Andrographolide protects against atrial fibrillation by alleviating oxidative stress injury and promoting impaired mitochondrial bioenergetics / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia seen in clinical settings, which has been associated with substantial rates of mortality and morbidity. However, clinically available drugs have limited efficacy and adverse effects. We aimed to investigate the mechanisms of action of andrographolide (Andr) with respect to AF. We used network pharmacology approaches to investigate the possible therapeutic effect of Andr. To define the role of Andr in AF, HL-1 cells were pro-treated with Andr for 1 h before rapid electronic stimulation (RES) and rabbits were pro-treated for 1 d before rapid atrial pacing (RAP). Apoptosis, myofibril degradation, oxidative stress, and inflammation were determined. RNA sequencing (RNA-seq) was performed to investigate the relevant mechanism. Andr treatment attenuated RAP-induced atrial electrophysiological changes, inflammation, oxidative damage, and apoptosis both in vivo and in vitro. RNA-seq indicated that oxidative phosphorylation played an important role. Transmission electron microscopy and adenosine triphosphate (ATP) content assay respectively validated the morphological and functional changes in mitochondria. The translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) to the nucleus and the molecular docking suggested that Andr might exert a therapeutic effect by influencing the Keap1-Nrf2 complex. In conclusions, this study revealed that Andr is a potential preventive therapeutic drug toward AF via activating the translocation of Nrf2 to the nucleus and the upregulation of heme oxygenase-1 (HO-1) to promote mitochondrial bioenergetics.

Documenting the need for teaching resourcefulness skills to family caregivers.

BACKGROUND: Before pursuing randomized controlled trials to determine intervention effectiveness and translating interventions into clinical practice, the need for a specific intervention within a particular population must be established. This need can be determined by using established cut scores on validated measures of relevant constructs. AIM: This study examined differences on caregiver burden and resourcefulness among family caregivers of adults with various health conditions to determine their need for resourcefulness training. METHODS: This cross-sectional study sampled 234 caregivers of persons with amyotrophic lateral sclerosis, cancer, dementia, mental illness, Parkinson's disease, stroke, traumatic brain injury, and multiple or other conditions. They completed validated measures of caregiver burden and resourcefulness. Differences were examined using analysis of variance. Need for intervention was evaluated by comparison with established cut scores. RESULTS: Caregivers differed significantly on caregiver burden (F = 2.46; p = .014) and resourcefulness (F = 2.08; p = .038). Across the groups, average caregiver burden scores indicated severe to very severe burden with caregivers of persons with stroke scoring the highest (M = 26.33) and a moderate or greater need for resourcefulness with the greatest needs in caregivers of persons with stroke, traumatic brain injury, and dementia (M's = 74.83, 72.31, and 77.12). CONCLUSIONS: The findings suggest the need for intervention among all family caregiver groups to reduce their burden, with caregivers of persons with stroke showing greatest need. Specifically regarding resourcefulness training, the needs of family caregivers differed by care recipient condition. Using pre-determined cut scores on established, relevant measures provides support for proposing clinical trials, translation into practice, and intervention sustainability.

Antibacterial and Antifungal Sesquiterpenoids: Chemistry, Resource, and Activity.

Infectious diseases caused by bacteria and fungi are threatening human health all over the world. It is an increasingly serious problem that the efficacies of some antibacterial and antifungal agents have been weakened by the drug resistance of some bacteria and fungi, which makes a great need for new antibiotics. Sesquiterpenoids, with abundant structural skeleton types and a wide range of bioactivities, are considered as good candidates to be antibacterial and antifungal agents. In the past decades, many sesquiterpenoids were isolated from plants and fungi that exhibited good antibacterial and antifungal activities. In this review, the names, source, structures, antibacterial and antifungal degrees, and mechanisms of sesquiterpenoids with antibacterial and antifungal activity from 2012 to 2022 are summarized, and the structure-activity relationship of these sesquiterpenoids against bacteria and fungi is also discussed.

Cytochalasins from Xylaria sp. CFL5, an Endophytic Fungus of Cephalotaxus fortunei.

Three previously undescribed cytochalasins, named xylariasins A‒C (1‒3), together with six known ones (4‒9) were isolated from Xylaria sp. CFL5, an endophytic fungus of Cephalotaxus fortunei. The chemical structures of all new compounds were elucidated on the basis of extensive spectroscopic data analyses and electronic circular dichroism calculation, as well as optical rotation calculation. Biological activities of compounds 1, 4‒9 were evaluated, including cytotoxic, LAG3/MHC II binding inhibition and LAG3/FGL1 binding inhibition activities. Compounds 6 and 9 possessed cytotoxicity against AGS cells at 5 µM, with inhibition rates of 94% and 64%, respectively. In addition, all tested isolates, except compound 6, exhibited obvious inhibitory activity against the interaction of both LAG3/MHC II and LAG3/FGL1. Compounds 1, 5, 7, and 8 inhibited LAG3/MHC II with IC50 values ranging from 2.37 to 4.74 µM. Meanwhile, the IC50 values of compounds 1, 7, and 8 against LAG3/FGL1 were 11.78, 4.39, and 7.45 µM, respectively.

Halimane and labdane diterpenoids from Leonurus japonicus and their anti-inflammatory activity.

Ten highly oxygenated diterpenoids (nine undescribed ones) were isolated from the aerial parts of Leonurus japonicus Houtt. 14,15-Dinor-labd-5,8-dien-3,13-dione was a 14,15-dinor-labdane diterpenoid possessing a C18 skeleton. 7ß,9α-Dihydroxy-6-oxo-labd-13-en-15,16-amide represented a rare example of labdane diterpenoid featuring an α,ß-unsaturated-γ-lactam moiety. The structures of all compounds were elucidated using spectroscopic data analyses and comparisons. The effects of these obtained compounds on nitric oxide (NO) production induced by lipopolysaccharide (LPS) in RAW 264.7 cells were evaluated.(10R*,13R*,15R*)-15,16-Epoxy-6,13-dihydroxy-15-methoxy-labda-5,8-dien-7-one inhibited NO production with an IC50 value of 40.1 µM.

Phytotoxic neo-clerodane diterpenoids from the aerial parts of Scutellaria barbata.

Bioactivity guided the isolation of extracts from the aerial parts Scutellaria barbata D. Don to discover neo-clerodane diterpenoids with potent phytotoxic activity. Of the 34 isolates, 13 neo-clerodane diterpenoids were described for the first time. The structures of these undescribed compounds were elucidated by extensive analysis of NMR spectroscopic data, and the absolute configurations of scutebarbolides A and L and scutebata W were determined by X-ray diffraction. The phytotoxic activity of all compounds against the growth of the roots and shoots of L. perenne and L. sativa seedlings were first reported, and some compounds showed considerable inhibitory effects, especially scutebarbolide K, whose inhibition rates were higher than those of the positive control at concentrations ranging from 25 to 200 µg/mL. When L. perenne and L. sativa seedlings were treated at a concentration of 200 µg/mL, scutebarbolide K caused wilting symptoms on and finally death of these two tested plant seedlings. In addition, the structure-activity relationships of these neo-clerodane diterpenoids were also discussed.

Modified Disk-Up Sinus Reamer for Sinus Floor Elevation and Simultaneous Implant Placement: An Animal Study with Miniature Pigs.

Objective: The disk-up sinus reamer (DSR) is a modified instrument used to elevate the maxillary sinus floor. This study aimed to compare the effects of modified DSR sinus floor elevation (DSFE) with osteotome sinus floor elevation (OSFE), both with simultaneous implant placement. Methods: Twelve miniature pigs were treated with DSFE on one side and OSFE on the other. Implants 9 mm in length were placed in six pigs without grafting, while implants 11 mm in length were placed in the other six pigs with grafting. After submerged healing for 3 months, vertical bone gain (VBG), general and histological observation, and bone contact ratio (BCR) were analyzed. Results: The mean maxillary residual bone height (RBH) when implants were placed was 6.45 ± 0.36 mm. In the no-grafting group, DSFE and OSFE had a similar VBG after 3 months. The grafting group with DSFE recorded a significantly higher VBG (VBG0: 7.83 ± 0.44 mm, VBG1: 7.54 ± 0.40 mm) than the graft group with OSFE (VBG0: 5.45 ± 0.56 mm, VBG1: 4.34 ± 2.15 mm) (p < 0.05). One implant became loose and the sinus mucosa of three pigs appeared metallic in color on the control side (OSFE). Conclusions: The effect of OSFE and DSFE is similar when there is no need for grafting. DSFE seems a better alternative method for sinus floor elevation with grafting when more VBG is needed.

Anti-inflammatory evaluation and structure-activity relationships of diterpenoids isolated from Euphorbia hylonoma.

A phytochemical investigation to obtain chemical components with potential anti-inflammatory activity from E. hylonoma led to the isolation of nine new ent-isopimarane diterpenoids (1 and 3-10), a new ent-rosane diterpenoid (11), along with eight known ones (2 and 12-18) using various chromatographic techniques. Compounds 3, 4, 5, and 10 were rare examples of the epoxy-ent-isopimarane. The structures of these new compounds were confirmed by extensive spectroscopic data, crystal X-ray diffraction analysis, and electronic circular dichroism. And the isolates were evaluated for their inhibitory effects on nitric oxide production induced by lipopolysaccharide in RAW 264.7 cells. The results showed that compounds 2 and 12 exhibited noteworthy inhibitory effects against NO production with IC50 values of 7.12 and 12.73 µM, respectively, which were better than positive control (IC50 = 41.41 µM). The possible mechanism that compounds 2 and 12 could inhibit NO production was investigated by the Western blotting experiments.

Highly Oxygenated Triterpenoids and Rare Tetraterpenoids from Abies chensiensis and Their Antibacterial Activity.

Nine new cycloartane triterpenoids (1, 2, 4, 7, 8, 12, 15, 17, and 18) and two new rare tetraterpenoids (24 and 25) formed via a [4 + 2] Diels-Alder cycloaddition between a lanostane triterpenoid and a monoterpenoid, along with 14 previously known triterpenoids, were isolated from the bark of the branches of Abies chensiensis. The structures and absolute configurations of new compounds were elucidated based on spectroscopic data, X-ray diffraction analysis, and electronic circular dichroism. Some of the isolates were evaluated for their antibacterial activity by determining their minimum inhibitory concentrations and growth inhibition curves and examining for morphological alterations. Among the compounds tested, the new cycloartane triterpenoid 8 was the most active against Bacillus subtilis. Thus, morphological alterations of B. subtilis on treatment with 8 were observed by scanning electron microscopy, showing that the cells were irregular, wrinkled, and disrupted.

Labdane-Type Diterpenoids from Leonurus japonicus and Their Plant-Growth Regulatory Activity.

Thirteen new labdane-type diterpenoids 1-6, 9-11, 13, 14, 18, and 19 and seven known ones were isolated from the aerial parts of Leonurus japonicus. Compounds 1-5 represent rare examples of labdane-type diterpenoids, of which compounds 1-4 carry an N-chain linked at C-7 in their B-ring and compound 5 featured an α,ß-unsaturated-γ-lactam moiety. The structures and absolute configurations of these new diterpenoids were characterized by a combination of spectroscopic techniques, X-ray crystallography, electronic circular dichroism, and calculated specific rotations. The plant-growth regulatory activity of these compounds on the growth of the roots and shoots of Lactuca sativa and Lolium perenne seedlings were evaluated. Compound 3 showed a broad-spectrum inhibitory activity with the inhibition rates ranging from 60 to 83.5% at a concentration of 200 µg/mL, which were as active as those of glyphosate. Compound 8 had a selective inhibitory activity against the growth of the roots of L. perenne seedlings with an inhibition rate of 81.7%. However, compounds 11 and 16 exhibited significant stimulation effects on the roots of L. sativa with stimulation rates of 59.8 and 65.3%, respectively. In addition, compounds 3 and 8 exhibited inhibitory effects on the germination of L. perenne seeds.

Comparative evaluation of BioHPP and titanium as a framework veneered with composite resin for implant-supported fixed dental prostheses.

STATEMENT OF PROBLEM: High rates of veneering chipping are a common prosthodontic complication of restorations with a titanium framework. A new bio high-performance polymer (BioHPP) based on polyetheretherketone (PEEK) has been introduced for denture superstructures. Clinical reports suggest that BioHPP could be used as an alternative framework material to support complete-arch restorations. However, peer-reviewed information is lacking regarding the performance of BioHPP as a framework material for implant-supported screw-retained fixed dental prostheses (FDPs) veneered with composite resin. PURPOSE: The purpose of this in vitro study was to evaluate and compare the bond strength of modified PEEK (BioHHP) and titanium with a veneering composite resin and compare the marginal fit and fracture resistance of implant-supported screw-retained FDPs fabricated by using computer-aided design and computer-aided manufacturing (CAD-CAM) frameworks veneered with composite resin. MATERIAL AND METHODS: A composite resin was bonded to 2 framework materials (n=20/group): pure titanium (Ti) and BioHPP (Bi). The shear bond strength (SBS) was determined after 24-hour wet storage. Furthermore, 20 3-unit CAD-CAM BioHPP and titanium frameworks were fabricated (n=10/group). The marginal fit between frameworks and abutments was evaluated by scanning electron microscopy by using the single-screw test. After thermocycling and mastication simulation, the fracture resistance of FDPs veneered with the composite resin was examined. The independent sample t test was used to evaluate differences (α=.05). RESULTS: Significantly higher shear bond strengths were obtained in group Bi (31.1 ±3.5 MPa) than in group Ti (20.5 ±1.8 MPa). The mean marginal gap width was 19 ±4 µm in group Bi and 16 ±6 µm in group Ti. Statistical tests showed no significant differences (P>.05). After loading, veneering chipping was observed at a load of 1960 ±233 N in group Ti. Although the BioHPP frameworks fractured at 1518 ±134 N, no chipping occurred. CONCLUSIONS: The bond strength of BioHPP with the composite resin was greater than that of titanium. CAD-CAM BioHPP frameworks exhibit good marginal fit and fracture resistance. BioHPP may be a suitable alternative to metal as a framework to be veneered with composite resin.

Heliaquanoids A-E, Five Sesquiterpenoid Dimers from Inula helianthus-aquatica.

Heliaquanoid A (1), the first exo-2,4-linked Diels-Alder adduct between a pseudoguaianolide dienophile and a guaianolide diene, and heliaquanoids B-E (2-5), four new 2,4-linked Diels-Alder adducts between a xanthanolide dienophile and a guaianolide diene, were isolated from stems and leaves of Inula helianthus-aquatica. Their structures were determined by NMR spectroscopy, a modified Mosher's method, electronic circular dichroism, and X-ray diffraction analysis. Compounds 2 and 3 exhibited moderate cytotoxic activities against HL-60 cells with IC50 values of 7.5 and 4.9 µM, respectively.

Increased hepatic INSIG-SCAP-SREBP expression is associated with cholesterol metabolism disorder in assisted reproductive technology-conceived aged mice.

Although most children conceived by assisted reproductive technology (ART) are healthy, there are concerns regarding the potential long-term health implications of ART. It has been reported that alterations in insulin-induced gene (INSIG), sterol regulatory element binding protein (SREBP), and SREBP cleavage-activating protein (SCAP) are involved in cardiometabolic changes. Thus, ART mouse models were established via in vitro fertilization (IVF), intracytoplasmic injection (ICSI), and in vitro oocyte maturation (IVM). A significantly higher systolic blood pressure was identified in the IVM aged female mice. In addition, abnormalities in the blood lipids and liver function were identified in the IVM- or ICSI-conceived elderly mice. Furthermore, ICSI or IVM significantly affected the hepatic expression and methylation of INSIG-SCAP-SREBP from a young to old age. Our animal data indicated that ICSI or IVM result in a higher risk of cholesterol metabolism dysfunction in older mice, which may be associated with long-term alterations of INSIG-SCAP-SREBP.

Prognostic role of pretreatment neutrophil to lymphocyte ratio in breast cancer patients: A meta-analysis.

BACKGROUND: Inflammation and cancer are closely related to each other. As a parameter that can reflect inflammation and host immune reaction, elevated blood neutrophil to lymphocyte ratio (NLR) has been confirmed to be correlated with poor prognosis in a variety of cancers. However, this remains controversial in breast cancer. Thus, we performed this updated meta-analysis to further clarify whether high NLR could be a predictor of survival in breast cancer patients. METHODS: We searched on PubMed Database and Cochrane Library. Overall survival (OS), disease-free survival (DFS), and cancer-specific survival were used as outcome events, and hazard ratio (HR) was chosen as the parameter to evaluate the correlation. RESULT: Eighteen eligible studies were involved in this meta-analysis. The synthesized analysis demonstrated that elevated NLR was associated with poor DFS [HR = 1.72, 95% confidence interval (95% CI) = 1.30-2.27], OS (HR = 1.87, 95% CI = 1.41-2.48), and cancer-specific survival (HR = 2.09, 95% CI = 1.04-4.21). The correlation was stronger in triple-negative breast cancer (TNBC) (OS: HR = 2.58, 95% CI = 1.63-4.06; DFS: HR = 3.51, 95% CI = 1.97-6.24). CONCLUSION: Higher NLR was correlated to poor prognosis of breast cancer patients. As a clinical parameter that we can easily obtain, NLR might be a potential predictor in patients' survival to assist with physicians' treatment decisions.

Biomimetic Synthesis of Macahydantoins A and B from Lepidium meyenii, and Structure Revision of Macahydantoin B as a Class of Thiohydantoin with a 4-Methyl-hexahydropyrrolo[1,2-c]imidazole Skeleton.

Phytochemical investigation on Lepidium meyenii led to the discovery of macahydantoin C (3), a new thiohydantoin with a 1,3-diazabicyclo[3.3.1]nonane core, the spectral properties of which indicate a potential structural misassignment of its previously reported analogue, macahydantoin B (2a). To probe this hypothesis, a concise, scalable, and biomimetic synthesis of the originally proposed 2a and its revised structure (2b) was efficiently accomplished using the modified Edman degradation as the key step from commercially available materials in 65% (three steps) and 52% (three steps) overall yields, respectively. These synthetic endeavors undoubtedly reassigned the structure of macahydantoin B as an unreported type of thiohydantoin featuring a 4-methyl-hexahydropyrrolo[1,2-c]imidazole scaffold.

[A new cytotoxic alkaloid from roots of Alangium chinense].

We have carried out the chemical investigation on the roots of Alangium chinense. The chemical constituents from the roots of A.chinense were isolated and purified by various chromatographic techniques, such as silica gel, MCI-Gel resin, Sephadex LH-20 and high performance liquid chromatography. As a result, three alkaloids (1-3) were isolated from 90% EtOH extracts of the roots of this plant. Their structures were elucidated by physical-chemical properties and spectral data. Among them, compound 1 is a new compound, determined as 8-hydroxy-3-hydroxymethyl-6,9-dimethyl-7H-benzo[de]isoquinolin-7-one. Cytotoxicity of the compounds was evaluated by the MTT method. Compound 1 displayed cytotoxicity against NB4, A-549, SHSY5Y, PC-3 and MCF-7 cell lines with IC50 values of 4.2, 3.5, 5.7, 2.8 and 3.9 µmol•L⁻¹, respectively.

(+)-Meyeniins A-C, Novel Hexahydroimidazo[1,5-c]thiazole Derivatives from the Tubers of Lepidium meyenii: Complete Structural Elucidation by Biomimetic Synthesis and Racemic Crystallization.

(+)-Meyeniins A-C (1-3), a novel class of sulfur-containing hexahydroimidazo[1,5-c]thiazole derivatives, were isolated from the tubers of Lepidium meyenii (maca) cultivated in Lijiang, Yunnan province, China. Guided by their biosynthetic hypothesis, a stereocontrolled biomimetic synthesis of meyeniins A-C and their individual enantiomers was efficiently accomplished by a combination of a condensation reaction and Edman degradation. The formation of high-quality crystals for X-ray crystallography occurred much more readily from a racemic mixture of (±)-meyeniin A than with the single enantiomer alone in this case. These extensive strategies, combined with circular dichroism (CD) spectra, allowed the complete structural assignments of (+)-meyeniins A-C. Among them, (+)-meyeniin A showed moderate selective cytotoxicities against the HL-60, A549 and MCF-7 human cell lines with IC50 values of 14.41, 32.22, and 33.14 µM, respectively. To some extent, these findings support traditional applications of maca as healthy nutritional supplements or functional foods for cancer prevention.

A new cytotoxic alkaloid from roots of Alangium chinense / 中国中药杂志

We have carried out the chemical investigation on the roots of Alangium chinense. The chemical constituents from the roots of A.chinense were isolated and purified by various chromatographic techniques, such as silica gel, MCI-Gel resin, Sephadex LH-20 and high performance liquid chromatography. As a result, three alkaloids (1-3) were isolated from 90% EtOH extracts of the roots of this plant. Their structures were elucidated by physical-chemical properties and spectral data. Among them, compound 1 is a new compound, determined as 8-hydroxy-3-hydroxymethyl-6,9-dimethyl-7H-benzo[de]isoquinolin-7-one. Cytotoxicity of the compounds was evaluated by the MTT method. Compound 1 displayed cytotoxicity against NB4, A-549, SHSY5Y, PC-3 and MCF-7 cell lines with IC₅₀ values of 4.2, 3.5, 5.7, 2.8 and 3.9 μmol•L⁻¹, respectively.

High tumor-associated macrophages infiltration is associated with poor prognosis and may contribute to the phenomenon of epithelial-mesenchymal transition in gastric cancer.

BACKGROUND: Recent studies show that epithelial-mesenchymal transition (EMT) and tumor-associated macrophages (TAMs) contribute to the progression and poor prognosis of carcinoma through multiple mechanisms. Both inflammation and changing of epithelium have a close relationship with tumorigenesis of gastric cancer. However, the relevance between EMT and TAMs is still unclear in gastric cancer and needs more scientific research. This study is designed to explore the relationship between EMT and TAMs in gastric cancer. MATERIALS AND METHODS: Immunohistochemistry was used to detect the expression of EMT-related proteins and TAM markers in cancer tissues and normal gastric tissues. RESULTS: High levels of EMT and TAMs infiltration are related to aggressive features and independent prognostic factors in gastric cancer, respectively. In addition, expression of the two indicators is associated with expression of transforming growth factor-ß1 (TGF-ß1). Infiltration of TAMs is also associated with EMT-related marker in gastric cancer. CONCLUSION: Our results suggest that high levels of EMT and TAMs infiltration are related to aggressive features and independent prognostic factors in gastric cancer, respectively. A correlation was found between EMT- and TAM-related indicators, which may be associated with TGF-ß signaling pathway. The level of TAMs infiltration plays an important role in gastric cancer, the markers of which can be used as prognostic indicators.