[Mechanism of bulleyaconitine A in inhibiting bone destruction of rheumatoid arthritis via Src/PI3K/Akt signaling pathway].

Based on the sarcoma receptor coactivator(Src)/phosphatidylinositol 3-kinase(PI3K)/protein kinase B(Akt) signaling pathway, the mechanism of action of bulleyaconitine A in the treatment of bone destruction of experimental rheumatoid arthritis(RA) was explored. Firstly, key targets of RA bone destruction were collected through GeneCards, PharmGKB, and OMIM databa-ses. Potential targets of bulleyaconitine A were collected using SwissTargetPrediction and PharmMapper databases. Next, intersection targets were obtained by the Venny 2.1.0 platform. Protein-protein interaction(PPI) network and topology analysis were managed by utilizing the STRING database and Cytoscape 3.8.0. Then, Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses were conducted in the DAVID database. AutoDock Vina was applied to predict the molecular docking and binding ability of bulleyaconitine A with key targets. Finally, a receptor activator of nuclear factor-κB(RANKL)-induced osteoclast differentiation model was established in vitro. Quantitative real-time polymerase chain reaction(qRT-PCR) was used to detect the mRNA expression levels of related targets, and immunofluorescence and Western blot were adopted to detect the protein expression level of key targets. It displayed that there was a total of 29 drug-disease targets, and Src was the core target of bulleyaconitine A in anti-RA bone destruction. Furthermore, KEGG enrichment analysis revealed that bulleyaconitine A may exert an anti-RA bone destruction effect by regulating the Src/PI3K/Akt signaling pathway. The molecular docking results showed that bulleyaconitine A had better bin-ding ability with Src, phosphatidylinositol-4,5-diphosphate 3-kinase(PIK3CA), and Akt1. The result of the experiment indicated that bulleyaconitine A not only dose-dependently inhibited the mRNA expression levels of osteoclast differentiation-related genes cathepsin K(CTSK) and matrix metalloproteinase-9(MMP-9)(P<0.01), but also significantly reduced the expression of p-c-Src, PI3K, as well as p-Akt in vitro osteoclasts(P<0.01). In summary, bulleyaconitine A may inhibit RA bone destruction by regulating the Src/PI3K/Akt signaling pathway. This study provides experimental support for the treatment of RA bone destruction with bulleyaconitine A and lays a foundation for the clinical application of bulleyaconitine A.

Mechanisms of antiviral action and toxicities of ipecac alkaloids: Emetine and dehydroemetine exhibit anti-coronaviral activities at non-cardiotoxic concentrations.

The emergence of highly infectious pathogens with their potential for triggering global pandemics necessitate the development of effective treatment strategies, including broad-spectrum antiviral therapies to safeguard human health. This study investigates the antiviral activity of emetine, dehydroemetine (DHE), and congeneric compounds against SARS-CoV-2 and HCoV-OC43, and evaluates their impact on the host cell. Concurrently, we assess the potential cardiotoxicity of these ipecac alkaloids. Significantly, our data reveal that emetine and the (-)-R,S isomer of 2,3-dehydroemetine (designated in this paper as DHE4) reduce viral growth at nanomolar concentrations (i.e., IC50 ∼ 50-100 nM), paralleling those required for inhibition of protein synthesis, while calcium channel blocking activity occurs at elevated concentrations (i.e., IC50 ∼ 40-60 µM). Our findings suggest that the antiviral mechanisms primarily involve disruption of host cell protein synthesis and is demonstrably stereoisomer specific. The prospect of a therapeutic window in which emetine or DHE4 inhibit viral propagation without cardiotoxicity renders these alkaloids viable candidates in strategies worthy of clinical investigation.

Transcriptome dataset of two Pistacia species: Pistacia chinensis and Pistacia weinmannifolia.

Pistacia chinensis and Pistacia weinmannifolia are small trees and are distributed in East Asia, in particular China. The data on P. chinensis presented in this article is associated with the research article, "DOI: 10.5010/JPB.2019.46.4.274" [1]. Both P. chinensis and P. weinmannifolia have long been used as ethnobotanical plants to treat various illnesses, including dysentery, inflammatory swelling, rheumatism, liver diseases, influenza, lung cancer, etc. Many studies have been carried out to delve into the pharmaceutical properties of these Pistacia species using plant extracts, but genomic studies are very rarely performed to date. To enrich the genetic information of these two species, RNA sequencing was conducted using a pair-end Illumina HiSeq2500 sequencing system, resulting in 2.6 G of raw data from P. chinensis (Accession no: SRR10136265) and 2.7 G bases from P. weinmannifolia (Accession no: SRR10136264). Transcriptome shotgun assembly using three different assembly tools generated a total of 18,524 non-redundant contigs (N50, 1104 bp) from P. chinensis and 18,956 from P. weinmannifolia (N50, 1137 bp). The data is accessible at NCBI BioProject: PRJNA566127. These data would be crucial for the identification of genes associated with the compounds exerting pharmaceutical properties and also for molecular marker development.

The effectiveness of a 6-week biofeedback gait retraining programme in people with knee osteoarthritis: protocol for a randomised controlled trial.

BACKGROUND: Gait retraining is a common therapeutic intervention that can alter gait characteristics to reduce knee loading in knee osteoarthritis populations. It can be enhanced when combined with biofeedback that provides real-time information about the users' gait, either directly (i.e. knee moment feedback) or indirectly (i.e. gait pattern feedback). However, it is unknown which types of biofeedback are more effective at reducing knee loading, and also how the changes in gait affect pain during different activities of daily living. Therefore, this study aims to evaluate the acute (6 weeks of training) and chronic (1 month post training) effects of biofeedback based on personalised gait patterns to reduce knee loading and pain in people with knee osteoarthritis, as well as examine if more than one session of knee moment feedback is needed to optimise the gait patterns. METHODS: This is a parallel group, randomised controlled trial in a symptomatic knee osteoarthritis population in which participants will be randomised into either a knee moment biofeedback group (n = 20), a gait pattern biofeedback group (n = 20) or a control group (n = 10). Supervised training sessions will be carried out weekly for six continuous weeks, with real-time biofeedback provided using marker-based motion capture and an instrumented treadmill. Baseline, post-intervention and 1-month follow-up assessments will be performed to measure knee loading parameters, gait pattern parameters, muscle activation, knee pain and functional ability. DISCUSSION: This study will identify the optimal gait patterns for participants' gait retraining and compare the effectiveness of gait pattern biofeedback to a control group in reducing knee loading and index knee pain. Additionally, this study will explore how many sessions are needed to identify the optimal gait pattern with knee moment feedback. Results will be disseminated in future peer-reviewed journal articles, conference presentations and internet media to a wide audience of clinicians, physiotherapists, researchers and individuals with knee osteoarthritis. TRIAL REGISTRATION: This study was retrospectively registered under the International Standard Randomised Controlled Trial Number registry on 7th March 2023 (ISRCTN28045513).

Olfactory Three-Needle Electroacupuncture Improved Synaptic Plasticity and Gut Microbiota of SAMP8 Mice by Stimulating Olfactory Nerve.

OBJECTIVE: To investigate the effects and mechanisms of olfactory three-needle (OTN) electroacupuncture (EA) stimulation of the olfactory system on cognitive dysfunction, synaptic plasticity, and the gut microbiota in senescence-accelerated mouse prone 8 (SAMP8) mice. METHODS: Thirty-six SAMP8 mice were randomly divided into the SAMP8 (P8), SAMP8+OTN (P8-OT), and SAMP8+nerve transection+OTN (P8-N-OT) groups according to a random number table (n=12 per group), and 12 accelerated senescence-resistant (SAMR1) mice were used as the control (R1) group. EA was performed at the Yintang (GV 29) and bilateral Yingxiang (LI 20) acupoints of SAMP8 mice for 4 weeks. The Morris water maze test, transmission electron microscopy, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining, Nissl staining, Golgi staining, Western blot, and 16S rRNA sequencing were performed, respectively. RESULTS: Compared with the P8 group, OTN improved the cognitive behavior of SAMP8 mice, inhibited neuronal apoptosis, increased neuronal activity, and attenuated hippocampal synaptic dysfunction (P<0.05 or P<0.01). Moreover, the expression levels of synaptic plasticity-related proteins N-methyl-D-aspartate receptor 1 (NMDAR1), NMDAR2B, synaptophysin (SYN), and postsynaptic density protein-95 (PSD95) in hippocampus were increased by OTN treatment (P<0.05 or P<0.01). Furthermore, OTN greatly enhanced the brain-derived neurotrophic factor (BDNF)/cAMP-response element binding (CREB) signaling and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling compared with the P8 group (P<0.05 or P<0.01). However, the neuroprotective effect of OTN was attenuated by olfactory nerve truncation. Compared with the P8 group, OTN had a very limited effect on the fecal microbial structure and composition of SAMP8 mice, while specifically increased the genera Oscillospira and Sutterella (P<0.05). Interestingly, the P8-N-OT group showed an abnormal fecal microbiota with higher microbial α-diversity, Firmicutes/Bacteroidetes ratio and pathogenic bacteria (P<0.05 or P<0.01). CONCLUSIONS: OTN improved cognitive deficits and hippocampal synaptic plasticity by stimulating the olfactory nerve and activating the BDNF/CREB and PI3K/AKT/mTOR signaling pathways. Although the gut microbiota was not the main therapeutic target of OTN for Alzheimer's disease, the olfactory nerve was essential to maintain the homeostasis of gut microbiota.

[Effects and mechanisms of total flavones of Abelmoschus manihot in inhibiting podocyte necroptosis and renal fibrosis in diabetic kidney disease].

Previous studies have shown that high blood glucose-induced chronic microinflammation can cause inflammatory podocyte injury in patients with diabetic kidney disease(DKD). Therein, necroptosis is a new form of podocyte death that is closely associated with renal fibrosis(RF). To explore the effects and mechanisms in vivo of total flavones of Abelmoschus manihot(TFA), an extract from traditional Chinese herbal medicine Abelmoschus manihot for treating kidney diseases, on podocyte necroptosis and RF in DKD, and to further reveal its scientific connotation with multi-pathway and multi-target, the authors randomly divided all rats into four groups: a namely normal group, a model group, a TFA group and a rapamycin(RAP) group. After the modified DKD rat models were successfully established, four group rats were given double-distilled water, TFA suspension and RAP suspension, respectively by gavage every day. At the end of the 4th week of drug treatment, all rats were sacrificed, and the samples of their urine, blood and kidneys were collected. And then, the various indicators related to podocyte necroptosis and RF in the DKD model rats were observed, detected and analyzed, respectively. The results indicated that, general condition, body weight(BW), serum creatinine(Scr), urinary albumin(UAlb), and kidney hypertrophy index(KHI) in these modified DKD model rats were both improved by TFA and RAP. Indicators of RF, including glomerular histomorphological characteristics, fibronectin(FN) and collagen type Ⅰ(collagen Ⅰ) staining extent in glomeruli, as well as the protein expression levels of FN, collagen Ⅰ, transforming growth factor-ß1(TGF-ß1) and Smad2/3 in the kidneys were improved respectively by TFA and RAP. Podocyte damage, including foot process form and the protein expression levels of podocin and CD2AP in the kidneys was improved by TFA and RAP. In addition, tumor necrosis factor-α(TNF-α)-mediated podocyte necroptosis in the kidneys, including the morphological characteristics of podocyte necroptosis, the extent and levels of the protein expression of TNF-α and phosphorylated mixed lineage kinase domain like pseudokinase(p-MLKL) was improved respectively by TFA and RAP. Among them, RAP had the better effect on p-MLKL. More importantly, the activation of the receptor interacting serine/threonine protein kinase 1(RIPK1)/RIPK3/MLKL signaling axis in the kidneys, including the expression levels of its key signaling molecules, such as phosphorylated receptor interacting serine/threonine protein kinase 1(p-RIPK1), p-RIPK3, p-MLKL and cysteinyl aspartate specific proteinase-8(caspase-8) was improved respectively by TFA and RAP. Among them, the effect of TFA on p-RIPK1 was superior. On the whole, in this study, the authors demonstrated that TFA alleviates podocyte necroptosis and RF in DKD through inhibiting the activation of the TNF-α-mediated RIPK1/RIPK3/MLKL signaling axis in diabetic kidneys. The authors' findings provide new pharmacological evidence to reveal the scientific connotation of TFA in treating RF in DKD in more depth.

[Mechanism of Qilongtian Capsules in treatment of acute lung injury based on network pharmacology prediction and experimental validation].

This study aimed to explore the mechanism of Qilongtian Capsules in treating acute lung injury(ALI) based on network pharmacology prediction and in vitro experimental validation. Firstly, UPLC-Q-TOF-MS/MS was used to analyze the main chemical components of Qilongtian Capsules, and related databases were used to obtain its action targets and ALI disease targets. STRING database was used to build a protein-protein interaction(PPI) network. Metascape database was used to conduct enrichment analysis of Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG). AutoDock software was used to perform molecular docking verification on the main active components and key targets. Then, the RAW264.7 cells were stimulated with lipopolysaccharide(LPS) for in vitro experiments. Cell viability was measured by MTT and ROS level was measured by DCFH-DA. NO content was measured by Griess assay, and IL-1ß, IL-6, and TNF-α mRNA expression was detected by RT-PCR. The predicted targets were preliminarily verified by investigating the effect of Qilongtian Capsules on downstream cytokines. Eighty-four compounds were identified by UPLC-Q-TOF-MS/MS. Through database retrieval, 44 active components with 589 target genes were screened out. There were 560 ALI disease targets, and 65 intersection targets. PPI network topology analysis revealed 10 core targets related to ALI, including STAT3, JUN, VEGFA, CASP3, and MMP9. KEGG enrichment analysis showed that Qilongtian Capsules mainly exerted an anti-ALI effect by regulating cancer pathway, AGE-RAGE, MAPK, and JAK-STAT signaling pathways. The results of molecular docking showed that the main active components in Qilongtian Capsules, including crenulatin, ginsenoside F_1, ginsenoside Rb_1, ginsenoside Rd, ginsenoside Rg_1, ginsenoside Rg_3, notoginsenoside Fe, notoginsenoside G, notoginsenoside R_1, notoginsenoside R_2, and notoginsenoside R_3, had good binding affinities with the corresponding protein targets STAT3, JUN, VEGFA, CASP3, and MMP9. Cellular experiments showed that Qilongtian Capsules at 0.1, 0.25, and 0.5 mg·mL~(-1) reduced the release of NO, while Qilongtian Capsules at 0.25 and 0.5 mg·mL~(-1) reduced ROS production, down-regulated mRNA expression of IL-1ß, IL-6, TNF-α, and inhibited the inflammatory cascade. In summary, Qilongtian Capsules may exert therapeutic effects on ALI through multiple components and targets.

Insights into Hepatocellular Carcinoma in Patients with Thalassemia: From Pathophysiology to Novel Therapies.

Thalassemia is a heterogeneous congenital hemoglobinopathy common in the Mediterranean region, Middle East, Indian subcontinent, and Southeast Asia with increasing incidence in Northern Europe and North America due to immigration. Iron overloading is one of the major long-term complications in patients with thalassemia and can lead to organ damage and carcinogenesis. Hepatocellular carcinoma (HCC) is one of the most common malignancies in both transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT). The incidence of HCC in patients with thalassemia has increased over time, as better chelation therapy confers a sufficiently long lifespan for the development of HCC. The mechanisms of iron-overloading-associated HCC development include the increased reactive oxygen species (ROS), inflammation cytokines, dysregulated hepcidin, and ferroportin metabolism. The treatment of HCC in patients with thalassemia was basically similar to those in general population. However, due to the younger age of HCC onset in thalassemia, regular surveillance for HCC development is mandatory in TDT and NTDT. Other supplemental therapies and experiences of novel treatments for HCC in the thalassemia population were also reviewed in this article.

Effects of green tea powder on production performance, egg quality, and blood biochemical parameters in laying hens.

The paper aimed to evaluate the effects of dietary inclusion of green tea powder (GTP) on laying performance, egg quality, and blood biochemical parameters of laying hens. A total of 240 Jingfen No. 6 laying hens (age, 24 wk) were randomly allocated into 4 groups: control group (CON, basal diet), GTP0.5, GTP0.75, and GTP1.0 (basal diet included 0.5, 0.75, and 1.0% GTP, respectively). Each group has 5 replicates with 12 birds each. The feeding trial lasted 8 wk. The results showed that the hen-day egg production rate in GTP0.5 and GTP 0.75 group was higher than that of GTP1.0 group (P < 0.05), hen-day egg production rate in the GTP1.0 group was lower compared to the CON group (P > 0.05), the feed conversion ratio (FCR) in the GTP0.75 group was lower than that in CON and GTP 1.0 group (P < 0.05) during the entire experimental period. Albumen height and Haugh unit were higher in the GTP0.75 and GTP1.0 group compared to the CON group at d 56 (P < 0.05). At the end of experiment, plasma TG content in the GTP0.75 and GTP1.0 group was lower than that in the CON group (P < 0.05), the T-CH concentration in the GTP0.5 and GTP0.75 group was lower compared to the CON group (P < 0.05), plasma LDL-C and CORT concentrations were decreased by dietary GTP supplementation (P < 0.05), the HDL-C and BUN concentrations in the GTP0.75 and GTP1.0 group were higher than that in the CON group (P < 0.05). The antibody titers of H5N1 in the GTP0.75 and GTP1.0 group, and H7N9 in the GTP1.0 group were lower than that in the CON group (P < 0.05). In conclusion, dietary GTP inclusion could affect laying performance, regulate lipid metabolism, and have no favorable influence on antibody titers of H5N1 and H7N9, herein, dietary 0.5% GTP inclusion is suggested for Jingfen No. 6 laying hens during the peak laying period.

From Self-Assembly of Colloidal Crystals toward Ordered Porous Layer Interferometry.

Interferometry-based, reflectometric, label-free biosensors have made significant progress in the analysis of molecular interactions after years of development. The design of interference substrates is a key research topic for these biosensors, and many studies have focused on porous films prepared by top-down methods such as porous silicon and anodic aluminum oxide. Lately, more research has been conducted on ordered porous layer interferometry (OPLI), which uses ordered porous colloidal crystal films as interference substrates. These films are made using self-assembly techniques, which is the bottom-up approach. They also offer several advantages for biosensing applications, such as budget cost, adjustable porosity, and high structural consistency. This review will briefly explain the fundamental components of self-assembled materials and thoroughly discuss various self-assembly techniques in depth. We will also summarize the latest studies that used the OPLI technique for label-free biosensing applications and divide them into several aspects for further discussion. Then, we will comprehensively evaluate the strengths and weaknesses of self-assembly techniques and discuss possible future research directions. Finally, we will outlook the upcoming challenges and opportunities for label-free biosensing using the OPLI technique.

Curative effect of medicine cake sticking ultrasound drug penetration combined with body training on hemiplegia after stroke: An in vitro ultrasound targeted drug controlled release technology.

To explore the efficacy of ultrasound drugs in the treatment of hemiplegia after stroke. The evaluation included clinical symptoms and signs, the Stroke Scale, activities of daily living, sensory disorder Fugl-Meyer and Lindmark, electromyography sensory nerve amplitude, and conduction velocity indexes in both groups. There was no significant difference in the improved Fugl-Meyer and Lindmark score between treatment (26.97 ± 2.78) and the control group (27.45 ± 3.1) (t = 14.528, P = 0.593). After treatment, the observation group (37.10 ± 4.2) was significantly different from the control group (34.76 ± 4.36) (t = 11.259, P = 0.005) and (t = 10.15 ± 1.69), (40.87 ± 6.58) (t = 7.943,9.538, P = 0.564,0.826). After treatment, the observation group the Stroke Scale (4.27 ± 0.57), activities of daily living score (76.15 ± 12.38) and the control group (5.36 ± 0.89), (58.41 ± 9.69) (t = 16.274,5.379, P = 0.035,0.000) after treatment and F wave and M wave. The cure rate of the observation group was 77.50% (31/40), which was significantly better than that of the control group, 47.50% (19/40), with a significant difference (χ2 = 11.724,P = 0.000). After comparison, the total response rate of the observed group reached 92.500% (37 / 40), which was significantly higher than the 80.00% (32 / 40) of the control group. This difference was statistically significant (χ 2 = 9.458, P = 0.015). This therapy closely links the theoretical knowledge of modern medicine with the theoretical knowledge of traditional Chinese medicine, and uses the meridian theory to give full play to the unique advantages of traditional Chinese medicine.

[Effect and mechanism of Dahuang Zhechong Pills in improving liver aging in rats by regulating ROS-mediated PI3K/Akt/FoxO4 signaling pathway].

Recent studies have shown that the occurrence and development of common liver diseases, including non-alcoholic fatty liver disease, cirrhosis, and liver cancer, are related to liver aging(LA). Therefore, to explore the effect and mechanism of Dahuang Zhechong Pills(DHZCP), a traditional classic prescription in improving LA with multiple targets, the present study randomly divided 24 rats into a normal group, a model group, a DHZCP group, and a vitamin E(VE) group, with six rats in each group. The LA model was induced by continuous intraperitoneal injection of D-galactose(D-gal) in rats. For the LA model rats, the general situation was evaluated by aging phenotype and body weight(BW). LA was assessed by the pathological characteristics of hepatocyte senescence, hepatic function indexes, the staining characteristics of phosphorylated histone family 2A variant(γ-H2AX), and the expression levels of cell cycle arrest proteins(P21, P53, P16) and senescence-associated secretory phenotype(SASP) in the liver. The activation of the reactive oxygen species(ROS)-mediated phosphatidylinositol-3 kinase(PI3K)/protein kinase B(Akt)/forkhead box protein O4(FoxO4) signaling pathway was estimated by hepatic ROS expression feature and the protein expression levels of the key signaling molecules in the PI3K/Akt/FoxO4 signaling pathway. The results showed that after the treatment with DHZCP or VE for 12 weeks, for the DHZCP and VE groups, the characterized aging phenotype, BW, pathological characteristics of hepatocyte senescence, hepatic function indexes, relative expression of ROS in the liver, protein expression levels of key signaling molecules including p-PI3K, p-Akt, and FoxO4 in the liver, staining characteristics of γ-H2AX, and the protein expression levels of P16, P21, P53, interleukin-6(IL-6), and tumor necrosis factor-α(TNF-α) in the liver were improved, and the effects of DHZCP and VE were similar. Based on the D-gal-induced LA model in rats, this study demonstrates that DHZCP can ameliorate LA with multiple targets in vivo, and its effects and mechanism are related to regulating the activation of the ROS-mediated PI3K/Akt/FoxO4 signaling pathway in the liver. These findings are expected to provide new pharmacological evidence for the treatment of DHZCP in aging-related liver diseases.

[Effects and mechanisms of total flavones of Abelmoschus manihot in improving insulin resistance and podocyte epithelial-mesenchymal transition in diabetic kidney disease based on IRS1/PI3K/Akt pathway].

This study aimed to explore the effects and mechanisms of total flavones of Abelmoschus manihot(TFA), the extracts from traditional Chinese medicine indicated for kidney diseases, on insulin resistance(IR) and podocyte epithelial-mesenchymal transition(EMT) in diabetic kidney disease(DKD), and further to reveal the scientific connotation. Thirty-two rats were randomly divided into a normal group, a model group, a TFA group, and a rosiglitazone(ROS) group. The modified DKD model was induced in rats by methods including high-fat diet feeding, unilateral nephrectomy, and streptozotocin(STZ) intraperitoneal injection. After modeling, the rats in the four groups were given double-distilled water, TFA suspension, and ROS suspension correspondingly by gavage every day. At the end of the 8th week of drug administration, all rats were sacrificed, and the samples of urine, blood, and kidney tissues were collected. The parameters and indicators related to IR and podocyte EMT in the DKD model rats were examined and observed, including the general condition, body weight(BW) and kidney weight(KW), the biochemical parameters and IR indicators, the protein expression levels of the key signaling molecules and structural molecules of slit diaphragm in the renal insulin receptor substrate(IRS) 1/phosphatidylinositol 3-kinase(PI3K)/serine-threonine kinase(Akt) pathway, foot process form and glomerular basement membrane(GBM) thickness, the expression of the marked molecules and structural molecules of slit diaphragm in podocyte EMT, and glomerular histomorphological characteristics. The results showed that for the DKD model rats, both TFA and ROS could improve the general condition, some biochemical parameters, renal appearance, and KW. The ameliorative effects of TFA and ROS were equivalent on BW, urinary albumin(UAlb)/urinary creatinine(UCr), serum creatinine(Scr), triglyceride(TG), and KW. Secondly, they could both improve IR indicators, and ROS was superior to TFA in improving fast insulin(FIN) and homeostasis model assessment of insulin resistance(HOMA-IR). Thirdly, they could both improve the protein expression levels of the key signaling molecules in the IRS1/PI3K/Akt pathway and glomerulosclerosis in varying degrees, and their ameliorative effects were similar. Finally, both could improve podocyte injury and EMT, and TFA was superior to ROS. In conclusion, this study suggested that podocyte EMT and glomerulosclerosis could be induced by IR and the decreased activation of the IRS1/PI3K/Akt pathway in the kidney in DKD. Similar to ROS, the effects of TFA in inhibiting podocyte EMT in DKD were related to inducing the activation of the IRS1/PI3K/Akt pathway and improving IR, which could be one of the scientific connotations of TFA against DKD. This study provides preliminary pharmacological evidence for the development and application of TFA in the field of diabetic complications.

[Effects and mechanisms of total flavones of Abelmoschus manihot in attenuating diabetic tubulopathy by targeting endoplasmic reticulum stress-induced cell apoptosis].

Renal tubular injury in patients with diabetic kidney disease(DKD) may be accompanied by glomerular and microvascular diseases. It plays a critical role in the progression of renal damage in DKD, and is now known as diabetic tubulopathy(DT). To explore the multi-targeted therapeutic effects and pharmacological mechanisms in vivo of total flavones of Abelmoschus manihot(TFA), an extract from traditional Chinese medicine for treating kidney disease, in attenuating DT, the authors randomly divided all rats into four groups: a normal control group(normal group), a DT model group(model group), a DT model+TFA-treated group(TFA group) and a DT model+rosiglitazone(ROS)-treated group(ROS group). The DT rat model was established based on the DKD rat model by means of integrated measures. After successful modeling, the rats in the four groups were continuously given double-distilled water, TFA suspension, and ROS suspension, respectively by gavage every day. After 6 weeks of treatment, all rats were sacrificed, and the samples of their urine, blood, and kidneys were collected. The effects of TFA and ROS on various indicators related to urine and blood biochemistry, renal tubular injury, renal tubular epithelial cell apoptosis and endoplasmic reticulum stress(ERS), as well as the activation of the protein kinase R-like endoplasmic reticulum kinase(PERK)-eukaryotic translation initiation factor 2α(eIF2α)-activating transcription factor 4(ATF4)-C/EBP homologous protein(CHOP) signaling pathway in the kidney of the DT model rats were investigated. The results indicated that hypertrophy of renal tubular epithelial cells, renal tubular hyperplasia and occlusion, as well as interstitial extracellular matrix and collagen deposition occurred in the DT model rats. Moreover, significant changes were found in the expression degree and the protein expression level of renal tubular injury markers. In addition, there was an abnormal increase in tubular urine proteins. After TFA or ROS treatment, urine protein, the characteristics of renal tubular injury, renal tubular epithelial cell apoptosis and ERS, as well as the activation of the PERK-eIF2α-ATF4-CHOP signaling pathway in the kidney of the DT model rats were improved to varying degrees. Therein, TFA was superior to ROS in affecting the pathological changes in renal tubule/interstitium. In short, with the DT model rats, this study demonstrated that TFA could attenuate DT by multiple targets through inhibiting renal tubular ERS-induced cell apoptosis in vivo, and its effect and mechanism were related to suppressing the activation of the PERK-eIF2α-ATF4-CHOP signaling pathway in the kidney. These findings provided preliminary pharmacological evidence for the application of TFA in the clinical treatment of DT.

Scalable CMOS back-end-of-line-compatible AlScN/two-dimensional channel ferroelectric field-effect transistors.

Three-dimensional monolithic integration of memory devices with logic transistors is a frontier challenge in computer hardware. This integration is essential for augmenting computational power concurrent with enhanced energy efficiency in big data applications such as artificial intelligence. Despite decades of efforts, there remains an urgent need for reliable, compact, fast, energy-efficient and scalable memory devices. Ferroelectric field-effect transistors (FE-FETs) are a promising candidate, but requisite scalability and performance in a back-end-of-line process have proven challenging. Here we present back-end-of-line-compatible FE-FETs using two-dimensional MoS2 channels and AlScN ferroelectric materials, all grown via wafer-scalable processes. A large array of FE-FETs with memory windows larger than 7.8 V, ON/OFF ratios greater than 107 and ON-current density greater than 250 µA um-1, all at ~80 nm channel length are demonstrated. The FE-FETs show stable retention up to 10 years by extension, and endurance greater than 104 cycles in addition to 4-bit pulse-programmable memory features, thereby opening a path towards the three-dimensional heterointegration of a two-dimensional semiconductor memory with silicon complementary metal-oxide-semiconductor logic.

Electroacupuncture Improves Blood-Brain Barrier and Hippocampal Neuroinflammation in SAMP8 Mice by Inhibiting HMGB1/TLR4 and RAGE/NADPH Signaling Pathways.

OBJECTIVE: To investigate the molecular mechanisms underlying the beneficial effect of electroacupuncture (EA) in experimental models of Alzheimer's disease (AD) in vivo. METHODS: Senescence-accelerated mouse prone 8 (SAMP8) mice were used as AD models and received EA at Yingxiang (LI 20, bilateral) and Yintang (GV 29) points for 20 days. For certain experiments, SAMP8 mice were injected intravenously with human fibrin (2 mg). The Morris water maze test was used to assess cognitive and memory abilities. The changes of tight junctions of blood-brain barrier (BBB) in mice were observed by transmission electron microscope. The expressions of fibrin, amyloid- ß (Aß), and ionized calcium-binding adapter molecule 1 (IBa-1) in mouse hippocampus (CA1/CA3) were detected by reverse transcription-quantitative polymerase chain reaction (qRT-PCR), Western blot or immunohistochemical staining. The expression of fibrin in mouse plasma was detected by enzyme-linked immunosorbent assay. The expressions of tight junction proteins zonula occludens-1 and claudin-5 in hippocampus were detected by qRT-PCR and immunofluorescence staining. Apoptosis of hippocampal neurons was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. RESULTS: Fibrin was time-dependently deposited in the hippocampus of SAMP8 mice and this was inhibited by EA treatment (P<0.05 or P<0.01). Furthermore, EA treatment suppressed the accumulation of Aß in the hippocampus of SAMP8 mice (P<0.01), which was reversed by fibrin injection (P<0.05 or P<0.01). EA improved SAMP8 mice cognitive impairment and BBB permeability (P<0.05 or P<0.01). Moreover, EA decreased reactive oxygen species levels and neuroinflammation in the hippocampus of SAMP8 mice, which was reversed by fibrin injection (P<0.05 or P<0.01). Mechanistically, EA inhibited the promoting effect of fibrin on the high mobility group box protein 1 (HMGB1)/toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE)/nicotinamide adenine dinucleotide phosphate (NADPH) signaling pathways (P<0.01). CONCLUSION: EA may potentially improve cognitive impairment in AD via inhibition of fibrin/A ß deposition and deactivation of the HMGB1/TLR4 and RAGE/NADPH signaling pathways.

Chemical and metabolic profiling of Codonopsis Radix extract with an integrated strategy using ultra-high-performance liquid chromatography coupled with mass spectrometry.

Codonopsis radix was commonly used as food materials or herbal medicines in many countries. However, the comprehensive analysis of chemical constituents, and in vivo xenobiotics of Codonopsis radix remain unclear. In the present study, an integrated strategy with feature-based molecular networking using ultra-high-performance liquid chromatography coupled with mass spectrometry was established to systematically screen the chemical constituents and the in vivo xenobiotics of Codonopsis radix. A step-by-step manner based on a composition database, visual structure classification, discriminant ions, and metabolite software prediction was proposed to overcome the complexities due to the similar structure of chemical constituents and metabolites of Codonopsis radix. As a result, 103 compounds were tentatively characterized, 20 of which were identified by reference standards. Besides, a total of 50 xenobiotics were detected in vivo, including 26 prototypes and 24 metabolites, while the metabolic features of the pyrrolidine alkaloids were elucidated for the first time. The metabolism reactions of pyrrolidine alkaloids and sesquiterpene lactones included oxidation, methylation, hydration, hydrogenation, demethylation, glucuronidation, and sulfation. This study provided a generally applicable approach to the comprehensive investigation of the chemical and metabolic profile of traditional Chinese medicine and offered reasonable guidelines for further screening of quality control indicators and pharmacodynamics mechanism of Codonopsis radix.

Simultaneous determination of multiple constituents of Qi-Lin pill by UPLC-MS/MS: Applications to pharmacokinetics and testicular tissue distribution in rats.

Qi-Lin pill (QLP) is an effective traditional Chinese medicine prescription (TCMP) that has been used for the treatment of the oligoasthenozoospermia in China. Recently, some articles described the pharmacological effects of QLP and multiple ingredients in QLP contribute to its effects. However, the pharmacokinetic and target tissue distribution data of QLP are still unknown. In the present study, according to the Bioanalytical Method Validation Guidance of FDA, a sensitive and selective UPLC-MS/MS method was developed and validated for simultaneous determination of multiple constituents in rat plasma and testicular tissue, including morusimic acid A, codonopyrridium B, magnoflorine, emodin, 2,3,5,4'-tetrahydroxystilbene-2-O-ß-D-glucoside (THSG), ecliptasaponin A, paeoniflorin, albiflorin, gallic acid, danshensu, salvianolic acid A, catechin, isosinensetin, nobiletin, formononetin, calycosin, icariside II, icariin and epimedin C. For 19 analytes, the LLOQs reached 0.01-4 ng/mL. And all calibration curves showed favorable linearity (r ≥ 0.9903) in linear ranges. The intra-day and inter-day precision (relative standard deviation) for all analytes was less than 14.92 %, and the accuracies (as relative error) were in the range of - 6.44 % to 6.22 %. Extraction recoveries and matrix effects of analytes and IS were acceptable. All analytes were stable during the assay and storage in plasma samples. The method was successfully applied for the pharmacokinetics and testis distribution of multiple chemical constituents in QLP after a single oral dose. As a result, high exposure of danshensu, gallic acid, paeoniflorin and albiflorin were observed in rat plasma and testicular tissue. Among the flavonoids, isosinensetin and nobiletin had high exposure in testicular tissue. Moreover, alleviation of progesterone reduction was evaluated in H2O2-induced R2C leydig cells, and danshensu, gallic acid, paeoniflorin, albiflorin and nobiletin showed potent activity. Therefore, these five components were considered to be the effective components of QLP due to their relatively high exposure in vivo and biological activity. This finding also provided relevant information on action mechanism of QLP in the treatment of oligoasthenozoospermia.

Combined detection of urinary biomarkers noninvasively predicts extent of renal injury in patients with early diabetic kidney disease with kidney qi deficiency syndrome: A retrospective investigation.

Incipient diagnosis and noninvasive forecasts using urinary biomarkers are important for preventing diabetic kidney disease (DKD) progression, but they are also controversial. Previous studies have shown a potential relationship between urinary tubular biomarkers (UTBs) and traditional Chinese medicine (TCM) syndrome in patients with DKD. Thus, we further evaluated the clinical significance of combined detection of urinary biomarkers in noninvasively predicting the extent of renal damage in patients with early DKD with kidney qi deficiency syndrome, and preliminarily explored the potential biological link between UTBs and TCM syndrome in DKD. We categorized 92 patients with Type 2 diabetes mellitus into three groups as follows: 20 patients with normoalbuminuria, 50 patients with microalbuminuria, and 22 patients with macroalbuminuria. We found that, in all groups, 24 hr urinary albumin (24hUAlb) and urinary albumin-to-creatinine ratio (UACR) showed stepwise and significant increases. Urinary cystatin C (UCysC), urinary N-acetyl-ß-d-glucosaminidase (UNAG), and urinary retinol-binding protein (URBP) synchronously increased gradually, consistent with the degree of albuminuria in all groups. Moreover, 24hUAlb and UACR were positively correlated with UCysC, UNAG, and URBP, respectively. In 72 patients with Type 2 DKD with albuminuria, a positive correlation was observed between UNAG and URBP, UCysC was also positively correlated with UNAG and URBP, respectively. Additionally, TCM syndrome distributional characteristics in all patients were consistent with clinical manifestations of kidney qi deficiency syndrome. Therefore, the combined detection of UCysC, UNAG, URBP, and UAlb may be used as a practical clinical technique to noninvasively forecast the extent of renal injury in patients with early Type 2 DKD with kidney qi deficiency syndrome. UTBs may be one of the biological bases of the specific TCM syndromes in DKD.

Effects and mechanisms of Xiaochaihu Tang against liver fibrosis: An integration of network pharmacology, molecular docking and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Liver fibrosis is a potentially harmful chronic liver disease caused by various etiologies. There is currently no specific drug for liver fibrosis. Xiaochaihu Tang (XCHT) is a traditional formula combined of seven herbs, which was first recorded in the Treatise on Febrile Diseases in Han Dynasty of ancient China. It is widely used in clinic to hepatic protection, analgesic, antipyretic and anti-inflammatory treatment. And it has been recommended for treating chronic hepatitis and chronic cholecystitis in the latest guidelines for the diagnosis and treatment of liver fibrosis with integrated traditional and western medicine. However, the underlying regulatory mechanisms remain elusive. AIM OF THE STUDY: This study aims to explore the therapeutic effects of XCHT on liver fibrosis and its underlying molecular mechanisms from the perspective of network pharmacology and experimental research. MATERIALS AND METHODS: Carbon tetrachloride (CCl4) induced and bile duct ligation (BDL) induced liver fibrosis models in mice were established to evaluate the anti-fibrosis effects of XCHT in vivo. Potential anti-fibrosis targets of XCHT were screened via network establishment. The underlying mechanisms were uncovered through GO and pathway enrichment analysis. Then, the core targets were identified from protein-protein interaction network by means of the Cytohubba plug-in of Cytoscape. Furthermore, two effective monomer components of XCHT were recognized by molecular docking. Moreover, the predicted components and pathways were verified by in vitro experiments. RESULTS: When treated with XCHT, liver fibrosis was alleviated in both mice models, showing as the improvement of liver function, the protection of hepatocytes, the inhibition of HSC activation and the reduction of hepatic collagen accumulation. 540 monomer components, 300 therapeutic targets, 109 signaling pathways, 246 GO biological processes, 77 GO cellular components, 107 GO molecular functions items and core targets were identified by network analysis. Then, 6-gingerol and baicalein were identified as the core components of anti-fibrosis effects of XCHT via leptin or Nrf2 signaling pathway. Furthermore, the experiment in vitro also validated the results. CONCLUSIONS: Our study suggests XCHT could alleviate liver fibrosis through multi-targets and multi-pathways; 6-gingerol and baicalein are its core components which may play an important role via leptin or Nrf2 signaling pathway.