A novel GHH copolymer was synthesized using hyaluronic acid modified with glycyrrhetinic acid and L-histidine (His), and doxorubicin-loaded GHH nanoparticles (DOX/GHH) were prepared for liver-targeted drug delivery and pH-responsive drug release. In the present study, GHH nanoparticles were characterized, and their pH-responsive behaviors were evaluated at different pH levels. The antitumor effect of the DOX/GHH nanoparticles was investigated in vitro and in vivo. Results showed that the DOX/GHH nanoparticles were spherical, and the particle sizes ranged from 238.1 to 156.7 nm with an increase in the degree of substitution of His. The GHH nanoparticles were obviously internalized into human hepatoblastoma cells. In vitro cytotoxicity assay results showed that the DOX/GHH nanoparticles exhibited a dose-dependent antitumor effect. Compared with free DOX, the DOX/GHH nanoparticles displayed higher antitumor efficacy. These results indicate that GHH nanoparticles could be a promising nano-delivery carrier of hydrophobic drugs for liver-targeted therapy.

As an adverse form of early-life stress (ELS), maternal separation (MS) can interfere with the development of cognition and behaviors of adolescent rodents. Brain-derived neurotrophic factor (BDNF) is involved in the regulation of brain development and function, but the molecular mechanisms by which BDNF regulates brain function and behavior in MS with different stressor strengths remain unclear. This descriptive study characterized the levels of BDNF in the prefrontal cortex (PFC) and plasma corticosterone (CORT) from the offspring of rats exposed to early handling (EH, 15-min separation per day) and prolonged MS (PMS, 180-min separation per day), during postnatal days (PND) 1-21. The behavioral and biochemical analyses were performed during adolescence (PND 42-56). PMS resulted in reduced weight and decreased locomotor activity in the open field test and Y-maze task compared to control (CON) group, with EH showing an intermediate phenotype. BDNF protein levels in the PFC were lower in PMS compared to EH and further reduced in CON male rats. Plasma CORT levels were higher in PMS compared to CON with EH again showing intermediate levels. Neither PMS or EH affected spatial learning in the Y-maze task. These findings indicate that longer periods of maternal separation are necessary to increase anxiety-like behavior, elevate CORT levels, and further suppress BDNF levels in the PFC, providing a possible mechanism to explain why more severe forms of ELS lead to more significant psychiatric and medical consequences later in life.

5-Fluorouracil (5-Fu) is one of the most commonly used drugs to treat gastric cancer; however, drug-resistance in cancer cells reduces the efficacy of 5-Fu. Celecoxib may be able to reduce resistance to 5-Fu chemotherapy. The aim of the present study was to investigate the inhibitory effects of a combination of 5-Fu and celecoxib on implanted gastric cancer xenografts in nude mice and to elucidate the underlying mechanism. A tumor-bearing nude mice model was established. The mice were divided into blank control, 5-Fu, celecoxib and combination groups. The weight change and the tumor inhibition rate in each group were calculated. Immunocytochemistry, reverse transcription-polymerase chain reaction and western blotting methods were used to observe hypoxia-inducible factor-2α (HIF-2α), ATP-binding cassette transporter G2 (ABCG2) and octamer-binding transcription factor 4 (Oct-4) expression in the SGC7901 cells. Inhibition of the growth of the implanted gastric cancer was observed in the 5-Fu, celecoxib and combination groups. In the celecoxib and combination treatment groups, the mean tumor mass was significantly less than that in the control group (P<0.05), and the mean tumor mass in the combination treatment group was significantly less than that in the 5-Fu group (P<0.05). The tumor inhibition rates in the 5-Fu, celecoxib and combination groups were 26.36, 59.70 and 88.37%, respectively. The combination group exhibited the highest inhibition rate; the inhibition rates of the combination and celecoxib groups were significantly higher compared with the 5-Fu group (P<0.05). The expression levels of HIF-2, ABCG2 and Oct-4 mRNA and protein were high in the blank control group, and were further increased in the 5-Fu group. However, in the celecoxib and combination groups, the expression levels were lower compared with those in the control group. Significant differences were identified among the 5-Fu, celecoxib and combination groups (P<0.01). Celecoxib has antitumor effects in vivo. The mechanism may be associated with the reduced expression of cancer stem cell markers HIF-2α, Oct-4 and ABCG2. 5-Fu and celecoxib have a synergistic antitumor effect. The mechanism associated with the amelioration of resistance to chemotherapy in gastric cancer and the enhancement of the effect of chemotherapy may be via the reduction of the expression of HIF-2α, ABCG2, Oct-4 and other cancer stem cell markers in the tumor tissues.

5‑fluorouracil (5‑FU) is commonly used in the treatment of gastric cancer; however, resistance to this drug occurs under hypoxic conditions. Celecoxib may be used to reverse this resistance. The aim of the present study was to elucidate the inhibitory effects and mechanisms of 5‑FU and celecoxib on the gastric cancer cell line SGC7901 under hypoxic conditions. SGC7901 cells were divided into four groups: Hypoxic control group, 5‑FU group, celecoxib group and 5‑FU/celecoxib combination group. Following treatment, the inhibition rates of cells were determined using an MTT assay. Protein and messenger RNA (mRNA) expression of hypoxia‑inducible factor 2α (HIF‑2α), adenosine triphosphate‑binding cassette sub‑family G member 2 (ABCG2) and octamer binding protein 4 (Oct‑4) were determined using immunohistochemistry, reverse transcription quantitative polymerase chain reaction (RT‑qPCR) and western blot analysis. The results demonstrated that the 5‑FU/celecoxib combination group had a significantly higher inhibition rate than the individually treated 5‑FU and celecoxib groups (P<0.05); inhibition rates were 66.09, 52.61 and 46.1%, respectively. mRNA and protein expression levels of HIF‑2α, ABCG2 and Oct‑4 were significantly lower in the celecoxib and 5‑FU/celecoxib combination groups (P<0.01) compared with those of the hypoxia control and 5‑FU groups. The 5‑FU group demonstrated the highest levels of the respective mRNA and proteins. In conclusion, the results of the present study indicated that celecoxib had anti‑tumor effects, as it was shown to inhibit tumor cell growth via the inhibition of HIF‑2α, ABCG2 and Oct‑4. The 5‑FU/celecoxib combination had a synergic effect on tumor growth inhibition. This therefore suggested that inhibition of HIF‑2α, ABCG2 and Oct‑4 may be a potential method of reducing chemotherapy resistance and enhancing the effectiveness of chemotherapy treatment.

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