Conformational change-based fluorometric aptasensor for sensitive cadmium(II) detection in fruits and vegetables.

Cadmium (Cd2+) is a highly toxic heavy metal that can accumulate in the human body through contaminated food and water, posing great health risks. In this study, a label-free fluorescent aptasensor based on SYBR Green I (SGI) for the rapid and sensitive detection of Cd2+ in food samples was designed. The aptasensor utilizes a Cd2+-specific aptamer (Cd-(21)) and its complementary strand (CSCd-(21)) to form a double-stranded DNA (dsDNA) structure in the absence of Cd2+. SGI intercalates into the dsDNA, resulting in a strong fluorescence signal. In the presence of Cd2+, the aptamer undergoes a conformational change, preventing the formation of dsDNA and leading to a decrease in fluorescence intensity. Under optimized conditions, the aptasensor exhibited a linear response to Cd2+ concentrations ranging from 0.11 to 157.37 ng mL-1, with a limit of detection (LOD) of 0.07 ng mL-1. The aptasensor demonstrated high specificity and was successfully applied to detect Cd2+ in fruits and vegetables, with satisfactory recovery rates (95-111%). The proposed aptasensor provides a promising tool for the rapid and sensitive detection of Cd2+ in food.

A lightweight intelligent laryngeal cancer detection system for rural areas.

OBJECTIVE: Early diagnosis of laryngeal cancer (LC) is crucial, particularly in rural areas. Despite existing studies on deep learning models for LC identification, challenges remain in selecting suitable models for rural areas with shortages of laryngologists and limited computer resources. We present the intelligent laryngeal cancer detection system (ILCDS), a deep learning-based solution tailored for effective LC screening in resource-constrained rural areas. METHODS: We compiled a dataset comprised of 2023 laryngoscopic images and applied data augmentation techniques for dataset expansion. Subsequently, we utilized eight deep learning models-AlexNet, VGG, ResNet, DenseNet, MobileNet, ShuffleNet, Vision Transformer, and Swin Transformer-for LC identification. A comprehensive evaluation of their performances and efficiencies was conducted, and the most suitable model was selected to assemble the ILCDS. RESULTS: Regarding performance, all models attained an average accuracy exceeding 90 % on the test set. Particularly noteworthy are VGG, DenseNet, and MobileNet, which exceeded an accuracy of 95 %, with scores of 95.32 %, 95.75 %, and 95.99 %, respectively. Regarding efficiency, MobileNet excels owing to its compact size and fast inference speed, making it an ideal model for integration into ILCDS. CONCLUSION: The ILCDS demonstrated promising accuracy in LC detection while maintaining modest computational resource requirements, indicating its potential to enhance LC screening accuracy and alleviate the workload on otolaryngologists in rural areas.

High average power and high repetition rate eye-safe Raman laser driven by a two-crystal Nd:YVO4 laser.

We report on a high average power and high repetition rate nanosecond pulsed eye-safe KGW Raman laser intracavity driven by an acousto-optic Q-switched 1342 nm two-crystal Nd:YVO4 laser. Taking advantages of the carefully selected two-composite-laser-crystal configuration, the thoroughly optimized gate-open time of acousto-optic modulator and the ingeniously designed U-shaped resonator, substantial power and efficiency enhancements as well as superior mode matching have been enabled. Under the injected pump power of 64.5 W, the average output powers of the first-Stokes fields at 1496 and 1527 nm can be up to 8.1 and 9.5 W with 25 kHz repetition rate and 3.2 µs gate-open time, respectively, corresponding to the optical power conversion efficiencies of 12.6% and 14.7%. Meantime, the resultant pulse widths are determined to be 4.6 and 6.3 ns with the peak powers of approximately 70 and 60 kW, respectively. The beam quality can be maintained with M2 < 1.5 across the entire output power range.

Integrated single-cell RNA-seq analysis reveals mitochondrial calcium signaling as a modulator of endothelial-to-mesenchymal transition.

Endothelial cells (ECs) are highly plastic, capable of differentiating into various cell types. Endothelial-to-mesenchymal transition (EndMT) is crucial during embryonic development and contributes substantially to vascular dysfunction in many cardiovascular diseases (CVDs). While targeting EndMT holds therapeutic promise, understanding its mechanisms and modulating its pathways remain challenging. Using single-cell RNA sequencing on three in vitro EndMT models, we identified conserved gene signatures. We validated original regulators in vitro and in vivo during embryonic heart development and peripheral artery disease. EndMT induction led to global expression changes in all EC subtypes rather than in mesenchymal clusters. We identified mitochondrial calcium uptake as a key driver of EndMT; inhibiting mitochondrial calcium uniporter (MCU) prevented EndMT in vitro, and conditional Mcu deletion in ECs blocked mesenchymal activation in a hind limb ischemia model. Tissues from patients with critical limb ischemia with EndMT features exhibited significantly elevated endothelial MCU. These findings highlight MCU as a regulator of EndMT and a potential therapeutic target.

siRNA nanoparticle targeting Usp20 lowers lipid levels and ameliorates metabolic syndrome in mice.

Atherosclerotic cardiovascular disease (ASCVD) is closely correlated with elevated low-density lipoprotein cholesterol (LDL-C). In feeding state, glucose and insulin activate mTORC1 that phosphorylates the deubiquitylase USP20. USP20 then stabilizes HMG-CoA reductase (HMGCR), thereby increasing lipid biosynthesis. In this study, we applied clinically approved lipid nanoparticles (LNPs) to encapsulate the siRNA targeting Usp20. We demonstrated that silencing of hepatic Usp20 by siRNA decreased body weight, improved insulin sensitivity and increased energy expenditure through elevating UCP1. In Ldlr-/- mice, silencing Usp20 by siRNA decreased lipid levels and prevented atherosclerosis. This study suggests that the RNAi-based therapy targeting hepatic Usp20 has a translational potential to treat metabolic disease.

[Research progress on striatal D2-MSNs plasticity mediated improvement of motor dysfunction by exercises in Parkinson's disease].

Parkinson's disease (PD), a prevalent neurodegenerative condition, manifests predominantly through the degeneration of nigrostriatal dopaminergic (DA) pathways, culminating in a notable depletion of striatal dopamine. This pathophysiological process critically impairs the DA-mediated regulation of motor behaviors within the basal ganglia circuitry, particularly impacting various subtypes of striatal medium spiny neurons. Recent advancements in neuroscientific research have illuminated the pivotal role of D2-dopamine receptor expressing medium spiny neurons (D2-MSNs) plasticity in coordinating motor control in PD. Intriguingly, aerobic exercise emerges as a potent therapeutic intervention, capable of preventing or improving motor impairments. This ameliorative effect is mediated through the modulation of DA receptor activity and the consequent activation of downstream extracellular signal-regulated kinase (Erk) signaling pathway. This article meticulously reviewed the intricate regulatory mechanisms governing the structural and functional plasticity of striatal D2-MSNs in the context of PD. It particularly emphasized the transformative impact of aerobic exercise on motor deficits in PD, attributing this effect to the modulation of striatal D2-MSNs.

Stitching method for panoramic nail fold images based on capillary contour enhancement.

Nail fold capillaroscopy is an important means of monitoring human health. Panoramic nail fold images improve the efficiency and accuracy of examinations. However, the acquisition of panoramic nail fold images is seldom studied and the problem manifests of few matching feature points when image stitching is used for such images. Therefore, this paper presents a method for panoramic nail fold image stitching based on vascular contour enhancement, which first solves the problem of few matching feature points by pre-processing the image with contrast-constrained adaptive histogram equalization (CLAHE), bilateral filtering (BF), and sharpening algorithms. The panoramic images of the nail fold blood vessels are then successfully stitched using the fast robust feature (SURF), fast library of approximate nearest neighbors (FLANN) and random sample agreement (RANSAC) algorithms. The experimental results show that the panoramic image stitched by this paper's algorithm has a field of view width of 7.43 mm, which improves the efficiency and accuracy of diagnosis.

Unmasking Spatial Heterogeneity in Phytotoxicology Mechanisms Induced by Carbamazepine by Mass Spectrometry Imaging and Multiomics Analyses.

Previous studies have highlighted the toxicity of pharmaceuticals and personal care products (PPCPs) in plants, yet understanding their spatial distribution within plant tissues and specific toxic effects remains limited. This study investigates the spatial-specific toxic effects of carbamazepine (CBZ), a prevalent PPCP, in plants. Utilizing desorption electrospray ionization mass spectrometry imaging (DESI-MSI), CBZ and its transformation products were observed predominantly at the leaf edges, with 2.3-fold higher concentrations than inner regions, which was confirmed by LC-MS. Transcriptomic and metabolic analyses revealed significant differences in gene expression and metabolite levels between the inner and outer leaf regions, emphasizing the spatial location's role in CBZ response. Notably, photosynthesis-related genes were markedly downregulated, and photosynthetic efficiency was reduced at leaf edges. Additionally, elevated oxidative stress at leaf edges was indicated by higher antioxidant enzyme activity, cell membrane impairment, and increased free fatty acids. Given the increased oxidative stress at the leaf margins, the study suggests using in situ Raman spectroscopy for early detection of CBZ-induced damage by monitoring reactive oxygen species levels. These findings provide crucial insights into the spatial toxicological mechanisms of CBZ in plants, forming a basis for future spatial toxicology research of PPCPs.

PFOS impairs cardiac function and energy metabolism under high-fat diet: Insights into role of circulating macrophage emphasized by exposure distribution.

Per- and polyfluoroalkyl substances (PFAS), widely utilized in consumer products, have been linked to an increased risk of cardiovascular disease (CVD). With the increasing prevalence of high-fat diet, a common risk factor for CVD, the PFAS exposed populations who consume a high-fat diet will inevitably grow and may have a higher CVD risk. However, the potential toxic effect and mode of action remain elusive. We constructed a mouse model orally exposed to perfluorooctane sulfonate (PFOS), a prototypical PFAS, and fed a high-fat diet. PFOS exposure induced cardiomyopathy and structural abnormalities in the mice heart. Moreover, a characteristic of energy metabolism remodeling from aerobic to anaerobic process was observed. Interestingly, PFOS was rarely detected in heart but showed high level in serum, suggesting an indirect route of action for PFOS-caused cardiac toxicity. We further demonstrated that PFOS-caused circulating inflammation promoted metabolic remodeling and contractile dysfunction in cardiomyocytes. Wherein, PFOS stimulated the release of IL-1ß from circulating proinflammatory macrophages mediated by NF-κB and caspase-1. This study provides valuable data on PFAS-induced cardiac risks associated with exposed populations with increasing high-fat diet consumption, highlighting the significance of indirect pathways in PFOS's impact on the heart, based on the distribution of internal exposure.

Global health costs of ambient PM2·5 from combustion sources: a modelling study supporting air pollution control strategies.

BACKGROUND: Climate actions targeting combustion sources can generate large ancillary health benefits via associated air-quality improvements. Therefore, understanding the health costs associated with ambient fine particulate matter (PM2·5) from combustion sources can guide policy design for both air pollution and climate mitigation efforts. METHODS: In this modelling study, we estimated the health costs attributable to ambient PM2·5 from six major combustion sources across 204 countries using updated concentration-response models and an age-adjusted valuation method. We defined major combustion sources as the sum of total coal, liquid fuel and natural gas, solid biofuel, agricultural waste burning, other fires, and 50% of the anthropogenic fugitive, combustion, and industrial dust source. FINDINGS: Global long-term exposure to ambient PM2·5 from combustion sources imposed US$1·1 (95% uncertainty interval 0·8-1·5) trillion in health costs in 2019, accounting for 56% of the total health costs from all PM2·5 sources. Comparing source contributions to PM2·5 concentrations and health costs, we observed a higher share of health costs from combustion sources compared to their contribution to population-weighted PM2·5 concentration across 134 countries, accounting for more than 87% of the global population. This disparity was primarily attributed to the non-linear relationship between PM2·5 concentration and its associated health costs. Globally, phasing out fossil fuels can generate 23% higher relative health benefits compared to their share of PM2·5 reductions. Specifically, the share of health costs for total coal was 36% higher than the source's contributions to corresponding PM2·5 concentrations and the share of health costs for liquid fuel and natural gas was 12% higher. Other than fossil fuels, South Asia was expected to show 16% greater relative health benefits than the percentage reduction in PM2·5 from the abatement of solid biofuel emissions. INTERPRETATION: In most countries, targeting combustion sources might offer greater health benefits than non-combustion sources. This finding provides additional rationale for climate actions aimed at phasing out combustion sources, especially those related to fossil fuels and solid biofuel. Mitigation efforts designed according to source-specific health costs can more effectively avoid health costs than strategies that depend solely on the source contributions to overall PM2·5 concentration. FUNDING: The Health Effects Institute, the National Natural Science Foundation of China, and NASA.

Real-World Clinical Performance of a Novolimus-Eluting Stent Versus a Sirolimus-Eluting Stent.

INTRODUCTION: The DESyne novolimus-eluting coronary stent (NES) is a new-generation drug-eluting stent (DES) that is widely used, but clinical data are rarely reported for this stent. We compared the safety and effectiveness of the DESyne NES and the Orsiro bioresorbable polymer sirolimus-eluting stent (SES) in patients undergoing percutaneous coronary intervention (PCI). METHODS: This was a retrospective, single-center, observational study. Between July 2017 and December 2022, patients who presented with chronic or acute coronary syndrome undergoing PCI with DESyne NES or Orsiro SES were consecutively enrolled in the present study. The primary endpoint, major adverse cardiovascular event (MACE), was a composite of cardiovascular death, target-vessel myocardial infarction, or clinically driven target-lesion revascularization. RESULTS: A total of 776 patients (age 68.8 ± 12.2; 75.9% male) undergoing PCI were included. Overall, 231 patients with 313 lesions received NES and 545 patients with 846 lesions received SES. During a follow-up duration of 784 ± 522 days, the primary endpoint occurred in 10 patients (4.3%) in the NES group and in 36 patients (6.6%) in the SES group. After multivariate adjustment, the risk of MACE did not significantly differ between groups (NES vs. SES, hazard ratio 0.74, 95% CI, 0.35-1.55, p = 0.425). The event rate of individual components of the primary endpoint was comparable between the two groups. CONCLUSIONS: Favorable and similar clinical outcomes were observed in patients undergoing PCI with either NES or SES in a medium-term follow-up duration. Future studies with adequately powered clinical endpoints are required for further evaluation.

Intermittent Fasting Targets Osteocyte Neuropeptide Y to Relieve Osteoarthritis.

Osteoarthritis is a highly prevalent progressive joint disease that still requires an optimal therapeutic approach. Intermittent fasting is an attractive dieting strategy for improving health. Here this study shows that intermittent fasting potently relieves medial meniscus (DMM)- or natural aging-induced osteoarthritic phenotypes. Osteocytes, the most abundant bone cells, secrete excess neuropeptide Y (NPY) during osteoarthritis, and this alteration can be altered by intermittent fasting. Both NPY and the NPY-abundant culture medium of osteocytes (OCY-CM) from osteoarthritic mice possess pro-inflammatory, pro-osteoclastic, and pro-neurite outgrowth effects, while OCY-CM from the intermittent fasting-treated osteoarthritic mice fails to induce significant stimulatory effects on inflammation, osteoclast formation, and neurite outgrowth. Depletion of osteocyte NPY significantly attenuates DMM-induced osteoarthritis and abolishes the benefits of intermittent fasting on osteoarthritis. This study suggests that osteocyte NPY is a key contributing factor in the pathogenesis of osteoarthritis and intermittent fasting represents a promising nonpharmacological antiosteoarthritis method by targeting osteocyte NPY.

Haplotype-resolved T2T genome assemblies and pangenome graph of pear reveal diverse patterns of allele-specific expression and the genomic basis of fruit quality traits.

Hybrid crops often exhibit increased yield and greater resilience, yet the genomic mechanism(s) underlying hybrid vigor or heterosis remain unclear, hindering our ability to predict the expression of phenotypic traits in hybrid breeding. Here, we generated haplotype-resolved T2T genome assemblies of two pear hybrid varieties, 'Yuluxiang' (YLX) and 'Hongxiangsu' (HXS), which share the same maternal parent but differ in their paternal parents. We then used these assemblies to explore the genome-scale landscape of allele-specific expression (ASE) and create a pangenome graph for pear. ASE was observed for close to 6000 genes in both hybrid cultivars. A subset of ASE genes related to aspects of fruit quality such as sugars, organic acids, and cuticular wax were identified, suggesting their important contributions to heterosis. Specifically, Ma1, a gene regulating fruit acidity, is absent in the paternal haplotypes of HXS and YLX. A pangenome graph was built based on our assemblies and seven published pear genomes. Resequencing data for 139 cultivated pear genotypes (including 97 genotypes sequenced here) were subsequently aligned to the pangenome graph, revealing numerous structural variant hotspots and selective sweeps during pear diversification. As predicted, the Ma1 allele was found to be absent in varieties with low organic acid content, and this association was functionally validated by Ma1 overexpression in pear fruit and calli. Overall, these results reveal the contributions of ASE to fruit-quality heterosis and provide a robust pangenome reference for high-resolution allele discovery and association mapping.

Patient tissue-derived FGFR4-variant and wild-type colorectal cancer organoid development and anticancer drug sensitivity testing.

Objectives: FGFR4-variant and wild-type colorectal cancer (CRC) organoids were developed to investigate the effects of FGFR4-targeted drugs, including FGFR4-IN and erdafitinib, on CRC and their possible molecular mechanism. Methods: Clinical CRC tissues were collected, seven CRC organoids were developed, and whole exome sequencing (WES) was performed. CRC organoids were cultured and organoid drug sensitivity studies were conducted. Finally, an FGFR4-variant (no wild-type) CRC patient-derived orthotopic xenograft mouse model was developed. Western blot measured ERK/AKT/STAT3 pathway-related protein levels. Results: WES results revealed the presence of FGFR4-variants in 5 of the 7 CRC organoids. The structural organization and integrity of organoids were significantly altered under the influence of targeted drugs (FGFR4-IN-1 and erdafitinib). The effects of FGFR4 targeted drugs were not selective for FGFR4 genotypes. FGFR4-IN-1 and erdafitinib significantly reduced the growth, diameter, and Adenosine Triphosphate (ATP) activity of organoids. Furthermore, chemotherapeutic drugs, including 5-fluorouracil and cisplatin, inhibited FGFR4-variant and wild-type CRC organoid activity. Moreover, the tumor volume of mice was significantly reduced at week 6, and p-ERK1/2, p-AKT, and p-STAT3 levels were down-regulated following FGFR4-IN-1 and erdafitinib treatment. Conclusions: FGFR4-targeted and chemotherapeutic drugs inhibited the activity of FGFR4-variant and wild-type CRC organoids, and targeted drugs were more effective than chemotherapeutic drugs at the same concentration. Additionally, FGFR4 inhibitors hindered tumorigenesis in FGFR4-variant CRC organoids through ERK1/2, AKT, and STAT3 pathways. However, no wild-type control was tested in this experiment, which need further confirmation in the next study.

High-power and narrow-linewidth nanosecond pulsed intracavity crystalline Raman laser operating at 1.7 µm.

We report on a high-power and narrow-linewidth nanosecond pulsed intracavity crystalline Raman laser at 1.7 µm. Driven by an acousto-optically Q-switched 1314 nm two-crystal Nd:YLF laser, the highly efficient cascaded YVO4 Raman laser at 1715nm was obtained within the well-designed L-shaped resonator. Thanks to the absence of spatial hole burning in the stimulated Raman scattering process, significant spectral purification of second-Stokes radiation was observed by incorporating a fused silica etalon in the high-Q fundamental cavity. Under the repetition rate of 4 kHz, the highest average output power for single longitudinal mode operation was up to 2.2 W with the aid of precision vibration isolation and precision temperature controlling, corresponding to the pulse duration of ∼2.8 ns and the spectral linewidth of ∼330 MHz. Further increasing the launched pump power, the second-Stokes laser tended toward be always multimode, and the maximum average output power amounted to 4.8 W with the peak power of ∼0.8 MW and the spectral linewidth of ∼0.08 nm. The second-Stokes emission was near diffraction limited with M2 < 1.4 across the whole pump power range.

N6-methyladenosine modified TGFB2 triggers lipid metabolism reprogramming to confer pancreatic ductal adenocarcinoma gemcitabine resistance.

Gemcitabine resistance is a major obstacle to the effectiveness of chemotherapy in pancreatic ductal adenocarcinoma (PDAC). Therefore, new strategies are needed to sensitize cancer cells to gemcitabine. Here, we constructed gemcitabine-resistant PDAC cells and analyzed them with RNA-sequence. Employing an integrated approach involving bioinformatic analyses from multiple databases, TGFB2 is identified as a crucial gene in gemcitabine-resistant PDAC and is significantly associated with poor gemcitabine therapeutic response. The patient-derived xenograft (PDX) model further substantiates the gradual upregulation of TGFB2 expression during gemcitabine-induced resistance. Silencing TGFB2 expression can enhance the chemosensitivity of gemcitabine against PDAC. Mechanistically, TGFB2, post-transcriptionally stabilized by METTL14-mediated m6A modification, can promote lipid accumulation and the enhanced triglyceride accumulation drives gemcitabine resistance by lipidomic profiling. TGFB2 upregulates the lipogenesis regulator sterol regulatory element binding factor 1 (SREBF1) and its downstream lipogenic enzymes via PI3K-AKT signaling. Moreover, SREBF1 is responsible for TGFB2-mediated lipogenesis to promote gemcitabine resistance in PDAC. Importantly, TGFB2 inhibitor imperatorin combined with gemcitabine shows synergistic effects in gemcitabine-resistant PDAC PDX model. This study sheds new light on an avenue to mitigate PDAC gemcitabine resistance by targeting TGFB2 and lipid metabolism and develops the potential of imperatorin as a promising chemosensitizer in clinical translation.

Perioperative outcomes and survival after neoadjuvant immunochemotherapy for locally advanced esophageal squamous cell carcinoma.

OBJECTIVE: This study aimed to compare the difference in perioperative outcomes and prognosis between neoadjuvant immunochemotherapy and neoadjuvant chemoradiotherapy for locally advanced esophageal squamous cell carcinoma. METHODS: The patients with locally advanced esophageal squamous cell carcinoma receiving neoadjuvant immunochemotherapy or neoadjuvant chemoradiotherapy were identified from a prospectively maintained database at Zhongshan Hospital of Fudan University between January 2018 and March 2022. Propensity score matching was performed to balance the 2 groups. RESULTS: A total of 124 patient pairs were enrolled in the final analysis. The complete pathological response rate (20.2% vs 29.0%, P = .140) was similar in the 2 groups, whereas the lower major pathological response rate (44.4% vs 61.3%, P = .011) was observed in the neoadjuvant immunochemotherapy group. Neoadjuvant immunochemotherapy was associated with a lower rate of adverse events (42.7% vs 55.6%, P = .047) without additional postoperative complications (38.7% vs 35.5%, P = .693). The neoadjuvant immunochemotherapy group had lower distant metastasis (6.5% vs 16.1%, P = .027) and overall recurrence (11.3% vs 23.4%, P = .019) in the postoperative 1 year. Also, neoadjuvant immunochemotherapy was associated with better progression-free survival (hazard ratio, 0.50; 95% CI, 0.32-0.77; P = .002). Cox proportional hazard analysis showed that neoadjuvant immunochemotherapy (univariable: hazard ratio, 0.55; 95% CI, 0.37-0.82; P = .003; multivariable: hazard ratio, 0.44; 95% CI, 0.29-0.65; P < .001) was one of the independent prognostic factors for progression-free survival. The 2 groups had similar overall survival (hazard ratio, 0.62; 95% CI, 0.36-1.09; P = .094) at the latest follow-up. CONCLUSIONS: This retrospective study showed that neoadjuvant immunochemotherapy was safe and effective for patients with locally advanced esophageal squamous cell carcinoma. Further verification is needed in randomized controlled trials.

Amplification editing enables efficient and precise duplication of DNA from short sequence to megabase and chromosomal scale.

Duplication is a foundation of molecular evolution and a driver of genomic and complex diseases. Here, we develop a genome editing tool named Amplification Editing (AE) that enables programmable DNA duplication with precision at chromosomal scale. AE can duplicate human genomes ranging from 20 bp to 100 Mb, a size comparable to human chromosomes. AE exhibits activity across various cell types, encompassing diploid, haploid, and primary cells. AE exhibited up to 73.0% efficiency for 1 Mb and 3.4% for 100 Mb duplications, respectively. Whole-genome sequencing and deep sequencing of the junctions of edited sequences confirm the precision of duplication. AE can create chromosomal microduplications within disease-relevant regions in embryonic stem cells, indicating its potential for generating cellular and animal models. AE is a precise and efficient tool for chromosomal engineering and DNA duplication, broadening the landscape of precision genome editing from an individual genetic locus to the chromosomal scale.

The impact of chitooligosaccharides with a certain degree of polymerization on diabetic nephropathic mice and high glucose-damaged HK-2 cells.

Diabetic nephropathy (DN) is a primary diabetic complication ascribed to the pathological changes in renal microvessels. This study investigated the nuclear factor erythroid 2-related factor 2 (Nrf2)/Kelch ECH associating protein (Keap1)/antioxidant response element (ARE) signaling pathway impact of chitooligosaccharides (COS) with a certain degree of polymerization (DP) on DN mouse models and high glucose-damaged human kidney 2 (HK-2) cells. The findings indicated that COS effectively reduced the renal function indexes (uric acid [UA], urinary albumin excretion rate [UAER], urine albumin-to-creatinine ratio [UACR], blood urea nitrogen [BUN], and creatinine [Cre]) of DN mice. It increased (p < .05) the superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) antioxidant enzyme activity in the serum and kidneys, and decreased (p < .05) the malondialdehyde (MDA) content. The mechanistic investigation showed that COS significantly increased (p < .05) Nrf2 and downstream target gene (GCLM, GCLC, HO-1, and NQO-1) expression, and substantially decreased (p < .05) Keap1 expression. The protein level was consistent with the messenger RNA (mRNA) level in in vitro and in vivo models. The docking data indicated that COS and Keap1 protein binding included six hydrogen bond formation processes (Gly364, Arg415, Arg483, His436, Ser431, and Arg380). The COS intervention mechanism may be related to the Nrf2/Keap1/ARE antioxidant pathway. Therefore, it provides a scientific basis for COS application in developing special medical food for DN patients.

Discovery of Novel 2-Oxoacetamide Derivatives as B3GAT3 Inhibitors for the Treatment of Hepatocellular Carcinoma.

Beta-1,3-glucuronosyltransferase (B3GAT3), overexpressed in hepatocellular carcinoma (HCC) and negatively correlated to prognosis, is a promising target for cancer therapy. Currently, no studies have reported small molecule inhibitors of B3GAT3. In this study, we designed and synthesized a series of small-molecule inhibitors of B3GAT3 through virtual screening and structure optimization. The lead compound TMLB-C16 exhibited potent B3GAT3 inhibitory activity (KD = 3.962 µM) by effectively suppressing proliferation and migration, and inducing cell cycle arrest and apoptosis in MHCC-97H (IC50= 6.53 ± 0.18 µM) and HCCLM3 (IC50= 6.22 ± 0.23 µM) cells. Furthermore, compound TMLB-C16 demonstrated favorable pharmacokinetic properties with a relatively high bioavailability of 68.37%. It significantly inhibited tumor growth in both MHCC-97H and HCCLM3 xenograft tumor models without causing obvious toxicity. These results indicate that compound TMLB-C16 is an effective small molecule inhibitor of B3GAT3, providing a basis for the future development of B3GAT3-targeted drugs.