Astragaloside IV mitigates hypoxia-induced cardiac hypertrophy through calpain-1-mediated mTOR activation.

BACKGROUND: Astragaloside IV (AsIV), a key functioning element of Astragalus membranaceus, has been recognized for its potential cardiovascular protective properties. However, there is a need to elucidate the impacts of AsIV on myocardial hypertrophy under hypoxia conditions and its root mechanisms. PURPOSE: This study scrutinized the influence of AsIV on cardiac injury under hypoxia, with particular emphasis on the role of calpain-1 (CAPN1) in mediating mTOR pathways. METHODS: Hypoxia-triggered cardiac hypertrophy was examined in vivo with CAPN1 knockout and wild-type C57BL/6 mice and in vitro with H9C2 cells. The impacts of AsIV, 3-methyladenine, and CAPN1 inhibition on hypertrophy, autophagy, apoptosis, [Ca2+]i, and CAPN1 and mTOR levels in cardiac tissues and H9C2 cells were investigated. RESULTS: Both AsIV treatment and CAPN1 knockout mitigated hypoxia-induced cardiac hypertrophy, autophagy, and apoptosis in mice and H9C2 cells. Moreover, AsIV, 3-methyladenine, and CAPN1 inhibition augmented p-mTOR level but reduced [Ca2+]i and CAPN1 level. Additionally, lentivirus-mediated CAPN1 overexpression in H9C2 cells exacerbated myocardial hypertrophy, apoptosis, and p-mTOR inhibition under hypoxia. Specifically, AsIV treatment reversed the impacts of increased CAPN1 expression on cardiac injury and the inhibition of p-mTOR. CONCLUSION: These findings suggest that AsIV may alleviate cardiac hypertrophy under hypoxia by attenuating apoptosis and autophagy through CAPN1-mediated mTOR activation.

To investigate the mechanism of Yiwei Decoction in the treatment of premature ovarian insufficiency-related osteoporosis using transcriptomics, network pharmacology and molecular docking techniques.

To investigate the molecular mechanism of Yiwei Decoction (YWD) in preventing Premature ovarian insufficiency (POI)-related osteoporosis from the hypothalamic perspective , and to screen for the key active and acting molecules in YWD. Cyclophosphamide was used to create the POI rat model. Groups A, B, and C were established. The Model + YWD group was group A, the model control group was group B, and the normal control group was group C. ELISA was used to determine serum GnRH and FSH levels after gavage. The transcription levels of mRNAs in each group's hypothalamus tissues were examined using RNA-seq sequencing technology. The GSEA method was used to enrich pathways based on the gene expression levels of each group. The TCM-active ingredient-target-disease network map was created using differentially expressed mRNAs (DEmRNAs) and network pharmacology. The molecular docking method was employed to investigate the affinity of the active ingredient with key targets. GnRH and FSH levels in POI rats' serum were reduced by YWD. Between groups A and B, there were 638 DEmRNAs (P < 0.05) and 55 high-significance DEmRNAs (P-adjust < 0.01). The MAPK, Hedgehog, Calcium, and B cell receptor pathways are primarily enriched in DEmRNAs from Group A and Group B. The GSEA pathway enrichment analysis indicates that YWD may regulate Long-term potentiation, Amphetamine addiction, and the Renin-angiotensin system and play a role in preventing osteoporosis. The Chinese herbal medicine (CHM)-Active ingredient-Target-disease network map includes 137 targets, 4 CHMs, and 22 active ingredients. The result of docking indicated that Stigmasterol, interacts well with the core proteins ALB, VCL and KAT5. Following the screening, we identified the targets, active components, and key pathways associated with YWD osteoporosis prevention. Most of these key targets and pathways are associated with osteoporosis, but further experimental validation is required.

The impact of Yiwei decoction on the LncRNA and CircRNA regulatory networks in premature ovarian insufficiency.

Premature ovarian insufficiency（POI）is a female reproductive aging illness. Yiwei decoction（YWD） is a traditional treatment for Yangming nourishment. YWD can treat premature ovarian insufficiency, but the exact molecular mechanism is unknown. As a result, the differential expression of Long noncoding RNAs (LncRNAs) and Circular RNAs(CircRNAs) in the ovary of POI rats after YWD treatment was investigated in this paper, and the CeRNA regulatory network was built. The model was created using cyclophosphamide. The model group + YWD was in Group A, the model control group was in Group B, and the regular control group was in Group C. In this study, 177 differential expression Long noncoding RNAs(DELncRNAs) and 190 differential expression Circular RNAs (DECircRNAs) were discovered between A and B (P＜0.05,|LogFC|＞1). Following the analysis, 27 DELncRNAs and 96 DECircRNAs (P-adjusted＜0.05,|LogFC|＞1) were discovered. At the same time, we built the CeRNA network using differentially expressed mRNAs and microRNAs (miRNAs) expression between groups A and B. The DELncRNAs were used to construct a lncRNA-miRNA-mRNA ceRNA network with 27 LncRNAs, 4 miRNAs, and 19 mRNAs. The DECircRNAs were utilized to establish a CircRNA-miRNA-mRNA ceRNA network that was made up of 15 CircRNAs, 4 miRNAs, and 20 mRNA. The highly correlated regulatory networks were the LncMSTRG.22691.3/miR-3102/ANGPT4 and Circ10_34698898_34699378/miR-33-5p/TTC22. Circ20_12035276_12036793、Circ20_30693935_30696337、Circ4_157723097_157723378 and Circ4_157923266_157923904 occurred concurrently in AvsB, BvsC, and AvsC. MiRDB predicted eight target miRNAs for these CircRNAs. The miRanda(score = 140，energy = -1) binding energy calculation revealed that seven miRNAs were well combined with three CircRNA base complementary pairs. This implies that 3 DECircRNAs could serve as spongy bodies for these miRNAs. Network pharmacological analysis showed that ten active components in YWD may regulate the expression of LncRNAs and CircRNAs, such as Stigmasterol, Uridine, Ophiopogonanone A, Gamma-Aminobutyric Acid, and others. In conclusion, this study combined transcriptomics and network pharmacological analysis to identify differentially expressed lncRNAs as well as CircRNAs in ovaries of YWD-treated POI rats, thereby constructing ceRNA networks implicated in POI. This would contribute to clarifying the pathways by which Chinese herbal compounds regulate gene expression in POI.

Cobalt-aluminum spinel supported on modified γ-alumina for peroxymonosulfate activation: Si-Al ratio of support to optimize performance and reusability.

The development of cobalt-based supported catalysts with high PMS catalytic activity and stability by adjusting the composition of the support is highly desirable yet remains scarce. In the work, a series of catalysts (Co2AlO4/Al2O3-xSiO2) were prepared by impregnation and high-temperature calcination using Al2O3-xSiO2 with a low Si-Al ratio as the support. Measurement techniques such as XRD, XPS, UV-DRS, FTIR, BET, SEM and HRTEM were used to characterize textural and chemical properties (ratio of Co3+/Co2+, specific surface area, pore size, pore volume, etc.). The ratio of Co3+/Co2+ and pore volume of Co2AlO4/Al2O3-xSiO2 can be turned by controlling the ratio of Si to Al, which are closely related to the catalytic performance and reusability of the catalysts. The optimized catalyst (Co2AlO4/Al2O3-0.25SiO2) can completely degrade 10 mg/L p-nitrophenol (PNP) in 40 min in the pH range of 3-9 with excellent reusability. The effects of several reaction parameters (i.e., PMS dosage, Co2AlO4/Al2O3-0.25SiO2 dosage, reaction temperature, initial pH value, and inorganic ions) on PNP removal were comprehensively investigated. Sulfate radical (SO4•-) and singlet oxygen (1O2) are making a major contribution to the degradation of PNP. Moreover, a millimeter-scale catalyst (CoSiAl-0.25/Al2O3 pellet) was prepared by sol adsorption and high-temperature calcination method, which maintained high oxidation activity after treatment of 18 L wastewater (PNP of 10 mg/L) in a continuous flow process. The method is simple and easy to operate on a large scale, providing a new perspective on the design and preparation of cobalt-aluminum spinel catalysts for activated PMS.

Effect of prolactin on cytotoxicity and oxidative stress in ovine ovarian granulosa cells.

Background: Prolactin (PRL) has been reported to be associated with oxidative stress, which is an important contributor leading to cell apoptosis. However, little is known about the mechanisms underlying the effects of PRL on cytotoxicity and oxidative stress in ovine ovarian granulosa cells (GCs). Methods: Ovine ovarian GCs were treated with 0, 4, 20, 100 and 500 ng/mL of PRL. Then, the cytotoxicity, cell viability, malondialdehyde (MDA), reactive oxygen species (ROS), superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) of GCs were detected. Additionally, 500 ng/mL PRL was chosen as the high PRL concentration (HPC) due to its high cytotoxicity and oxidative stress. Proteomic and metabonomic were performed to examine the overall difference in proteins and metabolic pathways between C (control: 0 ng/mL PRL) and P groups (500 ng/mL PRL). Results: The results indicated that GCs treated with 4 ng/mL PRL significantly decreased (P < 0.05) the cytotoxicity, ROS and MDA, increased (P < 0.05) the cell viability, SOD and T-AOC, and the GCs treated with 500 ng/mL PRL showed the opposite trend (P < 0.05). Supplementation with 500 ng/mL PRL significantly increased the proteins of MT-ND1, MAPK12, UBA52 and BCL2L1, which were enriched in ROS and mitophagy pathways. Pathway enrichment analysis showed that the pentose phosphate pathway was significantly enriched in the P group. Conclusion: A low concentration of PRL inhibited cytotoxicity and oxidative stress. HPC induced oxidative stress in ovine ovarian GCs via the pentose phosphate pathway by modulating the associated proteins MT-ND1 in ROS pathway and UBA52, MAPK12 and BCL2L1 in mitophagy pathway, resulting in cytotoxicity.

Genome-Wide Identification, Characterization and Expression Profiling of the CONSTANS-like Genes in Potato (Solanum tuberosum L.).

CONSTANS-like (COL) genes play important regulatory roles in flowering, tuber formation and the development of the potato (Solanum tuberosum L.). However, the COL gene family in S. tuberosum has not been systematically identified, restricting our knowledge of the function of these genes in S. tuberosum. In our study, we identified 14 COL genes, which were unequally distributed among eight chromosomes. These genes were classified into three groups based on differences in gene structure characteristics. The COL proteins of S. tuberosum and Solanum lycopersicum were closely related and showed high levels of similarity in a phylogenetic tree. Gene and protein structure analysis revealed similarities in the exon-intron structure and length, as well as the motif structure of COL proteins in the same subgroup. We identified 17 orthologous COL gene pairs between S. tuberosum and S. lycopersicum. Selection pressure analysis showed that the evolution rate of COL homologs is controlled by purification selection in Arabidopsis, S. tuberosum and S. lycopersicum. StCOL genes showed different tissue-specific expression patterns. StCOL5 and StCOL8 were highly expressed specifically in the leaves of plantlets. StCOL6, StCOL10 and StCOL14 were highly expressed in flowers. Tissue-specific expression characteristics suggest a functional differentiation of StCOL genes during evolution. Cis-element analysis revealed that the StCOL promoters contain several regulatory elements for hormone, light and stress signals. Our results provide a theoretical basis for the understanding of the in-depth mechanism of COL genes in regulating the flowering time and tuber development in S. tuberosum.

Efficacy and safety of sinomenine for diabetic kidney diseases: A meta-analysis.

BACKGROUND: In traditional Chinese medicine, Sinomenii Caulis contains Sinomenine (SIN), one of the major active ingredients. According to some studies, SIN can reduce proteinuria and provides clinical effectiveness rates in diabetic kidney disease (DKD) patients, however, the evidence is not strong and mechanisms of action are unclear. The efficacy and safety of SIN in treating DKD were evaluated by meta-analysis, and the potential mechanism of SIN therapy for DKD was initially explored by network pharmacology. METHODS: PubMed, Cochrane Library, Embase, Web of Science, CNKI, Wanfang, VIP, and SinoMed databases were comprehensively searched until March 28, 2022. Randomized controlled trials on DKD treated with SIN were selected. The main results were clinical effective rate and the secondary results were the decrease in 24-hour urine total protein (24-hour UTP), serum creatinine, adverse reactions, etc. Drug combinations and disease stages were analyzed in subgroups. Sensitivity analysis was performed for 24-hour UTP. The potential target genes and pathways of SIN in treating DKD were studied using protein-protein interactions, gene ontology, and the Kyoto Genome Encyclopedia and Genomes enrichment analysis. RESULTS: The meta-analysis included 7 randomized controlled trials. SIN treatment had a higher clinical effectiveness rate than conventional treatment (relative risk = 1.53, 95% confidence interval [1.30; 1.80], Z = 5.14, P < .0001); the decrease in 24-hour UTP, treatment group was higher than control group (standardized mean difference = -1.12, 95% confidence interval [-1.71; -0.52], Z = -3.69, P = .0002); In the experimental group, adverse reactions were more common than in the control group. SIN mainly affected 5 target genes, NFκB-1, TNF, interleukin 6, interleukin 1ß and signal transducer and activator of transcription 3, and IL-17, AGE-RAGE signaling pathways, lipids, and atherosclerosis were all controlled to achieve therapeutic effects. CONCLUSION: SIN is an effective and safe drug for treating DKD, enhancing clinical efficacy, and reducing proteinuria. The main potential mechanism is anti-inflammatory.

[Review on the mechanism of acupuncture therapy for regulating synaptic plasticity in treatment of ischemic stroke].

Acupuncture has an unique advantage in treatment of ischemic stroke, which not only promotes the repair of synaptic structure and function, but also regulates the transmission of neurotransmitters and receptors, as well as induces glial cell to repair neurons, and then to protect them. At present, the mechanism study on acupuncture for advancing synaptic plasticity in cerebral ischemia is of the high priority. In the paper, from the following three aspects, i.e. synaptic plasticity (structure and function), interaction between synapses (neurotransmitters and receptors), and interconnection between synapses and environments (synaptic-glial structure), the progress of mechanism study of acupuncture in recent years was reviewed on regulating synaptic plasticity in treatment of ischemic stroke.

[Effect of transcutaneous auricular vagus nerve stimulation on the expressions of GFAP and MAP2 in ischemic penumbra of rats with middle cerebral artery ischemia].

OBJECTIVE: To observe the effects of transcutaneous auricular vagus nerve stimulation (taVNS) on the motor function and the expression of glial fibrillary acidic protein (GFAP) and microtubule associated protein 2 (MAP2) in cerebral ischemic penumbra of rats with middle cerebral artery occlusion (MCAO) and explore the mechanism of taVNS in the improvement of motor function in MCAO rats. METHODS: A total of 48 male SD rats were randomized into a sham-operation group, a model group, a transcutaneous auricular non-vagus nerve stimulation (tnVNS) group and a taVNS group, with 12 rats in each group. The suture-occluded method was adopted to prepare MCAO rat model. The auricular rim was stimulated in the tnVNS group and the concha stimulated in the taVNS group, 2 mA in intensity, 10 Hz in frequency, 30 min each time, once a day, for 14 days consecutively. The nerve functional assessment was recorded in each group. The expressions of nicotinic acetylcholine receptor (α7nAchR) in the cerebral ischemic penumbra and the spleen were detected by using Western blot. With the immunofluorescence, the expressions of GFAP and MAP2 were detected. RESULTS: After modeling, compared with the sham-operation group, the nerve functional score was increased in the model group, the tnVNS group and the taVNS group (P<0.01), suggesting the success of modeling. After treatment, the score was increased in the model group (P<0.01) as compared with the sham-operation group. Compared with the model group, the neurological deficit score was reduced in the taVNS group (P<0.01). Compared with the sham-operation group, GFAP expression was increased and MAP2 expression was reduced remarkably in the cerebral ischemic penumbra in the model group (P<0.05). In comparison with the model group, GFAP expression was reduced, while MAP2 expression was increased remarkably in the cerebral ischemic penumbra in the taVNS group (P<0.05). There were no significant differences in the abovementioned indexes between the model group and tnVNS group (P>0.05). The differences in the expression of α7nAchR in the cerebral ischemic penumbra and the spleen had no statistical significance among groups (P>0.05). CONCLUSION: TaVNS is effective on neuroprotection in MCAO rats, which may be related to its function of inhibition of GFAP expression and promotion of MAP2 expression in the ischemic penumbra.

Long-acting CoAl2O4 spinel catalyst developed on activated alumina pellets by facile synthesis to activate peroxymonosulfate: Controllable cobalt leaching and environmental adaptability.

A novel composite catalyst prepared by fixing cobalt aluminate (CoAl2O4) spinel on formed alumina carrier by impregnation-calcination route is reported, which can be used to efficiently activate peroxymonosulfate (PMS) to degrade p-nitrophenol (PNP). The internal laws of phase composition and preparation conditions are explored in detail, and the results show that the introduction of additional aluminum ions in the preparation process changes the coordination environment and the electronic state of cobalt ions, which leads to the transformation of spinel/inverted spinel in the composition, and further affects the activity and stability of the catalyst. The selected CoAl-Aaps-600 catalyst has high CoAl2O4 content, showing good cycle performance and low cobalt leaching, and has great catalytic degradation performance at different temperatures and a wide pH range. Most notably, a fixed bed reactor packed with 20 g of CoAl-Aaps-600 exhibits excellent capacity to continuously treat 60 L of PNP solution with acceptable PNP removal ratio and low cobalt leaching content. Sulfate radical and singlet oxygen are identified as the main reactive oxygen species produced in CoAl-Aaps-600/PMS system, and the reaction mechanism is reasonably inferred. This work provides a potential application material and process for the treatment of continuous organic wastewater.

The mechanisms through which auricular vagus nerve stimulation protects against cerebral ischemia/reperfusion injury.

Previous studies have shown that vagus nerve stimulation can improve patients' locomotor function. The stimulation of the auricular vagus nerve, which is the only superficial branch of the vagus nerve, may have similar effects to vagus nerve stimulation. However, the precise mechanisms remain poorly understood. In this study, rat models of cerebral ischemia/reperfusion injury were established by modified Longa ligation. Twenty-four hours later, 7-day auricular vagus nerve stimulation was performed. The results showed that auricular vagus nerve stimulation promoted the secretion of acetylcholine, inhibited the secretion of interleukin-1ß, interleukin-6, and tumor necrosis factor-α, and reduced connexin 43 phosphorylation in the ischemic penumbra and motor cortex, promoting locomotor function recovery in rats with cerebral ischemia/reperfusion injury. These findings suggested that auricular vagus nerve stimulation promotes the recovery of locomotor function in rats with cerebral ischemia/reperfusion injury by altering the secretion of acetylcholine and inflammatory factors and the phosphorylation of connexin 43. This study was approved by the Animal Use and Management Committee of Shanghai University of Traditional Chinese Medicine on November 8, 2019 (approval No. PZSHUTCM191108014).

Combined Ultrahigh Pressure Extraction and High-Speed Counter-Current Chromatography for Separation and Purification of Three Glycoside Compounds from Dendrobium officinale Protocorm.

As an alternative to Dendrobium candidum, protocorm-like bodies (PLBs) of Dendrobium candidum are of great value due to their high yield and low cost. In this work, three glycoside compounds, ß-D-glucopyranose 1-[(E)-3-(4-hydroxyphenyl)-2-propenoat] (I), ß-D-glucopyranose 1-[(E)-3-(3, 4-dihydroxyphenyl)-2-propenoat] (II), and 1-O-sinapoyl glucopyranoside (III), were extracted and isolated by ultrahigh pressure extraction (UPE) coupled with high-speed counter-current chromatography (HSCCC) from PLBs of D. officinale. First, the target compounds were optimized and prepared with 50% ethanol solution at a 1:30 (g/mL) solid/liquid ratio in 2 min under 300 MPa by UPE. Then, the crude extract was chromatographed with a silica gel column, and primary separation products were obtained. In addition, the products (150 mg) were separated by HSCCC under the solvent system of MTBE-n-butyl alcohol-acetonitrile-water (5:1:2:6, v/v/v/v), yielding 31.43 mg of compound I, 10.21 mg of compound II, and 24.75 mg of compound III. Their structures were further identified by ESI-MS, 1H NMR, and 13C NMR. The antioxidant results showed that the three compounds expressed moderate effects on the DPPH· scavenging effect. Compound II had the best antioxidant capacity and its IC50 value was 0.0497 mg/mL.

Biomimetic Ca2+ nanogenerator based on ions interference strategy for tumour-specific therapy.

Intracellular Ca2+ ions as second messenger played key role in cell behaviour, which was often overlooked in traditional antitumor treatment. Disrupting Ca2+ ion homeostasis by Ca2+ overload might switch ions signal from 'regulating' to 'destroying'. Inspired by this, a biomimetic Ca2+ nanogenerator was constructed. Briefly, the curcumin (CUR) was loaded into mesoporous calcium carbonate nanoparticles (MCC NPs), and then coated with platelet (PLT) membrane. Upon reaching tumour cells by PLT membrane-mediated tumour targeting effect, PLT@MCC/CUR would instantaneously decompose in acidic lysosomes, concurrently accompanying with Ca2+ generation and CUR release. The CUR could further facilitate Ca2+ release from endoplasmic reticulum (ER) and inhibit Ca2+ efflux, aggravating Ca2+ overload to disrupt mitochondrial Ca2+ homeostasis for mitochondria apoptosis signalling pathway activation. Interestingly, such effect was ineffective in normal cells, realising the tumour-specific therapeutic therapy. Based on ions interference strategy, PLT@MCC/CUR herein offered synergistic combination of Ca2+ overload therapy and chemotherapy, which would pave the way towards more effective nanotherapeutics.

Hypoxia enhances the cytotoxic effect of As4S4 on rat ventricular H9c2 cells through activation of ubiquitin-proteasome system.

BACKGROUND: As4S4 is widely used in Chinese traditional medicine compound. However, based on some recent studies, we found that the cardiotoxicity risk of using As4S4 in ischemic heart disease patients may be increased. To study this potential risk, we compared the effects of As4S4 on rat ventricular H9c2 cell line with or without hypoxic pretreatment, and to elucidate mechanisms of c-Cbl mediated ubiquitination/degradation of integrin ß1. METHODS: The present study was conducted on rat ventricular H9c2 cell line in the absence or presence of hypoxic pretreatment for 6 h followed by As4S4 treatment for 24 h. Following As4S4 treatment, cell viability assay, flow cytometric quantification of apoptotic cells, caspase-3 activity assay and DAPI staining were conducted. Western blotting was carried out to detect expressions of ubiquitination related proteins. In addition, the ubiquitination/degradation of integrin ß1 and the role of c-Cbl in it was evaluated by immunoprecipitation and immunoblot assay. RESULTS: The viability of cells with hypoxic pretreatment followed by As4S4 treatment was decreased significantly, apoptosis rate and the activity of caspase-3 were increased than As4S4 treatment alone. The ubiquitin-proteasome degradation pathway induced by As4S4 was further enhanced by hypoxic pretreatment. The results of IP and immunoblot assay showed hypoxic enhanced down-regulation effect of As4S4 on integrin ß1 probably through c-Cbl activation. CONCLUSIONS: This study demonstrated that the hypoxia enhanced cytotoxicity of As4S4 on H9c2 cells may through increasing the ubiquitin-proteasome degradation of integrin ß1 mediated by the E3 ligase c-Cbl. The results provide an important clue that, in patients with ischemic heart disease, use of As4S4 may be associated with increased cardiotoxicity. We believe that the results worth to be further illuminated by in vivo and clinical research.

[Long course of polymyxin B for the treatment of brain abscess caused by carbapenem resistant Acinetobacter baumannii: a case report].

The clinical efficacy of polymyxins in severe infection caused by carbapenem resistant organism (CRO) has gradually been recognized, and the course of treatment is generally 2 to 4 weeks. The most common complications after intravenous injection are nephrotoxicity and neurotoxicity, however, there are few reports on the efficacy and safety of the long course use of polymyxins. A patient with carbapenem resistant Acinetobacter baumannii (CRAB) infection after neurosurgery was admitted to the department of neurosurgical intensive care unit (NICU) of Lanzhou University Second Hospital. As the family refused the excision of brain abscess and Ommaya reservoir placement, polymyxin B was given intravenous (3.0 mg×kg-1×d-1) combined with intrathecal (5 mg once daily) injection, and high-dose sulbactam (8 g/d) was intravenously injected for anti-infection therapy. Finally, the brain abscess was absorbed and the patient was successfully cured. The total course of polymyxin B was 69 days with a cumulative dosage of 7 500 mg. There were no complications such as polymyxin-related nephrotoxicity and neurotoxicity during the period, and no symptoms of respiratory inhibition or neuromuscular blockage were observed, but polymyxin-related skin pigmentation appeared about 1 month after intravenous administration of polymyxins B, which subsided after drug withdrawal. It is suggested that long course of polymyxins B is safe and effective for intracranial infection caused by CRAB.

Transcranial pulse current stimulation improves the locomotor function in a rat model of stroke.

Previous studies have shown that transcranial pulse current stimulation (tPCS) can increase cerebral neural plasticity and improve patients' locomotor function. However, the precise mechanisms underlying this effect remain unclear. In the present study, rat models of stroke established by occlusion of the right cerebral middle artery were subjected to tPCS, 20 minutes per day for 7 successive days. tPCS significantly reduced the Bederson score, increased the foot print area of the affected limbs, and reduced the standing time of affected limbs of rats with stroke compared with that before intervention. Immunofluorescence staining and western blot assay revealed that tPCS significantly increased the expression of microtubule-associated protein-2 and growth-associated protein-43 around the ischemic penumbra. This finding suggests that tPCS can improve the locomotor function of rats with stroke by regulating the expression of microtubule-associated protein-2 and growth-associated protein-43 around the ischemic penumbra. These findings may provide a new method for the clinical treatment of poststroke motor dysfunction and a theoretical basis for clinical application of tPCS. The study was approved by the Animal Use and Management Committee of Shanghai University of Traditional Chinese Medicine of China (approval No. PZSHUTCM190315003) on February 22, 2019.

An aqueous polyphenol extract from Rosa rugosa tea has antiaging effects on Caenorhabditis elegans.

Rosa rugosa aqueous polyphenol (RAP) is a kind of polyphenol from Rosa rugosa flower tea. In this study, the antiaging activities of RAP were studied in the model organism Caenorhabditis elegans. UHPLC-HESI-MS/MS was employed to identify the specific phenolic profile, revealing that there were 23 types of phenolic compounds in RAP and that quercetin glycoside was the principal component. RAP increased the mean lifespan of C. elegans and enhanced the thermotolerance and resistance to oxidative stress of C. elegans in a concentration-dependent manner. Furthermore, RAP showed powerful antioxidant effects in vitro and strong protection against oxidative DNA damage. RAP significantly improved the levels of total superoxide dismutase and total antioxidant capacity of C. elegans. In conclusion, RAP has antiaging effects on C. elegans, which might be related to its powerful antioxidant effects both in vitro and in vivo. PRACTICAL APPLICATIONS: In recent years, chronic diseases associated with aging have had a profound impact on quality of life. Many healthy foods have antiaging properties, especially flower teas, such as those made from Rosa rugosa. Our results indicated that Rosa rugosa tea is good for health and that RAP could potentially be developed as a bioactive product that could be used to combat aging.

Discovery of Novel Janus Kinase (JAK) and Histone Deacetylase (HDAC) Dual Inhibitors for the Treatment of Hematological Malignancies.

Concurrent inhibition of Janus kinase (JAK) and histone deacetylase (HDAC) could potentially improve the efficacy of the HDAC inhibitors in the treatment of cancers and resolve the problem of HDAC inhibitor resistance in some tumors. Here, a novel series of pyrimidin-2-amino-pyrazol hydroxamate derivatives as JAK and HDAC dual inhibitors was designed, synthesized, and evaluated, among which 8m possessed potent and balanced activities against both JAK2 and HDAC6 with half-maximal inhibitory concentration at the nanomolar level. 8m exhibited improved antiproliferative and proapoptotic activities over SAHA and ruxolitinib in several hematological cell lines. Remarkably, 8m exhibited more potent antiproliferation effect than the combination of SAHA and ruxolitinib in HEL cells bearing JAK2V617F mutation. Pharmacokinetic studies in mice showed that 8m possessed good bioavailability after intraperitoneal administration. Finally, 8m showed antitumor efficacy with no significant toxicity in a HEL xenograft model. Collectively, the results confirm the therapeutic potential of JAK and HDAC dual inhibitors in hematological malignancies and provide valuable leads for further structural optimization and antitumor mechanism study.

Intervention of integrative medicine treatment has impact on serum levels of ET-1, TNF-α, MLT in RA-CVD.

Rheumatoid arthritis (RA) is a systemic autoimmune disease that can destroy peripheral joints. However, very little is known regarding specific biological marker for RA in Chinese patients. In this study, we determined the serum biomarkers and clinical features of RA-CVD. We also evaluated the short-term efficacy of routine RA treatment combined with integrative medicine treatment on RA-CVD. We found that anti-cyclic citrullinated peptide (CCP) and disease activity score in 28 joints (DAS28) are associated with risks of cardiovascular disease (CVD) in RA. And, melatonin (MLT) may play a negative regulatory role in cardiovascular damage in patients with RA. Furthermore, endothelin (ET-1) and inflammatory markers may be subclinical cardiovascular damages in RA. Moreover, of the 17 patients with RA-CVD, test results of ET-1, TNF-α and OSCAR after integrative medicine treatment were significantly decreased than before treatment. Collectively, our results provide a therapeutic potential of integrative medicine to the treatment of RA-CVD.

Discovery of Novel Pazopanib-Based HDAC and VEGFR Dual Inhibitors Targeting Cancer Epigenetics and Angiogenesis Simultaneously.

Herein a novel series of pazopanib hybrids as polypharmacological antitumor agents were developed based on the crosstalk between histone deacetylases (HDACs) and vascular endothelial growth factor (VEGF) pathway. Among them, one ortho-aminoanilide 6d and one hydroxamic acid 13f exhibited considerable total HDACs and VEGFR-2 inhibitory activities. The HDAC inhibitory activities endowed 6d and 13f with potent antiproliferative activities, which was not observed in the approved VEGFR inhibitor pazopanib. Compounds 6d and 13f possessed comparable HDAC isoform selectivity profiles to the clinical class I HDAC inhibitor MS-275 and the approved pan-HDAC inhibitor SAHA, respectively. 6d and 13f also exhibited uncompromised multiple tyrosine kinases inhibitory activities relative to pazopanib. The intracellular dual inhibition to HDAC and VEGFR of 6d and 13f was validated by Western blot analysis. In both HUVECs tube formation assay and rat thoracic aorta rings assay, 6d and 13f showed comparable antiangiogenic potencies to pazopanib. What's more, 6d possessed desirable pharmacokinetic profiles with the oral bioavailability of 72% in SD rats and considerable in vivo antitumor efficacy in a human colorectal adenocarcinoma (HT-29) xenograft model.