The Mitochondrial Unfolded Protein Response Is Mediated Cell-Non-autonomously by Retromer-Dependent Wnt Signaling.

The mitochondrial unfolded protein response (UPRmt) can be triggered in a cell-non-autonomous fashion across multiple tissues in response to mitochondrial dysfunction. The ability to communicate information about the presence of mitochondrial stress enables a global response that can ultimately better protect an organism from local mitochondrial challenges. We find that animals use retromer-dependent Wnt signaling to propagate mitochondrial stress signals from the nervous system to peripheral tissues. Specifically, the polyQ40-triggered activation of mitochondrial stress or reduction of cco-1 (complex IV subunit) in neurons of C. elegans results in the Wnt-dependent induction of cell-non-autonomous UPRmt in peripheral cells. Loss-of-function mutations of retromer complex components that are responsible for recycling the Wnt secretion-factor/MIG-14 prevent Wnt secretion and thereby suppress cell-non-autonomous UPRmt. Neuronal expression of the Wnt ligand/EGL-20 is sufficient to induce cell-non-autonomous UPRmt in a retromer complex-, Wnt signaling-, and serotonin-dependent manner, clearly implicating Wnt signaling as a strong candidate for the "mitokine" signal.

A proposed simplified definition of metabolic syndrome in children and adolescents: a global perspective.

Metabolic syndrome (MetS) is becoming prevalent in the pediatric population. The existing pediatric MetS definitions (e.g., the International Diabetes Federation (IDF) definition and the modified National Cholesterol Education Program (NCEP) definition) involve complex cut-offs, precluding fast risk assessment in clinical practice.We proposed a simplified definition for assessing MetS risk in youths aged 6-17 years, and compared its performance with two existing widely used pediatric definitions (the IDF definition, and the NCEP definition) in 10 pediatric populations from 9 countries globally (n = 19,426) using the receiver operating characteristic (ROC) curve analyses. In general, the total MetS prevalence of 6.2% based on the simplified definition was roughly halfway between that of 4.2% and 7.7% estimated from the IDF and NCEP definitions, respectively. The ROC curve analyses showed a good agreement between the simplified definition and two existing definitions: the total area under the curve (95% confidence interval) of the proposed simplified definition for identifying MetS risk achieved 0.91 (0.89-0.92) and 0.79 (0.78-0.81) when using the IDF or NCEP definition as the gold standard, respectively.The proposed simplified definition may be useful for pediatricians to quickly identify MetS risk and cardiometabolic risk factors (CMRFs) clustering in clinical practice, and allow direct comparison of pediatric MetS prevalence across different populations, facilitating consistent pediatric MetS risk monitoring and the development of evidence-based pediatric MetS prevention strategies globally.

Caffeic acid alleviates cerebral ischemic injury in rats by resisting ferroptosis via Nrf2 signaling pathway.

There are few effective and safe neuroprotective agents for the treatment of ischemic stroke currently. Caffeic acid is a phenolic acid that widely exists in a number of plant species. Previous studies show that caffeic acid ameliorates brain injury in rats after cerebral ischemia/reperfusion. In this study we explored the protective mechanisms of caffeic acid against oxidative stress and ferroptosis in permanent cerebral ischemia. Ischemia stroke was induced on rats by permanent middle cerebral artery occlusion (pMCAO). Caffeic acid (0.4, 2, 10 mg·kg-1·d-1, i.g.) was administered to the rats for 3 consecutive days before or after the surgery. We showed that either pre-pMCAO or post-pMCAO administration of caffeic acid (2 mg·kg-1·d-1) effectively reduced the infarct volume and improved neurological outcome. The therapeutic time window could last to 2 h after pMCAO. We found that caffeic acid administration significantly reduced oxidative damage as well as neuroinflammation, and enhanced antioxidant capacity in pMCAO rat brain. We further demonstrated that caffeic acid down-regulated TFR1 and ACSL4, and up-regulated glutathione production through Nrf2 signaling pathway to resist ferroptosis in pMCAO rat brain and in oxygen glucose deprivation/reoxygenation (OGD/R)-treated SK-N-SH cells in vitro. Application of ML385, an Nrf2 inhibitor, blocked the neuroprotective effects of caffeic acid in both in vivo and in vitro models, evidenced by excessive accumulation of iron ions and inactivation of the ferroptosis defense system. In conclusion, caffeic acid inhibits oxidative stress-mediated neuronal death in pMCAO rat brain by regulating ferroptosis via Nrf2 signaling pathway. Caffeic acid might serve as a potential treatment to relieve brain injury after cerebral ischemia. Caffeic acid significantly attenuated cerebral ischemic injury and resisted ferroptosis both in vivo and in vitro. The regulation of Nrf2 by caffeic acid initiated the transcription of downstream target genes, which were shown to be anti-inflammatory, antioxidative and antiferroptotic. The effects of caffeic acid on neuroinflammation and ferroptosis in cerebral ischemia were explored in a primary microglia-neuron coculture system. Caffeic acid played a role in reducing neuroinflammation and resisting ferroptosis through the Nrf2 signaling pathway, which further suggested that caffeic acid might be a potential therapeutic method for alleviating brain injury after cerebral ischemia.

PHPB ameliorates memory deficits and reduces oxidative injury in Alzheimer's disease mouse model by activating Nrf2 signaling pathway.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia in elderly people and substantially affects patient quality of life. Oxidative stress is considered a key factor in the development of AD. Nrf2 plays a vital role in maintaining redox homeostasis and regulating neuroinflammatory responses in AD. Previous studies show that potassium 2-(1-hydroxypentyl)-benzoate (PHPB) exerts neuroprotective effects against cognitive impairment in a variety of dementia animal models such as APP/PS1 transgenic mice. In this study we investigated whether PHPB ameriorated the progression of AD by reducing oxidative stress (OS) damage. Both 5- and 13-month-old APP/PS1 mice were administered PHPB (100 mg·kg-1·d-1, i.g.) for 10 weeks. After the cognition assessment, the mice were euthanized, and the left hemisphere of the brain was harvested for analyses. We showed that 5-month-old APP/PS1 mice already exhibited impaired performance in the step-down test, and knockdown of Nrf2 gene only slightly increased the impairment, while knockdown of Nrf2 gene in 13-month-old APP/PS1 mice resulted in greatly worse performance. PHPB administration significantly ameliorated the cognition impairments and enhanced antioxidative capacity in APP/PS1 mice. In addition, PHPB administration significantly increased the p-AKT/AKT and p-GSK3ß/GSK3ß ratios and the expression levels of Nrf2, HO-1 and NQO-1 in APP/PS1 mice, but these changes were abolished by knockdown of Nrf2 gene. In SK-N-SH APPwt cells and primary mouse neurons, PHPB (10 µM) significantly increased the p-AKT/AKT and p-GSK3ß/GSK3ß ratios and the level of Nrf2, which were blocked by knockdown of Nrf2 gene. In summary, this study demonstrates that PHPB exerts a protective effect via the Akt/GSK3ß/Nrf2 pathway and it might be a promising neuroprotective agent for the treatment of AD.

The long rod-shaped Sr2 MgSi2 O7 :Eu2+ ,Dy3+ with ultrahigh afterglow performance.

The afterglow properties of long afterglow luminescent materials are greatly affected by their defects, which are distributed on the grain surface. Increasing the exposed surface area is an important method to improve the afterglow performance. In this research, long rod-shaped long afterglow materials Sr2 MgSi2 O7 :Eu2+ ,Dy3+ were prepared using the hydrothermal-coprecipitation method. When the reaction time reached 96 h, the length of the afterglow materials could grow to 2 mm, and the sintering temperature was just 1150°C. The emission spectra of all obtained samples upon excitation at 397 nm had a maximum of 465 nm, which belonged to the representative transition of Eu2+ . The initial brightness was 1.35 cd/m2 . The afterglow time could reach 19 h, giving a good afterglow performance. The research on this kind of material has essential significance in the exploration of luminescence mechanisms and their applications.

[Effect and mechanism of Yueju Pills on breast cancer induced by DMBA in rats].

This paper aims to explore the inhibitory effect of Yueju Pills on breast cancer and decipher the underlying mechanism. A total of 92 SPF-grade SD female rats were involved in this study, and 14 of them were randomly selected into control group. The remaining 78 rats were administrated with 7,12-dimethylbenzanthracene(DMBA) by gavage to establish the breast cancer model. The modeled rats were randomized into model, tamoxifen(1.9 mg·kg~(-1)·d~(-1)), and low-and high-dose(17, 34 g·kg~(-1)·d~(-1)) Yueju Pills groups. The mental state, food intake, and activities of the rats were observed daily, and the body weight was measured on alternate days. After 12 weeks of administration, the rats were sacrificed and the tumor weight was measured. The serum estrogen and progeste-rone levels were determined by enzyme-linked immunosorbent assay. The histopathological changes of the breast and tumor were observed by hematoxylin-eosin staining. Western blot was employed to measure the protein levels of glucose transporter 1(GLUT1), lactate dehydrogenase A(LDHA), phosphofructokinase muscle(PFKM), pyruvate kinase isozyme type M2(PKM2), hexokinase 2(HK2), nuclear factor-kappaB(NF-κB), and phosphorylated NF-κB. The intestinal microbiome was examined by 16S rRNA high-throughput sequencing. The results showed that compared with the model group, high and low-dose Yueju Pills showed the tumor inhibition rate of 15.8% and 64.5%, respectively, and the low dose group had stronger inhibitory effect. Compared with the control group, the model group presented elevated the levels of estrogen and progesterone in serum. The administration of Yueju Pills lowered such ele-vation, and the low-dose group showed stronger lowering effect(P<0.05). Compared with the model group, Yueju Pills reduced the glands with increased breast tissue, the degree of breast duct expansion, the number and area of acinar cavity, the secretions, and the layers of mammary epithelial cells. Furthermore, Yueju Pills down-regulated the expression of GLUT1, LDHA, PFKM, PKM2, HK2, and NF-κB(P<0.05) and altered the diversity, composition, structure, and abundance of intestinal flora. The results showed that Yueju Pills could inhibit breast cancer by regulating the secretion of estrogen and progesterone, glycolysis, inflammatory cytokines, and intestinal flora.

Establishing international optimal cut-offs of waist-to-height ratio for predicting cardiometabolic risk in children and adolescents aged 6-18 years.

BACKGROUND: Waist-to-height ratio (WHtR) has been proposed as a simple and effective screening tool for assessing central obesity and cardiometabolic risk in both adult and pediatric populations. However, evidence suggests that the use of a uniform WHtR cut-off of 0.50 may not be universally optimal for pediatric populations globally. We aimed to determine the optimal cut-offs of WHtR in children and adolescents with increased cardiometabolic risk across different countries worldwide. METHODS: We used ten population-based cross-sectional data on 24,605 children and adolescents aged 6-18 years from Brazil, China, Greece, Iran, Italy, Korea, South Africa, Spain, the UK, and the USA for establishing optimal WHtR cut-offs. We performed an external independent test (9,619 children and adolescents aged 6-18 years who came from other six countries) to validate the optimal WHtR cut-offs based on the predicting performance for at least two or three cardiometabolic risk factors. RESULTS: Based on receiver operator characteristic curve analyses of various WHtR cut-offs to discriminate those with ≥ 2 cardiometabolic risk factors, the relatively optimal percentile cut-offs of WHtR in the normal weight subsample population in each country did not always coincide with a single fixed percentile, but varied from the 75th to 95th percentiles across the ten countries. However, these relatively optimal percentile values tended to cluster irrespective of sex, metabolic syndrome (MetS) criteria used, and WC measurement position. In general, using ≥ 2 cardiometabolic risk factors as the predictive outcome, the relatively optimal WHtR cut-off was around 0.50 in European and the US youths but was lower, around 0.46, in Asian, African, and South American youths. Secondary analyses that directly tested WHtR values ranging from 0.42 to 0.56 at 0.01 increments largely confirmed the results of the main analyses. In addition, the proposed cut-offs of 0.50 and 0.46 for two specific pediatric populations, respectively, showed a good performance in predicting ≥ 2 or ≥ 3 cardiometabolic risk factors in external independent test populations from six countries (Brazil, China, Germany, Italy, Korea, and the USA). CONCLUSIONS: The proposed international WHtR cut-offs are easy and useful to identify central obesity and cardiometabolic risk in children and adolescents globally, thus allowing international comparison across populations.

Two-Step Enzymolysis of Antarctic Krill for Simultaneous Preparation of Value-Added Oil and Enzymolysate.

Antarctic krill is a crucial marine resource containing plenty of high-valued nutrients. However, krill oil as a single product has been developed by the current solvent extraction with high cost. From the perspective of comprehensive utilization of Antarctic krill, this study proposed a novel two-step enzymolysis-assisted extraction in attempt to produce value-added oil and enzymolysate simultaneously. After two-step chitinase/protease hydrolysis, the lipid yield increased from 2.09% to 4.18%, reaching 112% of Soxhlet extraction. The method greatly improved the yields of main components while reducing the impurity content without further refining. After optimization, the oil contained 246.05 mg/g of phospholipid, 80.96 mg/g of free eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and 0.82 mg/g of astaxanthin. The by-product enzymolysate was abundant in water-soluble proteins (34.35 mg/g), oligopeptides (13.92 mg/g), amino acids (34.24 mg/g), and carbohydrates (5.79 mg/g), which was a good source of functional nutrients. In addition, both oil and enzymolysate showed high antioxidant capacity. This novel method could simultaneously provide oil and enzymolysate amounting for 58.61% of dried krill.

[Discovery of miRNA and target signal molecules involved in inhibition of chlorogenic acid on N-acetyl-p-aminophenol-induced hepatotoxicity based on microRNA array].

This study aims to observe the effect of chlorogenic acid(CGA) on microRNA(miRNA) in the process of protecting against N-acetyl-p-aminophenol(APAP)-induced liver injury. Eighteen C57BL/6 mice were randomly assigned into a normal group, a model group(APAP, 300 mg·kg~(-1)), and a CGA(40 mg·kg~(-1)) group. Hepatotoxicity of mice was induced by intragastric administration of APAP(300 mg·kg~(-1)). The mice in the CGA group were administrated with CGA(40 mg·kg~(-1)) by gavage 1 h after APAP administration. The mice were sacrificed 6 h after APAP administration, and plasma and liver tissue samples were collected for the determination of serum alanine/aspartate aminotransferase(ALT/AST) level and observation of liver histopathology, respectively. MiRNA array combined with real-time PCR was employed to discover important miRNAs. The target genes of miRNAs were predicted via miRWalk and TargetScan 7.2, verified by real-time PCR, and then subjected to functional annotation and signaling pathway enrichment. The results showed that CGA administration lowered the serum ALT/AST level elevated by APAP and alleviate the liver injury. Nine potential miRNAs were screened out from the microarray. The expression of miR-2137 and miR-451a in the liver tissue was verified by real-time PCR. The expression of miR-2137 and miR-451a was significantly up-regulated after APAP administration, and such up-regulated expression was significantly down-regulated after CGA administration, consistent with the array results. The target genes of miR-2137 and miR-451a were predicted and verified. Eleven target genes were involved in the process of CGA protecting against APAP-induced liver injury. Gene Ontology(GO) annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment with DAVID and R language showed that the 11 target genes were enriched in Rho protein-related signal transduction, vascular patterning-related biological processes, binding to transcription factors, and Rho guanyl-nucleotide exchange factor activity. The results indicated that miR-2137 and miR-451a played an important role in the inhibition of CGA on APAP-induced hepatotoxicity.

[Trans-Douglas Retzius' space-sparing robot-assisted simple prostatectomy for large-volume benign prostate hyperplasia].

OBJECTIVE: To report the safety and efficacy of trans-Douglas Retzius' space-sparing robot-assisted simple prostatectomy (RSS-RASP) in the treatment of large-volume BPH. METHODS: This retrospective study included 24 cases of large-volume (>80 ml) BPH treated by trans-Douglas RSS-RASP from August 2019 to June 2021. The patients ranged in age from 55 to 80 (mean 68.5) years, with an average body mass index of 25.1 (20.5－34.9) kg/m2 , median prostate volume of 132.4 (85.6－235.7) ml, and preoperative tPSA of 10.8 (0.5－37.9) ng/ml, IPSS of 25 (3－35) and quality of life (QOL) score of 5 (3－8). Before surgery, 12 of the patients received catheterization for urinary retention, 1 underwent cystostomy, 2 were complicated with hydronephrosis, 1 had stones and diverticulum in the bladder, and 14 were excluded from the cases of PCa by prostatic biopsy. The operation time, intraoperative blood loss, hemoglobin level on the first day after surgery, blood transfusion, and intra- and postoperative complications were recorded. The patients were followed up for 3 to 21 months postoperatively. Comparisons were made before and after operation in the IPSS, maximum urinary flow rate (Qmax), postvoid residual volume (PVR), QOL score, IIEF score and Male Sexual Health Questionnaire (MSHQ) score. RESULTS: Trans-Douglas RSS-RASP was successfully completed in all the 24 cases, with a mean operation time of 175 (100－285) min, intraoperative blood loss of 200 (50－800) ml, hemoglobin decrease of 25 (4－57) g/L on the first day after surgery, postoperative drainage tube indwelling of 3 (2－7) d, and urinary catheterization of 12 (4－18) d. Six (25%) of the patients received intraoperative blood transfusion, 1 underwent transurethral electrocoagulation hemostasis 1 month after surgery because of postoperative bleeding, and 1 received transurethral resection of the cicatrical adhesive tissue of the bladder neck 12 months after surgery. No other complications occurred postoperatively. The IPSS (3 ［1－7］), Qmax (19.6 ［9.9－32.1］ ml/s), PVR (0 ［0－34.9］ ml) and QOL score (2 ［0－3］) of the patients were significantly improved after surgery (P < 0.05), but no statistically significant differences were observed in the IIEF (20 ［19－24］) and MSHQ scores (14 ［13－14］) as compared with the baseline (P > 0.05). CONCLUSION: Trans-Douglas RSS-RASP is a safe and effective minimally invasive method for the treatment of large-volume (>80 ml) BPH, which can improve the urinary function of the patient after operation.

High Enhancement in Proton Conductivity by Incorporating Sulfonic Acids into a Zirconium-Based Metal-Organic Framework via "Click" Reaction.

Taking a robust zirconium-based metal-organic framework, UiO-66, as a prototype, functional postmodification via the versatile Cu(I)-catalyzed azide-alkyne "click" reaction was carried out, and sulfonic acid groups were successfully grafted into its skeleton. Characterizations revealed that the MOF network was still well maintained after being treated by "clicked" modification. Investigations by electrochemical impedance spectroscopy measurements revealed that its proton conductivity increases exponentially up to 8.8 × 10-3 S cm-1 at 80 °C and 98% RH, while those of the UiO-66 and UiO-66-NH2 are only 6.3 × 10-6 and 3.5 × 10-6 S cm-1, respectively, at the same condition. Additionally, the continuous test shows it possesses long-life reusability. Such a remarkable enhancement on the proton conductivities and high performance in long-life reusability of the resultant MOF demonstrated that the "click" reaction is a facile reaction in postmodification of robust porous materials toward targeted applications, with which highly promising candidates of proton-conductive electrolytes for applying in proton-exchange-membrane (PEM) fuel cell can be achieved.

Layer thickness influenced irradiation effects of proton beam on MoS2 field effect transistors.

We investigated the influence of the flake thickness for molybdenum disulfide (MoS2) field effect transistors on the effect of a 150 keV high-energy proton beam applied on these devices. The electrical characteristics of the devices with channel thicknesses ranging from monolayer to bulk were measured before and after proton irradiation with a proton fluence of 5 × 1014 cm-2. The subthreshold swing (SS), threshold voltage shift and electron mobility were extracted with the Y-function method after proton irradiation and significant degradation were observed. It is found that, with the increase of layer thickness, mobility degradation and threshold voltage shift both eased, but the SS degradation was insensitive to the MoS2 flake thickness increase. We also demonstrate that the threshold voltage shift is dominated by oxide charges; however, the mobility and SS degradations are mainly affected by the interface traps. Our study will enhance the understanding of the influence of high-energy particles on MoS2-based nano-electronic devices. By increasing the MoS2 flake thickness to a certain extent, one can hopefully find a balance between effectively resisting [Formula: see text] shift and achieving high mobility and small SS degradation.

Reducing metal/graphene contact resistance via N, N-dimethylacetamide-assisted clean fabrication process.

Contact resistance (RC) is of great importance for radio frequency (RF) applications of graphene, especially graphene field effect transistors (FETs) with short channel. FETs and transmission line model test structures based on chemical vapor deposition grown graphene are fabricated. The effects of employing traditional lithography solvent (Acetone) and strong solvents for photo resist, such as N, N-Dimethylacetamide (ZDMAC) and N-Methyl pyrrolidone (NMP), are systematically investigated. It was found that ZDMAC and NMP have more proficiency than acetone to remove the photo-resist residues and contaminations attached on graphene surface, enabling clean surface of graphene. However, strong solvents are found to destroy the lattice structure of graphene channel and induce defects in graphene lattice. Clean surface contributes to a significant reduction in theRCbetween graphene channel and metal electrode, and the defects introduced on graphene surface underneath metal electrodes also contribute the reduction ofRC. But defects and deformation of lattice will increase the resistance in graphene channel and lead to the compromise of device performance. To address this problem, a mix wet-chemical approach employing both acetone and ZDMAC was developed in our study to realize a 19.07% reduction ofRC, without an unacceptable mass production of defects.

Stable p-type chemical doping of graphene with reduced contact resistance by single-layer perfluorinated polymeric sulfonic acid.

Recently, graphene has led to unprecedented progress in device performance at the atom limit. A high performance of field-effect transistors requires a low graphene-metal contact resistance. However, the chemical doping methods used to tailor or improve the properties of graphene are sensitive to ambient conditions. Here, we fabricate a single-layer perfluorinated polymeric sulfonic acid (PFSA), also known as Nafion, between the graphene and the substrate as a p-type dopant. The PFSA doping method, without inducing any additional structural defects, reduces the contact resistance of graphene by ∼28.8%, which has a significant impact on practical applications. This reduction can be maintained for at least 67 days due to the extreme stability of PFSA. Effective, uniform and stable, the PFSA doping method provides an efficient way to reduce the contact resistance of graphene applications.

In silico production of relative correction factor for the quantitative analysis of multi-components by single marker method.

INTRODUCTION: Traditional methods to derive experimentally-generated relative correction factors (RCFs) for the quantitative analysis of herbal multi-components by single marker (QAMS) method require reference standards and multiple validations with different instruments and columns, which hampers high throughput implementation. OBJECTIVES: To effectively reduce the application amounts of raw material and provide higher and more stable accuracy, this study aimed to develop a method to computationally generate RCFs of herbal components. MATERIALS AND METHODS: This strategy included the published data collection, calibration curves screening, computer algorithm-based RCFs generation and accuracy validation. RESULTS: Using the in silico approach, we have successfully produced 133 RCFs for the multi-component quantitative analysis of 63 widely used herbs. CONCLUSION: Compared with conventional RCFs, this in silico method would be a low cost and highly efficient way to produce practical RCFs for the QAMS method.

[Exploratory study on preparation of high drug loading granules with traditional Chinese medicine raw powder as carriers].

With Sangtang Yin granule as model drug,and based on the strategy of " unification of medicines and excipients",the feasibility of preparing high drug loading granules with traditional Chinese medicine( TCM) raw powder as carrier was explored. The powder yield,particle size and particle size distribution,fillibility,flowability,hygroscopicity,reconstituability and other key physical properties relating to preparations of 8 herbs( Dioscoreae Rhizoma,Euryales Semen,Atractylodis Macrocephalae Rhizoma,Coicis semen,Poria,Puerariae Lobatae Radix,Puerariae Thomsonii Radix and Coicis Semen by stir-frying with bran) were studied after being smashed,and the feasibility of taking them as excipients of TCM granules was evaluated by co-spray drying,dry granulation and other preparation techniques. According to the results of the physical properties of raw powders,raw powders of Dioscoreae Rhizoma,Euryales Semen and Puerariae Thomsonii Radix had a high powder yield,uniform particle size distribution,good fillibility,poor hygroscopicity and good reconstitutability,with the feature of assisting granule forming. Compared with the prescription of spray dry powder Sangtang Yin without any excipient,the co-sprayed powder had a high yield,good fillibility and compressibility. The yield of dry granules prepared by co-spraying dry powder was increased by more than 10%,and the particles had a uniform color,good fluidity and dissolubility with the drug-loading rate up to 100%. Based on the physical characteristics of TCM raw powder combined with the analysis of the preparation process,Dioscoreae Rhizoma and Puerariae Thomsonii Radix raw powder were selected as the carriers of granule preparations,and Sangtang Yin granule without any excipient was successfully prepared. The findings provide a feasible idea for the preparation of TCM granules with a high drug loading capacity.

Inhibitory effect of gallic acid on voltage-gated Na+ channels in rat cardiomyocytes.

Gallic acid (GA) has a protective effect on the cardiovascular system. To study its cardiac electrophysiological effects, voltage-gated Na+ channel currents (INa ) were recorded in rat cardiomyocytes using whole-cell patch clamp techniques. Moreover, the effects of GA on aconitine-induced arrhythmias were assessed using electrocardiograms in vivo. We found that the current-voltage characteristic curve (I-V curve) of INa significantly shifted in the presence of 1, 3, and 10 µmol/L of GA. The peak sodium current density (INa -Peak) was reduced from -84.02 ± 5.68 pA/pF to -65.78 ± 3.96 pA/pF with 1 µmol/L, -54.45 ± 5.18 pA/pF with 3 µmol/L, and -44.20 ± 4.35 pA/pF with 10 µmol/L, respectively. GA shifted the steady-state activation curve of INa and recovery curve to the right and the steady-state inactivation curve to the left. The observed inhibitory effect was comparable to that of amiodarone. GA pre-treatment significantly prolonged the onset of fatal ventricular fibrillation. Our results indicated that GA inhibited INa in rat ventricular myocytes and aconitine-induced arrhythmias in vivo. These results suggest the potential of GA for development as a novel anti-arrhythmic therapeutic.

Intestinal stem cell overproliferation resulting from inactivation of the APC tumor suppressor requires the transcription cofactors Earthbound and Erect wing.

Wnt/ß-catenin signal transduction directs intestinal stem cell (ISC) proliferation during homeostasis. Hyperactivation of Wnt signaling initiates colorectal cancer, which most frequently results from truncation of the tumor suppressor Adenomatous polyposis coli (APC). The ß-catenin-TCF transcription complex activates both the physiological expression of Wnt target genes in the normal intestinal epithelium and their aberrantly increased expression in colorectal tumors. Whether mechanistic differences in the Wnt transcription machinery drive these distinct levels of target gene activation in physiological versus pathological states remains uncertain, but is relevant for the design of new therapeutic strategies. Here, using a Drosophila model, we demonstrate that two evolutionarily conserved transcription cofactors, Earthbound (Ebd) and Erect wing (Ewg), are essential for all major consequences of Apc1 inactivation in the intestine: the hyperactivation of Wnt target gene expression, excess number of ISCs, and hyperplasia of the epithelium. In contrast, only Ebd, but not Ewg, mediates the Wnt-dependent regulation of ISC proliferation during homeostasis. Therefore, in the adult intestine, Ebd acts independently of Ewg in physiological Wnt signaling, but cooperates with Ewg to induce the hyperactivation of Wnt target gene expression following Apc1 loss. These findings have relevance for human tumorigenesis, as Jerky (JRK/JH8), the human Ebd homolog, promotes Wnt pathway hyperactivation and is overexpressed in colorectal, breast, and ovarian cancers. Together, our findings reveal distinct requirements for Ebd and Ewg in physiological Wnt pathway activation versus oncogenic Wnt pathway hyperactivation following Apc1 loss. Such differentially utilized transcription cofactors may offer new opportunities for the selective targeting of Wnt-driven cancers.

Saponins from Clematis mandshurica Rupr. regulates gut microbiota and its metabolites during alleviation of collagen-induced arthritis in rats.

Gut microbiota and their metabolites (short-chain fatty acids, SCFAs) are associated with the pathogenesis of rheumatoid arthritis (RA). Total Clematis triterpenoid saponins (CTSs) prepared from Clematis mandshurica Rupr. possess therapeutic benefits for arthritic diseases. However, the poor pharmacokinetic properties of CTSs have obstructed the translation of these natural agents to drugs. Here, we examined the effects of CTSs on arthritis symptoms, gut microbiota and SCFAs in rats with collagen-induced arthritis (CIA). Our results showed that the arthritis index scores of CIA rats treated with CTSs were significantly lower than those of the model group. Most importantly, CTSs moderated gut microbial dysbiosis and significantly downregulated the total SCFA concentration in CIA rats. Compared to the control group, CTSs treatment have no significant side effects on the gut microbiota and SCFA metabolism in normal rats. Two differential analyses (LEfSe and DESeq2) were combined to study the details of the changes in gut microbiome, and twenty-four marker taxa at the genus level were identified via a comparison among control, model and CIA rats treated with high doses of CTSs. In particular, the mostly significantly increased gram-negative (G-) and decreased gram-positive (G+) genera in CIA rats were well restored by CTSs. The observed SCFA concentrations demonstrated that CTSs tend to maintain the balance of the gut microbiota. The data presented herein suggest that CTSs could ameliorate arthritis-associated gut microbial dysbiosis and may be potential adjuvant drugs that could provide relief from the gastrointestinal damage caused as a side effect of commonly used drugs.

A uniform stable P-type graphene doping method with a gold etching process.

Graphene is one of the materials with the most potential for post-silicon electronics because of its outstanding electrical, optical, and mechanical properties. However, the lack of a uniform stable doping method extremely limits the various possible applications of graphene. Here, we developed a uniform and stable graphene efficient p-doping method. Through etching a thin gold film on graphene with a KI/I2 solution, iodine complexes are produced as the dopant absorbing on the graphene surface, and induce extra holes in graphene. Utilizing this method, the graphene film can be effectively doped to p-type without producing undesirable defects, and the roughness of the graphene surface can still be maintained at an ultra-low nanoscale (RMS roughness ∼0.739 nm). The doping effectiveness can be clearly verified by the changes in the Raman spectrum, and the Dirac point shift of the graphene-based transistor, and the reduction of sheet resistance (∼27.2%). Furthermore, the substantially coincident transfer curves after 45 days reveal the long-term stable doping effects. Therefore, this doping method can exploit a way for various graphene-based applications, such as phototransistors, sensors, and organic thin-film transistors.