Formulation study of PLGA in situ films for topical delivery of salicylates.

A film-forming system (FFS) represents a convenient topical dosage form for drug delivery. In this study, a non-commercial poly(lactic-co-glycolic acid) (PLGA) was chosen to formulate an FFS containing salicylic acid (SA) and methyl salicylate (MS). This unique combination is advantageous from a therapeutic point of view, as it enabled modified salicylate release. It is beneficial from a technological perspective too, because it improved thermal, rheological, and adhesive properties of the in situ film. DSC revealed complete dissolution of SA and good miscibility of MS with the polymer. MS also ensures optimal viscoelastic and adhesive properties of the film, leading to prolonged and sustained drug release. The hydrolysis of MS to active SA was very slow at skin pH 5.5, but it apparently occurred at physiological pH 7.4. The film structure is homogeneous without cracks, unlike some commercial preparations. The dissolution study of salicylates revealed different courses in their release and the influence of MS concentration in the film. The formulated PLGA-based FFS containing 5 % SA and 10 % MS is promising for sustained and prolonged local delivery of salicylates, used mainly for keratolytic and anti-inflammatory actions and pain relief.

The Solution Is a Solution.

BACKGROUND: Infections in neonates with herpes simplex virus 1 (HSV-1) following circumcision due to Metzitzah Be'Peh (MBP) performed by a Mohel occur each year in small numbers. One solution to this problem is the use of a mucus extractor device instead of MBP, which has been authorized by some rabbis. Yet, using a mucus extractor remains controversial among ultra-Orthodox Jews; thus, creating a need for additional solutions. OBJECTIVES: To seek to reduce HSV-1 infection of neonates due to MBP. METHODS: We tested several oral rinse solutions for their ability to destroy virus infectivity following incubation for 30 seconds and using plaque reduction assays. RESULTS: Corsodyl, Decapinol, and Listerine® all destroyed plaques formation of spiked virus, while Gengigel and Tantum Verde were found to be less effective. We focused specifically on Listerine® due to its efficacy in eliminating contagious HSV-1 from saliva after a 30-second oral rinse. Five different products of Listerine® reduced the infectivity of a spiked virus by more than 4 orders of magnitude in 30 seconds. We also showed that Listerine (up to 7% v/v) can stay in the mouth but did not harm living cells and therefore will not cause any damage to the injured tissue. CONCLUSIONS: Significant reduction in cases of infection with HSV-1 due to MBP can be achieved if Mohalim consistently adopt the practice of careful mouth washing with Listerine® just before performing MBP.

The Mechanism of Action of Ginkgolic Acid (15:1) against Gram-Positive Bacteria Involves Cross Talk with Iron Homeostasis.

With the increasing reports of community-acquired and nosocomial infection caused by multidrug-resistant Gram-positive pathogens, there is an urgent need to develop new antimicrobial agents with novel antibacterial mechanisms. Here, we investigated the antibacterial activity of the natural product ginkgolic acid (GA) (15:1), derived from Ginkgo biloba, and its potential mode of action against the Gram-positive bacteria Enterococcus faecalis and Staphylococcus aureus. The MIC values of GA (15:1) against clinical E. faecalis and S. aureus isolates from China were ≤4 and ≤8 µg/mL, respectively, from our test results. Moreover, GA (15:1) displayed high efficiency in biofilm formation inhibition and bactericidal activity against E. faecalis and S. aureus. During its inhibition of the planktonic bacteria, the antibacterial activity of GA (15:1) was significantly improved under the condition of abolishing iron homeostasis. When iron homeostasis was abolished, inhibition of planktonic bacteria by GA (15:1) was significantly improved. This phenomenon can be interpreted as showing that iron homeostasis disruption facilitated the disruption of the functions of ribosome and protein synthesis by GA (15:1), resulting in inhibition of bacterial growth and cell death. Genetic mutation of ferric uptake regulator (Fur) led to GA (15:1) tolerance in in vitro-induced resistant derivatives, while overexpression of Fur led to increased GA (15:1) susceptibility. Additionally, GA (15:1) significantly decreased the bacterial loads of S. aureus strain USA300 in the lung tissues of mice in a pneumonic murine model. Conclusively, this study revealed an antimicrobial mechanism of GA (15:1) involving cross talk with iron homeostasis against Gram-positive pathogens. In the future, the natural product GA (15:1) might be applied to combat infections caused by Gram-positive pathogens. IMPORTANCE The increasing emergence of infectious diseases associated with multidrug-resistant Gram-positive pathogens has raised the urgent need to develop novel antibiotics. GA (15:1) is a natural product derived from Ginkgo biloba and possesses a wide range of bioactivities, including antimicrobial activity. However, its antibacterial mechanisms remain unclear. Our current study found that the function of ferric uptake regulator (Fur) was highly correlated with the antimicrobial activity of GA (15:1) against E. faecalis and that the antibacterial activity of GA (15:1) could be strengthened by the disruption of iron homeostasis. This study provided important insight into the mode of action of GA (15:1) against Gram-positive bacteria and suggested that GA (15:1) holds the potential to be an antimicrobial treatment option for infection caused by multidrug-resistant Gram-positive pathogens.

Acute systemic inhibition of inflammation augments endothelium-dependent dilation in women with a history of preeclamptic pregnancy.

Women who have had preeclampsia demonstrate microvascular endothelial-dysfunction, mediated in part by reduced nitric oxide (NO)-dependent dilation. Preeclamptic pregnancies are associated with elevated inflammation, and inhibition of inflammation attenuates endothelial damage in animal models of preeclampsia. However, it is unclear if inhibition of vascular inflammation improves endothelial function in women after a preeclamptic pregnancy. Using the cutaneous microcirculation as a model, we hypothesized that acute systemic inhibition of vascular inflammation (oral salsalate; 1500 mg/twice daily, 4 days) would improve endothelium- and NO-dependent vasodilation in women with a history of preeclampsia (PE) but not in women with a history of uncomplicated pregnancy (HC). Twelve HC (30 ± 1yrs, 10 ± 2 months postpartum) and 10 PE (30 ± 2yrs, 8 ± 2 months postpartum) participated in a double-blind placebo-controlled study. Following each treatment, 2 intradermal microdialysis fibers were placed in the skin of the ventral forearm for graded infusion of acetylcholine (Ach, 10-7-102mM) or Ach + 15 mM L-NAME (NO synthase antagonist). Red blood cell flux was measured over each site by laser-Doppler flowmetry (LDF). Cutaneous vascular conductance was calculated (CVC = LDF/mean arterial pressure) and normalized to maximum (%CVCmax; 28 mM SNP + local heat 43 °C). ACh-induced (77 ± 3 vs. 92 ± 3%CVCmax; p = 0.01) and NO-dependent (20 ± 6 vs. 33 ± 4%; p = 0.02) vasodilation were attenuated in PE compared to HC. Salsalate augmented ACh-induced (95 ± 2%CVCmax; p = 0.002) and NO-dependent (39 ± 3%; p = 0.009) dilation in PE compared to placebo but had no effect in HC (all p > 0.05). Salsalate treatment augmented endothelium-dependent vasodilation via NO-mediated pathways in women who have had preeclampsia, suggesting that inflammatory signaling mediates persistent endothelial dysfunction following preeclampsia.

Treatment of difficult-to-treat-dermatophytosis: results of a randomized, double-blind, placebo-controlled study.

INTRODUCTION: Difficult-to-treat dermatophytosis is an emerging public health problem in Sri Lanka. Safe, effective and affordable treatment is needed to solve this problem. Therefore this study has assessed the effectiveness and safety of modified Whitfield ointment applied twice daily with oral griseofulvin 500 mg daily given over 8 weeks in patients with difficult-to-treat dermatophytosis. METHODOLOGY: A randomized, double-blind, within-patient-placebo-controlled trial was conducted in patients with clinico- mycologically (history, physical examination, direct light microscopy examination of scales in potassium hydroxide mount) confirmed difficult-to-treat dermatophytosis. Lesions were randomized to receive modified Whitfield ointment (5% benzoic acid and 5% salicylic acid) or emulsifying ointment. All patients were given oral griseofulvin 500mg once daily. The outcome measures were clinical assessment of disease severity, the total surface area of the lesions and the patient's perception of the disease severity at baseline and every two weeks up to a maximum of 8 weeks. RESULTS: Thirty patients completed the study. At two weeks, there was a statistically significant improvement in modified Whitfield ointment arm in the clinical assessment of disease severity and the patients' perception. There was a 7.59% reduction in the surface area of lesions in modified Whitfield ointment arm and a 5.83% increase in the surface area of lesions in the emulsifying ointment arm at two weeks. The difference between the two arms in surface area changes was not statistically significant (p = 0.107, df = 29). CONCLUSIONS: A combination of modified Whitfield ointment with griseofulvin is significantly effective, safe and affordable option for treating difficult-to-treat dermatophytosis in the tropics.

Drug distribution along the cochlea is strongly enhanced by low-frequency round window micro vibrations.

The cochlea's inaccessibility and complex nature provide significant challenges to delivering drugs and other agents uniformly, safely and efficiently, along the entire cochlear spiral. Large drug concentration gradients are formed along the cochlea when drugs are administered to the middle ear. This undermines the major goal of attaining therapeutic drug concentration windows along the whole cochlea. Here, utilizing a well-known physiological effect of salicylate, we demonstrate a proof of concept in which drug distribution along the entire cochlea is enhanced by applying round window membrane low-frequency micro vibrations with a probe that only partially covers the round window. We provide evidence of enhanced drug influx into the cochlea and cochlear apical drug distribution without breaching cochlear boundaries. It is further suggested that ossicular functionality is not required for the effective drug distribution we report. The novel method presented here of local drug delivery to the cochlea could be implemented when ossicular functionality is absent or impeded and can be incorporated in clinically approved auditory protheses for patients who suffer with conductive, sensorineural or mixed hearing loss.

Effectiveness of Personalized Low Salicylate Diet in the Management of Salicylates Hypersensitive Patients: Interventional Study.

Salicylic acid and its derivatives (including acetylsalicylic acid/aspirin) are popular in medicine. They also occur naturally in many food products. The aim of the study was to investigate the effect of the personalized low salicylate diet (PLSD) on the reduction of asthma, rhinosinusitis and urticaria symptoms in patients with hypersensitivity to aspirin (ASA) or nonsteroidal anti-inflammatory drugs (NSAIDs). To achieve the research goal, a prospective, nonrandomized, baseline-controlled intervention study was conducted. Thirty patients diagnosed with NSAIDs hypersensitivity, who despite pharmacotherapy had symptoms of hypersensitivity, were included in the study. The PLSD was recommended for all participants for a period of two to four weeks. The intensity of subjectively declared symptoms of asthma, rhinosinusitis and urticaria were measured before and after dietary intervention, using, respectively, the asthma control test (ACT), the sino-nasal outcome test (SNOT-22) and the four-item itch questionnaire (FIIQ). Diet adherence and salicylate intake were measured by a 3-day food record. The severity of symptoms improved significantly after the intervention. The median of the ACT score was 24 scores before and 25 after the dietary intervention (p < 0.002), the median of the SNOT-22 score was 25 before and 13 after a dietary intervention (p < 0.0002) and the median of the FIIQ score was 5 before and 0 after a dietary intervention (p < 0.0002). The intake of salicylates decreased from 0.79 mg/day (before intervention) to 0.15 mg/day (p < 0.001) (during intervention). Although the usefulness of a low salicylate diet in the treatment of salicylate hypersensitivity is controversial, the results of our study indicate that the PLSD may have a positive effect in reducing symptoms of salicylate hypersensitivity and could be an additional tool supporting the therapy of these patients.

Salicylates enhance CRM1 inhibitor antitumor activity by induction of S-phase arrest and impairment of DNA-damage repair.

Chromosome region maintenance protein 1 (CRM1) mediates protein export from the nucleus and is a new target for anticancer therapeutics. Broader application of KPT-330 (selinexor), a first-in-class CRM1 inhibitor recently approved for relapsed multiple myeloma and diffuse large B-cell lymphoma, have been limited by substantial toxicity. We discovered that salicylates markedly enhance the antitumor activity of CRM1 inhibitors by extending the mechanisms of action beyond CRM1 inhibition. Using salicylates in combination enables targeting of a range of blood cancers with a much lower dose of selinexor, thereby potentially mitigating prohibitive clinical adverse effects. Choline salicylate (CS) with low-dose KPT-330 (K+CS) had potent, broad activity across high-risk hematological malignancies and solid-organ cancers ex vivo and in vivo. The K+CS combination was not toxic to nonmalignant cells as compared with malignant cells and was safe without inducing toxicity to normal organs in mice. Mechanistically, compared with KPT-330 alone, K+CS suppresses the expression of CRM1, Rad51, and thymidylate synthase proteins, leading to more efficient inhibition of CRM1-mediated nuclear export, impairment of DNA-damage repair, reduced pyrimidine synthesis, cell-cycle arrest in S-phase, and cell apoptosis. Moreover, the addition of poly (ADP-ribose) polymerase inhibitors further potentiates the K+CS antitumor effect. K+CS represents a new class of therapy for multiple types of blood cancers and will stimulate future investigations to exploit DNA-damage repair and nucleocytoplasmic transport for cancer therapy in general.

Double-Blind Placebo-Controlled Trial of Bepotastine Salicylate in Patients With Allergic Rhinitis.

OBJECTIVES/HYPOTHESIS: To evaluate the efficacy and safety of a slow-release form of bepotastine salicylate (HL151, Belion CR) in patients with perennial allergic rhinitis (PAR). STUDY DESIGN: Double-blind, placebo-controlled multicenter comparative study. METHODS: Two hundred seventy-two PAR patients (aged 19-65 years) were studied to determine the efficacy and safety of HL151 (20 mg once daily administration) relative to those of a placebo in terms of improvements in total and nasal symptom scores. The subjects were randomized to the placebo (n = 138) or HL151 group (n = 134, 20 mg orally once daily for 4 weeks), and reflective and instantaneous total nasal symptom scores (TNSS) were measured daily in comparison with baseline. Among 272 subjects, 229 subjects (119 in the placebo group, 110 in the HL151 group) who completed the study were included for efficacy analysis. RESULTS: Instantaneous and reflective TNSS and nasal symptoms such as rhinorrhea, nasal itching, and sneezing at 2 and 4 weeks showed that HL151 was superior to the placebo (all P < .05). There were no significant differences in terms of adverse events and adverse drug reactions between the two groups. Regarding serious adverse events, there was only one case of acute hepatitis B, which was reported not to be associated with HL151. CONCLUSIONS: This multicenter trial showed that once-daily use of HL151 is efficacious and safe in adult patients with PAR and could improve compliance due to its convenience. LEVEL OF EVIDENCE: 1b Laryngoscope, 131:E702-E709, 2021.

Risk of toxicity from pediatric topical salicylate ingestions.

INTRODUCTION: Suspected pediatric ingestions of greater than or equal to one teaspoon topical salicylate analgesic are recommended by poison control centers to be managed at healthcare facilities. This cutoff is applied for both liquid and non-liquid (cream, ointment, gel) formulations. METHODS: California poison control cases involving topical salicylate exposures in children less than 6-years-old who were evaluated at a health care facility between 2003 and 2018 were analyzed. RESULTS: Of 599 patient cases, the majority described no or minor symptoms, with gastrointestinal distress being the most common. Signs of salicylate toxicity (metabolic acidosis, tachypnea) occurred in six cases. Seven patients were hospitalized, six of whom were exposed to liquid preparations. DISCUSSION: In line with previous research, liquid salicylate preparations were more frequently associated with the signs of salicylate toxicity and hospitalization. CONCLUSION: There was a low frequency of severe side effects and low hospitalization rates among those referred to a healthcare facility, especially for non-liquid topical salicylate ingestions.

Enhancing in vivo oral bioavailability of cajaninstilbene acid using UDP-glucuronosyl transferase inhibitory excipient containing self-microemulsion.

Cajaninstilbene acid (CSA) exerts wide pharmacological activities, such as anti-inflammation, hypoglycaemic activity, analgesic effect and cognition improvement. However, it underwent severe phase II metabolism mediated by UDP-glucuronosyltransferase (UGT) in the gastrointestinal (GI) tract after oral administration, affecting its oral bioavailability. In the present study, we utilize UGT inhibitory excipient containing self-microemulsion (SME) delivery system to reduce the production of glucuronide metabolites and increase its oral bioavailability. The present results showed that although similar properties in physiochemical, cytotoxicity, cellular uptake, absorption and transport across rat everted gut sacs between SME-1 (inhibitory excipient containing SME) and SME-2 (control SME, without inhibitory excipient), an improved absolute bioavailability of 57.3 % was conferred by SME-1, significantly higher than the value of 35.4 % by SME-2 and 34.0 % by free CSA. Noticeably, the significantly lower AUC value of CSA glucuronide was determined in rats treated with SME-1 than those either treated with SME-2 or free CSA. Thus, the ability of SME-1 to enhance oral bioavailability of CSA is mainly attributed to the inhibition of phase II metabolism in the GI tract.

Decontamination efficacy of soapy water and water washing following exposure of toxic chemicals on human skin.

Aim of the study: Following exposure to toxic chemicals, skin uptake is a potential route of intoxication. Therefore, efficient methods for rapid skin decontamination to mitigate systemic effects are of utmost importance. In operational guidelines, skin decontamination is recommended to be performed by dry absorption and washing with water or soapy water. In the present study, evaluation of decontamination efficacy using water or soapy water was performed for five chemicals, three toxic industrial chemicals and two simulants for chemical warfare agents.Materials and methods: Decontamination was initiated at time points 5, 15, 45 and 120 min after exposure in order to evaluate the time window for efficient decontamination. Experiments were conducted utilizing an in vitro skin penetration model to allow exposure of toxic chemicals on human skin. Results: For all test substances, it was clearly demonstrated that decontamination had greater efficacy when initiated at the earliest time-point while decontamination after 120 min was less efficient. Adding soap to the water showed no significant improvement for any of the tested substances.Conclusion: These results are of reledvance for the development of efficient operational decontamination procedures.

Neuroprotective Effect of S-trans, Trans-farnesylthiosalicylic Acid via Inhibition of RAS/ERK Pathway for the Treatment of Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD), a leading cause of dementia, becomes a serious health issue for individuals and society around the world. AD is a neurodegenerative disease characterized by the deposition of amyloid-ß (Aß) peptides and neurofibrillary tangles (NFT) and the loss of large numbers of neurons. To date, there is no effective treatment for AD, and thus, to enhance neurogenesis in the AD brain may be a therapeutic strategy. RAS signaling pathway involves in synaptic plasticity and memory formation, which is overexpressed in brains with AD. This study used Aß1-42-injected mice (Aß1-42-mice) as the AD model to investigate the effects of S-trans, trans-farnesylthiosalicylic acid (FTS), a synthetic Ras inhibitor, on the impairment of neurogenesis and the spatial cognitive deficits. MATERIALS AND METHODS: AD model mice were manufactured through intracerebroventricular injection of Aß1-42. Morris water maze (MWM) was performed to evaluate the capacity of spatial memory, and Nissl staining was applied to assess neuronal damage in the hippocampus CA1. Immunohistochemistry of 5-bromo-2-deoxyuridine (BrdU), BrdU/neuronal nuclei (NeuN), and doublecortin (DCX) were used to detect progenitor cell proliferation, maturation, and neurite growth, respectively. And the expression levels of RAS, ERK/ERK phosphorylation (p-ERK) and CREB/CREB phosphorylation (p-CREB) were detected by Western blot. RESULTS: The results demonstrated that FTS could prevent Aß1-42 to impair survival and neurite growth of newborn neurons in the hippocampal dentate gyrus (DG) in Aß1-42-mice. Furthermore, behavioral indexes and morphological findings showed that FTS improved the learning and spatial memory abilities of Aß1-42-mice. In addition, FTS could inhibit the levels of hippocampal p-ERK and p-CREB activated by Aß, which is the underlying molecular mechanism. CONCLUSION: In conclusion, these findings suggest that FTS as a RAS inhibitor could be a potential therapeutic agent for the treatment of AD.

Changes in cecum microbial community in response to total sulfur amino acid (TSAA: DL-methionine) in antibiotic-free and supplemented poultry birds.

The effect of essential total sulfur amino acids (TSAA) like methionine and cysteine on the cecal microbiome of broilers was investigated at 2 different time points (days 21 and 42) of broiler rearing. A total of 360-day-old Cobb male broiler chicks were randomly distributed to 6 dietary treatments in a 2 × 3 factorial arrangement, with 2 levels of antibiotic growth promoters (AGP: 0 and 0.05%) and 3 levels of TSAA (DL-methionine) either for starter (0.7, 0.8, and 0.9%) or finisher chicks (0.52, 0.62, and 0.72%), labeled as diets 1 to 6. Cecal digesta from each replicate (n = 10) were sampled on days 21 and 42. DNA was extracted for the amplification of the V4 region of bacterial 16S rRNA genes and subjected to Illumina sequencing. Bioinformatic analyses were performed using QIIME, Mothur, and ad hoc tools and functional profiles of the inferred metagenome were analyzed using PICRUST. Statistical difference was determined by 2-way ANOVA and PERMANOVA. Clustering of cecal communities using PCoA showed clear separation of microbial communities based on age (P < 0.05) of birds and between low and medium/ high levels of TSAA (DL-methionine). At day 21, bacterial richness and diversity were higher than at day 42 where Clostridium cluster XI and Lactobacillus were found most abundant. No variability in taxonomic richness at the genus level was observed with AGP and DL-methionine supplementation. Interbird variation for richness was greater at day 42 compared to day 21. The mean fold difference of richness was greater (1.5 mean fold) with diets 1 and 6, suggesting interactive effects of AGP and TSAA (DL-methionine) in the diet. KEGG function profiles calculated by PICRUST suggest that the cecal microbiome increased glycolysis and energy generation correlated with increased dietary TSAA (DL-methionine) supplementation levels during the late broiler growth period (day 42). This study increases our knowledge of microbial dynamics and functions that are relevant to host nutrition and performance that may help us tailoring alternative strategies for raising poultry birds under antibiotic-free conditions.

Nanoencapsulated methyl salicylate as a biorational alternative of synthetic antifungal and aflatoxin B1 suppressive agents.

In view of the suspected negative impact of synthetic fungicides to the human health, nutritional quality, and non-targeted organisms, the use of plant-based antifungal agents has gained considerable interest to the agri-food industries. The aim of this study was to explore the antifungal and aflatoxin B1 (AFB1) inhibitory activity of chitosan (low molecular weight) encapsulated methyl salicylate. The nanoencapsulation of methyl salicylate (Ne-MS) has been characterized by SEM, FTIR, and XRD analysis. The encapsulation efficiency and loading capacity of Ne-MS ranged between 32-34% and 5-7% respectively. The minimum inhibitory concentration of Ne-MS (1.00 µL/mL) against the growth and aflatoxin B1 production by Aspergillus flavus was found to be lower than the free MS (1.50 µL/mL). Mode of action studies demonstrated that the Ne-MS cause a significant decrease in the ergosterol content, leakage of vital ions (Ca2+, Mg2+, and K+), utilization of different carbon source by the A. flavus. Further, the docking result showed ver1 and omt A gene of AFB1 biosynthesis are the possible molecular site of action of methyl salicylate. The in situ study revealed that Ne-MS had no significant negative impact on the organoleptic properties of the food system (maize) which strengthen its potential as a biorational alternative of synthetic fungicides.

The Combination of Curcumin and Salsalate is Superior to Either Agent Alone in Suppressing Pro-Cancerous Molecular Pathways and Colorectal Tumorigenesis in Obese Mice.

SCOPE: High-fat diets (HFDs) and adiposity increase colorectal cancer risk, in part by elevating pro-inflammatory cytokines that activate pro-cancerous signaling pathways. Curcumin (CUR), a dietary polyphenol and salsalate (SAL), an non-steroidal anti-inflammatory drug (NSAID) lacking the gastrotoxicity of aspirin, each suppress inflammatory signaling, but via different cellular pathways. METHODS AND RESULTS: A/J mice (n = 110) are fed a low-fat diet (LFD, 10% kcal), a HFD (60% kcal), a HFD containing 0.4% CUR, a HFD containing 0.3% SAL, or a HFD containing both agents (CUR/SAL). All mice receive six injections of azoxymethane. Compared to LFD-fed mice, HFD-fed mice display elevated colonic cytokines, crypt cell proliferation, and increased tumorigenesis (p < 0.05). CUR/SAL significantly reduces colonic cytokines (p < 0.01), suppresses activation of the PI3K/Akt/mTOR/NF-κB/Wnt pathways (p < 0.01), activates AMPK (p < 0.01), attenuates abnormal proliferation of the colonic mucosa (p < 0.05), and reduces tumor multiplicity and burden (p < 0.05), in comparison to the HFD control. In contrast, CUR or SAL alone does not suppress abnormal crypt cell proliferation or tumor multiplicity, and is largely ineffective in modifying activation of these signaling pathways. CONCLUSION: These observations demonstrate the superiority of the CUR/SAL over the individual agents and provide a scientific basis for future translational studies in obese subjects and/or those habitually consuming HFDs.

Ginkgolic acid suppresses the invasion of HepG2 cells via downregulation of HGF/c­Met signaling.

Liver cancer is one of the most devastating types of cancer worldwide. Despite years of improvements in treatment, the prognosis of patients with this type of malignancy remains poor due to frequent recurrence and metastasis after surgical resection. Ginkgolic acid (GA) is a botanical drug extracted from the seed coat of Ginkgo biloba L. that possesses a wide range of bioactive properties. However, to the best of our knowledge, whether GA can inhibit the invasion of liver cancer cells and the underlying mechanisms remains unknown. The aim of the present study was to investigate the effects of GA on the migration and invasion abilities of liver cancer cells and the underlying molecular mechanism. The results revealed that GA suppressed the migration and invasion abilities of HepG2 cells. In addition, GA treatment inhibited the expression of invasion­related molecules (MMP­2 and MMP­9) and prevented the epithelial­mesenchymal transition (EMT) of HepG2 cells. Further experiments revealed that GA­reduced hepatocyte growth factor (HGF) production and suppressed c­Met phosphorylation may be the underlying mechanisms. Exogenous recombinant HGF supplementation improved the cell invasion ability impaired by GA. Moreover, the in vivo experiment revealed that GA inhibited the tumor growth of liver cancer and prevented EMT. Collectively, these data indicated that GA effectively suppressed the invasion and EMT of HepG2 cells via downregulation of HGF/c­Met signaling, thus GA may serve as a novel chemotherapeutic agent for the treatment of HCC.