Fufang Shenhua tablet inhibits renal fibrosis by inhibiting PI3K/AKT.

BACKGROUND: Fufang Shenhua tablet (SHT), a traditional Chinese medicine compound, has been utilized in the clinical management of chronic kidney disease (CKD) for a long time. Nevertheless, the fundamental active constituents and potential mechanism of action remain unclear. Thus, the objective of this study was to investigate the renoprotective effect of SHT on residual renal tissue in CKD model rats and to explore its primary efficacious components and their underlying mechanism. METHODS: After a 12-week period of SHT treatment through gavage in a 5/6 nephrectomized animal model of CKD, we evaluated the body weight, renal function, and renal pathological changes. Furthermore, the expression levels of fibronectin (FN), collagen I (COL-1), α-smooth muscle actin (α-SMA), and vimentin in renal tissues were assessed. In addition, network pharmacology analysis and molecular docking were utilized to predict the primary active components, potential therapeutic targets, and intervention pathways through which SHT could potentially exert its anti-kidney fibrosis effects. Subsequently, these predictions were validated in renal tissues of rats with CKD and in transforming growth factor ß1 (TGF-ß1)-induced HK-2 cells. RESULTS: SHT significantly improved renal function and reduced renal pathological damage and fibrosis in CKD model rats. Network pharmacological analysis identified 62 active components in SHT, with quercetin ranked first, and 105 protein targets shared by SHT and CKD. Based on the protein‒protein interaction network (PPI) and the SHT-CKD-pathway network, AKT1, MYC, IL2, and VEGFA were identified as key targets. Furthermore, GO and KEGG pathway enrichment analyses indicated that the renoprotective effect of SHT on CKD was closely associated with the PI3K/AKT signaling pathway. Molecular docking results demonstrated that the main active components of SHT had a strong binding affinity to the hub genes. During experimental validation, SHT hindered the activity of the PI3K/AKT signaling pathway in the renal tissue of CKD model rats. Furthermore, activation of the PI3K/AKT signaling pathway was correlated with a modified fibrotic phenotype in rats with 5/6 nephrectomy-induced CKD and TGF-ß1-induced HK-2 cells. Conversely, SHT and quercetin curtailed the activation of the PI3K/AKT signaling pathway and inhibited the formation of renal fibrosis, thus indicating that the PI3K/AKT signaling pathway is the basis of the antifibrotic effects of SHT. Ultimately, administration of the PI3K/AKT agonist 740Y-P counteracted the fibrotic phenotype of TGF-ß1-induced HK-2 cells induced by SHT. CONCLUSIONS: In this investigation, we employed a fusion of systems pharmacology and in vivo and in vitro experiments to elucidate the mechanism of SHT's antifibrotic properties via obstruction of the PI3K/AKT signaling pathway. Additionally, we surmised that AKT may be the principal target of SHT for the management of CKD and that quercetin may be its efficacious component. We have thus identified SHT as a promising drug for the amelioration of renal fibrosis and the progression of CKD.

Fufang shenhua tablet, astragali radix and its active component astragaloside IV: Research progress on anti-inflammatory and immunomodulatory mechanisms in the kidney.

Background: Given the limited treatment options available for kidney disease, a significant number of patients turn to alternative therapies, including traditional Chinese medicine. Among these therapies, the Fufang Shenhua tablet (SHT) has garnered attention for its effectiveness in addressing the most common deficiency of Qi and Yin in chronic glomerulonephritis. Notably, the sovereign drug of SHT is Astragali Radix (AR), with the most abundant and effective component being Astragaloside IV (AS-IV). AS-IV has been shown to possess anti-inflammatory and immunomodulatory properties, and it is extensively used in treating kidney diseases. Nevertheless, the molecular mechanisms underlying its action are numerous and intricate, and a comprehensive understanding is yet to be achieved. Aim of the review: Thus, we have thoroughly examined the existing research and outlined the advancements made in investigating the anti-inflammatory and immunomodulatory mechanisms of SHT, AR and its active component AS-IV, in relation to kidney health. This serves as a dependable foundation for conducting more comprehensive investigations, evaluating efficacy, and making further improvements in the future. Materials and methods: We conducted a comprehensive literature search utilizing multiple globally recognized databases, including Web of Science, Google Scholar, PubMed, ScienceDirect, Wiley, ACS, Springer, and CNKI. The search keywords used in this study were "Fufang Shenhua tablet," "Astragali Radix," "Astragaloside IV," and "Anti-inflammatory" or "Immunity." Results: The mechanism of inflammation inhibition by SHT, AR and its active component AS-IV is mainly related to the signaling pathways such as NF-κB, TLRs, PI3K/AKT, Wnt/ß-catenin, and JAK-STAT. Immunomodulation exerts not only activating, stimulating, and regulating effects on macrophages and dendritic cells, but also on immune organs, T-lymphocytes, B-lymphocytes, and a myriad of cytokines. Moreover, the SHT, AR and its active component AS-IV also demonstrate regulatory effects on renal cells, including glomerular mesangial cells, tubular epithelial cells, and podocytes. Conclusion: To summarize, SHT, AR and its active component AS-IV, exhibit notable therapeutic effects in kidney-related ailments, and their molecular mechanisms for anti-inflammatory and immunomodulatory effects have been extensively explored. However, further standard clinical trials are necessary to evaluate their safety and efficacy in the adjunctive treatment of kidney-related diseases. Moreover, in-depth studies of unverified chemical components and regulatory mechanisms in SHT are required. It is our belief that with continued research, SHT, AR and its active component AS-IV are poised to pave the way for enhancing therapeutic outcomes in kidney-related ailments.

Remote-Triggered Domino-like Cyclodehydrogenation in Second-Layer Topological Graphene Nanoribbons.

Cyclodehydrogenation reactions in the on-surface synthesis of graphene nanoribbons (GNRs) usually involve a series of Csp2-Csp2 and/or Csp2-Csp3 couplings and just happen on uncovered metal or metal oxide surfaces. It is still a big challenge to extend the growth of second-layer GNRs in the absence of necessary catalytic sites. Here, we demonstrate the direct growth of topologically nontrivial GNRs via multistep Csp2-Csp2 and Csp2-Csp3 couplings in the second layer by annealing designed bowtie-shaped precursor molecules over one monolayer on the Au(111) surface. After annealing at 700 K, most of the polymerized chains that appear in the second layer covalently link to the first-layer GNRs that have partially undergone graphitization. Following annealing at 780 K, the second-layer GNRs are formed and linked to the first-layer GNRs. Benefiting from the minimized local steric hindrance of the precursors, we suggest that the second-layer GNRs undergo domino-like cyclodehydrogenation reactions that are remotely triggered at the link. We confirm the quasi-freestanding behaviors in the second-layer GNRs by measuring the quasiparticle energy gap of topological bands and the tunable Kondo resonance from topological end spins using scanning tunneling microscopy/spectroscopy combined with first-principles calculations. Our findings pave the avenue to diverse multilayer graphene nanostructures with designer quantum spins and topological states for quantum information science.

Calycosin Influences the Metabolism of Five Probe Drugs in Rats.

BACKGROUND: Calycosin (CAL), a type of O-methylated isoflavone extracted from the herb Astralagusmembranaceus (AM), is a bioactive chemical with antioxidative, antiphlogistic and antineoplastic activities commonly used in traditional alternative Chinese medicine. AM has been shown to confer health benefits as an adjuvant in the treatment of a variety of diseases. AIM: The main objective of this study was to determine whether CAL influences the cytochrome P450 (CYP450) system involved in drug metabolism. METHODS: Midazolam, tolbutamide, omeprazole, metoprolol and phenacetin were selected as probe drugs. Rats were randomly divided into three groups, specifically, 5% Carboxymethyl cellulose (CMC) for 8 days (Control), 5% CMC for 7 days + CAL for 1 day (single CAL) and CAL for 8 days (conc CAL), and metabolism of the five probe drugs evaluated using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). RESULTS: No significant differences were observed for omeprazole and midazolam, compared to the control group. T max and t1/2 values of only one probe drug, phenacetin, in the conc CAL group were significantly different from those of the control group (T max h: 0.50±0.00 vs 0.23±0.15; control vs conc CAL). C max of tolbutamide was decreased about two-fold in the conc CAL treatment group (conc vs control: 219.48 vs 429.56, P<0.001). CONCLUSION: Calycosin inhibits the catalytic activities of CYP1A2, CYP2D6 and CYP2C9. Accordingly, we recommend caution, particularly when combining CAL as a modality therapy with drugs metabolized by CYP1A2, CYP2D6 and CYP2C9, to reduce the potential risks of drug accumulation or ineffective treatment.

Creation of the Dirac Nodal Line by Extrinsic Symmetry Engineering.

The formation of the Dirac nodal line (DNL) requires intrinsic symmetry that can protect the degeneracy of continuous Dirac points in momentum space. Here, as an alternative approach, we propose an extrinsic symmetry protected DNL. On the basis of symmetry analysis and numerical calculations, we establish a general principle to design the nonsymmorphic symmetry protected 4-fold degenerate DNL against spin-orbit coupling in the nanopatterned 2D electron gas. Furthermore, on the basis of experimental measurements, we demonstrate the approximate realization of our proposal in the Bi/Cu(111) system, in which a highly dispersive DNL is observed at the boundary of the Brillouin zone. We envision that the extrinsic symmetry engineering will greatly enhance the ability for artificially constructing the exotic topological bands in the future.

Landau Quantization of a Narrow Doubly-Folded Wrinkle in Monolayer Graphene.

Folding can be an effective way to tailor the electronic properties of graphene and has attracted wide study interest in finding its novel properties. Here we present the experimental characterizations of the structural and electronic properties of a narrow graphene wrinkle on a SiO2/Si substrate using scanning tunneling microscopy/spectroscopy. Pronounced and nearly equally separated conductance peaks are observed in the d I/d V spectra of the wrinkle. We attribute these peaks to pseudo-Landau levels (PLLs) that are caused by a gradient-strain-induced pseudomagnetic field up to about 42 T in the narrow wrinkle. The introduction of the gradient strain and thus the pseudomagnetic field can be ascribed to the lattice deformation. A doubly-folded structure of the wrinkle is suggested. Our density functional theory calculations show that the band structure of the doubly folded graphene wrinkle has a parabolic dispersion, which can well explain the equally separated PLLs. The effective mass of carriers is obtained to be about 0.02 me ( me: the rest mass of electron), and interestingly, it is revealed that there exists valley polarization in the wrinkle. Such properties of the strained doubly folded wrinkle may provide a platform to explore some exciting phenomena in graphene, like zero-field quantum valley Hall effect.

Effects of salidroside on rat CYP enzymes by a cocktail of probe drugs.

OBJECTIVES: In this study, we aimed to evaluate the effect of salidroside on the activities of the different drug-metabolizing enzymes CYP1A2, CYP2B6, CYP2C9, CYP2D6 and CYP3A4 in rats, in which a specific probe drug was used for each enzyme. MATERIALS AND METHODS: After pretreatment with salidroside, five probe drugs were simultaneously administered to rats by gavage. The given dose was 2.0 mg/kg for phenacetin (CYP1A2 activity), 4.0 mg/kg for bupropion (CYP2B6 activity), 2.0 mg/kg for losartan (CYP2C9 activity), 8.0 mg/kg for metoprolol (CYP2D6 activity) and 1.0 mg/kg for midazolam (CYP3A4 activity). Then, an ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to analyze the concentrations of rats' blood, which were collected at different corresponding times. RESULTS: Our data showed that salidroside exhibited an inductive effect on CYP1A2, CYP2B6, CYP2C9 and CYP3A4 activities by changing the main pharmacokinetic parameters (t1/2, CL/F, Cmax and AUC(0-∞)) of the four probe drugs in rats. However, no significant changes in CYP2D6 activity were observed. CONCLUSION: In a word, the results displayed that salidroside could induce the activities of CYP1A2, CYP2B6, CYP2C9 and CYP3A4, which may influence the disposition of the drugs that are mainly metabolized by these pathways. Our research can provide the basis for the study of related herb-drug interactions in clinic.

Resolving the one-dimensional singularity edge states of Bi(1 1 1) thin films.

We report our investigation on the electronic properties of the step edges on a Bi(1 1 1) surface in epitiaxially grown thin films, using scanning tunneling microscopy and spectroscopy. Our results show three differential conductance peaks including the previously reported peak in the spectra recorded at the step edges. Our analysis indicates that all of the three peaks can be ascribed to the van Hove singularities and thus to the band extrema of the one-dimensional edge bands, according to the quasiparticle interference and the Fourier transform patterns. These edge states show an overall penetration length of about 5 nm, but they also show different spatial distributions perpendicular to the edge. The well-determined band extrema may provide information for establishing a better model to describe the electronic topology of the step edge in the Bi(1 1 1) films.

A New Flavonoid Glycoside from Lysionotus pauciflorus.

Ten flavonoids (1-10), including a new glycoside (nevadensin-7-sambubioside, 7), together with a phenylpropanoid glycoside (11) were isolated from Lysionotus pauciflorus. Their structures were elucidated by a combination of spectroscopic methods and comparing with literature data. Five compounds (1, 3, 4, 8, and 9) were obtained from the family Gesneriaceae for the first time. The new compound was evaluated in vitro for anticholinesterase activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), but was found to be inactive.

Surface Landau levels and spin states in bismuth (111) ultrathin films.

The development of next-generation electronics is much dependent on the discovery of materials with exceptional surface-state spin and valley properties. Because of that, bismuth has attracted a renewed interest in recent years. However, despite extensive studies, the intrinsic electronic transport properties of Bi surfaces are largely undetermined due to the strong interference from the bulk. Here we report the unambiguous determination of the surface-state Landau levels in Bi (111) ultrathin films using scanning tunnelling microscopy under magnetic fields perpendicular to the surface. The Landau levels of the electron-like and the hole-like carriers are accurately characterized and well described by the band structure of the Bi (111) surface from density functional theory calculations. Some specific surface spin states with a large g-factor are identified. Our findings shed light on the exploiting surface-state properties of Bi for their applications in spintronics and valleytronics.

Anticholinesterases and antioxidant alkamides from Piper nigrum fruits.

The anticholinesterase and antioxidant effects of five different extracts of Piper nigrum were evaluated. Twenty-one known alkamides were isolated from active ethyl acetate extract and investigated for their cholinesterase inhibitory and antioxidant effects. Among them, piperine (2), piperettine (5) and piperettyline (20) exhibited dual inhibition against AChE and BChE, and feruperine (18) was the most potent selective inhibitor of BChE. Molecular docking simulation was performed to get insight into the binding interactions of the ligands and enzymes. In addition, N-trans-feruloyltyramine (3) contributed to the strongest DPPH radical-scavenging activity. The self-induced Aß aggregation inhibition of 2, 5 and 18 was further evaluated. Results indicated that some alkamides could be multifunctional lead candidates for Alzheimer's disease therapy.

The Effect of Memantine on Cognitive Function and Behavioral and Psychological Symptoms in Mild-to-Moderate Alzheimer's Disease Patients.

BACKGROUND/AIMS: Memantine has been approved by the Food and Drug Administration for the treatment of moderate-to-severe Alzheimer's disease (AD). However, the effect of memantine on patients with mild-to-moderate AD is unclear. METHODS: This study is a post hoc analysis of a double-blind clinical trial. Donepezil was used as the standard control treatment. Outcomes included score changes from baseline to week 24 on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog), a modified 20-item Activities of Daily Living Scale (ADL), the Neuropsychiatric Inventory (NPI), and the Mini-Mental State Examination (MMSE) as well as the score of the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-Plus). RESULTS: One hundred sixty-seven AD patients with an MMSE score of 10-24 were analyzed. No significant differences in the score changes from baseline to week 24 on all outcomes or the four subscales of the ADAS-cog were observed between the two treatment groups. Donepezil resulted in an improved score for naming ability on the ADAS-cog compared to memantine (p = 0.036), whereas memantine more effectively reduced agitation as measured by the NPI compared to donepezil (p = 0.039). CONCLUSION: These findings support the efficacy of memantine for the treatment of mild-to-moderate AD, especially in patients with agitation.

Structural and electronic properties of an ordered grain boundary formed by separated (1,0) dislocations in graphene.

We present an investigation of the structural and electronic properties of an ordered grain boundary (GB) formed by separated pentagon-heptagon pairs in single-layer graphene/SiO2 using scanning tunneling microscopy/spectroscopy (STM/STS), coupled with density functional theory (DFT) calculations. It is observed that the pentagon-heptagon pairs, i.e., (1,0) dislocations, form a periodic quasi-one-dimensional chain. The (1,0) dislocations are separated by 8 transverse rows of carbon rings, with a period of ∼2.1 nm. The protruded feature of each dislocation shown in the STM images reflects its out-of-plane buckling structure, which is supported by the DFT simulations. The STS spectra recorded along the small-angle GB show obvious differential-conductance peaks, the positions of which qualitatively accord with the van Hove singularities from the DFT calculations.

A new sesquiterpene glucoside from Lysionotus pauciflorus.

A new acorane sesquiterpene glucoside, 1R,3S,4R,5R,10R-3,10-dihydroxyacoronene-3-O-beta-D-gluc-oside (1), was isolated from the EtOAc-soluble partition of the ethanol extract of Lysionotus pauciflorus, together with six known compounds, namely p-hydroxybenzoic acid (2), vanillic acid (3). caffeic acid (4). beta-hydroxypropiosyringone (5), alpha,beta-dihydroxypropiosyringone (6), and lyoniresinol (7). The structure of the new compound was elucidated on the basis of spectroscopic methods, including 1D and 2D NMR, and high-resolution MS analysis. The absolute configuration of 1 was determined from CD spectra. When evaluated against several bacterial and fungal strains, and human cancer cell lines, compound 1 and its aglycone were inactive.

Phenanthrenes from Juncus effusus.

A chemical investigation of the EtOAc-soluble fraction from the ethanol extract of the medullae of Juncus effusus led to the isolation of three new 9,10-dihydrophenanthrenes, juncuenins E-G (1-3); two new phenanthrenes, dehydrojuncuenins D-E (4-5); one new feruloylated glycoside (6); and one known 9,10-dihydrophenanthrene (7). The structures of these compounds were determined by analyzing their spectroscopic data. Metabolites 1-4 and 7 were further evaluated for their in vitro cytotoxic activities against seven human cancer lines (A549, MCF-7, BEL-7402, HeLa, COLO205, BGC-823, and SK-OV-3). Among them, compound 1 exhibited weak cytotoxicity against MCF-7 and HeLa cell lines. Compound 7 showed moderate cytotoxicity against MCF-7 and HeLa cell lines, with IC50 values of 9.17 and 19.6 µM, respectively.

A pilot study on the relationship between thyroid status and neuropsychiatric symptoms in patients with Alzheimer disease.

BACKGROUND: Growing evidence links alternation of the thyroid function to the pathogenesis and progression of Alzheimer disease (AD). However, only a few studies evaluate the association between thyroid hormone levels and neuropsychiatric manifestations in patients with AD. This study aimed to investigate the relationship of thyroid hormone levels and neuropsychiatric symptoms in euthyroid patients with AD. METHODS: Forty patients with AD (26 women and 14 men), with no prior AD treatment within 4 weeks before study entry, were evaluated on their thyroid status (total triiodothyronine (TT3), total thyroxine (TT4), and thyroid-stimulating hormone (TSH)), cognition (Mini-Mental State Examination (MMSE) and Alzheimer's disease Assessment Scale-Cognitive Subscale (ADAS-cog)), neuropsychiatric symptoms (Neuropsychiatric Inventory (NPI)) and depression (Hamilton Rating Scale for Depression (HAMD(17))). The unique relationship between thyroid hormones and cognitive function and mood was examined with multivariate linear regression analyses. The thyroid status between the neuropsychiatric symptoms group and the non-neuropsychiatric symptoms group was examined with independent-samples t-test. RESULTS: In euthyroid AD patients with agitation and irritability has lower TSH serum level than those without these symptoms (t = -2.130, P < 0.05; t = -2.657, P < 0.05); and core score of HAMD is significantly associated with the serum level of TSH (ß = 0.395, P < 0.01). There is no significant association between thyroid hormone levels and cognition (MMSE, ADAS-cog and its subscale score). CONCLUSION: There might be a relationship between thyroid hormone levels and the neuropsychiatric symptoms in euthyroid patients with AD.