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Due to the special physiological and pathological characteristics of gliomas, most therapeutic drugs are prevented from entering the brain. To improve the poor prognosis of existing therapies, researchers have been continuously developing non-invasive methods to overcome barriers to gliomas therapy. Although these strategies can be used clinically to overcome the blood‒brain barrier (BBB), the accurate delivery of drugs to the glioma lesions cannot be ensured. Nano-drug delivery systems (NDDS) have been widely used for precise drug delivery. In recent years, researchers have gathered their wisdom to overcome barriers, so many well-designed NDDS have performed prominently in preclinical studies. These meticulous designs mainly include cascade passing through BBB and targeting to glioma lesions, drug release in response to the glioma microenvironment, biomimetic delivery systems based on endogenous cells/extracellular vesicles/protein, and carriers created according to the active ingredients of traditional Chinese medicines. We reviewed these well-designed NDDS in detail. Furthermore, we discussed the current ongoing and completed clinical trials of NDDS for gliomas therapy, and analyzed the challenges and trends faced by clinical translation of these well-designed NDDS. Well-designed nano-drug delivery systems have played a breakthrough role in overcoming barriers in the treatment of gliomas. [Display omitted] [ABSTRACT FROM AUTHOR]

Non-small cell lung cancer (NSCLC) is a highly prevalent and fatal form of lung cancer. In China, Aconiti Lateralis Radix Praeparata (Fuzi in Chinese), derived from the lateral root of Aconitum carmichaeli Debx. (Ranunculaceae, Aconitum), is extensively prescribed to treat cancer in traditional medicine and clinical practice. However, the precise mechanism by which Fuzi treats NSCLC remains unknown. This article aims to assess the efficacy of Fuzi against NSCLC and elucidate its underlying mechanism. Marker ingredients of Fuzi decoction were quantified using UPLC-TSQ-MS. The effectiveness of Fuzi on NSCLC was evaluated using a xenograft mouse model. Subsequently, a comprehensive approach involving network pharmacology, serum metabolomics, and 16S rDNA sequencing was employed to investigate the anti-NSCLC mechanism of Fuzi. Pharmacological evaluation revealed significant tumour growth inhibition by Fuzi , accompanied by minimal toxicity. Network pharmacology identified 29 active Fuzi compounds influencing HIF-1, PI3K/Akt signalling, and central carbon metabolism in NSCLC. Integrating untargeted serum metabolomics highlighted 30 differential metabolites enriched in aminoacyl-tRNA biosynthesis, alanine, aspartate, and glutamate metabolism, and the tricarboxylic acid (TCA) cycle. Targeted serum metabolomics confirmed elevated glucose content and reduced levels of pyruvate, lactate, citrate, α-ketoglutarate, succinate, fumarate, and malate following Fuzi administration. Furthermore, 16S rDNA sequencing assay showed that Fuzi ameliorated the dysbiosis after tumorigenesis, decreased the abundance of Proteobacteria, and increased that of Firmicutes and Bacteriodetes. PICRUSt analysis revealed that Fuzi modulated the pentose phosphate pathway of the gut microbiota. Spearman correlation showed that Proteobacteria and Escherichia_Shigella accelerated the TCA cycle, whereas Bacteroidota , Bacteroides, and Lachnospiraceae_NK4A136_group suppressed the TCA cycle. This study firstly introduces a novel NSCLC mechanism involving Fuzi , encompassing energy metabolism and intestinal flora. It clarifies the pivotal role of the gut microbiota in treating NSCLC and modulating the TCA cycle. Moreover, these findings offer valuable insights for clinical practices and future research of Fuzi against NSCLC. [Display omitted] [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs), natural nano-vesicles carrying multiple bioactive molecules, have been broadly applied in brain diseases due to their excellent biocompatibility, low immunogenicity, and superior physicochemical properties. However, owing to the complexity of the blood-brain barrier (BBB) and brain diseases, and under the common oral and injectable drug delivery, EVs still have poor brain delivery and retention capabilities, and cannot achieve clinical therapeutic effects. Intranasal (IN) delivery may be a potential way to address this issue. IN delivery can bypass the body circulation and BBB, and enter the brain directly through the nasal mucosa, which offers the advantages of painless, non-invasive, and repeated administration. Herein, we discuss recent developments in the therapy of brain diseases with IN-delivered EVs. We outline the basic properties of EVs and summarize the effects of EVs on the brain. We then discuss the mechanistic pathways and advantages of IN delivery of EVs and review studies that combine EVs with IN delivery for the treatment of brain diseases. Finally, we briefly outline the challenges and prospects for IN-delivered EVs and suggest possible recommendations to facilitate the clinical translation and development of IN-delivered EVs. [Display omitted] • EVs have been investigated as therapeutic agents or drug-delivery vehicles for brain diseases. • IN delivery can increase the brain delivery efficiency of EVs. • IN delivery can prolong the retention time of EVs in the lesion area. • IN delivery of EVs has great potential for clinical applications in brain diseases. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Glycyrrhizic acid and Glycyrrhetinic acid ameliorate the abnormal status of liver cirrhosis. • Only Glycyrrhizic acid down-regulates the TLR4 and LBP gene expressions, which related to intestinal flora disorder. • Glycyrrhizic acid significantly restores the composition of Lactobacillus. • The bioavailability of Glycyrrhizic acid was probably influenced by microbiome dysbiosis. Abstract Glycyrrhizic acid (GL) and its deglycosylated metabolite glycyrrhetinic acid (GA) have been recognized as effective drugs for liver diseases. However, the underlying molecular mechanism of GL and GA remains unclear. Here, CCl 4 was used to induce the liver cirrhosis in rat, GL and GA both significantly alleviate the liver fibrosis by decreasing the ALT, AST level in serum. While, only GL was observed to significantly down-regulate the TLR4 and LBP gene expression, which indicated that GL could have direct impact on the intestinal flora. Additionally, 16S rRNA gene sequencing showed that GL especially restore the abundance of Lactobacillus compared with the model group, however, GA has no effect on the cirrhosis-induced gut dysbiosis. Furthermore, PICRUSt analysis showed that GL could improve the relative abundance of phosphotransferase systems and phosphor-glucosidases which may promote the bioavailability of GL. These results may provide novel strategies for prevention and treatment of liver cirrhosis. [ABSTRACT FROM AUTHOR]

We investigated presence and distribution of glycosaminoglycans (GAGs) in Meretrix meretrix soft tissue by determining GAG composition in the different parts, namely, mantle edge, foot, gill, adductor muscle, and viscera. The occurrence of glycan ingredients was examined by histochemistry, whereas GAG and general polysaccharide contents in clam tissue were qualified through extraction and determination. Tissue sections stained with alcian blue or periodic acid–Schiff demonstrated the general existence of saccharides and trifling generation of GAGs in clam tissues. GAGs coexisting with glycogens appeared to be primarily produced in the mantle and foot tissues in mucus form by visualization. The GAG content of the polysaccharide extract ranged from 16.8 to 75.8 mg in 10 g of 5 dried tissue materials in comparison with total carbohydrate level in the range of 500–1760 mg, thereby indicating that GAGs were not the major components of polysaccharide extracts. GAG composition only accounted for approximately 4% of total glycan components, which consist of the determinations of amino sugar and uronic acid. The soft tissues of clam contained abundant saccharide compounds but sparse amounts of GAGs. The results will benefit the subsequent development of products made from the polysaccharide components of M. meretrix . [ABSTRACT FROM AUTHOR]

Increasing hepatic insulin signaling is found to be an important mechanism of Platycodon grandiflorus root to alleviate metabolic syndrome (MetS) symptoms such as insulin resistance, obesity, hyperlipidemia and hepatic steatosis, but the details are not yet clear. Since the main constituents of Platycodon grandiflorus root were hard to be absorbed by gastrointestinal tract, getting opportunity to interact with gut microbiota, we speculate the gut microorganisms may mediate its effect. Our work aimed to confirm the critical role of gut microbes in the intervention of Platycodon grandiflorus root extract (PRE) on MetS, and investigate the mechanism. Biochemical analyses, glucose tolerance test and hepatic lipidomics analysis were used to evaluate the anti-MetS effect of PRE on high fat diet (HFD) fed mice. Perform 16S rDNA analysis, qPCR analysis and in vitro co-incubation experiment to study its effect on gut microbes, followed by fecal microbiota transplantation (FMT) experiment and antibiotics intervention experiment. Also, the effect of Akkermansia muciniphila treatment on HFD mice was investigated. PRE alleviated lipid accumulation and insulin resistance in HFD mice and remodeled the fecal microbiome. It also increased the gene expression of colonic tight junction proteins, alleviated metabolic endotoxemia and inflammation, so that reduced TNF-α induced hepatic JNK-dependent IRS-1 serine phosphorylation and the impairment of PI3K/PIP3/Akt insulin signaling pathway. A. muciniphila was one of the most significantly enriched microbes by PRE treatment, and its administration to HFD mice showed similar effects to PRE, repairing the gut barrier and activating hepatic PI3K/PIP3/Akt pathway. Finally, anti-MetS effect of PRE could be delivered to FMT recipients, and PRE could not further attenuate MetS in gut microbiota depleted mice. We demonstrated for the first time that PRE alleviated MetS in a gut microbiota dependent manner, and found activation of hepatic insulin signaling mediated by gut A. muciniphila was a potential mechanism of it. [Display omitted] [ABSTRACT FROM AUTHOR]

Phenylethanoid glycosides, the main active ingredients in Fructus Forsythiae extract possesses strong antibacterial, antioxidant and antiviral effects, and their contents were higher largely than that of other ingredients such as lignans and flavones, but their absolute bioavailability orally was significantly low, which influenced clinical efficacies of its oral preparations seriously. In the present study, the absorption mechanism of phenylethanoid glycosides was studied using in vitro Caco-2 cell model. And the effect of chito-oligosaccharide (COS) on the intestinal absorption of phenylethanoid glycosides in Fructus Forsythiae extract was investigated using in vitro , in situ and in vivo models. The pharmacological effects such as antiviral activity improvement by COS were verified by MDCK cell damage inhibition rate after influenza virus propagation. The observations from in vitro Caco-2 cell showed that the absorption of phenylethanoid glycosides in Fructus Forsythiae extract so with that in monomers was mainly restricted by the tight junctions, and influenced by efflux transporters (P-gp and MRP2). Meanwhile, the absorption of phenylethanoid glycosides in Fructus Forsythiae extract could be improved by COS. Besides, COS at the same low, medium and high concentrations caused a significant, concentration-dependent increase in the P app -value for phenylethanoid glycosides compared to the control group ( p < 0.05), and was all safe for the Caco-2 cells. The observations from single-pass intestinal perfusion in situ model showed that the intestinal absorption of phenylethanoid glycosides can be enhanced by COS. Meanwhile, the absorption enhancing effect of phenylethanoid glycosides might be saturable in different intestine sites. In pharmacokinetics study, COS at dosage of 25 mg/kg improved the bioavailability of phenylethanoid glycosides in Fructus Forsythiae extract to the greatest extent, and was safe for gastrointestine from morphological observation. In addition, treatment with Fructus Forsythiae extract with COS at dosage of 25 mg/kg prevented MDCK cell damage upon influenza virus propagation better than that of control. All findings above suggested that COS at dosage of 25 mg/kg might be safe and effective absorption enhancer for improving the bioavailability of phenylethanoid glycosides and the antiviral activity in vitro in Fructus Forsythiae extract. [ABSTRACT FROM AUTHOR]

Abstract: Phenolic acids, the main active ingredients in Flos Lonicerae extract possess strong antibacterial, antioxidant and antiviral effects, and their contents was higher largely than that of other ingredients such as flavones, but the absolute bioavailability orally was significantly low, which is significant low influencing clinical efficacies of its oral preparations. In the present study, in vitro Caco-2 cell, in situ single-pass intestinal perfusion and in vivo pharmacokinetics study were performed to investigate the effects of COS on the intestinal absorption of phenolic acids. The pharmacological effects such as antiviral activity improvement by COS were verified by MDCK cell damage inhibition rate after influenza virus propagation. The observations from in vitro Caco-2 cell showed that the absorption of phenolic acids in Flos Lonicerae extract could be improved by COS. Meanwhile, COS at the same low, medium and high concentrations caused a significant, concentration-dependent increase in the P app-value for phenolic acids compared to the control group (p <0.05), and was all safe for the Caco-2 cells. The observations from single-pass intestinal perfusion in situ model showed that the intestinal absorption of phenolic acids can be enhanced by COS. Meanwhile, the absorption enhancing effect of phenolic acids might be saturable in different intestine sites. In pharmacokinetics study, COS at dosage of 25mg/kg improved the bioavailability of phenolic acids in Flos Lonicerae extract to the greatest extent, and was safe for gastrointestine from morphological observation. Besides, treatment with Flos Lonicerae extract with COS at dosage of 25mg/kg prevented MDCK cell damage upon influenza virus propagation better than that of control. All findings above suggested that COS at dosage of 25mg/kg might be safe and effective absorption enhancer for improving the bioavailability of phenolic acids and the antiviral activity in vitro in Flos Lonicerae extract. [Copyright &y& Elsevier]

Colon adenocarcinoma is the third most common cause of cancer-related deaths worldwide owing to its aggressive nature. Here, we developed a novel oral drug delivery system (DDS) that comprised active targeted nanoparticles made from gelatin and chitosan (non-toxic polymers). The nanoparticles were fabricated using a complex coacervation method, which was accompanied by conjugation of wheat germ agglutinin (WGA) onto their surface by glutaraldehyde cross-linking. Specifically, we integrated 5-fluorouracil (5-FU), the first-line treatment agent against colon cancer, and (−)-epigallocatechin-3-gallate (EGCG), which inhibits tumor growth via anti-angiogenesis and apoptosis-inducing effects, into the nanoparticles, named WGA-EF-NP. The 5-FU and EGCG co-loaded nanoparticles showed sustained drug release, enhanced cellular uptake, and longer circulation time. WGA-EF-NP exhibited superior anti-tumor activity and pro-apoptotic efficacy compared to the drugs and nanoparticles without WGA decoration owing to better bioavailability and longer circulation time in vivo. Thus, WGA-EF-NP shows promise as a DDS for enhanced efficacy against colon cancer. The complex coacervation method was employed with Chitosan (Gel) and Gelatin (Cs), as non-toxic polymers to fabricate the nanoparticles. While, (−)-epigallocatechin-3-gallate (EGCG) was packaged into the nanoparticles to enhance the efficacy of 5-fluorouracil (5-FU)-assisted chemotherapy against colon cancer. Further, Wheat germ agglutinin (WGA) was conjugated to the nanoparticle surface by glutaraldehyde cross-linking, which acted as the desirable mucoadhesive agent, named as WGA-EF-NP. Unlabelled Image [ABSTRACT FROM AUTHOR]

[Display omitted] Traditional herbal medicine (THM), an ancient science, is a gift from nature. For thousands of years, it has helped humans fight diseases and protect life, health, and reproduction. Nanomedicine, a newer discipline has evolved from exploitation of the unique nanoscale morphology and is widely used in diagnosis, imaging, drug delivery, and other biomedical fields. Although THM and nanomedicine differ greatly in time span and discipline dimensions, they are closely related and are even evolving toward integration and convergence. This review begins with the history and latest research progress of THM and nanomedicine, expounding their respective developmental trajectory. It then discusses the overlapping connectivity and relevance of the two fields, including nanoaggregates generated in herbal medicine decoctions, the application of nanotechnology in the delivery and treatment of natural active ingredients, and the influence of physiological regulatory capability of THM on the in vivo fate of nanoparticles. Finally, future development trends, challenges, and research directions are discussed. [ABSTRACT FROM AUTHOR]

Abstract: Aim of this study: Daphnetin was regarded as the mark compound for quality control of Zushima-Pian, a traditional Chinese medicine tablet for treating rheumatoid arthritis (RA). However, no in vivo study on the therapeutic effects of daphnetin for RA has been reported. Materials and methods: The adjuvant arthritic (AA) rat model was developed to evaluate the anti-arthritic effects of daphnetin. After immunized with Freund’s complete adjuvant (FCA), the rats were treated with daphnetin (2.25 and 4.5mg/kg) for three weeks. We determined the change of secondary paw swelling and the arthritis scores of these tested rats. The severity of arthritis in the knee joints was evaluated by histological assessment of cartilage destruction. The levels of IL-1, TNF-α and MIF in the serum were measured by ELISA. Results and conclusions: Our results showed that daphnetin significantly reduced paw swelling and decreased the arthritis scores. The pathological examination demonstrated that articular cartilage degeneration with synovial hyperplasia and inflammatory cells infiltration in AA rats were suppressed by daphnetin. There was significant reduction in production of interleukin-1 (IL-1), tumor necrosis factor (TNF-α) and macrophage migration inhibitory factor (MIF) in serum of AA rats treated with daphnetin except the low dose group (2.25mg/kg) on TNF-α. In conclusion, we demonstrates that daphnetin is highly effective on preventing and suppressing the development and progression of adjuvant-induced arthritis and provides direct evidences that daphnetin is one of the active principle of Zushima-Pian for treating rheumatoid arthritis. [Copyright &y& Elsevier]

• ALD prevalence is an urgent issue of public health. • Many polysaccharides have potentials in liver protection against ALD. • The hepatoprotective polysaccharides are summarized on biological sources and chemical profiles. • Representative polysaccharides are elaborated in term of their structure-activity relationship. • Actions of polysaccharides against ALD are discussed from several aspects of pathology. Many natural polysaccharides from bio-resources hold advantages of multi-functions, high efficiency, non-toxicity or low side effect, and have strong potentials in protection against alcoholic liver damages. This review summarized the bio-resources, chemical and structural characteristics of natural polysaccharides with potentials in inhibition against alcoholic liver damages, and also emphasized knowledge on correlations between their chemical structure and function. Approximately 95 species were confirmed in generation of hepatoprotective polysaccharides. Products as crude polysaccharides originated from 17 species were sum up despite the indetermination of their accurate structure. Additional four polysaccharides were described for their known chemical structures. Possible roles of hepatoprotective polysaccharides were provided with evidence on antioxidant promotion, lipids regulation, apoptosis inhibition and anti-inflammation, as well as confirmations in immune enhancement, iron removal and anti-fibrosis when currently treated against the alcoholic liver damages. To sum up, this overview could serve to guide development and utilization of natural hepatoprotective polysaccharides. [ABSTRACT FROM AUTHOR]

As polysaccharide from Bletilla striata (BSP) was anticipated with mucoadhesive improvement in sodium alginate (SA) microspheres, BSP was mixed with SA to construct a composite microsphere to retain in the gastrointestinal tract for a long time. The morphological properties, particle size and thermodynamic properties of the microspheres in combination with comprehensive evaluations in the swelling properties, mucin adsorption, ex vivo and in vivo gastric retention were determined to characterize the mucoadhesion of SA-BSP blend microspheres. Results showed that the prepared microspheres were discrete and spherical. The addition of BSP increased flexibility and reduced rigidity of SA microsphere. Furthermore, the swelling property, mucin adsorption ability and the retention rate on the gastric mucosa of SA matrix were increased after blending with BSP. Mucoadhesion tests showed the SA-BSP microspheres stayed much longer in rats' stomach than the SA microsphere did. Above all, the SA-BSP microspheres with the enhanced mucoadhesion suggested being a potential drug carrier in developing the gastroretentive drug delivery system. • The prepared SA-BSP blend microspheres are discrete and spherical. • SA microspheres become bigger and more flexible after blending with BSP. • BSP addition improves the mucoadhesive capability of SA microspheres. • SA-BSP blend microsphere has potential as gastroretentive drug carriers. [ABSTRACT FROM AUTHOR]

The purpose of this study was to optimize hot-melt extrusion (HME) preparation process and evaluate in vitro and in vivo for developing curcumin (CUR) sustained-release solid dispersion, to explore the possibility of HME for one-step preparation of insoluble drug sustained-release solid dispersion. The effect of 3 process parameters—barrel temperature, screw speed, and cooling rate—was systematically studied. Physical state of CUR sustained-release solid dispersion was characterized by differential scanning calorimetry, X-ray powder diffraction, and Fourier transform infrared spectroscopy. It was found that CUR–Eudragit RS/RL system exhibited a good miscibility. Curcumin in the solid dispersion existed in an amorphous state and had molecular interactions with carriers. Stability studies showed no apparent difference of physical state of solid dispersion after 6 months. The mechanism of the CUR release in sustained-release solid dispersion was a diffusion and dissolution coexisting action. Pharmacokinetics study showed the relative bioavailability of the CUR in sustained-release solid dispersion to CUR was 223.44%. The CUR sustained-release solid dispersion have been successfully prepared by HME, significantly extending the half-life, ensuring a stable and effective blood concentration, and improving the bioavailability of CUR. In conclusion, HME can be used to prepared sustained-release solid dispersion of a poorly water-soluble drug as a promising method. [ABSTRACT FROM AUTHOR]

The purpose of this study was to optimize the formulation for developing curcumin sustained-release solid dispersion to increase the solubility of curcumin, delay drug release by hot-melt extrusion, and to explore the possibility of hot-melt extrusion for one-step preparation of insoluble drug sustained-release solid dispersion. The miscibility of curcumin and Eudragit RSPO and Eudragit RLPO were assessed by solubility parameter and melting point depression. Orthogonal test was used to optimize the formulation, based on the results of single-factor experiment, and the final optimal formulation: the ratio of the sustained-release carrier material RS/RL was 1:3, the ratio of drug and carrier was 1:6, and the porogen was used in an amount of 40% of the sustained-release carrier material. The curcumin solid dispersion of the best formulation had been prepared and had a significant sustained-release effect compared to the curcumin and the physical mixture. [ABSTRACT FROM AUTHOR]

Abstract Saccharides have been applied as a water-soluble matrix for dispersing hydrophobic drugs homogeneously without the need to use surfactants in amorphous solid dispersions (ASD). Up to now, concomitant permeability improvement of BCS Class IV drug by such matrices have not been much appreciated. Herein, an amorphous chitosan oligosaccharide (COS) was used as matrix to prepare surfactant-free ASD of BCS class IV drug by the ball milling method, with curcumin (CUR) as a model drug. The DSC, XRPD, FTIR and physical stability experiments indicated that CUR was in an amorphous state with high physical stability and exhibited potential interactions with COS in the ASD. Non-sink dissolution in vitro studies showed the maximum dissolution concentration of all CUR-COS ASD (CUR and COS at weight ratios of 1:1, 1:2 and 1:4) reached ranging from 97.85 to 101.21 μg/mL, far above that of pure CUR. The supersaturated concentration remained for at least 24 h under non-sink condition. Caco-2 cell model revealed that, compared to the pure CUR group, the apparent permeability coefficients were increased by 1.72–4.44-fold in all three CUR-COS ASD, which was mainly attributed to opening the tight junctions of Caco-2 cells by COS. The pharmacokinetic study showed that all CUR-COS ASD groups exhibited significant enhancements in AUC 0-∞ , with 1.55–3.01-fold that of pure CUR (p < 0.01). T max of CUR was shortened after oral administration of all three ASD. The current study demonstrates the amorphous COS could be used as a promising matrix in ASD for enhancing the oral bioavailability of BCS class IV drug by improving dissolution behavior and membrane permeability. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Two polysaccharides of MMP-2 and MMP-3 are fractioned from marine clam M. meretrix. • MMP-2 and MMP-3 belong to gulcomannan and gulcogalactan homologs. • Their chemical structures are α(1→4)–glucan branched with Man or Gal. • MMP-2 and MMP-3 can stimulate splenocyte proliferation and cytokines secretion. • The bioactivity perhaps is correlated to their peculiar structures. Abstract The marine clam Meretrix meretrix was subjected to extraction with a combined procedure of water decoction, ethanol precipitation, and deproteinization to yield a water-soluble polysaccharide coded as MMP. The product was fractionated with DEAE-52 cellulose and resulted in two soluble fractions designated as MMP-2 and -3. The structures of the fractions were determined by chemical and physicochemical analysis, and their immunomodulation activities and cytokine production were assayed by lymphopoiesis. Results showed that MMP-2 and -3 were glucomannan and glucogalactan homologs, respectively. They possess average molecular masses of 272 and 257 kDa, respectively, and were elucidated as branched copolymers, elaborated as α(1→4)–glucan branching with mannose or galactose via β(1→6)-linkage. Bioassay indicated that MMP-2 and -3 held moderate potentials in restoring immune function because they augment splenocyte proliferation and enhance the cytokine secretion of lymphocytes dose-dependently. We speculated that their bioactivities are closely correlated with their peculiar structures. [ABSTRACT FROM AUTHOR]

Abstract This study described the rheological and mucoadhesive properties of one natural water-soluble polysaccharide from Bletilla striata (BSP). The rheological characteristics of BSP in aqueous solutions and BSP mixed with other polymers were investigated under various conditions, including concentration, temperature, pH, and salt addition. Viscometric studies and ex vivo mucoadhesion tests were also conducted to examine the mucoadhesive properties of BSP. Results indicated that BSP behaved as a shear-thinning fluid at various concentrations, and its viscosity decreased at high temperatures. The viscous flow properties of the BSP mixtures changed at high pH (>5.0). Conversely, the viscosity of the BSP solutions was slightly affected by electrolytes. The viscosities of the BSP mixtures with four other commonly used polymers (sodium alginate, sodium carboxymethyl cellulose, hypromellose, and chitosan) were enhanced. The synergistic viscosity of BSP/mucin mixtures increased as BSP concentrations increased, and the maximum value was observed in the SIF medium without enzymes. The adhesive abilities of 5.0% and 10.0% BSP were almost equivalent to that of 0.5% sodium alginate, suggesting that BSP exhibited a certain mucoadhesive property, although it was weaker than that of the other commonly used mucoadhesive materials. BSP showed potential for pharmaceutical excipient applications in bioadhesive drug delivery systems. Highlights • BSP solutions behave as shear-thinning fluids. • Viscosities of BSP are influenced by concentration, temperature and pH. • BSP blending could increase the viscosities of other polymers. • There is strong interaction between BSP molecules and mucin. • BSP exhibited some detachment force to rat's stomach mucosa. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Phospholipid complex (PC) markedly improved the log P and P eff of tanshinol. • Mesoporous silica (SD) improved in vitro dissolution tanshinol from PC. • TPGS 1000 was applied for hindering the efflux of tanshinol by P-gp in DDS. • PC combined with SD was first used to enhance the oral absorption of tanshinol. • Results showed that combined DDS markedly increased the bioavailability of tanshinol. Abstract Phenolic acids are widely distributed in the plant kingdom and possess a broad spectrum of pharmacological activity. However, low oral bioavailability restricts their application. In this study, a high dispersed phyto- phospholipid complex with mesoporous silica containing TPGS 1000 (TPC-SD) was fabricated using Tanshinol (Tan) as model drug. Phospholipid complex (PC) was employed to improve the n -octanol/water partition coefficient (log P ) and apparent permeability coefficients ( P app ) of Tan. Mesoporous silica was used to compensate for the negative effects of phospholipid on drug’s dispersion and dissolution owing to its viscosity and poor water-solubility. TPGS 1000, a P-gp inhibitor, was used to block the efflux of Tan. Log P tests showed that the lipophilicity of Tan was significantly enhanced by Tanshinol phospholipid complex (TPC) formation. In vitro dissolution results showed that the cumulative dissolution percentage of Tan from TPC-SD was 4.33- fold of that from TPC in 120 min A Caco-2 permeability test confirmed that P app (AP-BL) of TPC and TPC-SD increased approximately 2.22- and 3.53- fold compared to those of unformulated Tan, respectively ( p < 0.01, p < 0.01). Pharmacokinetic studies demonstrated that the AUC 0-∞ of TPC-SD was 2.23- and 1.47- fold compared with those of unformulated Tan and TPC, respectively ( p < 0.01, p < 0.01). These results indicated that the high dispersed phyto- phospholipid complex/TPGS 1000 by mesoporous silica can be a promising drug delivery system to improve the oral bioavailability of free phenolic acids. [ABSTRACT FROM AUTHOR]

Wine-processing, which is sauteing with rice wine, will change the inclination and direction of herbs’ actions. After being wine-processed, the effects of nourishing liver and kidney of Dipsacus asper will be strengthened. However, the underlying mechanism remains elusive. The following study is to establish and validate an UHPLC–MS/MS approach to determine six bioactive constituents in tissue samples, including loganin, loganic acid, chlorogenic acid, 3,5-dicaffeoylquinic acid, 4-caffeoylquinic acid and asperosaponin VI and apply the approach to a comparative tissue distribution study of raw and wine-processed Dipsacus asper in rats. A Shimadzu UHPLC system coupled with triple quadrupole mass spectrometer was employed for analysis of the six analytes using multiple reaction monitoring (MRM) mode. A one-step protein precipitation by methanol was employed to extract the six analytes from tissues. Chloramphenicol and glycyrrhetinic acid were selected as internal standards. The proposed approach was fully validated in terms of linearity, sensitivity, precision, repeatability as well as recovery. Our results revealed that all of the calibration curves displayed good linear regression (r 2 > 0.9991). Intra- and inter-assay variability for all analytes ranged from −4.62 to 4.93% and from −4.98 to 4.92%, respectively. The recovery rates for each analytes were determined to be 88.3–100.1%. All the samples showed satisfactory precision and accuracy after various stability tests, including storage at 25 °C for 4 h, −80 °C for 30 days, three-freeze-thaw cycles, and 4 °C for 24 h. Tissue pharmacokinetic parameters including AUC 0-t , t 1/2 , T max and C max were calculated. Collectively, the parameters of C max and AUC 0-t of the six analytes in wine-processed group were remarkably elevated ( p < 0.05) in the rat liver and kidney as compared with those of the raw group. But in the rat heart and spleen, the C max and AUC 0-t of asperosaponin VI was decreased as compared with those of the raw group. The accumulation of bioactive constituents in liver and kidney tissues after wine-processing will contribute to the enhancement of liver and kidney nourishing effects. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Dipsacus asper Wall. ex C.B. Clarke (DA) is an effectively traditional Chinese medicine for treating osteoporosis and bone fracture. Until now, studies on pharmacological mechanism of DA mostly centered on cell and gene level, little is known about its metabolic signatures. The aim of this study is to investigate the anti-osteoporosis effects of crude and wine-processed DA by global and untargeted metabolic profiling of rats serum, liver and kidney derived from sham, model and treated groups. Method A total of 25 female Wistar rats were divided into five groups: sham group, model group, E2, crude and wine-processed DA treated group. The treatment rats were orally administered 17 β -estradiol, crude and wine-processed DA extract at a therapeutic dose once daily throughout the experimental period, while sham group and model group were orally gavaged approximately volume of saline solution. After 16 weeks, all serum, liver and kidney samples of five groups were collected and their metabolomic alterations were monitored by gas chromatography–mass spectrometry (GC–MS). The resulting dataset was analyzed by principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA). The identification of all potential biomarkers was performed using reference standard or NIST library. Moreover, clinical chemistry and biomechanical analysis were also performed to ensure the success of the osteoporosis model and to validate the anti-osteoporosis effect of crude and wine-processed DA. Results Clear separation trend among sham, model and treatment group was observed in PCA score plot. The anti-osteoporosis effect of DA and wine-processed DA can be indicated in PLS-DA score plots. A total of 80 and 74 metabolite biomarkers were identified for DA and wine-processed DA treated groups, respectively. Pathway analysis revealed that phenylalanine, tyrosine and tryptophan biosynthesis, valine, leucine and isoleucine biosynthesis, methane metabolism, glycine, serine and threonine metabolism, galactose metabolism were the major intervened pathways. Compared with model group, levels of all biomarkers were gradually restored to normal after administration of DA and wine-processed DA. Conclusion The anti-osteoporosis effect of DA and wine-processed DA has been reliably confirmed by the metabolomics approach. The osteoporosis might be prevented by DA and wine-processed DA via intervening amino acid metabolism, carbohydrate metabolism and energy metabolism in vivo in rats. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance TMHM is a type of Chinese medicine commonly used in medical practice and has multiple functions, including clearing heat, detoxification, reducing swelling, and tumor therapy. Previous research has demonstrated that the OAC of TMHM (TMHM-OAC) displays advantageous therapeutic action against respiratory inflammation. However, the effect of TMHM-OAC on inflammatory injury and its anti-inflammatory role requires further clarification. Materials and methods An in vitro inflammation damage model was employed using NHBE cells and 100 ng/ml of (LPS). HPLC-DAD was conducted to analyze the components of TMHM-OAC. An ELISA was conducted to determine IL-1β, IL-6, TNF-α, and NO expression. An MTT assay was conducted to determine the cytotoxicity of TMHM-OAC. The levels of IL-1β, IL-6, TNF-α, caspase-3, caspase-8, iNOS, TLR4p-nuclear factor kappa-B kinase (p-IκκB), and p-NF-κB p65 in cellular protein, as well as the mRNA levels, were determined using WB, IF testing, and Q-PCR. Results TMHM-OAC significantly reduced LPS-induced NHBE cell inflammation, which was reflected in the reduced expression of relevant cytokines such as TNF-α, IL-1β, IL-6 and NO, caspase-3, and caspase-8. In addition, this component suppressed TLR4, p-IKKβ, and p-NF-κB p65 levels in both mRNA and cellular protein. Conclusion TMHM-OAC can reduce LPS-induced inflammation in NHBE cells and this function could be linked to the regulation of the TLR4/IKK/NF-kB pathway. [ABSTRACT FROM AUTHOR]

Ginsenoside Rb 1 , an active ingredient in Panax ginseng , was widely used for its various biological activities. To clarify the role of the gut microbiota in pharmacokinetics and metabolism of Rb 1 , a comprehensive and comparative study of colonic deglycosylation metabolism and systemic exposure of ginsenoside Rb 1 in normal rats, antimicrobials (ATMs) treated rats, and restraint stressed rats was conducted. ATMs treated rats received oral administration of non-absorbable antimicrobial mixtures for 7 consecutive days. Restraint stressed rats were subjected to repeated restraint stress for a period of 2 h once daily for 7 days. Plasma concentration dynamics, urine and fecal excretion of Rb 1 and its deglycosylation metabolites (Rd, F 2 , and C-K) were studied. Moreover, the in vitro metabolism of Rb 1 in fecal suspension and the fecal β- d -glucosidase activity were profiled. Systemic exposure of the deglycosylation metabolites of ginsenoside Rb 1 (F 2 , C-K) were significantly higher in restraint stressed rats, but ATMs treated rats exhibited a decreased plasma levels of F 2 and C-K, compared with normal rats. Further studies illustrated that altered systemic Rb 1 and its deglycosylation metabolites exposure in restraint-stressed rats and ATMs treated rats may be partially attributed to alternations in cumulative fecal excretion. The distinguishing fecal β- d -glucosidase, in vitro elimination of Rb 1 , and formation of these deglycosylation metabolites afforded further evidence for the in vivo data. In conclusion, the dys-regulated fecal β- d -glucosidase activity and deglycosylation metabolism may contribute to the altered pharmacokinetic of ginsenoside Rb 1 and its hydrolysis metabolites after ATMs treatment or restraint stress exposure. Our results may offer valuable insights into the pharmacological changes of bioactive ginsenosides in dys-regulated gut microbiota statue. [ABSTRACT FROM AUTHOR]

Inflammation plays an important role in the pathogenesis of acute tracheobronchitis. Taraxacum mongolicum Hand.-Mazz (TMHM) is a dietic herb for heat-clearing and detoxifying functions as well as swell-reducing and mass-resolving effect in Traditional Chinese Medicine. Studies have shown that its major ingredient organic acid component (OAC) possesses favorable anti-inflammatory activity. However, the protective effect of OAC from TMHM (TMHM-OAC) on inflammatory injury of acute tracheobronchitis and its possible mechanism remains poorly understood. In this study, HPLC-DAD was used to analyze the components of TMHM-OAC. Lipopolysaccharide of 1 mg/ml was used to induce respiratory inflammation in ICR mice at the dose of 5 mg/kg by intratracheally aerosol administration. Enzyme-linked immunosorbent assay (ELISA) was employed to detect the levels of inflammation factors such as interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and nitric oxide in serum and supernatant of trachea tissue. Western blotting (WB) and Immunohistochemistry analysis (IHC) were conducted in parallel to determine TNF-α, IL-6, inducible nitric oxide synthase (iNOS), Toll-like receptors 4(TLR4) protein expressions and nuclear factor-kappa B p65 (NF-κB p65) phosphorylation. Hematoxylin-Eosin staining (HE) was applied to evaluate pathological lesions of trachea tissue. Experimental results showed that TMHM-OAC significantly reduced the levels of the TNF-α, IL-6 and NO in serum and supernatant of tracheal of LPS-induced ICR mice. The protein expression levels of TNF-α, IL-6 and iNOS in tracheal tissue were also down-regulated significantly by the treatment of TMHM-OAC. Moreover, TMHM-OAC downregulated phosphorylation of NF-κB p65 and protein expression of TLR4. Our results indicated that TMHM-OAC could improve LPS-induced histopathological damage of tracheal tissues through the regulation of TLR4/NF-κB signaling pathway and could be beneficial for the treatment of acute tracheobronchitis. [ABSTRACT FROM AUTHOR]

Previously , we have reported the evaluations of alginate and Bletilla striata polysaccharide (BSP) in formulation of microsphere, which is a muco-adhesive carrier and can achieve a long duration of gastric retention. The combination of Panax notoginseng (Burk.) and B. striata is a traditional Chinese herbal formula that is used to treat gastric ulcers. BSP, an effective ingredient of B. striata , possesses both medicinal and excipient functions. Panax notoginseng saponin (PNS), which can easily dissolve in water, is the main effective ingredient in P. notoginseng (Burk.) for the treatment of gastric ulcers. However, microspheres containing PNS could directly cause drug leakage, ultimately reducing the encapsulation rate. In this study, PNS was fabricated into a hydrophobic dispersion with slow-release characteristics. Subsequently, PNS was packaged into BSP/alginate microspheres to improve the encapsulation rate. The prepared PNS-loaded microspheres were round, the release characteristics aligned with the Weibull equation, and the active ingredients were released by diffusion and erosion. The developed microspheres improved the effects of PNS and synergistically exerted the pharmaceutical effects of BSP on acute gastric ulcers. [ABSTRACT FROM AUTHOR]