MyoFold: Joint myocardial tissue composition and wall motion quantification via a highly folded sequence.

PURPOSE: This study aims to develop and evaluate a novel cardiovascular MR sequence, MyoFold, designed for the simultaneous quantifications of myocardial tissue composition and wall motion. METHODS: MyoFold is designed as a 2D single breathing-holding sequence, integrating joint T1/T2 mapping and cine imaging. The sequence uses a 2-fold accelerated balanced SSFP (bSSFP) for data readout and incorporates electrocardiogram synchronization to align with the cardiac cycle. MyoFold initially acquires six single-shot inversion-recovery images, completed during the diastole of six successive heartbeats. T2 preparation (T2-prep) is applied to introduce T2 weightings for the last three images. Subsequently, over the following six heartbeats, segmented bSSFP is performed for the movie of the entire cardiac cycle, synchronized with an electrocardiogram. A neural network trained using numerical simulations of MyoFold is used for T1 and T2 calculations. MyoFold was validated through phantom and in vivo experiments, with comparisons made against MOLLI, SASHA, T2-prep bSSFP, and the conventional cine. RESULTS: In phantom studies, MyoFold exhibited a 10% overestimation in T1 measurements, whereas T2 measurements demonstrated high accuracy. In vivo experiments revealed that MyoFold T1 had comparable accuracy to SASHA and precision similar to MOLLI. MyoFold demonstrated good agreement with T2-prep bSSFP in myocardial T2 measurements. No significant differences were observed in the quantification of left-ventricle wall thickness and function between MyoFold and the conventional cine. CONCLUSION: MyoFold presents as a rapid, simple, and multitasking approach for quantitative cardiovascular MR examinations, offering simultaneous assessment of tissue composition and wall motion. The sequence's multitasking capabilities make it a promising tool for comprehensive cardiac evaluations in clinical settings.

Morphology-Tailored Hydroxyapatite Nanocarrier for Rhizosphere-Targeted Phosphorus Delivery.

High hydrophilicity and soil fixation collectively hamper the delivery of phosphorus (P) released from conventional chemical phosphorus fertilizers (CPFs) to plant rhizosphere for efficient uptake. Here, a phosphorus nutrient nanocarrier (PNC) based on morphology-tailored nanohydroxyapatite (HAP) is constructed. By virtue of kinetic control of building blocks with designed calcium phosphate intermediates, rod-like and hexagonal prism-like PNCs are synthesized, both having satisfactory hydrophobicity (water contact angle of 105.4- 132.9°) and zeta potential (-17.43 to -58.4 mV at pH range from 3 to 13). Greenhouse experiments demonstrate that the P contents increase by up to 183% in maize rhizosphere and up to 16% in maize biomass when compared to the CPF. Due to the water potential gradient driven by photosynthesis and transpiration, both PNCs are stably transported to maize rhizosphere, and they are capable to counteract soil fixation prior to uptake by plant roots. Within the synergies of the HAP morphological characteristics and triggered phosphate starvation response, root anatomy confirms that two pathways are elucidated to enhance plant P replenishment from the PNCs. Together with structure tunability and facile synthesis, our results offer a new nanodelivery prototype to accommodate plant physiological traits by tailoring the morphology of HAP.

Design, synthesis and anti-Chikungunya virus activity of lomerizine derivatives.

Chikungunya fever is an acute infectious disease caused by Chikungunya virus (CHIKV) and transmitted by Aedes mosquito. It is characterized by fever, rash and arthralgia with no effective drugs. Lomerizine (Lom) is a new generation calcium antagonist, which is mainly used in the treatment of migraine. Certain antiviral function of Lom was shown by some research. In our study, a series of new derivatives of Lom were designed and synthesized, and their in-vitro anti-CHIKV activity was tested. The results showed that Lom and its derivatives had potent anti-CHIKV activity and low cytotoxicity. Among them, compounds B1 and B7 showed most potent antiviral activity. Besides, structure-activity relationships, in-silico ADMET properties were also analyzed. Molecular docking study was performed to rationalize the SAR and analyze the possible binding modes between B1 and amino acid residues in the active site of nsP3 protein to enhance the understanding of their action as antiviral agents. These finding provides research basis for the design and synthesis of effective anti-CHIKV drugs with Lom as the lead compound.

Design, synthesis and in vitro biological studies of novel triazoles with potent and broad-spectrum antifungal activity.

A series of novel triazole derivatives containing aryl-propanamide side chains was designed and synthesised. In vitro antifungal activity studies demonstrated that most of the compounds inhibited the growth of six human pathogenic fungi. In particular, parts of phenyl-propionamide-containing compounds had excellent, broad-spectrum antifungal activity against Candida albicans SC5314, Cryptococcus neoformans 22-21, Candida glabrata 537 and Candida parapsilosis 22-20 with MIC values in the range of ≤0.125 µg/mL-4.0 µg/mL. In addition, compounds A1, A2, A6, A12 and A15 showed inhibitory activities against fluconazole-resistant Candida albicans and Candida auris. Preliminary structure-activity relationships (SARs) are also summarised. Moreover, GC-MS analysis demonstrated that A1, A3, and A9 interfered with the C. albicans ergosterol biosynthesis pathway by inhibiting Cyp51. Molecular docking studies elucidated the binding modes of A3 and A9 with Cyp51. These compounds with low haemolytic activity and favourable ADME/T properties are promising for the development of novel antifungal agents.

Exploration of Baicalein-Core Derivatives as Potent Antifungal Agents: SAR and Mechanism Insights.

Baicalein (BE), the major component of Scutellaria Baicalensis, exhibited potently antifungal activity against drug-resistant Candida albicans, and strong inhibition on biofilm formation. Therefore, a series of baicalein-core derivatives were designed and synthesized to find more potent compounds and investigate structure-activity relationship (SAR) and mode of action (MoA). Results demonstrate that A4 and B5 exert a more potent antifungal effect (MIC80 = 0.125 µg/mL) than BE (MIC80 = 4 µg/mL) when used in combination with fluconazole (FLC), while the MIC80 of FLC dropped from 128 µg/mL to 1 µg/mL. SAR analysis indicates that the presence of 5-OH is crucial for synergistic antifungal activities, while o-dihydroxyls and vic-trihydroxyls are an essential pharmacophore, whether they are located on the A ring or the B ring of flavonoids. The MoA demonstrated that these compounds exhibited potent antifungal effects by inhibiting hypha formation of C. albicans. However, sterol composition assay and enzymatic assay conducted in vitro indicated minimal impact of these compounds on sterol biosynthesis and Eno1. These findings were further confirmed by the results of the in-silico assay, which assessed the stability of the complexes. Moreover, the inhibition of hypha of this kind of compound could be attributed to their effect on the catalytic subunit of 1,3-ß-d-glucan synthase, 1,3-ß-d-glucan-UDP glucosyltransferase and glycosyl-phosphatidylinositol protein, rather than inhibiting ergosterol biosynthesis and Eno1 activity by Induced-Fit Docking and Molecular Dynamics Simulations. This study presents potential antifungal agents with synergistic effects that can effectively inhibit hypha formation. It also provides new insights into the MoA.

Synthesis of baicalein derivatives and evaluation of their antiviral activity against arboviruses.

Natural plant-derived baicalein which is extracted from Chinese herb Scutellaria baicalensis Georgi belongs to the flavonoid compounds and possesses multiple pharmacological activities. In this study, we designed and synthesized new series of derivatives of baicalein (BE) through catalytic coupling reactions, and screened for their antiviral activity against arboviruses including Chikungunya virus (CHIKV), West Nile virus (WNV) or Zika virus (ZIKV). Our results revealed for the first time that BE and its derivatives had potent anti-CHIKV, anti-WNV and anti-ZIKV effects. And modification of 8 or 4' position could lead to obtain potent antiviral compounds against CHIKV, WNV and ZIKV with lower cytotoxicity. Among the baicalein derivatives, C3 and F3 showed the most potent antiviral activities against CHIKV, WNV and ZIKV, which were 5-10 times more potent than baicalein. Our findings will provide research basis for the development of baicalein derivatives as effective antiviral agents.

Design, synthesis, and in vitro evaluation of novel antifungal triazoles containing substituted 1,2,3-triazole-methoxyl side chains.

In order to develop new triazole derivatives, we optimized the lead compound a6 by structural modifications to obtain a series of (2R,3R)-3-((1-substituted-1H-1,2,3-triazol-4-yl) methoxy)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl) butan-2-ol, compounds 5-36. Most of the target compounds exhibited excellent in vitro antifungal activity against Candida albicans 10231 and Candida glabrata 537 with MIC ≤ 0.125 µg/mL. Of particular note, compounds 6, 22, 28, 30 and 36 were highly active against Candida neoformans 32609 with MIC ≤ 0.125 µg/mL and showed broad-spectrum antifungal activity including against fluconazole-resistant Candida auris 891. In addition, compounds 6 and 22 demonstrated inhibitory effects on filamentation in the azole-resistant C. albicans isolate. Moreover, compounds 6 and 22 were minimally toxic to HUVECs and possessed weak inhibitory effects on the human CYP3A4 and CYP2D6. SARs and docking study further indicated that ortho-substituted groups in the terminal phenyl ring can promote the compounds to improve their antifungal activity.

[Composition and histopathological features of prostatic calculi in patients with benign prostatic hyperplasia].

OBJECTIVE: To analyze the composition of prostatic calculus in patients with BPH and explore its pathogenic factors and histopathological characteristics. METHODS: Strictly following the inclusion and exclusion criteria, we included in this retrospective study 580 cases of bipolar transurethral plasma kinetic prostatectomy (TUPKP) performed in our hospital from May 2015 to May 2019, analyzed the histopathological and calculus-composition features of the patients with BPH complicated by prostatic calculi (the BPH+PC group) and the histopathological data of those with BPH only (the BPH group). We compared the related factors between the two groups of patients and performed uni- and multivariate logistic regression analyses of the data on those in the BPH+PC group. RESULTS: The incidence rate of chronic inflammation was significantly higher in the BPH+PC than in the BPH group (83.1% vs 61.1%, P < 0.05), 90% of the cases moderate to severe and 81% with inflammatory cells mainly distributed in the prostate gland in the BPH+PC group, and 74% with inflammatory cells chiefly distributed in the prostate gland and stroma in the BPH group, with statistically significant difference between the two groups (P < 0.05). Prostatic calculi were found in 302 (52.1%) of the patients, including 71 cases of simple calculi (23.5%) and 231 cases of mixed calculi (76.5%). As for the chemical composition, calcium oxalate was detected in 212 cases (70.2%), carbonate apatite in 206 (68.2%), magnesium ammonium phosphate in 158 (52.3%), and uric acid calculi in 19 (6.3%). The calculus composition was not correlated with the age of the patients. There were statistically significant differences between the two groups of patients in age, prostate volume and IPSS (P < 0.05), but not in the PSA level, postvoid residual urine volume (PRV) or maximum urinary flow rate (Qmax) (P > 0.05). Logistic regression analyses showed that prostatic calculus was significantly correlated with chronic inflammation of the prostate, the patient's age and IPSS (P < 0.05) but not with the PSA level, PRV or Qmax (P > 0.05). CONCLUSIONS: Prostatic calculus has a high incidence in BPH patients and varies widely in composition, chiefly consisting of calcium oxalate and carbonate apatite. The major factors contributing to prostatic calculi include chronic inflammation of the prostate (primarily the severe type), age and BPH. Prostate calculi may aggravate lower urinary tract symptoms, especially urinary storage symptoms, in patients with BPH, but not significantly affect the PSA level.？.

Design, synthesis, and structure-activity relationship studies of novel triazole agents with strong antifungal activity against Aspergillus fumigatus.

The incidence of invasive fungal infections has dramatically increased for several decades. In order to discover novel antifungal agents with broad spectrum and anti-Aspergillus efficacy, a series of novel triazole derivatives containing 1,2,3-benzotriazin-4-one was designed and synthesized. Most of the compounds exhibited stronger in vitro antifungal activities against tested fungi than fluconazole. Moreover, 6m showed comparable antifungal activity against seven pathogenic strains as voriconazole and albaconazole, especially against Aspergillus fumigatus (MIC = 0.25 µg/ml), and displayed moderate antifungal activity against fluconazole-resistant strains of Candida albicans. A clear SAR study indicated that compounds with groups at the 7-position resulted in novel antifungal triazoles with more effectiveness and a broader-spectrum.

Hexafluorotitanic acid-assisted synthesis of large-sized, ultrathin titania nanosheets as multifunctional and high-performance photocatalysts.

A fast cyclohexanol solvothermal pathway was developed to prepare highly dispersed anatase titania (TiO2) nanosheets with an edge length of ∼800 nm and a thickness of ∼6 nm. Under the synergistic control of hexafluorotitanic acid and cyclohexanol, the exposed 001 facets reached ∼98.5% on the TiO2 nanosheets obtained by the treatment at 180 °C for 150 min. Moreover, it was found that the phase transformation and structural development drastically occurred during the solvothermal treatment. When used as a catalyst for photodegradation of rhodamine B, the TiO2 nanosheets exhibited a good recycling stability and a much higher photocatalytic degradation rate (nearly 99% degradation within 2.5 h) than the commercial P25 (93.6%). After being uniformly loaded with 4 wt.% of the Pt nanoparticles, the TiO2 nanosheets displayed a photocatalytic hydrogen production rate of 2.239 mmol g-1 h-1 under simulated solar light, which was much higher than the pristine TiO2 nanosheets (0.045 mmol g-1 h-1) as well as most of the reported TiO2-based photocatalysts. The remarkable photocatalytic activity and good stability of the TiO2 nanosheets with highly exposed 001 facets would make them find potential applications in both water treatment and hydrogen generation from water splitting under solar light.

Design, synthesis, and in vitro evaluation of novel triazole analogues featuring isoxazole moieties as antifungal agents.

In order to develop novel antifungal agents, based on our previous work, a series of (2R,3R)-3-((3-substitutied-isoxazol-5-yl)methoxy)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl) butan-2-ol (a1-a26) were designed and synthesized. All of the compounds exhibited good in vitro antifungal activities against eight human pathogenic fungi. Among them, compound a6 showed excellent inhibitory activity against Candida albicans and Candida parasilosis with MIC80 values of 0.0313 µg/mL. In addition, compounds a6, a9, a12, a13 and a14 exhibited moderate inhibitory activities against fluconazole-resistant isolates with MIC80 values ranging from 8 µg/mL to 16 µg/mL. Furthermore, compounds a6, a12 and a23 exhibited low inhibition profiles for CYP3A4. Clear SARs were analyzed, and the molecular docking experiment was carried out to further investigate the relationship between a6 and the target enzyme CYP51.

Design and synthesis of novel desfluoroquinolone-aminopyrimidine hybrids as potent anti-MRSA agents with low hERG activity.

Despite the fact that the introduction of a fluorine atom at the C-6 position has resulted in the evolution of fluoroquinolones, fluoroquinolone-induced cardiac toxicity has drawn considerable attention. In this context, desfluoroquinolone-based hybrids with involvement of C-7 aminopyrimidine functional group were designed and synthesized. The biological results showed majority of these hybrids still demonstrated potent anti-MRSA activity with MIC values between 0.38 and 1.5 µg/mL, despite the lack of the typical C-6 fluorine atom. Particularly, the most active B14 exhibited activities at submicromolar concentrations against a panel of MRSA strains including vancomycin-intermediate strains, levofloxacin-resistant isolates, and linezolid-resistant isolates, etc. As expected, it also displayed highly selective toxicity toward bacterial cells and low hERG inhibition. Further resistance development study indicated MRSA is unlikely to acquire resistance against B14. The docking study revealed that two hydrogen bonds were formed between the C-7 substituent and the surrounding DNA bases, which might contribute to overcome resistance by reducing the dependence on the magnesium-water bridge interactions with topoisomerase IV. These results indicate a promising strategy for developing new antibiotic quinolones to combat multidrug resistance and cardiotoxicity.

Synthesis of phthalide derivatives and evaluation on their antiplatelet aggregation and antioxidant activities.

As part of our continuing efforts to discover structurally interesting bioactive phthalide derivatives, 23 of them with a structure incorporating thiophen or halogens were designed and synthesized, 17 of which are previously unreported. In vitro antiplatelet aggregation activity screening showed that 14b could significantly inhibit platelet aggregation induced by arachidonic acid, compared with edaravone (p < 0.01). Meanwhile, oxidative damage models using SH-SY5Y and PC12 cells induced by H2O2 were built to evaluate the antioxidant activity of the phthalide derivatives. In SH-SY5Y cells, compared with aspirin, 1a significantly increased the relative cell survival rate (p < 0.05). Compared with edaravone, 1a (p < 0.01) and 15b (p < 0.05) significantly increased the relative cell survival rate. In PC12 cells, 1a (p < 0.01), 15b (p < 0.01), and 12a (p < 0.05) remarkably increased the cell survival rate compared with edaravone. The present study identified lead structures to develop potential anti-ischemic stroke agents.

Recent advances in natural antifungal flavonoids and their derivatives.

The resistance of pathogenic fungi and failure of drug therapy increased dramatically. Numerous studies have reported the individual or synergistic antifungal potency of natural and synthesized flavonoids, especially against drug-resistant fungi. This brief review summarizes the structure and individual or synergistic antifungal activity of natural and synthesized flavonoids (literatures mainly cover the past 10 years 2009-2019), with a special focus on the antifungal spectra, structure-activity relationship and mechanisms of actions. These may contribute to a better understanding of flavonoids as multi-target agents in the treatment of mycoses and provide some ideas on the development of novel flavonoids-based antifungals.

Folate of pregnant women after a nationwide folic acid supplementation in China.

Folate insufficiency during the periconceptional period increases the risk of neural tube defects (NTDs) in offspring, and folic acid supplementation substantially reduces the risk. Widespread large-scale folic acid supplementation (0.4-mg folic acid tablet) has been adopted as a main strategy to prevent NTDs in China since 2009. We examined folate concentrations in plasma and red blood cells (RBCs) of pregnant women and the factors associated with blood folate concentrations in a population with a high prevalence of NTDs in northern China. A cross-sectional survey was conducted in 2014, and 1,107 pregnant women were recruited from 11 county or city maternal and child health centres across Shanxi province. Microbiological assays were used to determine folate concentrations. Factors associated with blood folate insufficiency were identified. The median (25th and 75th percentiles) folate concentrations were 28.4 (17.6, 45.2) nmol L-1 and 1,001.2 (658.7, 1,402.5) nmol L-1 in plasma and RBCs, respectively. According to the proposed RBC (906 nmol L-1 ) concentrations for optimal NTD prevention, 42.4% participants had RBC folate insufficiency. Rural women had a higher proportion of folate insufficiency than urban women. Folic acid supplementation was the only factor associated with RBC folate insufficiency. A large proportion of women had RBC folate concentrations that are not optimal for the prevention of NTDs despite free access to folic acid supplements. Actions that aim to improve folic acid supplementation compliance are needed to reach the full potential of the nationwide folic acid supplementation programme in terms of NTD prevention.

Effects of glaucocalyxin A on human liver cancer cells as revealed by GC/MS- and LC/MS-based metabolic profiling.

Studies have documented the potential antitumor activities of glaucocalyxin A (GLA), an ent-kaurene diterpenoid isolated from Rabdosia japonica. However, the metabolic mechanism underlying the antitumor activity of GLA remains largely unknown. The effects of GLA on the metabolome of human liver cancer cells using GC/MS- and LC/MS-based metabolic profiling have been investigated. An untargeted metabolomics approach in conjunction with orthogonal projection to latent structures-discriminant analysis (OPLS-DA) has been developed to characterize the metabolic modifications induced by GLA treatment in human hepatoma cell line SMMC7721. Results demonstrated that cells cultured in the presence or absence of GLA displayed different metabolic profiles: the treatment induced an increased purine metabolism, pyrimidine metabolism, and sphingolipid metabolism and a decreased amino acid metabolism. At the same time, GLA treatment induced cell apoptosis and cell cycle arrested at G2/M phase in a dose-dependent manner. In addition, two representative apoptosis-inducing cytotoxic agents were selected as positive control drugs to validate the reasonableness and accuracy of our metabolomic investigation on GLA. The study displayed a systemic metabolic alteration induced by GLA treatment, showing the impaired physiological activity of SMMC7721 cells, which also indicated anti-proliferative and apoptotic effects of GLA. In the meantime, GC/MS- and LC/MS-based metabolomics applied to cell culture enhanced our current understanding of the metabolic response to GLA treatment and its mechanism; such an approach could be transferred to study the mechanism of other anticancer drugs. Graphical abstract A systemic metabolic alteration induced by glaucocalyxin A (GLA) treatment of SMMC-7721 cells.

Design, synthesis, and SAR study of 3-(benzo[d][1,3]dioxol-5-yl)-N-benzylpropanamide as novel potent synergists against fluconazole-resistant Candida albicans.

Based on our previous discovery and SAR study on the lead compounds 7d, 5 and berberine which can significantly enhance the susceptibility of fluconazole against fluconazole-resistant Candida albicans, a series of 3-(benzo[d][1,3]dioxol-5-yl)-N-(substituted benzyl)propanamides were designed, synthesized, and evaluated for their in vitro synergistic activity in combination with fluconazole. The series 2a-f were designed by replacing the amide moiety of the lead compound 7d with retro-amide moiety, and compounds 2a and 2b showed more activity than the lead 7d. Furthermore, introducing biphenyl moiety into series 2d-f afforded series 3a-r, most of which exhibited significantly superior activity to the series 2d-f. Especially, compound 3e, at a concentration of 1.0µg/ml, can enhance the susceptibility of fluconazole against fluconazole-resistant Candida albicans from 128.0µg/ml to 0.125-0.25µg/ml. A clear SAR of the compounds is discussed.

Design, synthesis, and in vitro evaluation of novel antifungal triazoles.

Twenty-nine novel triazole analogues of ravuconazole and isavuconazole were designed and synthesized. Most of the compounds exhibited potent in vitro antifungal activities against 8 fungal isolates. Especially, compounds a10, a13, and a14 exhibited superior or comparable antifungal activity to ravuconazole against all the tested fungi. Structure-activity relationship study indicated that replacing 4-cyanophenylthioazole moiety of ravuconazole with fluorophenylisoxazole resulted in novel antifungal triazoles with more effectiveness and a broader-spectrum.

Chemical constituents from the rhizome of Polygonum paleaceum and their antifungal activity.

A new compounds neopaleaceolactoside (1), along with nine known compounds phyllocoumarin (2), quercetin (3), quercitrin (4), quercetin-3-methyl ether (5), vincetoxicoside B (6), isoquercitrin (7), kaempferol (8), (-)-epicatechin (9), and chlorogenic acid (10), was isolated from Polygonum paleaceum Wall. Their chemical structures were established based on one-dimensional and two-dimensional nuclear magnetic resonance techniques, mass spectrometry and by comparison with spectroscopic data reported. Some selected compounds were screened for their antifungal activity. Quercetin (3), vincetoxicoside B (6), kaempferol (8), and (-)-epicatechin (9) showed synergistic antifungal activities with the FICI values <0.5. A preliminary structure-activity relationship could be observed that free 3-OH in the structure of flavonoids was important for synergistic antifungal activity.

Hepcidin and iron metabolism in the pathogenesis of prostate cancer.

PURPOSE: To investigate the relationship between Hepcidin and iron metabolism, and cell proliferation, migration, and apoptosis in prostate cancer cells. METHODS: PC3 prostate cancer cells were cultured in vitro and divided into the control group, Hepcidin overexpression group, and Hepcidin low expression group. Prostate specific antigen (PSA) and soluble transferrin receptor (sTfR) levels were measured by ELISA. The levels of the Hepcidin receptor membrane transporter, Ferroportin, were determined by Western blot. The intracellular iron distribution was determined by immunofluorescence assay. The cell proliferation rate was determined by MTT assay. Cell migration was measured by wound healing assay. Apoptosis was measured by flow cytometry. RESULTS: Compared with the control group, higher PSA level (p<0.05), lower sTfR level (p<0.05), lower Ferroportin level (p<0.05), lower intracellular iron level (p<0.05), higher cell proliferation and migration rate, and lower apoptotic rate (p<0.05) were found in the Hepcidin overexpression group. The opposite results were found in the Hepcidin low expression group. CONCLUSIONS: Hepcidin is highly expressed in prostate cancer cells, and can regulate cell proliferation, migration, and apoptosis by increasing intracellular iron transportation.