Five new flavan-4-ol glycosides jixueqiosides A-E (1-5) and two new flavan glycosides jixueqiosides F and G (6 and 7), along with twelve known flavan-4-ol glycosides (8-19), were isolated from the roots of Pronephrium penangianum. Comprehensive spectral analyses, X-ray single-crystal diffraction, and theoretical electronic circular dichroism (ECD) calculations established structures and absolute configurations. A single crystal structure of flavan-4-ol glycoside (14) was reported for the first time, while the characteristic ECD and NMR data for all isolated flavan-4-ol glycosides (1-5 , 8-19) were analyzed, establishing a set of empirical rules. Activity screening of these isolates showed that 8 and 9 could inhibit the proliferation of MDA-MB-231 and MCF-7 cells with IC₅₀ values of 7.93 ? 2.85 ?mol?L^-1 and 5.87 ? 1.58 ?mol?L^-1 (MDA-MB-231), and 2.21 ? 1.38 ?mol?L^-1 and 3.52 ? 1.55 ?mol?L^-1 (MCF-7), respectively. Western blotting and flow cytometry analyses demonstrated that 8 and 9 dose-dependently induced apoptosis in MDA-MB-231 cells by up-regulating BAX, activating caspase-3 and down-regulating BCL-2. Additionally, compound 8 affected autophagy-related proteins, increasing the ratio of LC3-II/LC3-I and Beclin-1 levels to inhibit MDA-MB-231 cell proliferation. Moreover, anti-inflammatory studies indicated that 2, 3, 7, 13, 14, and 18 moderately inhibited tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), and nitric oxide (NO) release.
Humans ; Plant Roots/chemistry* ; Glycosides/isolation & purification* ; Anti-Inflammatory Agents/isolation & purification* ; Flavonoids/isolation & purification* ; Cell Proliferation/drug effects* ; Antineoplastic Agents, Phytogenic/isolation & purification* ; Molecular Structure ; Apoptosis/drug effects* ; Cell Line, Tumor ; Tumor Necrosis Factor-alpha/immunology* ; Drugs, Chinese Herbal/pharmacology* ; Interleukin-6/immunology* ; Animals ; Mice

BACKGROUND: Over 20 million colonoscopies are performed in China annually. An automatic clinical decision support system (CDSS) with accurate semantic recognition of colonoscopy reports and guideline-based is helpful to relieve the increasing medical burden and standardize the healthcare. In this study, the CDSS was built under a hierarchical-label interpretable classification framework, trained by a state-of-the-art transformer-based model, and validated in a multi-center style. METHODS: We conducted stratified sampling on a previously established dataset containing 302,965 electronic colonoscopy reports with pathology, identified 2041 patients' records representative of overall features, and randomly divided into the training and testing sets (7:3). A total of five main labels and 22 sublabels were applied to annotate each record on a network platform, and the data were trained respectively by three pre-training models on Chinese corpus website, including bidirectional encoder representations from transformers (BERT)-base-Chinese (BC), the BERT-wwm-ext-Chinese (BWEC), and ernie-3.0-base-zh (E3BZ). The performance of trained models was subsequently compared with a randomly initialized model, and the preferred model was selected. Model fine-tuning was applied to further enhance the capacity. The system was validated in five other hospitals with 3177 consecutive colonoscopy cases. RESULTS: The E3BZ pre-trained model exhibited the best performance, with a 90.18% accuracy and a 69.14% Macro-F1 score overall. The model achieved 100% accuracy in identifying cancer cases and 99.16% for normal cases. In external validation, the model exhibited favorable consistency and good performance among five hospitals. CONCLUSIONS The novel CDSS possesses high-level semantic recognition of colonoscopy reports, provides appropriate recommendations, and holds the potential to be a powerful tool for physicians and patients. The hierarchical multi-label strategy and pre-training method should be amendable to manage more medical text in the future.
Humans ; Colonoscopy/methods* ; Deep Learning ; Decision Support Systems, Clinical ; Female ; Male

Objective:To improve the quality standards for Portulaca oleracea medicinal materials and decoction pieces.Methods:Fourteen batches of P.oleracea medicinal materials and 20 batches of its decoction pieces from different producing areas across the country were collected.In accordance with the relevant methods in the general chapters of the Chinese Pharmacopoeia(2020 Edition,Volume Ⅰ),the thin-layer chromatography(TLC)identi-fication method was optimized.The contents of impurities,moisture,total ash,acid-insoluble ash,heavy metals and harmful elements,and extracts were determined.Meanwhile,the HPLC feature chromatograms and content determination methods for P.oleracea medicinal materials and decoction pieces were established.Results:The optimized TLC method showed clear spots,good separation effect and reproducibility.The average contents of impurities,moisture,total ash,acid-insoluble ash,and extracts in the 14 batches of P.oleracea medicinal materi-als were 0.01％,8.48％,21.68％,5.33％,and 28.44％respectively.The average contents of impurities,moisture,total ash,acid-insoluble ash,and extracts in the 20 batches of P.oleracea decoction pieces were 0.01％,7.00％,21.09％,3.60％,and 29.63％respectively.The results of the tests for heavy metals and harmful elements showed that the contents of lead,cadmium,arsenic,mercury and copper in 34 batches of samples varied greatly.Moreover,the contents of cadmium,arsenic and copper in some samples exceeded the limit guid-ance values specified in the Pharmacopoeia.Nine common peaks were calibrated in the established HPLC feature chromatogram of P.oleracea,and an HPLC method for simultaneously determining the contents of norepinephrine and dopamine was established.Conclusion:It is recommended to modify the developing solvent for the thin-layer identification of P.oleracea and its proportion to water-saturated n-butanol-acetone-glacial acetic acid-water=4∶1∶1∶1,and change the extraction method of the test sample to ultrasonic extraction for 30 minutes.It is proposed to add the stipulations that the total ash of P.oleracea medicinal materials and decoction pieces should not exceed 25.0％,the acid-insoluble ash should not exceed 6.0％,and the water-soluble extract should not be lower than 20.0％.For P.oleracea decoction pieces,the total ash should not exceed 28.0％,the acid-insoluble ash should not exceed 6.0％,and the water-soluble extract should not be lower than 20.0％.This study provides an experi-mental basis for the improvement of the quality standards of P.oleracea.

Objective:To investigate the effect and underlying mechanism of sonodynamic therapy (SDT) on inflammation-related atrial fibrillation (AF) susceptibility.Methods:Lipopolysaccharide (LPS)-stimulated mouse and HL-1 mouse atrial myocyte models were used. (1) In vivo study: experimental groups included control, LPS, LPS+SDT, and SDT groups, with 20 mice in each group. Atrial fibrillation inducibility and duration were assessed by electrical stimulation. Western blot was used to analyze atrial expression of NOD-like receptor family pyrin domain-containing protein 3 (NLRP3), interleukin (IL)-1β, and IL-18. Immunohistochemistry was used to detect calcium voltage-gated channel subunit alpha1 C (CACNA1C) expression. (2) In vitro study: cell counting kit-8 (CCK-8) and Western blot were used to determine the optimal and safe LPS concentration. The safe incubation condition for the sonosensitizer sinoporphyrin sodium was determined by CCK-8 and fluorometry. An LPS-induced inflammatory model in HL-1 atrial myocytes was used, with experimental groups including control, LPS, LPS+SDT, LPS+sinoporphyrin sodium, and LPS+ultrasound groups. NLRP3 was overexpressed using plasmid transfection, with experimental groups including control, NLRP3 plasmid, negative control plasmid, and NLRP3 plasmid+SDT groups. SDT was applied to LPS-stimulated or NLRP3-overexpressing HL-1 cells. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to measure mRNA and protein levels of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), Cleaved Caspase-1, IL-1β, IL-18, and CACNA1C. The NLRP3 inhibitor MCC950 was used to validate the relationship of NLRP3 and CACNA1C. The experimental groups included control, LPS, LPS+MCC950, and MCC950 groups. Intracellular reactive oxygen species (ROS) levels were detected using the probe DCFH-DA, and the ROS scavenger N-acetyl-L-cysteine (NAC) was used to test if the effects of SDT was ROS-dependent.Results:(1) In vivo: The LPS+SDT group exhibited a lower incidence of atrial fibrillation induction and a shorter duration of atrial fibrillation compared to the LPS group(both P<0.05). Protein expression levels of NLRP3 and IL-1β were lower than those in the LPS group (all P<0.05), while the expression of CACNA1C subunit tended to increase relative to the LPS group ( P>0.05). (2) In vitro: The safe concentration of LPS for administration was ≤20 μg/ml, with an optimal pro-inflammatory concentration of 4 μg/ml. The safe concentration of sinoporphyrin sodium for administration was 0.4 μmol/L, with an optimal incubation time of 4 hours. Compared to the LPS group or NLRP3 plasmid group, the LPS+SDT group or NLRP3 plasmid+SDT group exhibited lower expression levels of NLRP3, ASC, Cleaved Caspase-1, IL-1β, and IL-18, and higher mRNA and protein levels of CACNA1C (all P<0.05). The LPS+MCC950 group had higher CACNA1C protein expression than the LPS group ( P<0.05). SDT increased intracellular ROS levels, and NAC blocked the regulatory effects of SDT on NLRP3 and CACNA1C. Conclusion:SDT reduces atrial fibrillation susceptibility in mice by inhibiting NLRP3 inflammasome activation in atrial cardiomyocytes, thereby upregulating the L-type calcium channel subunit CACNA1C.

Objective:To improve the quality standards for Portulaca oleracea medicinal materials and decoction pieces.Methods:Fourteen batches of P.oleracea medicinal materials and 20 batches of its decoction pieces from different producing areas across the country were collected.In accordance with the relevant methods in the general chapters of the Chinese Pharmacopoeia(2020 Edition,Volume Ⅰ),the thin-layer chromatography(TLC)identi-fication method was optimized.The contents of impurities,moisture,total ash,acid-insoluble ash,heavy metals and harmful elements,and extracts were determined.Meanwhile,the HPLC feature chromatograms and content determination methods for P.oleracea medicinal materials and decoction pieces were established.Results:The optimized TLC method showed clear spots,good separation effect and reproducibility.The average contents of impurities,moisture,total ash,acid-insoluble ash,and extracts in the 14 batches of P.oleracea medicinal materi-als were 0.01％,8.48％,21.68％,5.33％,and 28.44％respectively.The average contents of impurities,moisture,total ash,acid-insoluble ash,and extracts in the 20 batches of P.oleracea decoction pieces were 0.01％,7.00％,21.09％,3.60％,and 29.63％respectively.The results of the tests for heavy metals and harmful elements showed that the contents of lead,cadmium,arsenic,mercury and copper in 34 batches of samples varied greatly.Moreover,the contents of cadmium,arsenic and copper in some samples exceeded the limit guid-ance values specified in the Pharmacopoeia.Nine common peaks were calibrated in the established HPLC feature chromatogram of P.oleracea,and an HPLC method for simultaneously determining the contents of norepinephrine and dopamine was established.Conclusion:It is recommended to modify the developing solvent for the thin-layer identification of P.oleracea and its proportion to water-saturated n-butanol-acetone-glacial acetic acid-water=4∶1∶1∶1,and change the extraction method of the test sample to ultrasonic extraction for 30 minutes.It is proposed to add the stipulations that the total ash of P.oleracea medicinal materials and decoction pieces should not exceed 25.0％,the acid-insoluble ash should not exceed 6.0％,and the water-soluble extract should not be lower than 20.0％.For P.oleracea decoction pieces,the total ash should not exceed 28.0％,the acid-insoluble ash should not exceed 6.0％,and the water-soluble extract should not be lower than 20.0％.This study provides an experi-mental basis for the improvement of the quality standards of P.oleracea.

Objective:To investigate the effect and underlying mechanism of sonodynamic therapy (SDT) on inflammation-related atrial fibrillation (AF) susceptibility.Methods:Lipopolysaccharide (LPS)-stimulated mouse and HL-1 mouse atrial myocyte models were used. (1) In vivo study: experimental groups included control, LPS, LPS+SDT, and SDT groups, with 20 mice in each group. Atrial fibrillation inducibility and duration were assessed by electrical stimulation. Western blot was used to analyze atrial expression of NOD-like receptor family pyrin domain-containing protein 3 (NLRP3), interleukin (IL)-1β, and IL-18. Immunohistochemistry was used to detect calcium voltage-gated channel subunit alpha1 C (CACNA1C) expression. (2) In vitro study: cell counting kit-8 (CCK-8) and Western blot were used to determine the optimal and safe LPS concentration. The safe incubation condition for the sonosensitizer sinoporphyrin sodium was determined by CCK-8 and fluorometry. An LPS-induced inflammatory model in HL-1 atrial myocytes was used, with experimental groups including control, LPS, LPS+SDT, LPS+sinoporphyrin sodium, and LPS+ultrasound groups. NLRP3 was overexpressed using plasmid transfection, with experimental groups including control, NLRP3 plasmid, negative control plasmid, and NLRP3 plasmid+SDT groups. SDT was applied to LPS-stimulated or NLRP3-overexpressing HL-1 cells. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to measure mRNA and protein levels of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), Cleaved Caspase-1, IL-1β, IL-18, and CACNA1C. The NLRP3 inhibitor MCC950 was used to validate the relationship of NLRP3 and CACNA1C. The experimental groups included control, LPS, LPS+MCC950, and MCC950 groups. Intracellular reactive oxygen species (ROS) levels were detected using the probe DCFH-DA, and the ROS scavenger N-acetyl-L-cysteine (NAC) was used to test if the effects of SDT was ROS-dependent.Results:(1) In vivo: The LPS+SDT group exhibited a lower incidence of atrial fibrillation induction and a shorter duration of atrial fibrillation compared to the LPS group(both P<0.05). Protein expression levels of NLRP3 and IL-1β were lower than those in the LPS group (all P<0.05), while the expression of CACNA1C subunit tended to increase relative to the LPS group ( P>0.05). (2) In vitro: The safe concentration of LPS for administration was ≤20 μg/ml, with an optimal pro-inflammatory concentration of 4 μg/ml. The safe concentration of sinoporphyrin sodium for administration was 0.4 μmol/L, with an optimal incubation time of 4 hours. Compared to the LPS group or NLRP3 plasmid group, the LPS+SDT group or NLRP3 plasmid+SDT group exhibited lower expression levels of NLRP3, ASC, Cleaved Caspase-1, IL-1β, and IL-18, and higher mRNA and protein levels of CACNA1C (all P<0.05). The LPS+MCC950 group had higher CACNA1C protein expression than the LPS group ( P<0.05). SDT increased intracellular ROS levels, and NAC blocked the regulatory effects of SDT on NLRP3 and CACNA1C. Conclusion:SDT reduces atrial fibrillation susceptibility in mice by inhibiting NLRP3 inflammasome activation in atrial cardiomyocytes, thereby upregulating the L-type calcium channel subunit CACNA1C.

Diabetes has long been considered a risk factor in implant therapy and impaired wound healing in soft and hard oral tissues.Magnesium has been proved to promote bone healing under normal conditions.Here,we elucidate the mechanism by which Mg2+ promotes angiogenesis and osseointegration in diabetic status.We generated a diabetic mice model and demonstrated the alveolar bone healing was compromised,with significantly decreased angiogenesis.We then developed Mg-coating implants with hydrothermal synthesis.These implants successfully improved the vascularization and osseointegration in diabetic status.Mechanically,Mg2+ promoted the degradation of Kelch-like ECH-associated protein 1(Keap1)and the nucleation of nuclear factor erythroid 2-related factor 2(Nrf2)by up-regulating the expression of sestrin 2(SESN2)in endothelial cells,thus reducing the elevated levels of oxidative stress in mitochondria and relieving endothelial cell dysfunction under hyperglycemia.Altogether,our data suggested that Mg2+ promoted angiogenesis and osseointegration in diabetic mice by regulating endothelial mitochondrial metabolism.

Diabetes has long been considered a risk factor in implant therapy and impaired wound healing in soft and hard oral tissues.Magnesium has been proved to promote bone healing under normal conditions.Here,we elucidate the mechanism by which Mg2+ promotes angiogenesis and osseointegration in diabetic status.We generated a diabetic mice model and demonstrated the alveolar bone healing was compromised,with significantly decreased angiogenesis.We then developed Mg-coating implants with hydrothermal synthesis.These implants successfully improved the vascularization and osseointegration in diabetic status.Mechanically,Mg2+ promoted the degradation of Kelch-like ECH-associated protein 1(Keap1)and the nucleation of nuclear factor erythroid 2-related factor 2(Nrf2)by up-regulating the expression of sestrin 2(SESN2)in endothelial cells,thus reducing the elevated levels of oxidative stress in mitochondria and relieving endothelial cell dysfunction under hyperglycemia.Altogether,our data suggested that Mg2+ promoted angiogenesis and osseointegration in diabetic mice by regulating endothelial mitochondrial metabolism.

Diabetes has long been considered a risk factor in implant therapy and impaired wound healing in soft and hard oral tissues.Magnesium has been proved to promote bone healing under normal conditions.Here,we elucidate the mechanism by which Mg2+ promotes angiogenesis and osseointegration in diabetic status.We generated a diabetic mice model and demonstrated the alveolar bone healing was compromised,with significantly decreased angiogenesis.We then developed Mg-coating implants with hydrothermal synthesis.These implants successfully improved the vascularization and osseointegration in diabetic status.Mechanically,Mg2+ promoted the degradation of Kelch-like ECH-associated protein 1(Keap1)and the nucleation of nuclear factor erythroid 2-related factor 2(Nrf2)by up-regulating the expression of sestrin 2(SESN2)in endothelial cells,thus reducing the elevated levels of oxidative stress in mitochondria and relieving endothelial cell dysfunction under hyperglycemia.Altogether,our data suggested that Mg2+ promoted angiogenesis and osseointegration in diabetic mice by regulating endothelial mitochondrial metabolism.

Diabetes has long been considered a risk factor in implant therapy and impaired wound healing in soft and hard oral tissues.Magnesium has been proved to promote bone healing under normal conditions.Here,we elucidate the mechanism by which Mg2+ promotes angiogenesis and osseointegration in diabetic status.We generated a diabetic mice model and demonstrated the alveolar bone healing was compromised,with significantly decreased angiogenesis.We then developed Mg-coating implants with hydrothermal synthesis.These implants successfully improved the vascularization and osseointegration in diabetic status.Mechanically,Mg2+ promoted the degradation of Kelch-like ECH-associated protein 1(Keap1)and the nucleation of nuclear factor erythroid 2-related factor 2(Nrf2)by up-regulating the expression of sestrin 2(SESN2)in endothelial cells,thus reducing the elevated levels of oxidative stress in mitochondria and relieving endothelial cell dysfunction under hyperglycemia.Altogether,our data suggested that Mg2+ promoted angiogenesis and osseointegration in diabetic mice by regulating endothelial mitochondrial metabolism.