Molecular recognition of niacin and lipid-lowering drugs by the human hydroxycarboxylic acid receptor 2.

Niacin, an age-old lipid-lowering drug, acts through the hydroxycarboxylic acid receptor 2 (HCAR2), a G-protein-coupled receptor (GPCR). Yet, its use is hindered by side effects like skin flushing. To address this, specific HCAR2 agonists, like MK-6892 and GSK256073, with fewer adverse effects have been created. However, the activation mechanism of HCAR2 by niacin and these new agonists is not well understood. Here, we present three cryoelectron microscopy structures of Gi-coupled HCAR2 bound to niacin, MK-6892, and GSK256073. Our findings show that different ligands induce varying binding pockets in HCAR2, influenced by aromatic amino acid clusters (W91ECL1, H1614.59, W1885.38, H1895.39, and F1935.43) from receptors ECL1, TM4, and TM5. Additionally, conserved residues R1113.36 and Y2847.43, unique to the HCA receptor family, likely initiate activation signal propagation in HCAR2. This study provides insights into ligand recognition, receptor activation, and G protein coupling mediated by HCAR2, laying the groundwork for developing HCAR2-targeted drugs.

Sodium p-hydroxybenzoate alleviates osteoporosis through inhibiting bone metabolism and oxidative stress via activating ERα.

As the population ages, the incidence of osteoporosis (OP) gradually increases and is becoming a growing public health problem. Meanwhile, although traditional pharmacological therapy is extremely efficient in the treatment of OP, its application is constrained because of irreversible adverse drug reactions. Therefore, scientists should actively develop safer drugs while ensuring the therapeutic effect of OP. Previous studies have shown that p-hydroxybenzoic acid (HA) can upregulate the expression of estrogen receptor (ER). Sodium p-hydroxybenzoate (DSN160) is a sodium salt of HA with a lethal dose greater than 5g/kg. However, whether DSN160 has demonstrable anti-osteoporotic activities remains unclear. In this study, DSN160 increased the organ index, length and diameter of the bone and bone mineral density and improved bone microstructure in retinoic acid-induced OP rats. Furthermore, DSN160 reduced bone metabolism-related indicators. In addition, fulvestrant (a specific antagonist of ER) blocked the anti-OP effect of DSN160. In conclusion, our findings showed that DSN160 exerts anti-OP effect through inhibiting bone metabolism and oxidative stress via activating ERα.

Licochalcone A induces cell cycle arrest and apoptosis via suppressing MAPK signaling pathway and the expression of FBXO5 in lung squamous cell cancer.

Lung squamous cell carcinoma (LSCC) is a highly heterogeneous malignancy with high mortality and few therapeutic options. Licochalcone A (LCA, PubChem ID: 5318998) is a chalcone extracted from licorice and possesses anticancer and anti­inflammatory activities. The present study aimed to elucidate the anticancer effect of LCA on LSCC and explore the conceivable molecular mechanism. MTT assay revealed that LCA significantly inhibited the proliferation of LSCC cells with less cytotoxicity towards human bronchial epithelial cells. 5­ethynyl­2'­deoxyuridine (EdU) assay demonstrated that LCA could reduce the proliferation rate of LSCC cells. The flow cytometric assays indicated that LCA increased the cell number of the G1 phase and induced the apoptosis of LSCC cells. LCA downregulated the protein expression of cyclin D1, cyclin E, CDK2 and CDK4. Meanwhile, LCA increased the expression level of Bax, cleaved poly(ADP­ribose)polymerase­1 (PARP1) and caspase 3, as well as downregulated the level of Bcl­2. Proteomics assay demonstrated that LCA exerted its antitumor effects via inhibiting mitogen­activated protein kinase (MAPK) signaling pathways and the expression of F­box protein 5 (FBXO5). Western blot analysis showed that LCA decreased the expression of p­ERK1/2, p­p38MAPK and FBXO5. In the xenograft tumors of LSCC, LCA significantly inhibited the volumes and weight of tumors in nude mice with little toxicity in vital organs. Therefore, the present study demonstrated that LCA effectively inhibited cell proliferation and induced apoptosis in vitro, and suppressed xenograft tumor growth in vivo. LCA may serve as a future therapeutic candidate of LSCC.

Dietary Supplementation of Ancientino Ameliorates Dextran Sodium Sulfate-Induced Colitis by Improving Intestinal Barrier Function and Reducing Inflammation and Oxidative Stress.

Ancientino, a complex dietary fiber supplement mimicking the ancient diet, has improved chronic heart failure, kidney function, and constipation. However, its effect on ulcerative colitis is unknown. This study explores the impact of Ancientino on colitis caused by dextran sulfate sodium (DSS) and its mechanisms. Data analyses showed that Ancientino alleviated bodyweight loss, colon shortening and injury, and disease activity index (DAI) score, regulated levels of inflammatory factors (tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), interleukin-1 beta (IL-1ß), and interleukin 6 (IL-6)), reduced intestinal permeability (d-lactate and endotoxin), fluorescein isothiocyanate-dextran (FITC-dextran), and diamine oxidase (DAO), repaired colonic function (ZO-1 and occludin), and suppressed oxidative stress (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and malondialdehyde (MDA)) in vivo and in vitro. In short, this study demonstrated that Ancientino alleviates colitis and exerts an anticolitis effect by reducing inflammatory response, suppressing oxidative stress, and repairing intestinal barrier function. Thus, Ancientino may be an effective therapeutic dietary resource for ulcerative colitis.

Relative safety and efficacy of topical and oral NSAIDs in the treatment of osteoarthritis: A systematic review and meta-analysis.

BACKGROUND: Osteoarthritis (OA) often affects the hands, knees, and hip joints, causing considerable pain and disability, and often affecting the patient's quality of life. Non-steroidal anti-inflammatory drugs (NSAIDs) are common pain relievers often applied as first line therapies for OA. However, prolonged NSAIDs application can have unwanted side effects. Given this, this study was designed to systematically evaluate the efficacy and safety of topical and oral NSAIDs for the treatment of OA. METHODS: We searched the PubMed, Embase, Cochrane Library, and Web of Science databases for relevant papers from their inception dates to May 2021. Our study only included randomized controlled trials comparing topical and oral NSAIDs and all data were analyzed using Review Manager version 5.3 (RevMan version 5.3). RESULTS: We identified 8 RCTs (2096 patients with OA), for evaluation and revealed that, in general, topical and oral NSAIDs presented with similar efficacies for the treatment of OA. The Western Ontario and McMaster Osteoarthritis Index for assessing pain relief in OA patients was (standardized mean difference [SMD] 0.07; 95%CI -0.02, 0.17) and visual analog scale was (SMD -0.01; 95%CI -0.02, 0.18), and improved stiffness in OA patients (SMD 0.09; 95%Cl 0.03, 0.20). CONCLUSIONS: Topical NSAIDs are as effective as oral NSAIDs for the treatment of OA and both topical and oral NSAIDs are equally effective in reducing pain and improving physical function in OA patients. In terms of safety, a larger number of samples are still needed to determine if there are any differences in the safety profile of topical or oral NSAIDs. REGISTRATION NUMBER: INPLASY 2021110009.

A novel ALG10/TGF-ß positive regulatory loop contributes to the stemness of colorectal cancer.

The roles of asparagine-linked glycosylation (ALG) members in tumorigenic process have been widely explored. However, their effects in colorectal cancer progression are still confusing. Here, we screened 12 ALGs' expression through online datasets and found that ALG10 was mostly upregulated in colorectal cancer tissues. We found that ALG10 knockdown significantly suppressed the expression of stemness markers, ALDH activity, and sphere-formation ability. In vivo tumorigenic analysis indicated that ALG10 knockdown attenuated the tumor-initiating ability and chemoresistance of colorectal cancer cells. Further mechanistic studies showed that ALG10 knockdown suppressed the activity of TGF-ß signaling by reducing TGFBR2 glycosylation, which was necessary for ALG10-mediated effects on colorectal cancer stemness; Conversely, TGF-ß signaling activated ALG10 gene promoter activity through Smad2's binding to ALG10 gene promoter and TGF-ß signaling promoted the stemness of colorectal cancer cells in an ALG10-dependent manner. This work identified a novel ALG10/TGF-ß positive regulatory loop responsible for colorectal cancer stemness.

Subchronic Oral Toxicity of Sodium p-Hydroxybenzoate in Sprague-Dawley Rats.

p-Hydroxybenzoic acid (p-HBA), which exists extensively in plants, is well known for its anti-inflammatory effects, but various adverse side effects have also been reported. Previous research has found that acid translated to its sodium salt improves the safety profile of compounds. Therefore, we hypothesized that p-HBA translated to sodium p-hydroxybenzoate would improve its safety profile. In the present study, we evaluated the toxicity of sodium p-hydroxybenzoate after 90 days of repeated oral toxicity experiments according to OECD guidelines in male and female Sprague-Dawley rats. Sodium p-hydroxybenzoate was administered orally to SD rats at doses of 0, 125, 250, and 500 mg/kg body weight (BW)/day for 90 days. All animals survived to the end of the study, and no sodium p-hydroxybenzoate treatment-associated mortality or clinical changes were observed during the study period. Sodium p-hydroxybenzoate did not promote any clinical signs of toxicologically relevant effects, including changes in body weight, food intake and urinalysis parameters, in male or female SD rats. Dose-related alterations in hematological parameters, organ weights and histopathological findings in hepatic tissue were examined in animals of both sexes in the 500 mg/kg BW/day group. Based on the study, the no-observed-adverse-effect level (NOAEL) for sodium p-hydroxybenzoate was determined to be 250 mg/kg BW/day in both male and female rats.

VSP­17 suppresses the migration and invasion of triple­negative breast cancer cells through inhibition of the EMT process via the PPARγ/AMPK signaling pathway.

VSP­17, a novel peroxisome proliferator­activated receptor γ (PPARγ) agonist, has been previously demonstrated to suppress the metastasis of triple­negative breast cancer (TNBC) by upregulating the expression levels of E­cadherin, which is a key marker of epithelial­mesenchymal transition (EMT). However, the mechanism of action of VSP­17, in particular whether it may be associated with the EMT process, remains unknown. The present study investigated the ability of VSP­17 to inhibit the invasiveness and migratory ability of TNBC cell lines (MDA­MB­231 and MDA­MB­453) performed in in vitro experiments. including cell migration assay, cell invasion assay, cell transfection, RT­qPCR, western blot (WB) analysis and immunofluorescence. The present study aimed to ascertain whether and how the PPARγ/AMP­activated protein kinase (AMPK) signaling pathway serves a role in the inhibitory effects of VSP­17 on cell migration and invasion. The results revealed that both treatment with compound C (an AMPK inhibitor) and transfection with small interfering RNA (si)AMPK notably diminished the inhibitory effect of VSP­17 treatment on the migration and invasion of MDA­MB­231 and MDA­MB­453 cells, indicating that VSP­17 may, at least partly, exert its effects via AMPK. Furthermore, both compound C and siAMPK markedly diminished the VSP­17­induced downregulation of vimentin expression levels and upregulation of E­cadherin expression levels, further indicating that the VSP­17­induced inhibition of the EMT process may be dependent on AMPK. The combination of GW9662 (a PPARγ antagonist) or siPPARγ diminished the inhibitory effect of VSP­17 treatment on the migration and invasion of the TNBC cells, indicating that PPARγ may serve an important role in the VSP­17­induced inhibition of the migration and invasion of TNBC cells. In addition, both GW9662 and siPPARγ significantly reversed the VSP­17­induced downregulation of vimentin expression levels and upregulation of E­cadherin expression levels, implying that the VSP­17­induced inhibition of the EMT process may be dependent on PPARγ. VSP­17 treatment also upregulated the expression levels of p­AMPK, which could be reversed by either GW9662 or siPPARγ, indicating that the VSP­17­induced activation of the AMPK signaling pathway was PPARγ­dependent. In conclusion, the findings of the present study indicated that VSP­17 treatment may inhibit the migration and invasion of TNBC cells by suppressing the EMT process via the PPARγ/AMPK signaling pathway.

Palmatine-loaded electrospun poly(ε-caprolactone)/gelatin nanofibrous scaffolds accelerate wound healing and inhibit hypertrophic scar formation in a rabbit ear model.

Hypertrophic scar (HS) has been considered as a great concern for patients and a challenging problem for clinicians as it can cause functional debility, cosmetic disfigurement and psychological trauma. Although many methods have been developed to prevent and treat HS, the scarless healing is still a worldwide medical problem. In this study, palmatine-loaded poly(ε-caprolactone)/gelatin nanofibrous scaffolds (PCL/GE/PALs) were fabricated by electrospinning, and their effects on wound healing and HS formation were investigated. These nanofiber mats exhibit good antibacterial and antioxidant activities. In vitro studies indicate PCL/GE/PAL scaffolds can facilitate the adhesion, spreading and proliferation of L929 fibroblasts. In vivo tests demonstrate the full-thickness wounds treated with PCL/GE/PAL scaffolds heal about 3.5 days earlier than those in the control group. Scar elevation index measurements and histological analyses reveal PCL/GE/PAL scaffolds significantly inhibit HS formation, with the decrease in the thickness of dermis and epidermis, the number of fibroblasts, as well as the density of collagen and microvascular. Accelerating wound healing and inhibiting HS formation of these scaffolds are contributed to the sustained release of palmatine. The present work validates the potential use of palmatine-loaded electrospun nanofibrous scaffold PCL/GE/PALs as a functional wound dressing for healing wounds and preventing HS formation.

Species Quantification in Complex Herbal Formulas-Vector Control Quantitative Analysis as a New Method.

Product mislabeling and/or species fraud in Traditional Chinese Medicine (TCM) not only decrease TCM quality, but also pose a potential health issue to the end user. Up to now, methods to control TCM quality have been developed to detect specific metabolites or identify the original species. However, species quantification in complex herbal formulas is rarely concerned. Here, we reported a simple Vector Control Quantitative Analysis (VCQA) method for flexible and accurate multiplex species quantification in traditional Chinese herbal formulas. We developed PCR-based strategy to quickly generate the integrated DNA fragments from multiple targeted species, which can be assembled into the quantitative vector in one round of cloning by Golden Gate ligation and Gateway recombination technique. With this method, we recruited the nuclear ribosomal DNA Internal Transcribed Spacer (ITS) region for the quantification of Ligusticum sinense "Chuanxiong," Angelica dahurica (Hoffm.) Benth. & Hook.f. ex Franch. & Sav., Notopterygium incisum K. C. Ting ex H. T. Chang, Asarum sieboldii Miq., Saposhnikovia divaricata (Turcz.) Schischk., Nepeta cataria L., Mentha canadensis L., and Glycyrrhiza uralensis Fisch. ex DC. in ChuanXiong ChaTiao Wan, a classic Chinese herbal formula with very long historical background. We found that, firstly, VCQA method could eliminate the factors affecting such as the variations in DNA extracts when in combination with the use of universal and species-specific primers. Secondly, this method detected the limit of quantification of A. sieboldii Miq. in formula products down to 1%. Thirdly, the stability of quality of ChuanXiong ChaTiao Wan formula varies significantly among different manufacturers. In conclusion, VCQA method has the potential power and can be used as an alternative method for species quantification of complex TCM formulas.

Targeting SLC7A11 specifically suppresses the progression of colorectal cancer stem cells via inducing ferroptosis.

Recent studies have revealed the critical roles of ferroptosis in different physiological and pathological processes, however, its effects on the progression of colorectal cancer stem cells (CSCs) are still unclear. Here, we found that colorectal CSCs exhibited a remarkably lower level of reactive oxygen species (ROS), a higher level of cysteine, glutathione and SLC7A11 compared to colorectal cancer cells. Knockout of SLC7A11 increased the ROS level and reduced the levels of cysteine and glutathione, subsequently attenuating the viability of colorectal CSCs. Erastin, an inhibitor of SLC7A11, was found to hold a remarkably stronger cytotoxic effect on colorectal CSCs via in vitro and in vivo experiments. Finally, it was found that Erastin attenuated the chemoresistance of colorectal CSCs. This work indicates that colorectal CSCs are more sensitive to ferroptosis, which could be targeted to attenuate colorectal cancer progression and chemoresistance.

Hepatocyte nuclear factor-1ß suppresses the stemness and migration of colorectal cancer cells through promoting miR-200b activity.

The effects of hepatocyte nuclear factors (HNFs) have been established in various tumors; however, the roles of HNF-1ß in colorectal cancer progression are never been found. In the present study, HNF-1ß expression was initially detected in clinical tissue samples and online datasets and HNF-1ß was found to be highly expressed in colorectal cancer tissues. In addition, a positive correlation existed between HNF-1ß expression and the overall survival of patients with colorectal cancer. In vitro and in vivo experiments revealed that HNF-1ß suppressed the stemness and migration of colorectal cancer cells. Combined with microRNAs (miRNAs) based on transcriptome-sequencing analysis, mechanistic studies showed that HNF-1ß directly bound to miR-200b promoter and thus promoted miR-200b expression, this HNF-1ß/miR-200b resulted in the downregulation of the expression of miR-200b downstream effectors. Furthermore, HNF-1ß inhibits the stemness and migration of colorectal cancer cells through miR-200b. This study reveals a novel HNF-1ß/miR-200b axis responsible for the stemness of colorectal cancer cells.

Natural product-derived icaritin exerts anti-glioblastoma effects by positively modulating estrogen receptor ß.

Glioblastoma is the most common malignancy of the central nervous system, and patients typically have a poor prognosis. Previous studies indicate a gender bias in the development of glioblastoma; women are at a lower risk compared with men, suggesting that estrogen may confer protective effects. Icaritin, a prenylflavonoid derivative from a Chinese herb of the Epimedium genus, selectively regulates the estrogen receptor (ER) and possesses anti-cancer properties. The aim of the present study was to investigate the protective effects of icaritin on glioblastoma and its underlying mechanisms, with a particular focus on its association with the ER. The results demonstrated that icaritin inhibited the growth of C6 and U87-MG glioblastoma cells in a dose- and time-dependent manner. At a concentration of 12.5 µM, icaritin induced apoptosis, which was characterized by the increased expression of the cleaved forms of caspases 3, 7, 8 and 9 and poly (ADP-ribose) polymerase, downregulation of BCL2 apoptosis regulator and upregulation of BCL2-associated X, apoptosis regulator expression. Additionally, icaritin inhibited the migration of C6 and U87-MG cells. The protein expression levels of matrix metalloproteinase (MMP)-2 and MMP-9 were also downregulated following icaritin treatment. Furthermore, icaritin treatment increased the expression of estrogen receptor (ER)ß and the phosphatase and tensin (PTEN) homolog oncoprotein, thus reducing the expression of downstream targets of PTEN; protein kinase B (Akt) and phosphorylated Akt. Subsequent experiments demonstrated that icaritin cooperates with 17ß-estradiol to inhibit the growth of glioblastoma cells, and the inhibition of ERß with the ERß-specific antagonist ICI 182,780, attenuated the anti-glioblastoma effects of icaritin. In conclusion, the results of the present study demonstrate that the anti-glioblastoma effects of icaritin may be mediated by its modulation of ERß.

Design, synthesis and biological evaluation of novel hybrids of N-aryl pyrrothine-base α-pyrone as bacterial RNA polymerase inhibitors.

Antibiotic resistance in bacteria has been an emerging public health problem, thus discovery of novel and effective antibiotics is urgent. A series of novel hybrids of N-aryl pyrrothine-base α-pyrone hybrids was designed, synthesized and evaluated as bacterial RNA polymerase (RNAP) inhibitors. Among them, compound 13c exhibited potent antibacterial activity against antibiotic-resistant S. aureus with the minimum inhibitory concentration (MIC) in the range of 1-4 µg/mL. Moreover, compound 13c exhibited strong inhibitory activity against E.coli RNAP with IC50 value of 16.06 µM, and cytotoxicity in HepG2 cells with IC50 value of 7.04 µM. The molecular docking study further suggested that compound 13c binds to the switch region of bacterial RNAP. In summary, compound 13c is a novel bacterial RNAP inhibitor, and a promising lead compound for further optimization.

Paris saponin VII extracted from trillium tschonoskii suppresses proliferation and induces apoptosis of human colorectal cancer cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Saponins of many herbs could inhibit the growth of colorectal cancer cells. In the study, we investigated the effects of Paris saponin Ⅶ (PSⅦ), and elucidated its mechanism in colorectal carcinoma cells and a xenograft mouse model. MATERIALS AND METHODS: HT-29 and HCT-116 cells were treated with different concentrations of PSⅦ (0-100 µM). The effects of PSⅦ on HCT-116 cells were assessed using a microarray. Then, apoptotic cells were detected by flow cytometric analysis and apoptosis related protein expression was evaluated by Western blot. A xenograft model of nude mice was used to assess the effect of PSⅦ in vivo. RESULTS: MTT assay showed the IC50 values of PSⅦ for growth inhibition of HT-29 and HCT-116 cells were 1.02 ±â€¯0.05 µM and 3.50 ±â€¯0.79 µM respectively. Edu assay demonstrated that PSⅦ effectively suppressed the growth of HT-29 and HCT-116 cells. Treatment with 0-3 µM PSⅦ not only triggered apoptosis, but also activated caspase-3 and caspase-9 of HT-29 and HCT-116 cells in a concentration dependent manner. In parallel to the alterations, Bax and Cyto-c expression increased while Bcl-2 decreased. In nude mice, PSⅦ reduced the tumor size and induced the apoptosis of tumor cells. PSVII could suppress IL-6-induced phosphorylation of STAT3 in vitro and blocked STAT3 phosphorylation in vivo. CONCLUSION: Our results suggest that PSVII suppressed the activation of IL-6/STAT3 pathway, consequently suppressed the growth and proliferation and triggered the apoptosis of CRC cells. These findings indicate that PSⅦ might be an effective tumouristatic agent for the treatment of colorectal cancer.

GVS-12 attenuates non-alcoholic steatohepatitis by suppressing inflammatory responses via PPARγ/STAT3 signaling pathways.

Non-alcoholic steatohepatitis (NASH), a type of fatty liver disease, is characterized by excessive inflammation and fat accumulation in the liver. Peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone has great potential in protecting against the development of NASH. However, long-term usage of rosiglitazone probably leads to many adverse reactions. In this research, GVS-12 was designed and synthesized as a PPARγ agonist with high selectivity, evidenced by increasing the activity of the PPARγ reporter gene and promoting the mRNA expression of the PPARγ responsive gene cluster of differentiation 36 (CD36). It was noteworthy that GVS-12 could ameliorate dysfunction and lipid accumulation by down-regulating the mRNA expression of interleukin-1ß (IL-1ß), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in the liver of high fat diet (HFD)-induced rats and palmitic acid (PA)-stimulated hepatocellular carcinoma G2 (HepG2) cells. Moreover, PPARγ siRNA (siPPARγ) markedly diminished GVS-12 induced the down-regulation of mRNA expression of IL-1ß, IL-6 and TNF-α in PA-stimulated HepG2 cells. Additionally, GVS-12 could reduce the phosphorylation level of STAT3 and up-regulate the protein expression of a suppressor of cytokine signaling 3 (SOCS3), which could be reversed by siPPARγ. In detail, SOCS3 siRNA (siSOCS3) diminished the inhibitory effect of GVS-12 on the mRNA expression of IL-1ß, IL-6 and TNF-α. In conclusion, GVS-12 suppressed the development of NASH by down-regulating the mRNA expression of IL-1ß, IL-6 and TNF-α via PPARγ/STAT3 signaling pathways.

Preparation, characterization and in vitro and in vivo evaluation of a solid dispersion of Naringin.

Naringin (NA) is one of typical flavanone glycosides widely distributed in nature and possesses several biological activities including antioxidant, anti-inflammatory, and antiapoptotic. The aim of this study was to develop solid dispersion (SD) and to improve the dissolution rate and oral bioavailability of NA. NA-SD was prepared by the traditional preparation methods using PEG6000, F68, or PVP K30 as carrier at different drug to carrier ratios. According to the results of solubility and in vitro dissolution test, the NA-PEG6000 (1:3) SD was considered as an optimal formulation to characterize by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry and powder X-ray diffraction. Furthermore, oral bioavailabilities of NA-PEG6000 (1:3) SD and NA-suspension with the same dosage were investigated in SD rats. The results confirmed the formation of SD and the pharmacokinetic parameters of NA-PEG6000 (1:3) SD (Cmax = 0.645 ± 0.262 µg/ml, AUC0-t = 0.471 ± 0.084 µg/ml h) were higher than that of NA-suspension (Cmax = 0.328 ± 0.183 µg/ml, AUC0-t = 0.361 ± 0.093 µg/ml h). Based on the results, the SD is considered as a promising approach to enhance the dissolution rate and oral bioavailability of NA.

VSP-17, a New PPARγ Agonist, Suppresses the Metastasis of Triple-Negative Breast Cancer via Upregulating the Expression of E-Cadherin.

Triple-negative breast cancer (TNBC), an aggressive subtype of breast cancer, shows higher metastases and relapse rates than other subtypes. The metastasis of TNBC is the main reason for the death of TNBC patients. Increasing evidence has shown that inhibiting the metastasis of TNBC is a good method for TNBC treatment. Here, VSP-17 was designed and synthesized as an agonist of PPARγ, evidenced by upregulating the expression of CD36 and increasing the activity of PPARγ reporter gene. VSP-17 obviously inhibited the migration and invasion process of MDA-MB-231 cells but showed little effect on the viability of MDA-MB-231 cells. Notably, VSP-17 could selectively promote the expression of E-cadherin without affecting the expression of BRMS1, CXCL12, MMP9, Orai1, Stim1, TGF-ß, and VEGF. In addition, VSP-17 significantly suppressed the metastasis of liver and promoted the expression of E-cadherin in MDA-MB-231 xenograft model. In conclusion, VSP-17 inhibited the metastasis process of TNBC via upregulating the expression of E-cadherin.

Hepatoprotective effects of Dicliptera chinensis polysaccharides on dimethylnitrosamine-induced hepatic fibrosis rats and its underlying mechanism.

ETHNOPHARMACOLOGICAL RELEVANCE: Dicliptera chinensis is a traditional herbal medicine used anciently in China for hepatopathy treatment, especially in south areas. Our several studies have demonstrated that dicliptera chinensis polysaccharides (DCP), which has a markedly protective effects on chemistry-induced models of acute liver injury in rats. In this study, we further investigated the potentially hepatoprotective effect of dicliptera chinensis polysaccharides (DCP) on hepatic fibrosis (HF) rats induced by dimethylnitrosamine (DMN). MATERIAL AND METHODS: The 96 rats were randomly divided into six groups (n=16, per group), the normal control group intragastrically administrated normal saline, model control group intraperitoneally injected with 0.5% DMN solution at 1.6mL per kg (three times a week); colchicine intragastrically administrated group (0.2mgkg(-)(1)d(-1))+DMN-treated rats; DCP intragastrically administrated groups (100mgkg(-)(1)d(-)(1), 200mgkg(-1)d(-1), 300mgkg(-1)d(-1))+DMN-treated rats. At the end of 8 weeks, all rats were sacrificed. RESULTS: Pathological examination showed that high and medium doses of DCP presented remarkable effect in ameliorating hepatic fibrosis, alleviate the inflammation, necrosis and reduced collagen deposits. DCP effectively improved the liver function, as revealed in being lowered sero-enzyme levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) while increased albumin (ALB), and being reduced sero-concentrations of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6) in the HF rats. Additionally, the contents of hyaluronic acid (HA), collagen type Ⅳ (Ⅳ-C), type III precollagen (PCIII) and laminin (LN) in the hepatic tissue of HF rats were markedly decreased, whereas the expressions of transforming growth factor-ß l (TGF-ß l), collagen type I (Col- I), metal protease-1 (TIMP-1), nuclear factor-kappa B (NF-κB) expression in the hepatic tissue were notably down-regulated. CONCLUSION: DCP exerts effectively antagonistic activity on DMN-caused hepatotoxicity in HF rats, which the anti-fibrotic mechanisms are associated with regulating functionally serous enzymes, improving metabolic function and inhibiting inflammatory reaction in liver tissue.

Preclinical pharmacokinetic studies of 3-deazaneplanocin A, a potent epigenetic anticancer agent, and its human pharmacokinetic prediction using GastroPlus™.

DZNep is a potential epigenetic drug, and exerts potent anti-proliferative and pro-apoptotic effects on broad-spectrum carcinomas via disruption of the EZH2 pathway. Antitumor studies on DZNep have been stuck in the preclinical phase because of the lack of information about its integral pharmacokinetic (PK) properties. To circumvent this problem, we extensively investigated the disposition characteristics of the DZNep in rats. By incorporating the disposition data across species into a whole-body physiologically based pharmacokinetic (PBPK) models using the GastroPlus(TM) software, we simulated human PK properties of DZNep and determined whether DZNep could be developed for human cancer therapy. Firstly, DZNep was found to cause nephrotoxicity in a dose-dependent manner in rats and its safe dose was determined to be 10mg/kg. DZNep showed a short plasma elimination half-life (1.1h) in rats, a low protein binding in plasma (18.5%), a low partitioning to erythrocyte (0.78), and a low intrinsic hepatic clearance in rats and humans. There was extensive tissue distribution and predominant renal excretion (80.3%). The simulated rat PBPK model of DZNep was well-verified with satisfactory coefficients of determination for all the tested tissues (R(2)>0.781). The simulated human PBPK model successfully identified that intravenous administration of DZNep at appropriate dosing regimen could be further developed for human non-small cell lung carcinoma treatments. The present findings provide valuable information regarding experimental or in silico PK characteristics of DZNep in rats and humans, which is helpful to guide future studies of DZNep in both preclinical and clinical phases.