Role of jianxin granules in heart failure: evidence from network pharmacology, molecular docking and experimental verification.

BACKGROUND: Jianxin (JX) granules is a traditional Chinese medicine widely used in the treatment of heart failure (HF), but the mechanism is unclear. This study aimed to investigate the mechanism of JX granules in the treatment of HF based on network pharmacology analysis and in-vivo experiments. METHODS: A series of network pharmacology methods was employed to ascertain potential targets and critical pathways implicated in the therapeutic action of JX granules against HF. Subsequently, molecular docking was utilized to investigate the binding affinity of key active constituents within JX granules to these targets. In-vivo experiments, echocardiography, hematoxylin and eosin, Masson's trichrome assay, and western blot analysis were conducted to validate the efficacy and mechanism of JX granules in treating rats with HF. RESULTS: A total of 122 active components, 896 drug targets, 1216 HF-related targets, and 136 targets pertinent to drug-disease interactions were identified. 151 key targets and 725 core clusters were detected through protein-protein interaction network analysis. Among these, interleukin 6 (IL-6), vascular endothelial growth factor a (VEGFA), and serine/threonine kinase 1 (AKT1) were core hub genes. Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis revealed the critical pathways, including epidermal growth factor receptor (EGFR), advanced glycation end products (AGEs) and their receptors (RAGE) pathway, along with hypoxia-inducible factor 1 (HIF-1) signaling pathway. Molecular docking studies demonstrated high binding affinities between key targets and the pivotal active ingredients of Danshenol A, salvianolic acid B, and arachidonic acid. Furthermore, animal studies corroborated that JX granules improve cardiac function and reduce myocardial fibrosis, potentially by modulating the expression of IL-6, VEGFA, and p-AKT1. CONCLUSIONS: The bioactive components within JX granules, such as Danshenol A, salvianolic acid B, and arachidonic acid may exert therapeutic effects on HF through modulation of IL-6, VEGFA, and AKT1 gene expression. This study provides a scientific basis for subsequent clinical application of JX granules and an in-depth investigation of their mechanisms of action.

Male reproductive toxicity of polystyrene microplastics: Study on the endoplasmic reticulum stress signaling pathway.

Microplastics (MPs) have raised health concerns in public for its potential reproductive toxicity. In this study, we subjected the Kunming mice to 0.01, 0.1 and 1.0 mg/day polystyrene MPs (10 µm, PS-MPs) for 35 days, aiming to investigate the relevant male reproductive toxicity and latent molecular mechanism. The results showed the decreased sperm counts and motility, while the elevated sperm abnormality in PS-MPs-exposed mice. Testicular H&E staining displayed the vacuolization, atrophy, and even shedding of germ cells in seminiferous tubule. And the testosterone content in serum also decreased with PS-MPs treatment. Moreover, molecular analysis indicated that PS-MPs upregulated the expression trait factors for ERS (e.g., immunoglobulin-binding protein [BIP], inositol-requiring protein 1α [IRE1α], X-box-binding protein 1 splicing [XBP1s], Jun kinase [JNK], and the transcription of CCAAT/enhancer-binding protein (C/EBP) homologous protein [CHOP]) and downstream apoptotic modulator (e.g., Caspase-12, -9, and -3) in the testis. The steroidogenic acute regulatory protein (StAR), the testosterone synthetic initiator, was also downregulated. With the supplementation of ERS inhibitor, the MPs-induced testicular damage and decreased testosterone were improved to almost normal level. Overall, this study suggested that PS-MPs generate reproductive toxicity possibly via activating ERS and apoptosis signaling pathway.

Personalise vitamin D3 using physiologically based pharmacokinetic modelling.

Plasma concentration of vitamin D3 metabolite 25-hydroxyvitamin D3 (25(OH)D3 ) is variable among individuals. The objective of this study is to establish an accurate model for 25(OH)D3 pharmacokinetics (PKs) to support selection of a suitable dose regimen for an individual. We collated vitamin D3 and 25(OH)D3 plasma PK data from reported clinical trials and developed a physiologically-based pharmacokinetic (PBPK) model to appropriately recapitulate training data. Model predictions were then qualified with 25(OH)D3 plasma PKs under vitamin D3 and 25(OH)D3 dose regimens distinct from training data. From data exploration, we observed the increase in plasma 25(OH)D3 after repeated dosing was negatively correlated with 25(OH)D3 baseline levels. Our final model included a first-order vitamin D3 absorption, a first-order vitamin D3 metabolism, and a nonlinear 25(OH)D3 elimination function. This structure explained the apparent paradox. Remarkably, the model accurately predicted plasma 25(OH)D3 following repeated dosing up to 1250 µg/d in the test set. It also made sensible predictions for large single vitamin D3 doses up to 50,000 µg in the test set. Model predicts 10 µg/d regimen may be ineffective for achieving sufficiency (plasma 25(OH)D3 ≥ 75 nmol/L) for a severely deficient individual (baseline 25(OH)D3 = 10 nmol/L), and it might take the same person over 200 days to reach sufficiency at 20 µg/d dose. We propose to personalize vitamin D3 supplementation protocol with this PBPK model. It would require measuring 25(OH)D3 baseline levels, which is not routinely performed under the current UK public health advice. STUDY HIGHLIGHTS: WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC? Vitamin D PK exhibits substantial inter-individual variability. Different officially recommended daily doses are confusing. ​ WHAT QUESTION DID THIS STUDY ADDRESS? Is the UK's recommended 10 µg daily dose sufficient? Should everyone be given same dose? ​ WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE? Our model accurately predicts plasma 25(OH)D under daily oral administration of vitamin D3 . The 10 µg daily vitamin D3 dose is insufficient for prophylaxis (plasma 25(OH)D at 75 nmol/L). ​ HOW MIGHT THIS CHANGE DRUG DISCOVERY, DEVELOPMENT, AND/OR THERAPEUTICS? Combining blood test to measure 25(OH)D baseline with this PBPK model will help inform dosage selection and select follow-up date to improve effectiveness of Hypovitaminosis D treatment.

A comparative study of three tissue-cultured Dendrobium species and their wild correspondences by headspace gas chromatography-mass spectrometry combined with chemometric methods.

Plant tissue culture technique is widely used in the conservation and utilization of rare and endangered medicinal plants and it is crucial for tissue culture stocks to obtain the ability to produce similar bioactive components as their wild correspondences. In this paper, a headspace gas chromatography-mass spectrometry method combined with chemometric methods was applied to analyze and evaluate the volatile compounds in tissue-cultured and wild Dendrobium huoshanense Cheng and Tang, Dendrobium officinale Kimura et Migo and Dendrobium moniliforme (Linn.) Sw. In total, 63 volatile compounds were separated, with 53 being identified from the three Dendrobium spp. SAMPLES: Different provenances of Dendrobiums had characteristic chemicals and showed remarkable quantity discrepancy of common compositions. The similarity evaluation disclosed that the accumulation of volatile compounds in Dendrobium samples might be affected by their provenance. Principal component analysis showed that the first three components explained 85.9% of data variance, demonstrating a good discrimination between samples. Gas chromatography-mass spectrometry techniques, combined with chemometrics, might be an effective strategy for identifying the species and their provenance, especially in the assessment of tissue-cultured Dendrobium quality for use in raw herbal medicines.

Efficacy of docetaxel combined with oxaliplatin and fluorouracil against stage III/IV gastric cancer.

AIM: To investigate the clinical efficacy and toxic effects of neoadjuvant chemotherapy using docetaxel combined with oxaliplatin and fluorouracil for treating stage III/IV gastric cancer. METHODS: A total of 53 stage III/IV gastric cancer patients were enrolled into the study and treated with neoadjuvant chemotherapy. Two of the cases were excluded. The program was as follows: 75 mg/m(2) docetaxel and 85 mg/m(2) oxaliplatin on day 1 and 1500 mg/m(2) fluorouracil on days 1 to 3 for three weeks. RESULTS: The tumour changes, postoperative remission rate, changes in the symptoms and adverse reactions were observed. The overall clinical efficacy (complete remission + partial remission) of the neoadjuvant chemotherapy was 62.7%. R0 radical resection was performed on 60.8% of the patients, with a remission rate (pathological complete response + pathological subtotal response + pathological partial response) of 74.2%. The Karnofksy score improved in 42 cases. The toxicity reactions mostly included myelosuppression, followed by gastrointestinal mucosal lesions, nausea, vomiting and diarrhoea. CONCLUSION: Neoadjuvant chemotherapy consisting of docetaxel combined with oxaliplatin and fluorouracil is effective for stage III/IV gastric cancer. However, the treatment is associated with a high incidence of bone marrow suppression, which should be managed clinically.

[Curcumin combined FOLFOX induced cell apoptosis of gastric cancer and its mechanism research].

OBJECTIVE: To observe the effect of curcumin combined folinic acid fluorouracil oxaliplatin (FOLFOX) on the gastric adenocarcinoma cell line BGC-823 and to explore its possible mechanisms. METHODS: Cells were divided into five groups, i.e. the blank control group, the curcumin group, the FOLFOX group (0.1 mmol/L 5-FU +5 micromol/L oxaliplatin), and the curcumin combined FOLFOX group. CCK-8 was used to detect cell activity. The cell apoptosis was observed using Hoechst dyeing. Caspase-3 test kit was applied to test Caspase-3 vitality. The mRNA expressions of Bcl-2 and Bax were detected by real time fluorescent quantitative PCR. The expressions of Bcl-2 and Bax protein were determined by Western blot. RESULTS: The BGC-823 cells' proliferation could be inhibited, apoptosis induced, the Caspase-3 activity increased, expressions of Bcl-2 mRNA and Bcl-2 protein lowered, while Bax mRNA and Bax protein expressions increased in each medicated group. Besides, the efficacy of the curcumin combined FOLFOX group was superior to that of the curcumin group and the FOLFOX group, showing statistical difference (P < 0.01). CONCLUSION: Curcumin combined FOLFOX could significantly inhibit the proliferation of BGC-823 cells possibly via promoting Bax expression and Caspase-3 activity, inhibiting Bcl-2 expression, thus inducing apoptosis.

Antimicrobial activity of nanoemulsion in combination with cetylpyridinium chloride in multidrug-resistant Acinetobacter baumannii.

Acinetobacter baumannii has emerged as a serious problematic pathogen due to the ever-increasing presence of antibiotic resistance, demonstrating a need for novel, broad-spectrum antimicrobial therapeutic options. Antimicrobial nanoemulsions are emulsified mixtures of detergent, oil, and water (droplet size, 100 to 800 nm) which have broad antimicrobial activity against bacteria, enveloped viruses, and fungi. Here, we screened the antimicrobial activities of five nanoemulsion preparations against four Acinetobacter baumannii isolates to identify the most suitable preparation for further evaluation. Among them, N5, which contains 10% (vol/vol) Triton X-100, 25% (vol/vol) soybean oil, and 1% (wt/vol) cetylpyridinium chloride (CPC), showed the best efficacy against A. baumannii in both its planktonic and biofilm forms and was selected for further study. Our data demonstrate that, while the killing of planktonic forms of A. baumannii was due to the 1% CPC component of our nanoemulsions, the breakdown of biofilms was achieved via the emulsified oil and detergent fractions. Furthermore, we documented the effect of ethanol and NaCl in combination with N5 on planktonic A. baumannii. In killing curves of N5 combined with other agents (ethanol or NaCl), a synergistic effect of a ≥ 2-log decrease in CFU/ml was observed. The antibiofilm activity of N5 was confirmed via a cell proliferation test and scanning electron microscopy. The effects of exposure to severe environmental conditions, which simulates the field conditions in Iraq and Afghanistan, were evaluated, and this exposure did not affect the overall antimicrobial activity of N5. These studies lay a solid foundation for the utilization of nanoemulsions against the antibiotic-resistant forms of A. baumannii.

Anthelmintic activity of steroidal saponins from Dioscorea zingiberensis C. H. Wright against Dactylogyrus intermedius (Monogenea) in goldfish (Carassius auratus).

Dactylogyrus intermedius is one of the most pathogenic monogenean parasites on the gills of captive fish and can cause serious problem in aquaculture. To attempt controlling this parasite and explore novel potential antiparasitic agents, the present study was designed to investigate the anthelmintic activity of Dioscorea zingiberensis C. H. Wright against D. intermedius in goldfish under in vivo conditions. Bioactivity-guided fractionation and isolation of the compounds responsible for anthelmintic activity was carried out with the ethanolic extract yielding two bioactive compounds. Using MS, (1)H NMR, (13)C NMR spectroscopic analyses, the two compounds were identified as trillin and gracillin. The results of in vivo anthelmintic efficacy assay showed that the 48-h median effective concentrations (EC(50)) are 26.48 mg L(-1) for trillin and 0.18 mg L(-1) for gracillin. The 48-h acute toxicity tests (LD(50)) of trillin and gracillin were found to be 73.11 and 1.40 mg L(-1) for goldfish, respectively. The resulting therapeutic indices for the two active compounds are 2.76 and 7.78, respectively. These data confirmed that both trillin and gracillin are effective against D. intermedius, and the gracillin exhibits more interesting perspectives for the development of a candidate antiparasitic agent.

In vivo anthelmintic activity of crude extracts of Radix angelicae pubescentis, Fructus bruceae, Caulis spatholobi, Semen aesculi, and Semen pharbitidis against Dactylogyrus intermedius (Monogenea) in goldfish (Carassius auratus).

In search of a natural antiparasitic, in vivo anthelmintic activity of petroleum ether, chloroform, ethyl acetate, methanol, and aqueous extracts of Angelica pubescens roots (Radix angelicae pubescentis), Brucea javanica fruits (Fructus bruceae), Spatholobus suberectus stems (Caulis spatholobi), Aesculus chinensis Bge. seeds (Semen aesculi), and Pharbitis purpurea (L.) Voigt seeds (Semen pharbitidis) were tested against Dactylogyrus intermedius (Monogenea) in goldfish (Carassius auratus). Among the extracts tested, the methanolic and aqueous extracts of S. aesculi were observed to be more efficient than the other plant extracts with EC(50) and EC(90) values of 5.23 and 7.33 mg/L and 6.48 and 12.29 mg/L after 48 h, respectively, followed by methanolic extracts of Fructus bruceae, Radix angelicae pubescentis, Caulis spatholobi, and Semen pharbitidis with EC(50) 49.96, 57.45, 64.92, and 309.47 mg/L. The methanolic and aqueous extracts of S. aesculi exhibited potential results and can be exploited as a preferred natural antiparasitic for the control of D. intermedius.