Tauroursodeoxycholic Acid Reverses Dextran Sulfate Sodium-Induced Colitis in Mice via Modulation of Intestinal Barrier Dysfunction and Microbiome Dysregulation.

Ulcerative colitis (UC) is an immune-mediated inflammatory disease that can lead to persistent damage and even cancer without any intervention. Conventional treatments can alleviate UC symptoms but are costly and cause various side effects. Tauroursodeoxycholic acid (TUDCA), a secondary bile acid derivative, possesses anti-inflammatory and cytoprotective properties for various diseases, but its potential therapeutic benefits in UC have not been fully explored. Mice were subjected to colitis induction using 3% dextran sulfate sodium (DSS). The therapeutic effect of TUDCA was evaluated by body weight loss, disease activity index (DAI), colon length, and spleen weight ratio. Tissue pathology was assessed using H&E staining, while the levels of pro-inflammatory and anti-inflammatory cytokines in colonic tissue were quantified via ELISA. Tight junction proteins were detected by immunoblotting and intestinal permeability was assessed using fluorescein isothiocyanate (FITC)-dextran. Moreover, the gut microbiota was profiled using high-throughput sequencing of the 16S rDNA gene. TUDCA alleviated the colitis in mice, involving reduced DAI, attenuated colon and spleen enlargement, ameliorated histopathological lesions, and normalized levels of pro-inflammatory and anti-inflammatory cytokines. Furthermore, TUDCA treatment inhibited the downregulation of intestinal barrier proteins, including zonula occludens-1 and occludin, thus reducing intestinal permeability. The analysis of gut microbiota suggested that TUDCA modulated the dysbiosis in mice with colitis, especially for the remarkable rise in Akkermansia TUDCA exerted a therapeutic efficacy in DSS-induced colitis by reducing intestinal inflammation, protecting intestinal barrier integrity, and restoring gut microbiota balance. SIGNIFICANCE STATEMENT: This study demonstrates the potential therapeutic benefits of Tauroursodeoxycholic acid (TUDCA) in ulcerative colitis. TUDCA effectively alleviated colitis symptoms in mice, including reducing inflammation, restoring intestinal barrier integrity and the dysbiosis of gut microbiota. This work highlights the promising role of TUDCA as a potentially alternative treatment, offering new insights into managing this debilitating condition.

Functional metabolomics revealed the dual-activation of cAMP-AMP axis is a novel therapeutic target of pancreatic cancer.

Pancreatic cancer (PC) is one of the most malignant cancers, owing to extremely high aggressiveness and mortality. Yet, this condition currently incurs widely drug resistance and therapeutic deficiency. In this study, we proposed a novel functional metabolomics strategy as Spatial Temporal Operative Real Metabolomics (STORM) to identify the determinant functional metabolites in a dynamic and visualized pattern whose level changes are mechanistically associated with therapeutic efficiency of gemcitabine against PC. Integrating quantitative analysis and spatial-visualization characterization of functional metabolites in vivo, we identified that the AMP-cAMP axis was a novel therapeutic target of PC to intermediate therapeutic efficiency of gemcitabine. Gemcitabine could induce the dual accumulation of cyclic AMP (cAMP) and AMP in tumor tissues. Quantitative analysis of associated biosynthetic enzymes and genes revealed that two independent intracellular ATP derived biosynthetic pathways to promote the dual activation of AMP-cAMP axis in a lower-level energetic environment. Then, gemcitabine induced the dual accumulation of AMP and cAMP can separately activate signaling pathways of AMPK and PKA, leading to the inhibition of tumor growth by the upregulation of the downstream tumor suppressor GADD45A. Collectively, our new STORM strategy was the first time to identify novel target of PC from a metabolic perspective as the dual activation of AMP-cAMP axis induced by gemcitabine can efficiently suppress PC tumor growth. In addition, such discovery has the capability to lower drug resistance of gemcitabine by specifically interacting with novel target, contributing to the improvement of therapeutic efficiency.

The Novel Interplay between Commensal Gut Bacteria and Metabolites in Diet-Induced Hyperlipidemic Rats Treated with Simvastatin.

Hyperlipidemia is one kind of metabolic syndrome for which the treatment commonly includes simvastatin (SV). Individuals vary widely in statin responses, and growing evidence implicates gut microbiome involvement in this variability. However, the associated molecular mechanisms between metabolic improvement and microbiota composition following SV treatment are still not fully understood. In this study, combinatory approaches using ultrahigh-performance liquid chromatography coupled with hybrid triple quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF MS/MS)-based metabolomic profiling, PCR-denaturing gradient gel electrophoresis (PCR-DGGE), quantitative PCR (qPCR), and 16S rRNA gene sequencing-based gut microbiota profiling were performed to investigate the interplay of endogenous metabolites and the gut microbiota related to SV treatment. A total of 6 key differential endogenous metabolites were identified that affect the metabolism of amino acids (phenylalanine and tyrosine), unsaturated fatty acids (linoleic acid and 9-hydroxyoctadecadienoic acid (9-HODE)), and the functions of gut microbial metabolism. Moreover, a total of 22 differentially abundant taxa were obtained following SV treatment. Three bacterial taxa were identified to be involved in SV treatment, namely, Bacteroidaceae, Prevotellaceae, and Porphyromonadaceae. These findings suggested that the phenylalanine and tyrosine-associated amino acid metabolism pathways, as well as the linoleic acid and 9-HODE-associated unsaturated fatty acid metabolism pathways, which are involved in gut flora interactions, might be potential therapeutic targets for improvement in SV hypolipidemic efficacy. The mass spectrometric data have been deposited to MassIVE (https://massive.ucsd.edu/ProteoSAFe/static/massive.jsp). Username: MSV000087842_reviewer. Password: hardworkingzsr.

Emerging pharmacotherapy for inflammatory bowel diseases.

Inflammatory bowel disease (IBD) refers to a gamut of disorders that are characterized by chronic intestinal inflammation, including ulcerative colitis (UC) and Crohn's disease (CD), which often leads to mucosal ulceration and progressive loss of intestinal function. The etiopathogenesis of IBD has not been completely clarified, although multiple factors involving genetic modifications, host immune dysfunction, intestinal dysbiosis and environmental effects have been implicated. Currently, pharmacotherapies including both non-targeted and targeted biological agents are widely used for the clinical treatment of IBD. In addition, novel therapeutic approaches that target the intestinal microorganisms, such as fecal microbiota transplantation, antibiotics, probiotics and microbial metabolite inhibitors, are also under development. However, these treatments are either accompanied by side effects or cannot achieve complete clinical remission when used alone. The efficacy and safety of drugs are currently a clinical challenge. Thus, advanced drug delivery systems are needed for targeted delivery of drugs to the inflammatory sites and avoid absorption by healthy tissues. In this review, we have summarized the latest research on the pathogenesis of IBD and the emerging pharmacotherapies, and discussed potential therapeutic targets for innovative therapies.

Dihydromyricetin improves DSS-induced colitis in mice via modulation of fecal-bacteria-related bile acid metabolism.

Recent studies show that the nutraceutical supplement dihydromyricetin (DHM) can alleviate IBD in murine models by downregulating the inflammatory pathways. However, the molecular mechanistic link between the therapeutic efficiency of DHM, gut microbiota, and the metabolism of microbial BAs remains elusive. In this study, we explored the improvement of DHM on the dysregulated gut microbiota of mice with dextran sulfate sodium (DSS)-induced colitis. We found that DHM could markedly improve colitis symptoms, gut barrier disruption, and colonic inflammation in DSS-treated mice. In addition, bacterial 16S rDNA sequencing assay demonstrated that DHM could alleviate gut dysbiosis in mice with colitis. Furthermore, antibiotic-mediated depletion of the gut microflora and fecal microbiome transplantation (FMT) demonstrated that the therapeutic efficiency of DHM was closely associated with gut microbiota. BA-targeted metabolomics analysis revealed that DHM restored the metabolism of microbial BAs in the gastrointestinal tract during the development of colitis. DHM significantly enriched the proportion of the beneficial Lactobacillus and Akkermansia genera, which were correlated with increased gastrointestinal levels of unconjugated BAs involving chenodeoxycholic acid and lithocholic acid, enabling the BAs to activate specific receptors, such as FXR and TGR5, and maintaining intestinal integrity. Taken together, DHM could alleviate DSS-induced colitis in mice by restoring the dysregulated gut microbiota and BA metabolism, leading to improvements in intestinal barrier function and colonic inflammation. Increased microbiota-BAs-FXR/TGR5 signaling may be the potential targets of DHM in colitis. Therefore, our findings provide novel insights into the development of novel DHM-derived drugs for the management of IBD.

Berberine improves colitis by triggering AhR activation by microbial tryptophan catabolites.

Inflammatory bowel diseases (IBD) are kind of recurrent inflammatory issues that occur in the gastrointestinal tract, and currently clinical treatment is still unideal due to the complex pathogenesis of IBD. Basically, gut barrier dysfunction is triggered by gut microbiota dysbiosis that is closely associated with the development of IBD, we thus investigated the therapeutic capacity of berberine (BBR) to improve the dysregulated gut microbiota, against IBD in rats, using a combinational strategy of targeted metabolomics and 16 s rDNA amplicon sequencing technology. Expectedly, our data revealed that BBR administration could greatly improve the pathological phenotype, gut barrier disruption, and the colon inflammation in rats with dextran sulfate sodium (DSS)-induced colitis. In addition, 16S rDNA-based microbiota analysis demonstrated that BBR could alleviate gut dysbiosis in rats. Furthermore, our targeted metabolomics analysis illustrated that the levels of microbial tryptophan catabolites in the gastrointestinal tract were significantly changed during the development of the colitis in rats, and BBR treatment can significantly restore such changes of the tryptophan catabolites accordingly. At last, our in vitro mechanism exploration was implemented with a Caco-2 cell monolayer model, which verified that the modulation of the dysregulated gut microbiota to change microbial metabolites coordinated the improvement effect of BBR on gut barrier disruption in the colitis, and we also confirmed that the activation of AhR induced by microbial metabolites is indispensable to the improvement of gut barrier disruption by BBR. Collectively, BBR has the capacity to treat DSS-induced colitis in rats through the regulation of gut microbiota associated tryptophan metabolite to activate AhR, which can greatly improve the disrupted gut barrier function. Importantly, our finding elucidated a novel mechanism of BBR to improve gut barrier function, which holds the expected capacity to promote the BBR derived drug discovery and development against the colitis in clinic setting.

Cell Metabolomics Reveals Berberine-Inhibited Pancreatic Cancer Cell Viability and Metastasis by Regulating Citrate Metabolism.

Pancreatic cancer (PC) is becoming one of the deadliest cancers, with mortality among the highest worldwide because of its pathogenic latency and the lack of efficient drugs in the clinic. Considering that cancer cells undergo proliferation and differentiation at substantial metabolic costs, as indicated by dysregulated glycolysis and an abnormal TCA cycle induced by mitochondrial damage, we investigated the therapeutic capacity of berberine (BBR) in pancreatic cancer using a cell metabolomics method. A phenotypic assay revealed the significant inhibitory role of BBR in PC cell viability and metastasis. In addition, a precision-targeted metabolome assay showed that BBR profoundly dysregulated the energy metabolism of PC cells, and phenotypic observations based on imaging indicated that PC cell mitochondria were markedly damaged after BBR treatment. Notably, citrate metabolism and transportation in cell mitochondria were significantly influenced by BBR, which led to the blocked biosynthesis of the defined fatty acids (FAs) through the regulation of ACLY, ACO1, and SLC25A1. Therefore, the regulatory effects of FAs on PC cell proliferation and metastasis may be regulated by BBR through targeting citrate metabolism. Collectively, our in vitro data preliminarily reveals the therapeutic potential of BBR against pancreatic cancer by targeting citrate metabolism, citrate might be a new target for drug development and the treatment against PC, but further experimental verification will be required subsequently. Moreover, our study demonstrated that the cell metabolomics method pertains to the capacity to rapidly explore biochemical functions of natural products.

Route of intestinal absorption and tissue distribution of iron contained in the novel phosphate binder ferric citrate.

BACKGROUND: Anemia of chronic kidney disease (CKD) is, in part, caused by hepcidin-mediated impaired iron absorption. However, phosphate binder, ferric citrate (FC) overcomes the CKD-induced impairment of iron absorption and increases serum iron, transferrin saturation, and iron stores and reduces erythropoietin requirements in CKD/ESRD patients. The mechanism and sites of intestinal absorption of iron contained in FC were explored here. METHODS: Eight-week old rats were randomized to sham-operated or 5/6 nephrectomized (CKD) groups and fed either regular rat chow or rat chow containing 4% FC for 6 weeks. They were then euthanized, and tissues were processed for histological and biochemical analysis using Prussian blue staining, Western blot analysis to quantify intestinal epithelial tight junction proteins and real-time PCR to measure Fatty Acid receptors 2 (FFA2) and 3 (FFA3) expressions. RESULTS: CKD rats exhibited hypertension, anemia, azotemia, and hyperphosphatemia. FC-treated CKD rats showed significant reductions in blood pressure, serum urea, phosphate and creatinine levels and higher serum iron and blood hemoglobin levels. This was associated with marked increase in iron content of the epithelial and subepithelial wall of the descending colon and modest iron deposits in the proximal tubular epithelial cells of their remnant kidneys. No significant difference was found in hepatic tissue iron content between untreated and FC-treated CKD or control groups. Distal colon's epithelial tight Junction proteins, Occludin, JAM-1 and ZO-1 were markedly reduced in the CKD groups. The FFA2 expression in the jejunum and FFA3 expression in the distal colon were significantly reduced in the CKD rats and markedly increased with FC administration. CONCLUSION: Iron contained in the phosphate binder, FC, is absorbed by the distal colon of the CKD animals via disrupted colonic epithelial barrier and upregulation of short chain fatty acid transporters.

Comparative pharmacokinetics of verapamil and norverapamil in normal and ulcerative colitis rats after oral administration of low and high dose verapamil by UPLC-MS/MS.

In this study, UC rat model was established by administration of 5% (w/v) dextran sulfate sodium, and the pharmacokinetics of verapamil and norverapamil were evaluated in normal and UC rats using UPLC-MS/MS after oral administration of 5 mg/kg and 50 mg/kg verapamil.The peak concentration (Cmax) and the area under plasma concentration-time curves (AUC) of verapamil in UC rats after oral administration of 5 mg/kg were significantly greater (2.5 times and 2 times, respectively) than those in normal rats, but the clearance rate (Cl) was significantly lower (by 50%). For norverapamil, Cmax and AUC were significantly greater (2.8 times and 2.5 times, respectively), and Cl was significantly lower (by 45%). But, pharmacokinetic parameters of verapamil and norverapamil after oral administration of 50 mg/kg were no significant differences between UC and normal rats.The better absorption and poor excretion for low-dose verapamil may be attributed to down-regulation of P-gp expression in the intestine and kidney. No significant differences of pharmacokinetic parameters for high-dose verapamil may be explained as the saturation of an efflux mechanism.The findings of this study suggested that in UC patients, doses of verapamil should be decreased when low-dose verapamil was orally administrated.

The Role of Tyramine ß-Hydroxylase in Density Dependent Immunityof Oriental Armyworm (Mythmina separata) Larva.

High population density alters insect prophylactic immunity, with density-dependent prophylaxis (DDP) being reported in many polyphonic insects. However, the molecular mechanism for DDP remains unclear. In current study, the role of tyramine ß-hydroxylase (Tßh) in the immune response of M. separata larvae that were subject to different rearing densities conditions was investigated. The tyramine ß-hydroxylase activity of larvae from high density treatments (10 and 30 larvae per jar) was significantly higher than that of the larvae from low density treatments (one, two, and five larvae/jar). A tyramine ß-hydroxylase (designated MsTßh) containing a 1779 bp open reading frame was identified. Multiple sequence alignment and phylogenetic analysis indicated that MsTßh was orthologous to the Tßh that was found in other lepidopterans. Elevated MsTßh expression was observed in larvae under high density (10 larvae per jar). Silencing MsTßh expression by the injection of dsRNA in larvae from the high density treatment produced a 25.1% reduction in octopamine levels, while at the same time, there was a significant decrease in phenoloxidase (PO) and lysozyme activity, total haemocyte counts, and survival against Beauveria infection 56.6%, 88.5%, 82.0%, and 55.8%, respectively, when compared to control larvae. Our findings provide the first insights into how MsTßh mediates the octopamine level, which in turn modulates the immune response of larvae under different population densities.

Phosphate Binder, Ferric Citrate, Attenuates Anemia, Renal Dysfunction, Oxidative Stress, Inflammation, and Fibrosis in 5/6 Nephrectomized CKD Rats.

Chronic kidney disease (CKD) causes anemia and impairs intestinal iron absorption. However, use of the phosphate binder ferric citrate (FC) increases body iron stores and hemoglobin levels in CKD patients. By intensifying oxidative stress and inflammation iron overload resulting from excessive use of intravenous iron can accelerate CKD progression. The present study explored the route of absorption and tissue distribution of iron with FC administration and its effect on renal function, histology, and inflammatory, oxidative, and fibrosis pathways in CKD rats. Male Sprague Dawley rats were randomized to sham-operated control (CTL) group and 5/6 nephrectomized (CKD) groups fed either regular or 4% FC-supplemented diets for 6 weeks. Animals were then sacrificed, and blood and target tissues were harvested and processed. The untreated CKD rats exhibited anemia, hypertension, upregulation of renal tissue inflammatory, oxidative, and fibrotic pathways, impaired nuclear translocation, and downregulation of Nrf2's target gene products and depletion of colonic epithelial tight junction proteins. FC administration raised serum iron, improved anemia, attenuated hyperphosphatemia, partially improved renal function, reduced oxidative stress, inflammation, and fibrosis, and restored colonic epithelial zonula occludens-1 protein abundance. Tissue iron staining detected presence of iron in epithelial cells and subepithelium of colon and in renal proximal tubules. In conclusion ferric citrate administration resulted in modest amelioration of renal function and histology and partial improvements of fibrosis, inflammation, and oxidative stress in the kidney tissues of CKD rats.

Berberine Upregulates P-Glycoprotein in Human Caco-2 Cells and in an Experimental Model of Colitis in the Rat via Activation of Nrf2-Dependent Mechanisms.

Downregulation of P-glycoprotein (P-gp) is implicated in the pathophysiology of inflammatory bowel disease (IBD). Berberine, a principal isoquinoline alkaloid extracted from Berberis species, has been reported to exhibit therapeutic potential in IBD. In this study, we used a dextran sulfate sodium (DSS)-induced colitis rat model to evaluate the effect of berberine on P-gp and explore its mechanism of action. Berberine treatment improved DSS-induced colitis symptoms, attenuated inflammatory markers (myeloperoxidase, tumor necrosis factor-α, and interleukin-1ß and -6), and enhanced P-gp expression in a dose-dependent manner. Although colonic expression of the P-gp-related nuclear receptor pregnane X receptor and transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) were downregulated in the colitis model, gene and protein expression analysis revealed that berberine treatment reversed only the downregulation of Nrf2. In vitro studies using Caco-2 cells showed that the multidrug resistance 1 (MDR1) gene and P-gp protein were upregulated by berberine in a dose- and time-dependent manner. Significant upregulation of the MDR1 gene by berberine was abrogated by Nrf2 silencing, indicating that the Nrf2-mediated pathway was responsible for this activation. Luciferase assays showed a dose-dependent increase in Nrf2 reporter gene activity after berberine treatment in Caco-2 cells, with a significant 2-fold elevation at 2.5 µM berberine, suggesting that berberine is a strong Nrf2 activator. These results indicate the possible involvement of Nrf2-mediated upregulation of P-gp in the therapeutic effect of berberine on colitis and highlight the potential of P-gp and/or Nrf2 as new therapeutic targets for IBD.

LCZ696 (Sacubitril/Valsartan), an Angiotensin-Receptor Neprilysin Inhibitor, Attenuates Cardiac Hypertrophy, Fibrosis, and Vasculopathy in a Rat Model of Chronic Kidney Disease.

BACKGROUND: Chronic kidney disease (CKD) is associated with cardiac hypertrophy, fibrosis, and increased risk of cardiovascular mortality. LCZ696 (sacubitril/valsartan) is a promising agent that has shown significant potential in treatment of heart failure. We hypothesized that LCZ696 is more effective than valsartan alone in the treatment of cardiovascular abnormalities associated with experimental CKD. METHODS AND RESULTS: Male Sprague-Dawley rats underwent 5/6 nephrectomy and were subsequently randomized to no treatment (CKD), 30 mg/kg valsartan (VAL), or 60 mg/kg LCZ696 (LCZ). After 8 weeks, cardiovascular parameters, including markers of inflammation, oxidative stress, mitochondrial abundance/function, hypertrophy, and fibrosis, were measured. Treatment with LCZ resulted in significant improvements in the heart-body weight ratio and serum concentrations of N-terminal pro-B-type natriuretic peptide and fibroblast growth factor 23 along with improvement of kidney function. In addition, LCZ ameliorated aortic fibrosis and cardiac hypertrophy and fibrosis, reduced markers of cardiac oxidative stress and inflammation, and improved indicators of mitochondrial mass/function. Although VAL also improved some of these indices, treatment with LCZ was more effective than VAL alone. CONCLUSIONS: CKD-associated cardiovascular abnormalities, including myocardial hypertrophy, fibrosis, inflammation, oxidative stress, and mitochondrial depletion/dysfunction, were more effectively attenuated by LCZ treatment than by VAL alone.

Preparation and evaluation of a molecularly imprinted sol-gel material as the solid-phase extraction adsorbents for the specific recognition of cloxacilloic acid in cloxacillin.

Highly selective molecularly imprinted polymers on the surface of silica gels were prepared by a sol-gel process and used as solid-phase extraction adsorbents for the specific recognition, enrichment and detection of cloxacilloic acid in cloxacillin. The obtained polymers were characterized by scanning electron microscopy, FTIR spectroscopy, nitrogen adsorption and desorption, elemental analysis and thermogravimetric analysis. The imprinted polymers not only possessed high adsorption capacity (6.5 µg/mg), but also exhibited fast adsorption kinetics (they adsorb 80% of the maximum amount within 20 min) and excellent selectivity (the imprinted factor was 3.6). A method using the imprinted polymers as solid-phase extraction adsorbents coupled with high-performance liquid chromatography was established with good specificity, linearity (r = 0.9962), precision (ranging from 0.5 to 6.7%), accuracy (ranging from 93.9 to 97.7%) and extraction recoveries (ranging from 78.8 to 89.8%). The limits of detection and quantification were 0.07 and 0.25 mg/g, respectively. This work could provide a promising method in the enrichment, extraction and detection of allergenic impurities in the manufacture, storage and application of cloxacillin.

Pharmacokinetic and Metabolic Characteristics of Herb-Derived Khellactone Derivatives, A Class of Anti-HIV and Anti-Hypertensive: A Review.

A vast number of structural modifications have been performed for khellactone derivatives (KDs) that have been widely concerned owing to their diverse biological properties, including anti-hypertension, anti-HIV, reversing P-glycoprotein (P-gp) mediated multidrug resistance, and anti-inflammation effects, to find the most active entity. However, extensive metabolism of KDs results in poor oral bioavailability, thus hindering the clinical trial performance of those components. The primary metabolic pathways have been revealed as hydrolysis, oxidation, acyl migration, and glucuronidation, while carboxylesterases and cytochrome P450 3A (CPY3A), as well as UDP-glucuronosyltransferases (UGTs) primarily mediate these metabolic pathways. Attention was mainly paid to the pharmacological features, therapeutic mechanisms and structure-activity relationships of KDs in previous reviews, whereas their pharmacokinetic and metabolic characteristics have seldom been discussed. In the present review, KDs' metabolism and their pharmacokinetic properties are summarized. In addition, the structure-metabolism relationships of KDs and the potential drug-drug interactions (DDIs) induced by KDs were also extensively discussed. The polarity, the acyl groups substituted at C-3' and C-4' positions, the configuration of C-3' and C-4', and the moieties substituted at C-3 and C-4 positions play the determinant roles for the metabolic profiles of KDs. Contributions from CYP3A4, UGT1A1, P-gp, and multidrug resistance-associated protein 2 have been disclosed to be primary for the potential DDIs. The review is expected to provide meaningful information and helpful guidelines for the further development of KDs.

Research progress of the studies on the roots of Peucedanum praeruptorum dunn (Peucedani radix).

As a commonly employed traditional Chinese medicine, Peucedani Radix (Qian-hu in Chinese), which consists of the dried roots of Peucedanum praeruptorum Dunn, has a long history of application for the treatment of cough with thick sputum and dyspnea, nonproductive cough and upper air-way infections in traditional medicinal practice. The current review aims to summarize the research progress on the botany, phytochemistry, chemical analysis, pharmacological assay, and pharmacokinetic profile of this famous herbal drug. All available information on this traditional medicine was obtained via electronic search (using ACS, PubMed, Web of Science, Google Scholar, Baidu Scholar, and CNKI). Phytochemical investigations revealed that angular-type pyranocoumarins (APs), mainly (±)-praeruptorin A (Pd-Ia), (+)-praeruptorin A, (±)-praeruptorin B, (+)-praeruptorin B (Pd-II) and (+)-praeruptorin E (Pd-III), were the main active components in Qian-hu, while some other types of ingredients were also identified from this herb. The crude extract and pure compounds from Peucedani Radix exhibited a wide spectrum of in vitro and in vivo pharmacological activities, including vasorelaxant, cardioprotective, hepatoprotective, anti-tumor and anti-platelet aggregative effects. Conversely to the well-defined chemical constituents and activities, the properties of absorption, pharmacokinetics, and metabolism were rarely characterized. However, further investigations are wistful for the development of new drugs and therapies for various diseases, especially cardiovascular disorders. Collectively, the present review on the phytochemistry, chemical analysis, pharmacological evaluation, and pharmacokinetic profile of Peucedani Radix will provide meaningful information for further studies and commercial exploitation of the herbal medicine.

A mannitol-modified emodin nano-drug restores the intestinal barrier function and alleviates inflammation in a mouse model of DSS-induced ulcerative colitis.

BACKGROUND: Ulcerative colitis (UC) is an inflammatory disease of the colon that is characterized by mucosal ulcers. Given its increasing prevalence worldwide, it is imperative to develop safe and effective drugs for treating UC. Emodin, a natural anthraquinone derivative present in various medicinal herbs, has demonstrated therapeutic effects against UC. However, low bioavailability due to poor water solubility limits its clinical applications. METHODS: Emodin-borate nanoparticles (EmB) were synthesized to improve drug solubility, and they modified with oligomeric mannitol into microgels (EmB-MO) for targeted delivery to intestinal macrophages that express mannose receptors. UC was induced in a mouse model using dextran sulfate sodium (DSS), and different drug formulations were administered to the mice via drinking water. The levels of inflammation-related factors in the colon tissues and fecal matter were measured using enzyme-linked immunosorbent assay. Intestinal permeability was evaluated using fluorescein isothiocyanate dextran. HE staining, in vivo imaging, real-time PCR, and western blotting were performed to assess intestinal barrier dysfunction. RESULTS: Both EmB and EmB-MO markedly alleviated the symptoms of UC, including body weight loss, stool inconsistency, and bloody stools and restored the levels of pro- and anti-inflammatory cytokines. However, the therapeutic effects of EmB-MO on the macroscopic and immunological indices were stronger than those of EmB and similar to those of 5-aminosalicylic acid. Furthermore, EmB-MO selectively accumulated in the inflamed colon epithelium and restored the levels of the gut barrier proteins such as ZO-1 and Occludin. CONCLUSIONS: EmB-MO encapsulation significantly improved water solubility, which translated to greater therapeutic effects on the immune balance and gut barrier function in mice with DSS-induced UC. Our findings provide novel insights into developing emodin-derived drugs for the management of UC.

Ferric iron loaded porphyrinic zirconium MOFs on corncob for the enhancement of diuretics extraction.

Herein, corncob waste was used as a scaffold for the fabrication of effective adsorbents. Porphyrinic zirconium metal-organic frameworks (MOFs) PCN-223 and PCN-224 constructed by different numbers of Zr6 cluster nodes were grown on the surface of the corncob. Fe (Ш) ions were implanted in the porphyrin ring by post-synthesis modification. The results showed that the extraction capacity of diuretics on PCN-224@corncob containing suitable pore size was larger than that of PCN-223@corncob. The adsorption of diuretics was further enhanced because of the electrostatic effect caused by implantation of Fe (Ш) ions. PCN-224-Fe@corncob was recyclable and selective for the extraction of furosemide (Fur) and bumetanide (Bum). Coupled in-syringe solid phase extraction (IS-SPE) with ultra-performance liquid chromatography (UPLC), an efficient, sensitive, and stable method was established. With a sensitivity between 0.6 and 1.0 µg/L and a recovery between 83.2% and 119.2%, it is used for the analysis of trace amounts of Fur and Bum in weight loss products and environmental water. The functionalized corncob has potential application for the adsorption of diuretics, and the metal ions implantation in MOFs provides a promising strategy for enhancing extraction capacity.

Effective extraction of fluoroquinolones from water using facile modified plant fibers.

In this study, ecofriendly and economic carboxy-terminated plant fibers (PFs) were used as adsorbents for the effective in-syringe solid phase extraction (IS-SPE) of fluoroquinolone (FQ) residues from water. Based on the thermal esterification and etherification reaction of cellulose hydroxy with citric acid (CA) and sodium chloroacetate in aqueous solutions, carboxy groups grafted onto cotton, cattail, and corncob fibers were fabricated. Compared with carboxy-terminated corncob and cotton, CA-modified cattail with more carboxy groups showed excellent adsorption capacity for FQs. The modified cattail fibers were reproducible and reusable with relative standard deviations of 3.2%-4.2% within 10 cycles of adsorption-desorption. A good extraction efficiency of 71.3%-80.9% was achieved after optimizing the extraction condition. Based on carboxylated cattail, IS-SPE coupled with ultra-performance liquid chromatography with a photodiode array detector was conducted to analyze FQs in environmental water samples. High sensitivity with limit of detections of 0.08-0.25 µg/L and good accuracy with recoveries of 83.8%-111.7% were obtained. Overall, the simple and environment-friendly modified waste PFs have potential applications in the effective extraction and detection of FQs in natural waters.

Hyaluronic Acid-Melatonin Nanoparticles Improve the Dysregulated Intestinal Barrier, Microbiome and Immune Response in Mice with Dextran Sodium Sulfate-Induced Colitis.

Although the cause of inflammatory bowel disease (IBD) is unclear, current studies have found that the main factors involved in its pathogenesis include imbalance of mucosal immune response, intestinal dysbiosis, and destruction of the intestinal barrier. We synthesized an amphiphilic conjugate of hyaluronic acid (HA) and melatonin (MT), which have established immunomodulatory and antioxidant properties, by stimulating their nano-aggregation. Inducing colitis by dextran sodium sulfate (DSS), HA-MT accumulated in the inflamed colon epithelium of colitis mice, and markedly improved the colitis symptoms, repaired the damaged intestinal barrier and inhibited colon inflammation. In addition, through bacterial 16S rDNA sequencing, it was found that HA-MT can restore the ratio of Firmicutes/Bacteroidetes by increasing the overall microbial richness and diversity, and alleviate the intestinal dysbiosis of mice with colitis. In the analysis of the intestinal flora at the species level, the abundance of Lactobacillus increased in colitis mice treated with HA-MT while that of Bacteroides, Blautia and Streptococcus decreased in the colitis mice treated with HA-MT. Our findings suggest that the HA-MT system is a promising prebiotic, which can relieve the symptoms of IBD by regulating the intestinal microflora and restoring intestinal homeostasis, inhibiting inflammation.