Foreseen as foundational in forthcoming oncology interventions are multimodal therapeutic systems. Nevertheless, the tumor microenvironment (TME), marked by heightened glucose levels, hypoxia, and scant concentrations of endogenous hydrogen peroxide could potentially impair their effectiveness. In this research, two-dimensional (2D) Ti3C2 MXene nanosheets are engineered with CeO2 nanozymes and glucose oxidase (GOD), optimizing them for TME, specifically targeting cancer therapy. Following our therapeutic design, CeO2 nanozymes, embodying both peroxidase-like and catalase-like characteristics, enable transformation of H2O2 into hydroxyl radicals for catalytic therapy while also producing oxygen to mitigate hypoxia. Concurrently, GOD metabolizes glucose, thereby augmenting H2O2 levels and disrupting the intracellular energy supply. When subjected to a near-infrared laser, 2D Ti3C2 MXene accomplishes photothermal therapy (PTT) and photodynamic therapy (PDT), additionally amplifying cascade catalytic treatment via thermal enhancement. Empirical evidence demonstrates robust tumor suppression both in vitro and in vivo by the CeO2/Ti3C2-PEG-GOD nanocomposite. Consequently, this integrated approach, which combines PTT/PDT and enzymatic catalysis, could offer a valuable blueprint for the development of advanced oncology therapies.

Lung cancer is a leading cause of cancer-related deaths worldwide. Recent studies have identified pyroptosis, a type of programmed cell death, as a critical process in the development and progression of lung cancer. In this study, we investigated the effect of EEBR, a new compound synthesized by our team, on pyroptosis in non-small cell lung cancer cells (NSCLC) and the underlying molecular mechanisms. Our results demonstrated that EEBR significantly reduced the proliferation and metastasis of NSCLC cells in vitro. Moreover, EEBR-induced pyroptosis in NSCLC cells, as evidenced by cell membrane rupture, the release of cytokines such as interleukin-18 and interleukin-1 beta and the promotion of Gasdermin D cleavage in a Caspase-1-dependent manner. Furthermore, EEBR promoted the nuclear translocation of NF-κB and upregulated the protein level of NLRP3. Subsequent studies revealed that EEBR-induced pyroptosis was suppressed by the inhibition of NF-κB. Finally, EEBR effectively suppressed the growth of lung cancer xenograft tumours by promoting NSCLC pyroptosis in animal models. Taken together, our findings suggest that EEBR induces Caspase-1-dependent pyroptosis through the NF-κB/NLRP3 signalling cascade in NSCLC, highlighting its potential as a candidate drug for NSCLC treatment.

BACKGROUND:Postoperative abdominal adhesions (PAAs) represent a frequent condition occurring in more than 90% of patients undergoing abdomen and pelvic surgeries, which can cause chronic abdominal pain, female infertility, and repeated bowel obstruction, requiring repetitive surgical interventions causing morbidity and mortality, as well as high costs. It is therefore of paramount clinical importance and significance to develop practical and reliable strategies for preventing the occurrence of PAAs.METHODS AND RESULTS:In this study, we demonstrated that Nianfukang (NFK, composed of polyethylene glycol 1450 and diclofenac sodium) is highly effective in preventing PAAs, likely by reducing leukocytes and inflammatory factors in the abdominal cavity, and inhibiting intestinal fibrosis in a rat model of PAAs induced by postoperative cecum scraping. We further uncovered that NFK downregulates the expression of TGF-β1, a key factor for adhesion formation, to suppress the TGF-β1/TGF-βRIII/Smad2 signaling pathway, thereby inhibiting the proliferation and migration of fibroblasts and provided evidences for the involvement of the TGF-β1/TGF-βRIII/Smad2 axis in the prevention of PAAs in normal human colon fibroblast CCD-18Co.CONCLUSIONS:Our findings support NFK as a potential anti-adhesive product that has the advantages of significant effectiveness, safety profile, and low cost, as well as clear mechanism of action.

Cardiac fibrosis is a common pathological manifestation accompanied by various heart diseases, and antifibrotic therapy is an effective strategy to prevent diverse pathological processes of the cardiovascular system. We currently report the pharmacological evaluation of a novel anthraquinone compound (1,8-dihydroxy-6-methyl-9,10-anthraquinone-3-oxy ethyl succinate) named Kanglexin (KLX), as a potent cardioprotective agent with antifibrosis activity. Our results demonstrated that the administration of KLX by intragastric gavage alleviated cardiac dysfunction, hypertrophy, and fibrosis induced by transverse aortic constriction (TAC) surgical operation. Meanwhile, KLX administration relieved endothelial to mesenchymal transition of TAC mice. In TGF β1-treated primary cultured adult mouse cardiac fibroblasts (CFs) and human umbilical vein endothelial cells (HUVECs), KLX inhibited cell proliferation and collagen secretion. Also, KLX suppressed the transformation of fibroblasts to myofibroblasts in CFs. Further studies revealed that KLX-mediated cardiac protection was due to the inhibitory role of TGF-β1/ERK1/2 noncanonical pathway. In summary, our study indicates that KLX attenuated cardiac fibrosis and dysfunction of TAC mice, providing a potentially effective therapeutic strategy for heart pathological remodeling.

BACKGROUND:Anthocyanins are a type of flavonoids that are natural water soluble glycosidic pigments with efficacious anti-cancer effects, which have good biological activity against many cancers including colorectal cancer (CRC). However, the exact molecular mechanism used by anthocyanins against cancer is unclear; it is also unclear what a reasonable dosage might be for their use against colorectal cancer.METHODS:Western blotting, immunohistochemistry, MTT assay, xenograft model, and hematoxylin-eosin (HE) staining were used to perform the experiments.RESULTS:Compared with the control group, anthocyanins could significantly inhibit the cell viability and proliferation and promote the apoptosis of human colon cancer HT29 cells. Furthermore, anthocyanins reduced tumor weight and volume in a colon tumor mouse model and downregulated the expression of PI3K protein, inhibited AKT expression and phosphorylation, decreased the Bcl-2 and Bax ratio and reduced survivin protein expression in the tumor tissue.CONCLUSION:Anthocyanins promoted apoptosis of CRC cells and inhibited colon cancer growth of xenografted tumors. Mechanistically, anthocyanins enhanced the Bcl-2/Bax and caspase-dependent apoptotic pathways through targeting the PI3K/AKT/survivin pathway, resulting in impairment of growth of CRC.

Cucurbitacin B (CuB), the active component of a traditional Chinese herbal medicine, Pedicellus Melo, has been shown to exhibit antitumor and anti-inflammation effects, but its role in tumor angiogenesis, the key step involved in tumor growth and metastasis, and the involved molecular mechanism are unknown. Tumor angiogenesis is one of the hallmarks of the development in malignant neoplasias and metastasis. Effective targeting of tumor angiogenesis is a key area of interest for cancer therapy. Here, we demonstrated that CuB significantly inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, migration, tubulogenesis in vitro, and blocked angiogenesis in chick embryo chorioallantoic membrane (CAM) assay in vivo. Furthermore, CuB induced HUVEC apoptosis and may induce apoptosis by triggering the mitochondrial apoptotic pathway. Finally, we found that CuB inhibiting angiogenesis was associated with inhibition of the activity of vascular endothelial growth factor receptor 2 (VEGFR2). Our investigations suggested that CuB was a potential drug candidate for angiogenesis related diseases.

Thymoquinone, an active ingredient isolated from Nigella sativa, has been reported to have anti-inflammatory effects. However, the anti-inflammatory effect of thymoquinone on IL-1β-stimulated osteoarthritis chondrocytes remains unclear. In this study, we designed to investigate the anti-inflammatory effects and elucidated the underlying mechanism of thymoquinone on IL-1β-stimulated human osteoarthritis chondrocytes. The effects of thymoquinone on inflammatory mediators COX-2, iNOS, NO, PGE2, as well as MMP-1, MMP3, MMP13 production were detected. The results demonstrated that thymoquinone concentration-dependently inhibited IL-1β-induced COX-2, iNOS, NO, and PGE2 production. Thymoquinone also suppressed IL-1β-induced MMP-1, MMP3, and MMP13 production. We found that thymoquinone significantly inhibited IL-1β-induced NF-κB activation and IκBα degradation. In addition, thymoquinone was found to suppress IL-1β-induced mitogen-activated protein kinases (MAPKs) activation. In conclusion, thymoquinone inhibited IL-1β-induced inflammatory mediator production by inhibition of NF-κB and MAPKs signaling pathways in osteoarthritis chondrocytes. Thymoquinone may be a potential agent in the treatment of osteoarthritis.

Objective To explore the expression and mechanisms of fibroblast growth factor 4 (FGF-4) in cytarabine-induced polydactyly of thumb.Methods An intraperitoneal injection of cytarabine was used to establish a rat model of polydactyl and syndactyl.For different periods of gestational rats (11.5,12.5,13.5,14.5 days),whole mount in situ hybridization was used to detect the expression of FGF-4 in polydactyly.The stains of hematoxylin & eosin and cartilage were used to detect the embryonic development of skeleton and tissues.And radiology was employed for detecting the aberration of skeleton.Results In test group,the expression of FGF-4 was up-regulated in limb bud and its expanded domain persisted longer than control group.In test group,the FGF4 expression relative areas at Days 11.5,12.5,13.5 and 14.5 were around 22.21％,84.81％,58.43％ and 47.59％ versus 6.74％,30.80％,19.64％ and 15.44％ respectively.Conclusions FGF-4 is up-regulated in cytarabine-induced limb bud of polydactyl embryos.

Objective To observe the expression offibroblast growth factor4 (FGF-4) in polydactyly of the thumb induced by cytarabine and investigate the pathogenesis of polydactyly. Methods Sixty-six 2 to 3 months old Sprague Dawley rats were caged together daily from 6 pm to 8 am next morning by a male:female ratioof 1:2.The day that a vaginal plug was found was considered as embryonic day 0.5 ( E0.5).30 pregnant rats were assigned to the experimental group, while another 30 were assigned as controls.At day E10.5 intraperitoneal injection of cytarabine ( 100 mg/kg) was carried out in the experimental rats to induce polydactyly and syndactyly in the pupa.Normal saline was injected to the control rats.E10.5 to E12.5 embryos were removed from the pregnant female rats and limb buds were taken out and fast frozen.mRNA was extracted from the limb buds.The expression of FGF-4 mRNA was quantified using RT-PCR. Results In the experimental group FGF-4 expression in the limb buds was significantly higher and lasted much longer than the control group (P ＜0.01).Conclusion The rat embryo's polydactyly of the thumb can be induced by cytarabine.FGF-4 expression in the limb buds in the polydactyly embryo is increased.

Objective To observe the influence of iodine on mRNA expression of iodide transporter (NIS),insulin-like growth factor Ⅰ (IGF- Ⅰ ) and transforming growth factor beta(TGF-β) in thyroid and mammary glands of lactating rats and to explore the role of NIS,IGF- Ⅰ and TGF-β mRNA in iodine uptake in thyroid and mammary glands of lactating rats.Methods One hundred and one Wistar rats(80 female and 21 male),weighting 8 - 100 g were selected.These female rats were randomly divided into five groups according to their body weight:control group(NI,normal feed,drank deionized water containing iodine 50 μg/L) ; low iodine group 1 and 2(LI-1,LI-2,low iodine feed,drank deionized water containing iodine 0 and 5 μg/L,respectively); high iodine group 1 and 2(HI-1,HI-2,normal feed,drank deionized water containing iodine 3000 and 10 000 μg/L,respectively),16 rats in each group.After feeding for 3 months,the female and male rates were mated 3:1.The female rats in each group were sacrificed at the fifth and tenth day after postpartum.Thyroid and mammary glands were taken.The mRNA levels of NIS,IGF- Ⅰ and TGF-β in thyroid and mammary glands of lactating rats were determined by real time quantitative PCR.Results The fifth days after postartum,NIS,IGF- Ⅰ and TGF-β mRNA expression levels of thyroid and lactating mammary glands were different between groups,and the differences were statistically significant ( NIS:F =631.46,64.91,all P ＜ 0.01 ; IGF- Ⅰ:F =11.45,6.56,all P ＜ 0.01 ; TGF-β:F =291.83,304.53,all P ＜ 0.01).Compared with control group [NIS:0.0066 ± 0.0023, (0.1481 ± 0.0711 ) × 10-2; IGF- Ⅰ:0.0419 ± 0.0062,0.0542 ± 0.0044; TGF-β:0.1416 ± 0.0277,0.1670 ± 0.0499],regardless of thyroid or mammary gland,the NIS,IGF- Ⅰ and TGF-β mRNA expression of LI-1 [NIS:0.0447 ± 0.0110,(0.3030 ± 0.1831) × 10-2;IGF- Ⅰ:0.0662 ± 0.0078,0.0902 ± 0.008; IGF- Ⅰ:0.5514 ± 0.0508,0.6942 ± 0.0367],LI-2[NIS:0.0317 ±0.0081,(0.3017 ± 0.1601) × 10-2; IGF-I:0.0645 ± 0.0054,0.0894 ± 0.0093; TGF-β:0.5292 ± 0.0332,0.6704 ± 0.0277 ] was significantly increased (all P ＜ 0.01 ); the NIS mRNA expression of HI-1 [0.0043 ± 0.0011,(0.1233 ± 0.0954) × 10-2],HI-2[0.0037 ± 0.0017,(0.1058 ± 0.0854) × 10-2] was decreased(all P ＜ 0.05),while the expression of IGF-Ⅰ mRNA [0.0521 ± 0.0910,0.0715 ± 0.0026; 0.0516 ± 0.0078,0.0697 ± 0.0038] and TGF-β mRNA [0.2087 ± 0.0425,0.2361 ± 0.0425; 0.1971 ± 0.0237,0.2257 ± 0.0752 ] was increased (all P ＜ 0.05 ).The tenth days after postpartum,the mRNA expression levels of NIS,IGF- Ⅰ and TGF-β of thyroid and lactating mammary gland in rats were different between groups,and the differences were statistically significant (NIS:F =103.55,116.32,all P ＜ 0.01; IGF-Ⅰ:F =67.67,11.98,all P ＜ 0.01; TGF-β:F =74.30,381.30,all P ＜0.01 ).Compared with the control group[NIS:0.0069 ± 0.0011,(0.1337 ± 0.0599) × 10-2; IGF-Ⅰ:0.0390 ±0.0071,0.0534 ± 0.0056; TGF-β:0.1351 ± 0.0336,0.1534 ± 0.0320],the mRNA expression levels of NIS,IGF- Ⅰ and TGF-β of LI-1 [ NIS:0.0432 ± 0.0165,(0.2962 ± 0.0985 ) × 10-2; IGF- Ⅰ:0.0643 ± 0.0088,0.0873 ± 0.0055 ; TGF-β:0.5042 ± 0.0912,0.6408 ± 0.0420],LI-2[NIS:0.0287 ± 0.0111,(0.2873 ± 0.0862) × 10-2; IGF- Ⅰ:0.0621 ± 0.0094,0.0862 ± 0.0038; TGF-β:0.4893 ± 0.0504,0.6372 ± 0.0389] were significantly increased(all P ＜ 0.01 ); the NIS mRNA levels of HI-1 [ 0.0042 ± 0.0029,(0.1006 ± 0.0909) × 10-2],HI-2[0.0035 ± 0.0020,(0.0890 ± 0.0119) × 10-2] were decreased(all P＜ 0.05),while the expression of IGF-Ⅰ mRNA[0.0516 ± 0.0078,0.0668 ± 0.0071; 0.0508 ± 0.0089,0.0621 ± 0.0064] and TGF-β mRNA[0.2007 ± 0.0546,0.2175 ± 0.0370;0.1959 ± 0.0393,0.2097 ± 0.0425] were increased(all P ＜ 0.05 ).In thyroid and mammary glands,the comparisons of NIS,IGF,TGF-β mRNA expression of the fifth and tenth day after postartum,between each group were not statistically significant(all P ＜ 0.05).Conclusions There are regulatory mechanisms of thyroid and mammary glands of lactating rats in response to low or high iodine conditions.In low iodine,the expressions of NIS,IGF- Ⅰ and TGF-β mRNA in thyroid and mammary glands increase and iodide uptake ability is enhanced to meet the body needs.In high iodine,the expression of NIS mRNA decreases in thyroid and mammary glands.Due to the reduced ability of iodine uptake,iodine intake is reduced,thereby reducing the hazards of high iodine in filial rats.