract genome-wide association studies-based information, which is fused into GPformer as prior knowledge. KGM is very flexible and can be plugged into any DL network. Ablation studies of KGM on three datasets illustrate the efficiency of KGM adequately. Moreover, GPformer is robust and stable to hyperparameters and can generalize to each phenotype of every dataset, which is suitable for practical application scenarios.

In vitro pharmacodynamics of nemonoxacin and other antimicrobial agents against Mycoplasma pneumoniae.

IMPORTANCE: This study first reported the in vitro effector kinetics of the new non-fluorinated quinolone, nemonoxacin, against macrolide-resistant M. pneumoniae (MRMP) and macrolide susceptible M. pneumoniae (MSMP) strains along with other antimicrobial agents. The time-kill assays and pharmacodynamic analysis showed that nemonoxacin has significant mycoplasmacidal activity against MRMP and MSMP. This study paves the road to establish appropriate dosing protocols of a new antimicrobial drug for children infected with M. pneumoniae.

Diamond-shaped versus side-to-side anastomotic duodenoduodenostomy in laparoscopic management of annular pancreas in children: a single-center retrospective comparative study.

Background: Annular pancreas is a rare congenital disorder that requires surgical management once diagnosed. Diamond-shaped and side-to-side duodenoduodenostomy are both popular worldwide nowadays in the surgical management of annular pancreas. Here we present our experience with laparoscopic management of annular pancreas in the last 5 years and compare the clinical results of the diamond-shaped versus side-to-side anastomotic techniques. Methods: Fifty-two patients diagnosed with annular pancreas who underwent duodenoduodenostomy at our medical center between January 2016 and April 2021 were included in the study. Forty-four patients underwent laparoscopic diamond-shaped duodenoduodenostomy (DS group) and eight underwent laparoscopic side-to-side duodenoduodenostomy (STS group). Clinical data, including surgical indices and early outcomes after surgery, with at least 19 months of follow-up, were collected and analyzed. Results: Of the 52 patients, 61.5% were prenatally diagnosed, and vomiting was the most common clinical manifestation after birth. The operative time and bleeding volume were 187.5 [interquartile range (IQR), 150-228)] min and 2 (IQR, 2-5) mL in the DS group, compared to 175 (IQR, 155-270) min and 2 (IQR, 2-4.25) mL in the STS group (P=0.89 and 0.32 respectively). The mean time from surgery to initial oral feeding and full oral feeding was 6 (IQR, 4-10) and 12 (IQR, 10-15) days in the DS group, compared to 8 (IQR, 4.75-11.25) and 14.5 (IQR, 13-16.75) days in the STS group (P=0.61 and 0.46 respectively). The mean hospital stay was 16 (IQR, 14-19) and 20 (IQR, 17.75-26) days in the DS and STS groups respectively (P=0.13). No severe complications such as anastomotic leakage, anastomotic stenosis, reoperation or unsuspected rehospitalization were noted in either group. Feeding intolerance was revealed in six cases in the DS group and two cases in the STS group, and there was no significant difference between the two groups (P=0.50). Conclusions: Both laparoscopic diamond-shaped and side-to-side techniques showed good clinical results in treating annular pancreas. The surgical technique, trans-anastomotic tube and early feeding are not likely to increase the risk of postoperative feeding intolerance.

Impact of dietary plant flavonoids on 7,8-dihydroxyflavone transepithelial transport in human intestinal Caco-2 cells.

7,8-dihydroxyflavone (7,8-DHF) is a biologically active flavone with various physiological activities, including neuroprotection, anti-inflammation, and weight loss. Previous studies have found that the efflux protein P-glycoprotein (P-gp) significantly affects the transepithelial transport of 7,8-DHF in the intestine, resulting in its low oral bioavailability. Based on this, in this study, a Caco-2 monolayer cell model was used to investigate 14 dietary plant flavonoids as potential P-gp inhibitors, and their effects on the transepithelial transport and in vitro digestion of 7,8-DHF were explored. The results showed that among the 14 plant flavonoids, hesperetin, epigallocatechin gallate, fisetin, kaempferol, quercetin, and isoorientin increased and the apparent permeability coefficients (P app) of 7,8-DHF at AP → BL direction and lowered P app value at BL → AP direction to varying degrees, reducing the efflux ratio of 7,8-DHF less than 1.5. In particular, kaempferol and quercetin exhibited the best effect on promoting the transepithelial transport of 7,8-DHF, especially when used at molar concentration ratios of 1:1 and 1:2 with 7,8-DHF. This is beneficial for improving the oral bioavailability of 7,8-DHF. Meanwhile, 7,8-DHF was found to maintain structural stability in simulated saliva, gastric juice, and intestinal juice, and its stability was not affected by the coexistence of quercetin and kaempferol. Overall, this study provided a theoretical basis for seeking natural and safe P-gp inhibitors to improve the oral absorption of natural products.

Inhibition of mitochondrial calcium uptake by Ru360 enhances the effect of 1800 MHz radio-frequency electromagnetic fields on DNA damage.

Today, the existence of radio-frequency electromagnetic fields (RF-EMF) emitted from cell phones, wireless routers, base stations, and other sources are everywhere around our living environment, and the dose is increasing. RF-EMF have been reported to be cytotoxic and supposed to be a risk factor for various human diseases, thus, more attention is necessary. In recent years, interfere with mitochondrial calcium uptake by using mitochondrial calcium uniporter (MCU) inhibitor were suggested to be potential clinical treatment in mitochondrial calcium overload diseases, like neurodegeneration, ischemia/reperfusion injury, and cancer, but whether this approach increases the health risk of RF-EMF exposure are unknown. To address our concern, we did a preliminary study to determine whether inhibition of MCU will increase the genotoxicity of RF-EMF exposure in cells, and found that short-time (15 min) exposure to 1800 MHz RF-EMF induced significant DNA damage and cell apoptosis in mouse embryonic fibroblasts (MEFs) treated with Ruthenium 360 (Ru360), a specific inhibitor of MCU, but no significant effects on cell cycle, cell proliferation, or cell viability were observed. In conclusion, our results indicated that inhibiting MCU increases the genotoxicity of RF-EMF exposure, and more attention needs to be paid to the possible health impact of RF-EMF exposure under these treatments.

Multifunctional nanocarriers for targeted drug delivery and diagnostic applications of lymph nodes metastasis: a review of recent trends and future perspectives.

Lymph node metastasis is a frequent occurrence in a variety of tumour forms and poses an enormous challenge to cancer treatment. This process is critical to the development of the disease and is frequently linked to a poor prognosis. Over 90% of cancerous cells move through lymph nodes, making them important entry routes for the spread of cancer cells. The prognosis of cancer patients is significantly impacted by lymph node metastases, which also affects treatment choices. Targeting lymph node metastases presents numerous difficulties for conventional medication delivery techniques. It is still very difficult to selectively target cancer cells in lymph nodes without risking injury to healthy organs and unforeseen consequences. Additionally, systemic delivery of drugs is hampered by the slow flow rate of lymphatic vessels. Chemotherapeutic medicines' poor solubility and stability further reduce their effectiveness when taken orally. Additionally, the extracellular matrix that surrounds lymph node tumours is extensive, which makes it difficult for conventional pharmaceutical delivery systems to reach cancer cells. The development of nanocarriers for precise drug delivery to LNs has attracted a lot of interest to overcome these obstacles. Most solid tumours first spread through the lymphatic system, hence effective drug administration to these tissues is essential for better therapeutic results. Nanocarriers have several benefits, including the capacity to pass through barriers like blood-brain barriers and membranes to reach the lymphatic system. High medication dosages can be enclosed thanks to the physicochemical characteristics of nanocarriers, such as their higher surface-to-volume ratio. Additionally, ligands, antibodies, polymers, or biological molecules can be attached to nanocarrier surfaces to change their properties, allowing for the targeted delivery of lymph node epithelial cells. This use of nanocarriers for drug delivery maximizes on-target effects and related adverse effects while improving the effectiveness of medication delivery to target locations. More research and development in this field is needed to optimize nanocarrier design, increase targeting capabilities, and expand clinical applications for better cancer care.