Targeted inhibition of the PI3K/AKT/mTOR pathway by (+)-anthrabenzoxocinone induces cell cycle arrest, apoptosis, and autophagy in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC), characterized by low survival rates and a high recurrence rate, is a major cause of cancer-related mortality. Aberrant activation of the PI3K/AKT/mTOR signaling pathway is a common driver of NSCLC. Within this study, the inhibitory activity of (+)-anthrabenzoxocinone ((+)-ABX), an oxygenated anthrabenzoxocinone compound derived from Streptomyces, against NSCLC is demonstrated for the first time both in vitro and in vivo. Mechanistically, it is confirmed that the PI3K/AKT/mTOR signaling pathway is targeted and suppressed by (+)-ABX, resulting in the induction of S and G2/M phase arrest, apoptosis, and autophagy in NSCLC cells. Additionally, the augmentation of intracellular ROS levels by (+)-ABX is revealed, further contributing to the inhibition of the signaling pathway and exerting inhibitory effects on tumor growth. The findings presented in this study suggest that (+)-ABX possesses the potential to serve as a lead compound for the treatment of NSCLC.

Hypoxia Potentiated Lung Cancer Cell Migration and Invasion by up-regulating HIF1α/JAK2/STAT3 Axis and Activating MMP13 Transcription.

Excessive aggressive migration and invasion are important factors that increase the mortality of cancer patients. Matrix metalloproteinase 13 (MMP13) expression is positively correlated with lung cancer malignancy. However, the mechanism underlying an elevated MMP13 expression is not clearly defined. In this study, we demonstrated that hypoxia induced by CoCl2 enhanced the expression of HIF1α, JAK2, STAT3 and MMP13 in A549 cells. A positive correlation between HIF1α and MMP13 expression was observed in lung adenocarcinoma patients. Mechanically, hypoxia upregulated HIF1α/JAK2/STAT3 signal axis, promoted transcription factor STAT3 to bind to MMP13 promoter region, and activated MMP13 transcription, finally promoted cell invasion and migration. However, stattic (STAT3 inhibitor) could reverse this effect caused by STAT3 in A549 cells. Together our data indicated that hypoxia might promote lung cancer cell migration and invasion through the HIF1α/JAK2/STAT3 axis by activating MMP13 transcription. MMP13 could be a promising therapeutic target for lung adenocarcinoma metastasis.

The Effects and Mechanisms of the Rapamycin-eluting Stent in Urethral Stricture Prevention in Rabbits.

Background: Rapamycin was shown to reduce transforming growth factor ß1 (TGF-ß1) expression, inhibit the Mammalian target of rapamycin function, and prevent TGF-ß1-induced pulmonary fibrosis. Rapamycin-eluting stents (RES) were successfully used to prevent coronary artery restenosis. Urethral stricture is one of the most challenging problems in urology. Thus, combining the pharmacological effects of rapamycin and the mechanical support of the stent on the urethra may prevent urethral stricture formation. However, the use of RES for urethral stricture treatment has not been studied. Aims: To observe the effects of RES in urethral stricture in a rabbit model. Study Design: Animal experimentation. Methods: Twenty adult male New Zealand rabbits were randomly divided into control, urethral stricture model, bare-metal stent, and RES groups. The rabbits in the control group underwent urethroscopy alone without electrocoagulation. The rabbit model of urethral stricture was established by electrocoagulation using a self-made electrocoagulation device under direct vision using ureteroscopy. After model establishment, the rabbits in the bare-metal stent and RES groups received stent placement by ureteroscopy. On day 30, retrograde urethrography was performed to assess urethral stricture formation, ureteroscopy to remove the stents, and histological examinations to assess the degree of fibrosis. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis were used to evaluate the expression levels of TGF-ß1, Smad3, and matrix metalloproteinase 1 (MMP1). Results: Urethral stricture formation was seen in the model group, whereas not in the bare-metal stent group. The bare-metal stents did not displace but were difficult to remove. In the RES group, RES was dislodged in itself at postoperative day 27 in one rabbit, whereas successfully removed by ureteroscopy in the remaining four rabbits, and urethral stricture formation was not seen on retrograde urethrography after stent removal. Histological examination revealed a large number of dense fibroblasts and blue-stained collagen fibers in the bare-metal stent group, whereas the number of fibroblasts and collagen fibers under the mucosa was reduced in the RES group. RT-qPCR and Western blot analyses showed that the messenger ribonucleic acid (mRNA) and protein expression of TGF-ß1and Smad3 was significantly decreased, and mRNA and protein expression of MMP1 was significantly increased in the RES group than that in the model ((P < 0.001) and bare-metal stent groups (P < 0.001). Conclusion: RES can effectively prevent electrocoagulation-induced urethral stricture in rabbits. The mechanism may be related to the effect of rapamycin on inhibiting TGF-ß1 and Smad3 expression and promoting MMP1 expression in urethral tissues.

Premature Ovarian Insufficiency (POI) Induced by Dynamic Intensity Modulated Radiation Therapy via P13K-AKT-FOXO3a in Rat Models.

This study is aimed to investigate the mechanisms of radiation-induced mouse models of premature ovarian insufficiency (POI). Wistar female rats were grouped into the control, 3.2 Gy, 4.0 Gy, and 4.8 Gy groups. Overall ovarian functions were assessed with the H&E staining and ELISA. Proinflammatory cytokine secretion was analyzed ELISA, and the reactive oxygen species (ROS) levels were analyzed with immunohistochemistry. Protein expressions were analyzed by Western blot analysis. The 4.0 Gy and 4.8 Gy groups had significantly lower ovarian weight coefficients than the control and 3.2 Gy groups (after only one irradiation therapy). The 3.2 Gy radiation group induced periodic disturbance and hormone change at 4 weeks after radiation. In the 4.0 Gy and 4.8 Gy groups, the preantral follicles and antral follicles were decreased, while Atresia follicles were increased. E2 was decreased, while FSH and LH secretions were increased. The ovaries in the 4.0 Gy group were not completely atrophied, and some preantral follicles remained. Ovarian atrophy and follicular Atresia were found in the 4.8 Gy group. Inflammatory and oxidative markers were upregulated. PI3K and AKT were downregulated in the 4.0 Gy and 4.8 Gy groups, while FOXO3a was upregulated. Ovarian injuries may lead to oxidative damages and inflammatory injuries, downregulate the expression of P13k and Akt, upregulate the expression of FOXO3a, and lead to follicular atresia in the ovary.

Molecular Epidemiology and Clinical Features of Enteroviruses-Associated Hand, Foot, and Mouth Disease and Herpangina Outbreak in Zunyi, China, 2019.

Background: Hand, foot and mouth disease (HFMD) and herpangina (HA), two of the most common childhood infectious diseases, are associated with enteroviruses (EVs) infection. The aim of this study was to identify the molecular epidemiology of enterovirus causing HFMD/HA in Zunyi, China, during 2019, and to describe the clinical features of the cases. Methods: We collected the information on demographic and clinical characteristics, laboratory data of laboratory-confirmed EVs associated HFMD/HA cases in Zunyi Medical University Third Affiliated Hospital between March 1 and July 31, 2019. EV types were determined by either one-step real time RT-PCR or partial VP1 gene sequencing and sequence alignment. Phylogenetic analysis of CVA6, CVA2, and CVA5 were established based on the partial VP1 gene sequences by neighbor-joining method. Differences in clinical characteristics and laboratory results of the cases were compared among patients infected with the most prevalent EV types. Results: From 1 March to 31 July 2019, 1,377 EVs associated HFMD/HA inpatients were confirmed. Of them, 4 (0.3%, 4/1,377) were EV-A71-associated cases, 84 (6.1%, 84/1,377) were CVA16-associated cases, and 1,289 (93.6%, 1,289/1,377) were non-EV-A71/CVA16-associated cases. Of the randomly selected 372 non-EV-A71/CVA16 cases, EV types have been successfully determined in 273 cases including 166 HFMD and 107 HA cases. For HFMD cases, the three most common types were CVA6 (80.7%, 134/166), CVA2 (5.4%, 9/166) and CVA5 (3.0%, 5/166); similarly, for HA cases, the three most prevalent serotypes were CVA6 (36.5%, 39/107), CVA2 (21.5%, 23/107) and CVA5 (18.7%, 20/107). Phylogenetic analysis showed that subclade D of CVA5, and subclade E of CVA6 and CVA2 were predominant in Zunyi during the outbreak in 2019. Compared with the cases caused by CVA16, the incidence of high fever and severe infection associated with CVA2, CVA5, and CVA6 was higher. Conclusions: The recent HFMD/HA outbreak in Zunyi is due to a larger incidence of CVA6, CVA2, and CVA5. Novel diagnostic reagents and vaccines against these types would be important to monitor and control EV infections.

Expression of survivin, fibronectin-1, VEGF and ezrin in thyroid tumors and their relationship with tumor pathological characteristics / 中国肿瘤生物治疗杂志

@# Objective: To investigate the expression of survivin, fibronectin-1, vascular endothelial growth factor (VEGF) and ezrin in thyroid tumors and their relationship with the pathological characteristics of thyroid tumors. Methods: Ninety patients with thyroid tumors admitted to the third affiliated hospital of Zunyi Medical University and the first hospital during Oct. 2016 and Oct. 2018 were selected as the observation group. Seventy-five patients with normal thyroid confirmed by pathology in the same period were selected as the control group. The protein levels of survivin, fibronectin-1, VEGF and ezrin were detected by immunohistochemical method. Results: The positive rates of survivin, fibronectin-1, VEGF and Ezrin in the control group were 2.67%, l4.00%, 1.33% and 1.33%, which were lower than 97.78%, 96.67%, 93.33% and 95.56% in the observation group, respectively (all P<0.05 or P<0.01). The expressions of survivin, fibronectin-1, VEGF and ezrin were significantly correlated with TNM staging, tumor diameter, extrathyroid invasion and lymphatic metastasis (all P<0.05). Conclusion: Survivin, fibronectin-1, VEGF and ezrin proteins are all involved in the occurrence and development of thyroid tumors. The combined detection of these four indicators is of great significance in the diagnosis, treatment and prognosis of thyroid tumors.