Objective To explore the effects of different doses of sodium fluoride (NaF) on cartilage lesion and expression of interleukin-6 (IL-6) in serum and cartilage tissue of Balb/c mice.Methods Sixty-four 5-week-old male Balb/c mice were divided into 4 groups based on body weight via the random number table method and 16 mice were in each group.The mice in control group were fed with distilled water,and experimental animals in low,middle and high fluoride groups were fed with distilled water containing NaF 25,50 and 100 mg/L,respectively.The mice were weighed once a week and fed for three months to establish the drinking water fluorosis model.The fluoride contents in spine were detected via the fluorin-ion selective electrode method.The pathological changes in articular cartilage and epiphyseal plate cartilage were observed through optical microscope.The levels of serum IL-6 and souble IL-6 receptor (sIL-6R) were detected via the enzyme-linked immunosorbent assay.The expression of IL-6 protein in articular cartilage and epiphyseal plate cartilage was examined by immunohistochemistry.Results From the sixth week of the experiment,compared with other 3 groups,the body weight of high fluoride group decreased significantly (all P ＜ 0.05);from the seventh week,compared with control and low fluoride groups,the body weight of middle fluoride group decreased significantly (all P ＜ 0.05);throughout the experiment,compared with control group,the body weight of low fluoride group had not changed significantly (all P ＞ 0.05).The fluoride contents of bone in control group,low fluoride group,middle fluoride group and high fluoride group were (842.46 ± 89.27),(1 705.05 ± 105.76),(2 614.17 ± 156.10) and (3 444.58 ± 233.69) mg/kg,respectively.The differences between groups were statistically significant (F =309.716,P ＜ 0.05),and fluoride contents of bone increased with increase of fluoride doses (all P ＜ 0.05).Under optical microscope,the cartilage tissue of control group was normal,while articular cartilage and epiphyseal plate cartilage showed different degrees of cartilage ossification in fluorosis mice and the changes increased with the increase of fluoride doses.The levels of serum IL-6 in control group,low fluoride group,middle fluoride group and high fluoride group were (5.98 ± 1.43),(7.54 ± 2.16),(5.25 ± 1.97) and (6.31 ±-1.36) ng/L,respectively.The differences between groups were statistically significant (F =3.840,P ＜ 0.05),low fluoride group was significantly higher than control group (P ＜ 0.05),and middle fluoride group was significantly lower than low fluoride group (P ＜ 0.05).The levels of serum slL-6R in control group,low fluoride group,middle fluoride group and high fluoride group were (0.83 ± 0.20),(0.93 ± 0.23),(0.82 ±0.27) and (0.92 ± 0.28) μg/L,respectively.The differences between groups were not statistically significant (F =0.738,P ＞ 0.05).Immunohistochemical results showed that articular cartilage full-layer cells in each group expressed IL-6 protein especially in the middle layer of chondrocytes,while IL-6 protein only expressed in hypertrophic chondrocytes of epiphyseal plate cartilage.Comparing with other groups,IL-6 positive cells were the most and had the deepest staining in low fluoride group.Conclusions Different doses of NaF could not only cause cartilage lesion,but also change the expression of IL-6 in serum and cartilage tissue of Balb/c mice.The results indicate that IL-6 may be involved in the cartilage lesion caused by fluoride.

Objective To investigate the relationship between Cytochrome P-450 1A1 (CYP1A1) gene polymorphism and the ethnic differences to brick-tea fluorosis and the gene-environment interaction.Methods Inhabitants over the age of 16 years old in Inner Mongolia,Qinghai and Xinjiang were investigated.The questionnaire survey included basic information,dietary survey and total fluoride intake,and peripheral venous blood was collected.The CYP1A1 gene single nucleotide polymorphism (SNP) genotyping was determined using mass spectrometry;the diagnosis of skeletal fluorosis was based on the X-ray method;combined genetic factors with environmental factors,the interaction of gene-environment was analyzed.Results In the 1 414 copies of whole blood samples (308 Tibetans,290 Kazakhs,261 Mongolians,425 Han people,130 Russians),CYP1A1 genes rs1048943 sites were typed into AA,AG and GG genotypes,and gene distribution met Hardy-Weinberg equilibrium (P ＞ 0.05).The frequencies of genotypes AA,AG and GG in Tibetans were 55.8％ (172/308),37.3％ (115/308) and 6.8％ (21/308),respectively;the frequencies of the three genotypes in Kazakhs were 69.7％ (202/290),27.6％ (80/290) and 2.8％ (8/290),respectively;the frequencies of the three genotypes in Mongolians were 60.5％ (158/261),36.0％ (94/261) and 3.4％ (9/261),respectively;the frequencies of the three genotypes in Han people were 60.9％ (259/425),33.6％ (143/ 425) and 5.4％ (23/425),respectively;the frequencies of genotypes in Russians were 72.3％ (94/130),26.9％ (35/130) and 0.8％ (1/130),respectively;the differences of the three genotype frequencies between different ethnic groups were statistically significant (x2 =24.757,P ＜ 0.05).The skeletal fluorosis detection rates in different ethnic from high to low were Tibetans (39.94％,123/308),Kazakhs (33.79％,98/290),Mongolians (22.22％,58/261),Han people (13.41％,57/425) and Russians (8.46％,11/130),and the differences were statistically significant (x2 =100.156,P＜ 0.05).Skeletal fluorosis detection rates of different genotypes were AA (24.18％,214/885),AG/GG (25.14％,133/529),the difference was not statistically significant between the groups (x2 =0.165,P ＞ 0.05).After the ethnic stratification,the differences were also not statistically significant (P ＞ 0.05).Only in the group of Tibetans whose urine fluoride level was 1.6-3.2 mg/L and Mongolians under age 45 were found that the G gene was one of the risk factors in skeletal fluorosis [OR =2.035,95％ CI (1.003-4.128);OR =5.602,95％CI (1.461-21.479)];G gene might be a protective factor in the Mongolians aged 45 years and over [OR =0.422,95％CI(0.190-0.938)].Conclusion This study does not find a positive correlation between CYP1A1 gene polymorphism and the ethnic differences to bricktea fluorosis.

Breast cancer has become the most commonly diagnosed cancer type in the world. A combination of chemotherapy and photothermal therapy (PTT) has emerged as a promising strategy for breast cancer therapy. However, the intricacy of precise delivery and the ability to initiate drug release in specific tumor sites remains a challenging puzzle. Therefore, to ensure that the therapeutic agents are synchronously delivered to the tumor site for their synergistic effect, a multifunctional nanoparticle system (PCRHNs) is developed, which is grafted onto the prussian blue nanoparticles (PB NPs) by reduction-responsive camptothecin (CPT) prodrug copolymer, and then modified with tumor-targeting peptide cyclo(Asp-d-Phe-Lys-Arg-Gly) (cRGD) and hyaluronic acid (HA). PCRHNs exhibited nano-sized structure with good monodispersity, high load efficiency of CPT, triggered CPT release in response to reduction environment, and excellent photothermal conversion under laser irradiation. Furthermore, PCRHNs can act as a photoacoustic imaging contrast agent-guided PTT. In vivo studies indicate that PCRHNs exhibited excellent biocompatibility, prolonged blood circulation, enhanced tumor accumulation, allow tumor-specific chemo-photothermal therapy to achieve synergistic antitumor effects with reduced systemic toxicity. Moreover, hyperthermia-induced upregulation of heat shock protein 70 in the tumor cells could be inhibited by CPT. Collectively, PCRHNs may be a promising therapeutic way for breast cancer therapy.