Evaluation of Blue Honeysuckle Berries (Lonicera caerulea L.) Dried at Different Temperatures: Basic Quality, Sensory Attributes, Bioactive Compounds, and In Vitro Antioxidant Activity.

This study aims to comprehensively investigate the effects of hot-air dehydration on the quality of blue honeysuckle berries (Lonicera caerulea L.). The results demonstrated that drying with hot air at 40-65 °C for 7-72 h resulted in blue honeysuckle berries with a moisture content of 0.21-1.10 g H2O/g dry weight. Generally, low to medium temperatures (40-55 °C) showed a better effect on the quality than high temperatures (60-65 °C). Specifically, drying at 40 °C exclusively resulted in better retention of cuticular wax, the best sensory appearance, and the highest total phenolic content. Drying at 45 °C and 50 °C resulted in the highest antioxidant capacity and the optimal sensory flavor. Drying at 55 °C led to the highest soluble solid/acid ratio, ascorbic acid concentration, total flavonoid, and total anthocyanin. The work introduces an innovative raw berry product and provides a comprehensive practical and theoretical framework for convective dehydration of blue honeysuckle berries.

Discovery and Optimization of Selective Brain-Penetrant EBP Inhibitors that Enhance Oligodendrocyte Formation.

The inhibition of emopamil binding protein (EBP), a sterol isomerase within the cholesterol biosynthesis pathway, promotes oligodendrocyte formation, which has been proposed as a potential therapeutic approach for treating multiple sclerosis. Herein, we describe the discovery and optimization of brain-penetrant, orally bioavailable inhibitors of EBP. A structure-based drug design approach from literature compound 1 led to the discovery of a hydantoin-based scaffold, which provided balanced physicochemical properties and potency and an improved in vitro safety profile. The long half-lives of early hydantoin-based EBP inhibitors in rodents prompted an unconventional optimization strategy, focused on increasing metabolic turnover while maintaining potency and a brain-penetrant profile. The resulting EBP inhibitor 11 demonstrated strong in vivo target engagement in the brain, as illustrated by the accumulation of EBP substrate zymostenol after repeated dosing. Furthermore, compound 11 enhanced the formation of oligodendrocytes in human cortical organoids, providing additional support for our therapeutic hypothesis.

Long-Term Efficacy Analysis of Surgical Resection of 70 Primary Right Heart Tumors.

INTRODUCTION: The aim of the study was to investigate the clinical characteristics, surgical treatment, and long-term efficacy of primary right heart tumors. METHODS: This study is retrospective analysis of the clinical data of 70 patients with primary right heart tumors admitted to our department between 1980 and 2022 (observation group) and 70 patients with left heart tumors during the same period (control group). The surgical treatment was performed under cardiopulmonary bypass after differential diagnosis by echocardiography, cardiac CTA, and PET-CT before the surgery. The perioperative characteristics, recurrence rate, and long-term survival rates of right heart tumor versus left heart tumor were compared. RESULTS: The most common pathological types of right heart tumors were myxoma (60%), lipoma (8.57%), and papillary elastofibroma (7.14%). During the perioperative period, there were 1 case of systemic embolism in the observation group, compared with 6 in the control group (p = 0.026), 13 cases of malignant tumor in the observation group versus 1 in the control group (p = 0.01). During the follow-up period, there were 15 cases of tumor recurrence and 17 cases of death in the observation group versus 4 (p = 0.002) and 7 in the control group (p = 0.006), comparatively. CONCLUSION: Compared with left heart tumors, primary right heart tumors had a higher incidence of malignant tumors and a lower risk of systemic embolism during perioperative period. During the follow-up period, primary right heart tumors had a higher rate of tumor recurrence and a lower long-term survival rate.

[Research on the method of loading exosomes onto absorbable stents].

Objective: To explore a method of loading exosomes onto absorbable stents. Methods: By building a stent-(3-aminopropyl) triethoxysilane-1, 2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol) 5000]-exosomes connection, the exosomes were loaded onto absorbable stents to obtained the exosome-eluting absorbable stents. The surface conditions of the stents and absorption of exosomes were observed by scanning electron microscope and identified through the time-of-flight mass spectrometry; the roughness of the stents' surfaces was observed by atomic force microscope; the appearances and sizes of the stents were observed by stereomicroscope; and the radial force was tested by tensile test machine. The absorbable stents were used as control. Results: The scanning electron microscope observation showed that the exosome-eluting absorbable stents had some small irregular cracks on the surface where many exosomes could be seen. The atomic force microscopy observation showed that within the range of 5 µm 2, the surface roughness of the absorbable stents was ±20 nm, while the surface roughness of the exosome-eluting absorbable stents was ±70 nm. In the results of time-of-flight mass spectrometry, both the exosome-eluting absorbable stents and exosomes had a peak at the mass charge ratio of 81 (m/z 81), while the absorbable stents did not have this peak. The peak of exosome-eluting absorbable stents at m/z 73 showed a significant decrease compared to the absorbable stents. The stereomicroscope observation showed that the sizes of exosome-eluting absorbable stents met standards and the surfaces had no cracks, burrs, or depressions. The radial force results of the exosome-eluting absorbable stents met the strength standards of the original absorbable stent. Conclusion: By applying the chemical connection method, the exosomes successfully loaded onto the absorbable stents. And the sizes and radial forces of this exosome-eluting absorbable stents meet the standards of the original absorbable stents.

Apolipoprotein L1 (APOL1) renal risk variant-mediated podocyte cytotoxicity depends on African haplotype and surface expression.

Homozygous Apolipoprotein L1 (APOL1) variants G1 and G2 cause APOL1-mediated kidney disease, purportedly acting as surface cation channels in podocytes. APOL1-G0 exhibits various single nucleotide polymorphisms, most commonly haplotype E150K, M228I and R255K ("KIK"; the Reference Sequence is "EMR"), whereas variants G1 and G2 are mostly found in a single "African" haplotype background ("EIK"). Several labs reported cytotoxicity with risk variants G1 and G2 in KIK or EIK background haplotypes, but used HEK-293 cells and did not verify equal surface expression. To see if haplotype matters in a more relevant cell type, we induced APOL1-G0, G1 and G2 EIK, KIK and EMR at comparable surface levels in immortalized podocytes. G1 and G2 risk variants (but not G0) caused dose-dependent podocyte death within 48h only in their native African EIK haplotype and correlated with K+ conductance (thallium FLIPR). We ruled out differences in localization and trafficking, except for possibly greater surface clustering of cytotoxic haplotypes. APOL1 surface expression was required, since Brefeldin A rescued cytotoxicity; and cytoplasmic isoforms vB3 and vC were not cytotoxic. Thus, APOL1-EIK risk variants kill podocytes in a dose and haplotype-dependent manner (as in HEK-293 cells), whereas unlike in HEK-293 cells the KIK risk variants did not.

Myricetin exerts anti-biofilm activity and attenuates osteomyelitis by inhibiting the TLR2/MAPK pathway in experimental mice.

AIMS: To evaluate the potential of Myricetin against S.aureus induced osteomyelitis. BACKGROUND: Osteomyelitis is infected condition of bone by micro-organisms. The mitogen-activated protein kinase (MAPK), inflammatory cytokines and Toll-like receptor-2 (TLR-2) pathway are mainly involved in osteomyelitis. Myricetin is a plant-food derived flavonoid which shows anti-inflammatory activity. OBJECTIVE: In the present study, we evaluated the potential of Myricetin against S.aureus induced osteomyelitis. MC3T3-E1 cells were used for in vitro studies. METHOD: Murine model of osteomyelitis was developed in BALB/c mice by injecting S.aureus in the medullary cavity of the femur. The mice were studied for bone destruction, anti-biofilm activity, osteoblast growth markers alkaline phosphatase (ALP), osteopontin (OCN) and collagen type-I (COLL-1) were studied by RT-PCR, ELISA analysis for levels of proinflammatory factors CRP, IL-6 and IL-1ß. Expression of proteins by Western blot analysis and anti-biofilm effect by Sytox green dye fluorescence assay. Target confirmation was done by performing in silico docking analysis. RESULTS: Myricetin reduced bone destruction in osteomyelitis induced mice. The treatment decreased bone levels of ALP, OCN, COLL-1 and TLR2. Myricetin decreased serum levels of CRP, IL-6 and IL-1ß. The treatment suppressed activation of MAPK pathway and showed anti-biofilm effect. Docking studies suggested high binding affinity of Myricetin with MAPK protein in silico, by showing lower binding energies. CONCLUSION: Myricetin suppresses osteomyelitis by inhibiting ALP, OCN, COLL-1 via the TLR2 and MAPK pathway involving inhibition of biofilm formation. In silico studies suggested MAPK as potential binding protein for myricetin.

Cryo-EM reveals an unprecedented binding site for NaV1.7 inhibitors enabling rational design of potent hybrid inhibitors.

The voltage-gated sodium (NaV) channel NaV1.7 has been identified as a potential novel analgesic target due to its involvement in human pain syndromes. However, clinically available NaV channel-blocking drugs are not selective among the nine NaV channel subtypes, NaV1.1-NaV1.9. Moreover, the two currently known classes of NaV1.7 subtype-selective inhibitors (aryl- and acylsulfonamides) have undesirable characteristics that may limit their development. To this point understanding of the structure-activity relationships of the acylsulfonamide class of NaV1.7 inhibitors, exemplified by the clinical development candidate GDC-0310, has been based solely on a single co-crystal structure of an arylsulfonamide inhibitor bound to voltage-sensing domain 4 (VSD4). To advance inhibitor design targeting the NaV1.7 channel, we pursued high-resolution ligand-bound NaV1.7-VSD4 structures using cryogenic electron microscopy (cryo-EM). Here, we report that GDC-0310 engages the NaV1.7-VSD4 through an unexpected binding mode orthogonal to the arylsulfonamide inhibitor class binding pose, which identifies a previously unknown ligand binding site in NaV channels. This finding enabled the design of a novel hybrid inhibitor series that bridges the aryl- and acylsulfonamide binding pockets and allows for the generation of molecules with substantially differentiated structures and properties. Overall, our study highlights the power of cryo-EM methods to pursue challenging drug targets using iterative and high-resolution structure-guided inhibitor design. This work also underscores an important role of the membrane bilayer in the optimization of selective NaV channel modulators targeting VSD4.

Acute Type A Aortic Dissection and Late Pregnancy: What Should We Do?

ABSTRACT Introduction: Acute type A aortic dissection (AAAD) in late pregnancy is a rare but severe disease. Lack of clinical experience is the main cause of high mortality. This study tries to investigate the multidisciplinary therapeutic strategy for these patients. Case presentation: We reported three patients with AAAD in late pregnancy. Sudden chest pain was the main clinical symptom before operation. All three patients and their newborns survived through multidisciplinary approach in diagnosis and treatment. No serious complications occurred during the mid-term follow-up. Conclusion: Multidisciplinary diagnosis and treatment strategy play a crucial role in saving the lives of pregnant women with AAAD.

Acute Type A Aortic Dissection and Late Pregnancy: What Should We Do?

INTRODUCTION: Acute type A aortic dissection (AAAD) in late pregnancy is a rare but severe disease. Lack of clinical experience is the main cause of high mortality. This study tries to investigate the multidisciplinary therapeutic strategy for these patients. CASE PRESENTATION: We reported three patients with AAAD in late pregnancy. Sudden chest pain was the main clinical symptom before operation. All three patients and their newborns survived through multidisciplinary approach in diagnosis and treatment. No serious complications occurred during the mid-term follow-up. CONCLUSION: Multidisciplinary diagnosis and treatment strategy play a crucial role in saving the lives of pregnant women with AAAD.

Enhanced catalytic reduction of p-nitrophenol and azo dyes on copper hexacyanoferrate nanospheres decorated copper foams.

Catalytic reduction of nitroaromatic compounds using low-cost non-precious metal containing catalyst remains an essential topic in wastewater treatment. Herein, copper hexacyanoferrate nanospheres decorated copper foams (CF) were prepared by a facile method, and it was used as structured catalysts for the reduction of p-nitrophenol (p-NP) and azo dyes. The catalyst obtained by calcination at 200 °C shows the highest catalytic activity, with an almost complete reduction of p-NP within 3 min with a rate of 2.057 min-1 at room temperature, and it exhibited excellent reusability in successive 6 cycles. The effects of temperature, initial concentration, pH, and flow rate on p-NP reduction were investigated. Moreover, the mechanistic investigation revealed that fast electron transfer ability and enhanced adsorption for p-NP contributed to its enhanced catalytic performances. This work put forward an efficient approach for the construction of structured catalysts with enhanced performance in catalytic reduction applications.

An efficient and scalable data analysis solution for automated electrophysiology platforms.

Ion channels are drug targets for neurologic, cardiac, and immunologic diseases. Many disease-associated mutations and drugs modulate voltage-gated ion channel activation and inactivation, suggesting that characterizing state-dependent effects of test compounds at an early stage of drug development can be of great benefit. Historically, the effects of compounds on ion channel biophysical properties and voltage-dependent activation/inactivation could only be assessed by using low-throughput, manual patch clamp recording techniques. In recent years, automated patch clamp (APC) platforms have drastically increased in throughput. In contrast to their broad utilization in compound screening, APC platforms have rarely been used for mechanism of action studies, in large part due to the lack of sophisticated, scalable analysis methods for processing the large amount of data generated by APC platforms. In the current study, we developed a highly efficient and scalable software workflow to overcome this challenge. This method, to our knowledge the first of its kind, enables automated curve fitting and complex analysis of compound effects. Using voltage-gated sodium channels as an example, we were able to immediately assess the effects of test compounds on a spectrum of biophysical properties, including peak current, voltage-dependent steady state activation/inactivation, and time constants of activation and fast inactivation. Overall, this automated data analysis method provides a novel solution for in-depth analysis of large-scale APC data, and thus will significantly impact ion channel research and drug discovery.

Combination of kaempferol and azithromycin attenuates Staphylococcus aureus-induced osteomyelitis via anti-biofilm effects and by inhibiting the phosphorylation of ERK1/2 and SAPK.

Osteomyelitis is bacterial infection of bone, commonly caused by Staphylococcus aureus. This work aims to study the potential of azithromycin and kaempferol against chronic osteomyelitis induced by azithromycin-resistant Staphylococcus aureus (ARSA). It was noticed that rats tolerated the treatments with no diarrhoea or weight loss; also, no deaths were observed in rats. The treatment by azithromycin alone failed to inhibit bacterial growth and also had no effect on the infection condition of bone, although the treatment decreased the levels of interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α), but did not improve the oxidative stress levels. Kaempferol monotherapy slightly inhibited bacterial growth and bone infection; the treatment also inhibited the levels of IL-6 and (TNF-α). The treatment also improved the antioxidant status. However, the combined treatment of azithromycin and kaempferol significantly suppressed bacterial growth and bone infection and modulated oxidative stress. In vitro, the combined treatment inhibited the levels of IL-6 and TNF-α, and also suppressed the phosphorylation of ERK1/2 and stress-activated protein kinase (SAPK). The combined treatment also showed anti-biofilm activity in ARSA. The combination attenuates ARSA-induced osteomyelitis in rats compared with their treatments alone by reducing oxidative stress, inhibiting the phosphorylation of ERK1/2 and SAPK and inhibiting biofilm formation.

Successful application of extracorporeal circulation compression perfusion in the treatment of diabetic foot: a retrospective cross-sectional study.

OBJECTIVE: To investigate the clinical effect of extracorporeal circulation compression perfusion (ECCP) in the treatment of diabetic foot. METHODS: We retrospectively evaluated 89 patients with diabetic foot admitted from January 2017 to April 2019. The patients were grouped according to whether they received ECCP treatment; experimental group: 27 patients, controls: 62 patients. After applying the inclusion criteria and exclusion criteria, there were 21 patients in the experimental group and 21 patients in the control group. Foot microcirculation was evaluated by measuring the percutaneous oxygen partial pressure (TcPO2) and infrared thermography (IRT). Wound healing time and ulcer recurrence rate 1 year after discharge were compared between the groups. RESULTS: TcPO2 and IRT values in the experimental group differed significantly compared with the control group. Foot ulcer healing time in the experimental group was shorter than that in the control group (17.10 ± 3.08 days vs 25.38 ± 4.40 days, respectively), and the recurrence rate after 1 year in the experimental group was lower than that in the control group (2/21, 9.5% vs 9/21, 42.8%, respectively). CONCLUSION: ECCP improved foot microcirculatory perfusion in diabetic foot treatment. ECCP has clinical practicality and may accelerate wound healing speed and reduce ulcer recurrence.

Nanoscale Au@SiO2-drug/VEGF as an in vivo probe for osteosarcoma diagnosis and therapy.

Osteosarcoma is a common primary bone malignancy, with a 5-year survival rate of only 20-30% in patients undergoing surgical treatment. Thus, it is important to identify novel methods for diagnosing and treating osteosarcoma, which was the aim of the present study. Vascular endothelial growth factor (VEGF) was used as the tumor-targeting protein to synthesize a multifunctional core-shell nanostructure, Au@SiO2-drug/VEGF, in which the drug can be indocyanine green (ICG; as an optical tracer) or doxorubicin (DOX; as a chemotherapeutic agent). With VEGF as the osteosarcoma-targeting protein, Au exhibited optimal photothermal transformation performance, while SiO2 served as the carrier for the drug. Au@SiO2-ICG/VEGF nanoparticles (NPs) were evaluated for imaging and for the monitoring of drug accumulation in a tumor region in mice. Once the optimal drug accumulation was achieved, combined treatment of osteosarcoma (chemotherapy and photothermal therapy) was assessed. In the perioperative period associated with minimal invasive embolization of osteosarcoma, photothermal therapy and chemotherapy were applied for osteosarcoma diagnosis using Au@SiO2-DOX/VEGF NPs. Taken together, the results of the present study provide a promising strategy for tumor detection prior to surgical treatment to improve the survival outcome of patients with osteosarcoma.

Structural Pharmacology of Voltage-Gated Sodium Channels.

Voltage-gated sodium (NaV) channels initiate and propagate action potentials in excitable tissues to mediate key physiological processes including heart contraction and nervous system function. Accordingly, NaV channels are major targets for drugs, toxins and disease-causing mutations. Recent breakthroughs in cryo-electron microscopy have led to the visualization of human NaV1.1, NaV1.2, NaV1.4, NaV1.5 and NaV1.7 channel subtypes at high-resolution. These landmark studies have greatly advanced our structural understanding of channel architecture, ion selectivity, voltage-sensing, electromechanical coupling, fast inactivation, and the molecular basis underlying NaV channelopathies. NaV channel structures have also been increasingly determined in complex with toxin and small molecule modulators that target either the pore module or voltage sensor domains. These structural studies have provided new insights into the mechanisms of pharmacological action and opportunities for subtype-selective NaV channel drug design. This review will highlight the structural pharmacology of human NaV channels as well as the potential use of engineered and chimeric channels in future drug discovery efforts.

Mid-term follow-up of aortic valve replacement for bicuspid aortic valve.

OBJECTIVE: The purpose of this study was to evaluate the mid-term outcome of aortic valve replacement for bicuspid aortic valve and tricuspid aortic valve and the related risk factors. METHODS: From January 2014 to June 2019, 177 tricuspid aortic valve patients and 101 bicuspid aortic valve patients who underwent aortic valve replacement in our hospital were collected. 1:1 propensity score matching analysis was used to control the bias in patient selection. The perioperative and follow-up data between the two groups were compared. Independent risk factors which were associated with the continued dilatation of the ascending aorta were identified by univariate or multivariate logistic regression analysis. RESULTS: After the matching procedure, 160 patients were included in the analysis (80 in each group). Baseline characteristics, intraoperative, and perioperative outcomes were similar between the two groups (all p > 0.05). Moreover, 67 patients in the tricuspid aortic valve group and 70 in the bicuspid aortic valve group completed the follow-up. The ascending aorta change, annual change rate, and the proportion of continuous dilation of ascending aorta in bicuspid aortic valve group were significantly higher than those in the tricuspid aortic valve group (p < 0.05). Multivariate logistic regression analysis showed that type 1 in bicuspid aortic valve (OR 5.173; 95% CI 1.772, 15.101; p = 0.003), aortic regurgitation (OR 3.673; 95% CI 1.133, 11.908; p = 0.030), and aortic valve stenosis with regurgitation (OR 6.489; 95% CI 1.726, 24.404; p = 0.006) were independent risk factors for the continued dilatation of the ascending aorta in all AV patients. Furthermore, the multivariate logistic regression analysis showed that type 1 in bicuspid aortic valve (OR 5.157; 95% CI 1.053, 25.272; p = 0.043), age ≥ 40 years (OR 6.956; 95% CI 1.228, 39.410; p = 0.028), and aortic regurgitation (OR 4.322; 95% CI 1.174, 15.911; p = 0.028) were independent risk factors for the continued dilatation of the ascending aorta in bicuspid aortic valve patients. CONCLUSION: Compared with tricuspid aortic valve patients, the ascending aorta of bicuspid aortic valve patients is more likely to continue to enlarge after aortic valve replacement. Type 1 in bicuspid aortic valve, age ≥ 40 years, and aortic regurgitation were the independent risk factors.

A Non-covalent Ligand Reveals Biased Agonism of the TRPA1 Ion Channel.

The TRPA1 ion channel is activated by electrophilic compounds through the covalent modification of intracellular cysteine residues. How non-covalent agonists activate the channel and whether covalent and non-covalent agonists elicit the same physiological responses are not understood. Here, we report the discovery of a non-covalent agonist, GNE551, and determine a cryo-EM structure of the TRPA1-GNE551 complex, revealing a distinct binding pocket and ligand-interaction mechanism. Unlike the covalent agonist allyl isothiocyanate, which elicits channel desensitization, tachyphylaxis, and transient pain, GNE551 activates TRPA1 into a distinct conducting state without desensitization and induces persistent pain. Furthermore, GNE551-evoked pain is relatively insensitive to antagonist treatment. Thus, we demonstrate the biased agonism of TRPA1, a finding that has important implications for the discovery of effective drugs tailored to different disease etiologies.

Conservation and divergence in NaChBac and NaV1.7 pharmacology reveals novel drug interaction mechanisms.

Voltage-gated Na+ (NaV) channels regulate homeostasis in bacteria and control membrane electrical excitability in mammals. Compared to their mammalian counterparts, bacterial NaV channels possess a simpler, fourfold symmetric structure and have facilitated studies of the structural basis of channel gating. However, the pharmacology of bacterial NaV remains largely unexplored. Here we systematically screened 39 NaV modulators on a bacterial channel (NaChBac) and characterized a selection of compounds on NaChBac and a mammalian channel (human NaV1.7). We found that while many compounds interact with both channels, they exhibit distinct functional effects. For example, the local anesthetics ambroxol and lidocaine block both NaV1.7 and NaChBac but affect activation and inactivation of the two channels to different extents. The voltage-sensing domain targeting toxin BDS-I increases NaV1.7 but decreases NaChBac peak currents. The pore binding toxins aconitine and veratridine block peak currents of NaV1.7 and shift activation (aconitine) and inactivation (veratridine) respectively. In NaChBac, they block the peak current by binding to the pore residue F224. Nonetheless, aconitine has no effect on activation or inactivation, while veratridine only modulates activation of NaChBac. The conservation and divergence in the pharmacology of bacterial and mammalian NaV channels provide insights into the molecular basis of channel gating and will facilitate organism-specific drug discovery.

A highly active Rh1/CeO2 single-atom catalyst for low-temperature CO oxidation.

Rh1/CeO2 single-atom catalyst is highly active for CO oxidation and has the potential to serve as a multifunctional catalyst to save the usage of other noble metals in three-way catalysts. The high activity is achieved on single-atom active sites via the Mars-van Krevelen mechanism, thus avoiding CO poisoning at low temperatures.