Divergent Total Syntheses of Lycorine Alkaloids via a Sequential C-H Functionalization Strategy.

A Pd-catalyzed one-pot sequential C-H functionalization strategy was utilized to prepare four lycorine alkaloids and one pseudo-lycorine alkaloid from the common intermediate 4. By switching the followed oxidative conditions of air, DMSO/H2O/I2, and DMSO/O2, based on the Pd(PPh3)4/K2CO3/toluene catalytic system, three key intermediates 12a, 12b, and 12c with different substitution patterns could be obtained in a well-controlled manner. As a result, four natural products γ-lycorane, hippadine, anhydrolycorinone, and anhydrolycorine as well as a pseudo-lycorine alkaloid Δ(4a,10b)-6-oxodihydrolycorine were successfully synthesized within 10 steps through this divergent route.

Effects of comprehensive nursing intervention on pressure ulcer after traumatic brain injury surgery: A meta-analysis.

Pressure ulcers (PUs) are a common complication in postoperative patients with traumatic brain injury, and this study used a meta-analysis to assess the effects of comprehensive nursing applied in PUs intervention in postoperative patients with traumatic brain injury. A computerised systematic search of the PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure, Chinese Biomedical Literature Database (CBM), VIP and Wanfang databases was performed to collect publicly available articles on randomised controlled trials (RCTs) on the effects of comprehensive nursing interventions in postoperative patients with traumatic brain injury published up to August 2023. Two researchers independently completed the search and screening of the literature, extraction of data and quality assessment of the included literature based on the inclusion and exclusion criteria. Meta-analysis was performed using RevMan 5.4 software. Twenty-eight articles were finally included, for a cumulative count of 2641 patients, of which 1324 were in the intervention group and 1317 in the control group. The results of the meta-analysis showed that, compared with conventional nursing, comprehensive nursing intervention helped to reduce the incidence of PUs in postoperative patients with traumatic brain injury (5.14% vs. 19.67%, odds ratio [OR]: 0.22, 95% confidence interval [CI]: 0.16-0.29, p < 0.00001) and reduced the incidence of postoperative complications (7.87% vs. 25.84%, OR: 0.22, 95% CI: 0.11-0.43, p < 0.0001), while increasing patient satisfaction (96.67% vs. 75.33%, OR: 9.5, 95% CI: 3.63-24.88, p < 0.00001). This study concludes that a comprehensive nursing intervention applied to postoperative patients with traumatic brain injury can significantly reduce the incidence of PUs and postoperative complications as well as improve nursing satisfaction, and it is recommended for clinical promotion. However, due to the limitations of the studies' number and quality, more high-quality, large-sample RCTs are needed to further validate the conclusions of this study.

Primary nature of brown carbon absorption in a frigid atmosphere with strong haze chemistry.

Severe haze hovered over Harbin during the heating season of 2019-2020, making it one of the ten most polluted Chinese cities in January of 2020. Here we focused on the optical properties and sources of brown carbon (BrC) during the extreme atmospheric pollution periods. Enhanced formation of secondary BrC (BrCsec) was evident as relative humidity (RH) became higher, accompanied with a decrease of ozone but concurrent increases of aerosol water content and secondary inorganic aerosols. These features were generally similar to the characteristics of haze chemistry observed during winter haze events in the North China Plain, and indicated that heterogeneous reactions involving aerosol water might be at play in the formation of BrCsec, despite the low temperatures in Harbin. Although BrCsec accounted for a substantial fraction of brown carbon mass, its contribution to BrC absorption was much smaller (6 vs. 28%), pointing to a lower mass absorption efficiency (MAE) of BrCsec compared to primary BrC. In addition, emissions of biomass burning BrC (BrCBB) were inferred to increase with increasing RH, coinciding with a large drop of temperature. Since both the less absorbing BrCsec and the more absorbing BrCBB increased as RH became higher, the MAE of total BrC were largely unchanged throughout the measurement period. This study unfolded the contrast in the source apportionment results of BrC mass and absorption, and could have implications for the simulation of radiative forcing by brown carbon.

[Structural Analysis of Salivary Bacterial and Fungal Microbiome in Oral Lichen Planus Patients].

Objective: To explore the differences of oral mycobiome and bacteriome between the healthy controls (H) and oral lichen planus (OLP) patients, and the co-occurrence patterns of the salivary mycobiome and bacteriome and the association with host immunity. Methods: Saliva samples were collected from clinical OLP patients (n=35) and healthy volunteers (n=18). Microbiome DNA was extracted for bacterial 16S rRNA genes sequencing and fungal internal transcribed spacer 2 (ITS2) sequencing. Bioinformatics analysis was performed on the data.The levels of IL-17 and IL-23, two pro-inflammatory cytokines, in the saliva were examined, and their correlation with the bacteria was analyzed. Results: There was no significant difference in the overall community structure of the mycobiome and the bacteriome between OLP patients and healthy controls. The abundance of Prevotellaand Solobacterium in the saliva bacteriome was significantly increased in the OLP group (P<0.05), and the relative abundance of Candidaand Aspergillusin the saliva mycobiome was also significantly increased (P<0.05). The co-occurrence pattern of the salivary mycobiome and bacteriome showed that the aforementioned difference was not related. However, the correlation between Aspergillusand bacteria was altered in the H group and the OLP group, and co-occurrence was reduced in the latter group. The level of IL-17 in the saliva was significantly increased in the OLP group. IL-17 and clinical scores were significantly correlated with the abundance of Porphyromonas. Conclusion: The increased abundance of Prevotella, Solobacterium, Candida, and Aspergillus was associated with the pathogenesis of OLP, and the changes of the microbiome co-occurrence relationship and host immunity may be involved in the pathogenesis of OLP.

Rutaecarpine targets hERG channels and participates in regulating electrophysiological properties leading to ventricular arrhythmia.

Drug-mediated or medical condition-mediated disruption of hERG function accounts for the main cause of acquired long-QT syndrome (acLQTs), which predisposes affected individuals to ventricular arrhythmias (VA) and sudden death. Many Chinese herbal medicines, especially alkaloids, have risks of arrhythmia in clinical application. The characterized mechanisms behind this adverse effect are frequently associated with inhibition of cardiac hERG channels. The present study aimed to assess the potent effect of Rutaecarpine (Rut) on hERG channels. hERG-HEK293 cell was applied for evaluating the effect of Rut on hERG channels and the underlying mechanism. hERG current (IhERG ) was measured by patch-clamp technique. Protein levels were analysed by Western blot, and the phosphorylation of Sp1 was determined by immunoprecipitation. Optical mapping and programmed electrical stimulation were used to evaluate cardiac electrophysiological activities, such as APD, QT/QTc, occurrence of arrhythmia, phase singularities (PSs), and dominant frequency (DF). Our results demonstrated that Rut reduced the IhERG by binding to F656 and Y652 amino acid residues of hERG channel instantaneously, subsequently accelerating the channel inactivation, and being trapped in the channel. The level of hERG channels was reduced by incubating with Rut for 24 hours, and Sp1 in nucleus was inhibited simultaneously. Mechanismly, Rut reduced threonine (Thr)/ tyrosine (Tyr) phosphorylation of Sp1 through PI3K/Akt pathway to regulate hERG channels expression. Cell-based model unables to fully reveal the pathological process of arrhythmia. In vivo study, we found that Rut prolonged QT/QTc intervals and increased induction rate of ventricular fibrillation (VF) in guinea pig heart after being dosed Rut for 2 weeks. The critical reasons led to increased incidence of arrhythmias eventually were prolonged APD90 and APD50 and the increase of DF, numbers of PSs, incidence of early after-depolarizations (EADs). Collectively, the results of this study suggest that Rut could reduce the IhERG by binding to hERG channels through F656 and Y652 instantaneously. While, the PI3K/Akt/Sp1 axis may play an essential role in the regulation of hERG channels, from the perspective of the long-term effects of Rut (incubating for 24 hours). Importantly, the changes of electrophysiological properties by Rut were the main cause of VA.

Glucagon-Like Peptide-1 Analog Liraglutide Attenuates Pressure-Overload Induced Cardiac Hypertrophy and Apoptosis through Activating ATP Sensitive Potassium Channels.

PURPOSE: This study aimed to investigate whether inhibition of glucagon-like peptide-1 (GLP-1) on pressure overload induced cardiac hypertrophy and apoptosis is related to activation of ATP sensitive potassium (KATP) channels. METHODS: Male SD rats were randomly divided into five groups: sham, control (abdominal aortic constriction), GLP-1 analog liraglutide (0.3 mg/kg/twice day), KATP channel blocker glibenclamide (5 mg/kg/day), and liraglutide plus glibenclamide. RESULTS: Relative to the control on week 16, liraglutide upregulated protein and mRNA levels of KATP channel subunits Kir6.2/SUR2 and their expression in the myocardium, vascular smooth muscle, aortic endothelium, and cardiac microvasculature. Consistent with a reduction in aortic wall thickness (61.4 ± 7.6 vs. 75.0 ± 7.6 µm, p < 0.05), liraglutide enhanced maximal aortic endothelium-dependent relaxation in response to acetylcholine (71.9 ± 8.7 vs. 38.6 ± 4.8%, p < 0.05). Along with a reduction in heart to body weight ratio (2.6 ± 0.1 vs. 3.4 ± 0.4, mg/g, p < 0.05) by liraglutide, hypertrophied cardiomyocytes (371.0 ± 34.4 vs. 933.6 ± 156.6 µm2, p < 0.05) and apoptotic cells (17.5 ± 8.2 vs. 44.7 ± 7.9%, p < 0.05) were reduced. Expression of anti-apoptotic protein BCL-2 and contents of myocardial ATP were augmented, and expression of cleaved-caspase 3 and levels of serum Tn-I/-T were reduced. Echocardiography and hemodynamic measurement showed that cardiac systolic function was enhanced as evidenced by increased ejection fraction (88.4 ± 4.8 vs. 73.8 ± 5.1%, p < 0.05) and left ventricular systolic pressure (105.2 ± 10.8 vs. 82.7 ± 7.9 mmHg, p < 0.05), and diastolic function was preserved as shown by a reduction of ventricular end-diastolic pressure (-3.1 ± 2.9 vs. 6.7 ± 2.8 mmHg, p < 0.05). Furthermore, left ventricular internal diameter at end-diastole (5.8 ± 0.5 vs. 7.7 ± 0.6 mm, p < 0.05) and left ventricular internal diameter at end-systole (3.0 ± 0.6 vs. 4.7 ± 0.4 mm, p < 0.05) were improved. Dietary administration of glibenclamide alone did not alter all the parameters measured but significantly blocked liraglutide-exerted cardioprotection. CONCLUSION: Liraglutide ameliorates cardiac hypertrophy and apoptosis, potentially via activating KATP channel-mediated signaling pathway. These data suggest that liraglutide might be considered as an adjuvant therapy to treat patients with heart failure.

Activation of Opioid Receptors Attenuates Ischemia/Reperfusion Injury in Skeletal Muscle Induced by Tourniquet Placement.

METHOD: Mice were randomly assigned to the sham, I/R, Oxy, and I/R with Oxy groups. Oxy was injected intraperitoneally 30 min before tourniquet placement. Morphological changes of the gastrocnemius muscle in these mice were assessed by hematoxylin-eosin (HE) staining and electron microscopy. Expression levels of TLR4, NF-κB, SIRT1, and PGC-1α in the skeletal muscles were detected by western blot. Blood TNF-α levels, gastrocnemius muscle contractile force, and ATP concentration were examined. RESULTS: Compared with the I/R group, Oxy pretreatment attenuated skeletal muscle damage, decreased serum TNF-α levels, and inhibited the expression levels of TLR4/NF-κB in the gastrocnemius muscle. Furthermore, Oxy treatment significantly increased serum ATP levels and the contractility of the skeletal muscles. SIRT1 and PGC-1α levels were significantly reduced in gastrocnemius muscle after I/R. Oxy pretreatment recovered these protein expression levels. CONCLUSION: Tourniquet-induced acute limb I/R results in morphological and functional impairment in skeletal muscle. Pretreatment with Oxy attenuates skeletal muscle from acute I/R injury through inhibition of TLR4/NF-κB-dependent inflammatory response and protects SIRT1/PGC-1α-dependent mitochondrial function.

Glutathione protected bimetallic gold-platinum nanoclusters with near-infrared emission for ratiometric determination of silver ions.

A controlled method to prepare glutathione-protected bimetallic gold-platinum nanoclusters (Au-PtNCs) has been established. The Au-PtNCs show either strong red (625 nm) or near-infrared (NIR, 805 nm) emission. Further characterizations indicated that the average particle size grows from 1.42 to 1.78 nm, the larger particles being responsible for the redshift of emission. The NIR emitted Au-PtNCs are applied as a novel ratiometric probe of Ag(I), which induces a new emission peak at ~635 nm and quenches the initial emission gradually. The determination shows very high selectivity toward Ag(I) among other metal ions. A limit of determination (10 nM) and the linear range (0.10 to 15 µM) are achieved, which is much lower than the EPA mandate of 0.46 µM for Ag(I) in drinking water. The response mechanism is attributed to the fact that the added Ag(I) has been reduced by the core of Au-PtNCs and deposited on the surface, which induces new fluorescence emission around 635 nm. In addition, the ratiometric method is feasible for Ag(I) determination in serum serum with good recovery (between 98.3% and 102.0%, n = 3), showing very high application potential. The present study provides a controlled method to prepare Au-PtNCs with strong red and NIR emission and supplies a novel NIR ratiometric probe of Ag(I). Schematic presentation of the controlled preparation of glutathione-protected bimetallic gold-platinum nanoclusters (Au-PtNCs) with either red or near-infrared (NIR) emission, and application in ratiometric detection of Ag(I) with high selectivity and sensitivity.

Silencing of long non-coding RNA CRNDE promotes autophagy and alleviates neonatal hypoxic-ischemic brain damage in rats.

Hypoxic-ischemic (HI) brain damage (HIBD) leads to high neonatal mortality and severe neurologic morbidity. Autophagy is involved in the pathogenesis of HIBD. This study aims to investigate the effect of long non-coding RNA colorectal neoplasia differentially expressed (CRNDE) on HIBD and to validate whether autophagy is involved in this process. A HIBD model in rat pups and a HI model in rat primary cerebrocortical neurons were established. Autophagy was evaluated by western blot. The HIBD in rats was evaluated by hematoxylin and eosin staining, TUNEL staining, triphenyl tetrazolium chloride staining, and morris water maze test. The HI injury in vitro was evaluated by determining cell viability and apoptosis. The results showed that CRNDE expression was time-dependently increased in the brain after HIBD. Administration with CRNDE shRNA-expressing lentiviruses alleviated pathological injury and apoptosis in rat hippocampus, decreased infarct volume, and improved behavior performance of rats subjected to HIBD. Furthermore, CRNDE silencing promoted cell viability and inhibited cell apoptosis in neurons exposed to HI. Moreover, CRNDE silencing promoted autophagy and the autophagy inhibitor 3-methyladenine counteracted the neuroprotective effect of CRNDE silencing on HI-induced neuronal injury both in vivo and in vitro. Collectively, CRNDE silencing alleviates HIBD, at least partially, through promoting autophagy.

Long non-coding RNA CRNDE deteriorates intrauterine infection-induced neonatal brain injury.

BACKGROUND: This study aimed to test the hypothesis that long non-coding RNA (lncRNA) colorectal neoplasia differentially expressed (CRNDE) could exacerbate brain injury caused by intrauterine infection in neonatal rats. METHODS: Intrauterine infection was induced in pregnant rats by lipopolysaccharide (LPS). After delivery, newborn rats with brain injury caused by intrauterine infection were randomly divided into control, control shRNA, and CRNDE shRNA groups. CRNDE expression in serum and amniotic fluid of pregnant rats and neonatal brain tissues were determined by quantitative real-time PCR (qRT-PCR). Morris water maze (MWM) task was used to test the spatial learning and memory ability. Histological examination and apoptosis detection were performed by hematoxylin and eosin (H&E) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, respectively. Immunohistochemistry was conducted to evaluate the activation of astrocytes and microglia. RESULTS: LncRNA CRNDE was highly expressed in serum and amniotic fluid of maternal rats and in brain tissues of offspring rats. Furthermore, shRNA-mediated CRNDE downregulation could rescue the spatial learning and memory ability, improve brain histopathological changes and cell death, and inhibit the activation of astrocytes and microglia caused by LPS. CONCLUSION: CRNDE silencing possessed a cerebral protective effect in neonatal rats with brain injury caused by interauterine infection.

Fluorescent Properties of Morin in Aqueous Solution: A Conversion from Aggregation Causing Quenching (ACQ) to Aggregation Induced Emission Enhancement (AIEE) by Polyethyleneimine Assembly.

Unlike normal conversion from aggregation caused quenching (ACQ) to aggregation induced emission enhancement (AIEE) by introducing aromatic rotors tuning aggregation modes, in this study, it is achieved through a supramolecular assembly with polymer. Thus, it provides an easy approach for the inhibition of unwanted H-aggregation between luminogens. As a kind of flavonoid, morin has shown great potential in therapeutics. However, its poor solubility and weak emission in aqueous solution greatly limit its bioapplications. When morin is dissolved in aqueous solution, the presence of 30 × 10-6 m polyethyleneimine (PEI) induces significant emission enhancement and bathochromic shift. Consequently, the quantum yield (QY) of 24.5% is either achieved by assembling with PEI, versus 0.76% of its ACQ state composed of H-aggregation in aqueous solution. Particularly, the in-depth mechanism studies reveal that it is the assembly with PEI that disassociates the H-aggregation in aqueous solution and further restricts the stretching and/or rotation of morin, which eventually reduce the nonradiative decays and enhance the emission. Therefore, the present study reports a unique phenomenon of AIEE effects on morin. Particularly the in-depth investigation on intrinsic mechanisms will highlight and greatly expand the development of more luminogens from traditional Chinese herbals.

Silica nanomaterials induce organ injuries by Ca2+-ROS-initiated disruption of the endothelial barrier and triggering intravascular coagulation.

BACKGROUND: The growing use of silica nanoparticles (SiNPs) in many fields raises human toxicity concerns. We studied the toxicity of SiNP-20 (particle diameter 20 nm) and SiNP-100 (100 nm) and the underlying mechanisms with a focus on the endothelium both in vitro and in vivo. METHODS: The study was conducted in cultured human umbilical vein endothelial cells (HUVECs) and adult female Balb/c mice using several techniques. RESULTS: In vitro, both SiNP-20 and SiNP-100 decreased the viability and damaged the plasma membrane of cultured HUVECs. The nanoparticles also inhibited HUVECs migration and tube formation in a concentration-dependent manner. Both SiNPs induced significant calcium mobilization and generation of reactive oxygen species (ROS), increased the phosphorylation of vascular endothelial (VE)-cadherin at the site of tyrosine 731 residue (pY731-VEC), decreased the expression of VE-cadherin expression, disrupted the junctional VE-cadherin continuity and induced F-actin re-assembly in HUVECs. The injuries were reversed by blocking Ca2+ release activated Ca2+ (CRAC) channels with YM58483 or by eliminating ROS with N-acetyl cysteine (NAC). In vivo, both SiNP-20 and SiNP-100 (i.v.) induced multiple organ injuries of Balb/c mice in a dose (range 7-35 mg/kg), particle size, and exposure time (4-72 h)-dependent manner. Heart injuries included coronary endothelial damage, erythrocyte adhesion to coronary intima and coronary coagulation. Abdominal aorta injury exhibited intimal neoplasm formation. Lung injuries were smaller pulmonary vein coagulation, bronchiolar epithelial edema and lumen oozing and narrowing. Liver injuries included multifocal necrosis and smaller hepatic vein congestion and coagulation. Kidney injuries involved glomerular congestion and swelling. Macrophage infiltration occurred in all of the observed organ tissues after SiNPs exposure. SiNPs also decreased VE-cadherin expression and altered VE-cadherin spatial distribution in multiple organ tissues in vivo. The largest SiNP (SiNP-100) and longest exposure time exerted the greatest toxicity both in vitro and in vivo. CONCLUSIONS: SiNPs, administrated in vivo, induced multiple organ injuries, including endothelial damage, intravascular coagulation, and secondary inflammation. The injuries are likely caused by upstream Ca2+-ROS signaling and downstream VE-cadherin phosphorylation and destruction and F-actin remodeling. These changes led to endothelial barrier disruption and triggering of the contact coagulation pathway.

[Biological Product Development Strategies for Prevention and Treatment of Coronavirus Disease 2019].

Coronavirus disease 2019 (COVID-19) caused by the novel coronavirus, also known as severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), has become a Public Health Emergency of International Concern. Due to the large infection population, broad transmissibility and high mortality, it is urgent to find out the efficient and specific methods to prevent and treat COVID-19. As biological products have broadly applied in the prevention and treatment of severe epidemic diseases, they are promising in blocking novel coronavirus infection. According to the research advances of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), we reviewed the potential application of biological products such as interferon, convalescent plasma, intestinal micro-ecological regulators, vaccines and therapeutic antibodies, etc. , on prevention and treatment of COVID-19. May this review be helpful for conquering COVID-19 in the near future.

Intracellular Mechanism of Rosuvastatin-Induced Decrease in Mature hERG Protein Expression on Membrane.

The hERG potassium channel (IKr) encoded by human ether-a-go-go-related gene plays an important role in cardiac repolarization. Decreased IKr may lead to long QT syndrome, which subsequently causes torsade de pointes and sudden cardiac death. Previous studies have shown that statins inhibit IKr and are more potent in inhibiting hERG currents when combined with other drugs. Since chemical structure of rosuvastatin is similar to that of several IKr blockers (ibutilide and E-4031), the present study aimed to reveal the mechanism that underlies rosuvastatin-induced hERG current reduction and to evaluate the possibility of cardiac toxicity. The results showed that rosuvastatin reduced hERG currents by accelerating the inactivation and prolonged action potential duration (APD) in hiPSC-CMs. Meanwhile, it was observed that rosuvastatin reduced the expression of the mature hERG. Transcription factor Sp1 was involved in hERG protein downregulation induced by rosuvastatin, and the result was verified by Sp1 siRNA and Sp1 agonist epicatechin. These results indicated that rosuvastatin could potentially inhibit transcription and reduce hERG mRNA expression. The interaction between hERG and heat shock protein was evaluated to study the mechanism of trafficking inhibition through co-immunoprecipitation. We found that rosuvastatin reduces the interaction of heat shock protein 70 (Hsp70) with the hERG protein, thereby affecting the folding of the hERG channel. Additionally, rosuvastatin significantly activates ATF6, which plays a key role in the activation of the unfolded protein response (UPR) pathway. Increased expression of the molecular chaperone calnexin and calreticulin, which are activated by ATF6 to help channel folding, further confirmed UPR activation. Meanwhile, the degradation of the hERG channel was mediated by lysosomes and proteasomes. In conclusion, Rosuvastatin reduced the expression of hERG plasma membrane by two pathways, the first is to disrupt the transport of immature hERG channels to the membrane, and the second is to increase the degradation of mature hERG channels. In addition, Rosuvastatin potently blocked hERG current, delayed cardiac repolarization, and thereby prolonged APDs and QTc intervals. Therefore, caution should be taken when rosuvastatin is used in the treatment of hyperlipidemia, especially when combined with drugs that can prolong the QT interval.

Aggregation-induced emission enhancement of adenosine monophosphate-capped bimetallic nanoclusters by aluminum(III) ions, and its application to the fluorometric determination of cysteine.

The fluorescence of adenosine monophosphate-capped bimetallic gold and silver nanoclusters (type AuAgNC@AMP) is strongly enhanced and blue shifted in the presence of Al(III). As confirmed by transmission electron microscopy, the AuAgNC nanodots are converted to larger assembled spheres of type AuAgNC-Al(III). The fluorescence enhancement is attributed to aggregation-induced emission enhancement (AIEE). The fluorescence of the AuAgNC-Al(III) assembly (with excitation and emission maxima at 340 and 540 nm) is quenched by cysteine (Cys). The effect was applied to the fluorometric determination of Cys. The assay works in the 1.0 to 16.0 µM Cys concentration range and has a 50 nM limit of detection. The method was successfully applied to analyze Cys-spiked mineral waters and serum. The quenching mechanism is explored in depth. It is attributed to the partial replacement of AMP by Cys at the surface of the AuAgNC and alteration of the assembly structure from large spherical particles to a strip shape. Graphical abstractSchematic representation of the fluorescence enhancement of bimetallic nanoclusters capped with adenosine monophosphate by using Al(III), and its application in selective and sensitive determination of cysteine via ligand replacement and reassembly.

Paeoniflorin inhibits Th1 and Th17 cells in gut-associated lymphoid tissues to produce anti-arthritis activities.

Paeoniflorin shows distinct anti-arthritis and immunoregulatory activities, but its rather low bioavailability via oral administration greatly challenges its known mechanism of in vivo activity. Our data showed that oral administration, instead of intraperitoneal injection, of paeoniflorin significantly reduced the polyarthritis index by 44.4%, reduced paw swelling by 18.4% and delayed the onset of arthritis in collagen-induced arthritis (CIA) mice. Oral paeoniflorin treatment also downregulated the systemic pro-inflammatory cytokines IL-6 (by 52.2%), TNF-α (by 57.7%) and IL-1ß (by 34.1%). A pharmacokinetic study revealed that the maximal plasma concentration of paeoniflorin after oral administration was 4.8 ± 1.9 µM in the CIA mice, much lower than the effective concentration in vitro (30 µM). In contrast, paeoniflorin was highly concentrated in the gut content, intestine and Peyer's patches. T cell analysis showed that paeoniflorin markedly reduced transcription factors of Th1 and Th17, inhibited Th1 by 22.2% and 23.1% and Th17 by 43.2% and 25.4% (p < 0.05) in the mesenteric lymph node and Peyer's patches, respectively. Paeoniflorin did not have a significant impact on Th1 and Th17 in the spleen. For the first time, these data suggest that paeoniflorin accumulates in the intestine and primarily modulates Th1 and Th17 responses in the mesenteric lymph nodes and Peyer's patches, rather than in the spleen, to exert anti-arthritis effects.

Sortilin: a new player in dementia and Alzheimer-type neuropathology.

Age-related dementias are now a major mortality factor among most human populations in the world, with Alzheimer's disease (AD) being the leading dementia-causing neurodegenerative disease. The pathogenic mechanism underlying dementia disorders, and AD in particular, remained largely unknown. Efforts to develop drugs targeting the disease's hallmark lesions, such as amyloid plaque and tangle pathologies, have been unsuccessful so far. The vacuolar protein sorting 10p (Vps10p) family plays a critical role in membrane signal transduction and protein sorting and trafficking between intracellular compartments. Data emerging during the past few years point to an involvement of this family in the development of AD. Specifically, the Vps10p member sortilin has been shown to participate in amyloid plaque formation, tau phosphorylation, abnormal protein sorting and apoptosis. In this minireview, we update some latest findings from animal experiments and human brain studies suggesting that abnormal sortilin expression is associated with AD-type neuropathology, warranting further research that might lead to novel targets for the development of AD therapies.

Full spectral optical modeling of quantum-dot-converted elements for light-emitting diodes considering reabsorption and reemission effect.

Quantum dots (QDs) have attracted significant attention in light-emitting diode (LED) illumination and display applications, owing to their high quantum yield and unique spectral properties. However, an effective optical model of quantum-dot-converted elements (QDCEs) for (LEDs) that entirely considers the reabsorption and reemission effect is lacking. This suppresses the design of QDCE structures and further investigation of light-extraction/conversion mechanisms in QDCEs. In this paper, we proposed a full spectral optical modeling method for QDCEs packaged in LEDs, entirely considering the reabsorption and reemission effect, and its results are compared with traditional models without reabsorption or reemission. The comparisons indicate that the QDCE absorption loss of QD emission light is a major factor decreasing the radiant efficacy of LEDs, which should be considered when designing QDCE structures. According to the measurements of fabricated LEDs, only calculation results that entirely consider reabsorption and reemission show good agreement with experimental radiant efficacy, spectra, and peak wavelength at the same down-conversion efficiency. Consequently, it is highly expected that QDCE will be modeled considering the reabsorption and reemission events. This study provides a simple and effective modeling method for QDCEs, which shows great potential for their structure designs and fundamental investigations.

Isoflavones enhance pharmacokinetic exposure of active lovastatin acid via the upregulation of carboxylesterase in high-fat diet mice after oral administration of Xuezhikang capsules.

Xuezhikang capsule (XZK) is a traditional Chinese medicine that contains lovastatin (Lv) for hyperlipidemia treatment, although it has fewer side effects than Lv. However, the pharmacokinetic mechanisms contributing to its distinct efficacy and low side effects are unclear. Mice were fed a high-fat diet (HFD) for 6 weeks to induce hyperlipidemia. We first conducted the pharmacokinetic studies in HFD mice following oral administration of Lv (10 mg/kg, i.g.) and found that HFD remarkably decreased the active form of Lv (the lovastatin acid, LvA) exposure in the circulation system, especially in the targeting organ liver, with a declined conversion from Lv to LvA, whereas the Lv (responsible for myotoxicity) exposure in muscle markedly increased. Then we compared the pharmacokinetic profiles of Lv in HFD mice after the oral administration of XZK (1200 mg/kg, i.g.) or an equivalent dose of Lv (10 mg/kg, i.g.). A higher exposure of LvA and lower exposure of Lv were observed after XZK administration, suggesting a pharmacokinetic interaction of some ingredients in XZK. Further studies revealed that HFD promoted the inflammation and inhibited carboxylesterase (CES) activities in the intestine and the liver, thus contributing to the lower transformation of Lv into LvA. In contrast, XZK inhibited the inflammation and upregulated CES in the intestine and the liver. Finally, we evaluated the effects of monacolins and phytosterols, the fractional extracts of isoflavones, on inflammatory LS174T or HepG2 cells, which showed that isoflavones inhibited inflammation, upregulated CES, and markedly enhanced the conversion of Lv into LvA. For the first time, we provide evidence that isoflavones and Lv in XZK act in concert to enhance the efficacy and reduce the side effects of Lv.

Neutrophil Gelatinase-Associated Lipocalin Attenuates Ischemia/Reperfusion Injury in an In Vitro Model via Autophagy Activation.

BACKGROUND The aim of this study was to investigate the protective effects of neutrophil gelatinase-associated lipocalin (NGAL) on hypoxia/reoxygenation (H/R) induced acute kidney injury (AKI) in vitro. MATERIAL AND METHODS We used NRK-52E cells and H/R treatments to mimic ischemia/reperfusion injury (IRI) in vitro. Experimental groups were: the control group, the H/R group, the 3-methyladenine (3-MA)+H/R group, the NGAL (0.25, 0.5, and 1 ug/mL)+H/R group, and the NGAL (0.25, 0.5, 1 ug/mL)+3-MA+H/R group. After 24 hours of culture, cell proliferation was analyzed by CCK-8 assay. Expression of LC3-II was detected by immunoblot assay. Autophagy was detected by electron microscopy. RESULTS The expression of LC3-II was increased in the H/R group compared with normoxic condition (p<0.05) and proliferation also improved. Autophagy was significantly inhibited by 3-MA, with downregulated of LC3-II, followed by decreased cell viability (p<0.05). We further detected the effect of different doses of NGAL in H/R induced injury, and found that low doses of NGAL alone slightly increased LC3-II protein accumulation, and autophagy was further induced with higher dose of NGAL treatment. Meanwhile, cell viability assays showed induced cell survival. We found that in the NGAL+3-MA group, cell viability assays revealed reduced cell damage, followed concomitantly with depressed autophagy. The formulation of autophagosomes were correlated with LC3-II protein expression in each group. CONCLUSIONS Autophagy plays a renoprotective role in H/R injury, as well in AKI. NGAL might be related to attenuated tubular epithelial cell damage via adjusting autophagy.