Atractylenolide I (Atr-I) was found to sensitize a variety of human cancer cells in previous studies. Purinergic P2X7R plays important role in different cancers. However, whether Atr-I could generate antitumor activity in human cervical cancer cells and P2X7R get involved in this effect remain unclear. In this study, Hela (HPV 18 +) and SiHa (HPV 16 +) cells were treated with different doses of Atr-I. The results indicated that agonist and antagonist of P2X7 receptors, BzATP and JNJ-47965567 (JNJ), could suppress the proliferation of Hela and SiHa cells. Atr-I demonstrated a considerable antitumor effect in both human cervical cancer cells in vitro. Atr-I combined with P2X7R agonist, BzATP, restored Atr-I-induced growth inhibition in Hela cells but not in SiHa cells. However, the combinatorial treatment of P2X7R antagonist JNJ and Atr-I has an additive effect on cell growth inhibition in SiHa cells rather than in Hela cells. It implied that P2X7R would get involved in the anti-human cervical cancer cells effect of Atr-I.

Despite extensive research, urosepsis remains a life-threatening, high-mortality disease. Currently, animal models of urosepsis widely accepted by investigators are very scarce. This study aimed to establish a standardized and reproducible model of urosepsis in rats. Forty adult Wistar rats were randomly divided into four groups according to the concentration of injected E. coli suspensions: Sham, Sep 3×, Sep 6×, and Sep 12×. Because the ureter is so thin and fragile, no conventional needle can be inserted into the ureter, which is probably why rats are rarely used to develop models of urosepsis. To solve this problem, the left ureter was ligated in the first procedure. After 24 hours, the left ureter above the ligation was significantly dilated, then saline or different concentrations of E. coli at 3 ml/kg were injected into the left renal pelvis using a 30G needle. The left ureter was subsequently ligated again at a distance of 1 cm from the renal hilum to maintain high pressure in the renal pelvis. Following injection of E. coli or saline for 24 h, three rats from each group were sacrificed and their organs (lung, liver, and right kidney) were collected. In contrast, the remaining seven rats continued to be observed for survival. At 10 days after E. coli injection, rats in the sep12× group had a higher mortality rate (100%) compared to the sep3× group (28.6%) or the sep6× group (71.4%). The significant changes in peripheral blood WBC count, serum IL-6 and TNF-α levels were also in the sep12× group. In addition, rats in the sepsis group showed multi-organ dysfunction, including damage to the lungs, liver, and kidneys. The establishment of a standardized rat model of urosepsis may be of great value for studying the pathophysiological of urosepsis.

Effective chemotherapy drugs for colorectal cancer remain a challenge. In this research, Ziyuglycoside II (Ziyu II), exhibits considerable antitumor activity against CRC cells both in vitro and in vivo. The results showed that Ziyu II induced apoptosis through the accumulation of reactive oxygen species (ROS), which was necessary for Ziyu II to inhibit colorectal cancer cells. Intriguingly, The treatment of Ziyu II triggered complete autophagic flux in CRC cells. Inhibition of autophagy partially reversed Ziyu II-induced growth inhibition, demonstrating a cytotoxic role of autophagy in response to Ziyu IItreated. Mechanism indicated that Ziyu II-induced autophagy by inhibiting Akt/mTOR pathway. Akt reactivation partially reduced Ziyu II-induced LC3-II turnover and LC3 puncta accumulation. Especially, Ziyu II improves the sensitivity of 5-fluorouracil which is the first-line chemotherapy drug in colorectal cancer cells. This research provides novel insight into the molecular mechanism of Ziyu II's anti-proliferation, including apoptosis and autophagy, and lays a foundation for the potential application of Ziyu II in clinical CRC treatment.

Ubiquitin C-terminal hydrolase L5 (UCHL5) is a deubiquitinating enzyme (DUB) that removes ubiquitin from its substrates. Associations between UCHL5 and cancer have been reported in various tissues, but the effect of UCHL5 on bladder cancer has not been thoroughly investigated. This study investigates the expression and function of UCHL5 in bladder cancer. UCHL5 was shown to be abnormally expressed using IHC of tissue microarray and Western blotting. Several procedures were performed to assess the effect of UCHL5 overexpression or knockdown on bladder cancer, such as cell proliferation, colony formation, wound-healing, and Transwell assays. In addition, RNA-Seq and Western blotting experiments were used to verify the status of downstream signaling pathways. Finally, bladder cancers with knockdown or overexpression of UCHL5 were treated with either SC79 or LY294002 to examine the participation of the AKT/mTOR signaling pathway and the expression of downstream targets c-Myc, SLC25A19, and ICAM5. In contrast to adjacent tissue samples, we discovered that UCHL5 was substantially expressed in bladder cancer samples. We also found that UCHL5 downregulation significantly suppressed both tumor growth in vivo and cell proliferation and migration in vitro. According to RNA-Seq analyses and Western blotting experiments, the expression of c-Myc, SLC25A19, and ICAM5 was modified as a result of UCHL5 activating AKT/mTOR signaling in bladder cancer cells. All things considered, our findings show that increased UCHL5 expression stimulates AKT/mTOR signaling, subsequently triggering the expression of c-Myc, SLC25A19, and ICAM5, which in turn promotes carcinogenesis in bladder cancer. UCHL5 is therefore a potential target for therapy in bladder cancer patients.

Background and Purpose: Colorectal cancer (CRC) is one of the most diagnosed cancer worldwide, and effective chemotherapeutic drugs for CRC still remain a challenge. Ziyuglycoside II (Ziyu II) is one of the major active compounds of Sanguisorba officinalis L. Previous study has identified Ziyu II as a potent anti-tumor agent, but limited data on the efficacy and potential mechanism of Ziyu II in the treatment of CRC. Experimental Approach: CRC cells were used to examine the tumor suppression effect of Ziyu II alone or in combination with autophagy inhibitors in vitro and in vivo. A variety of biochemical assays were conducted to elucidate the underlying mechanisms of Ziyu II in CRC cells. Key Results: Ziyu II exhibits antitumor activity against CRC cells both in vitro and in vivo. It demonstrated that treatment with Ziyu II induced apoptosis via accumulation of reactive oxygen species (ROS). Intriguingly, Ziyu II treatment triggered complete autophagic flux in CRC cells. Inhibition of autophagy partially reversed Ziyu II-induced growth inhibition in CRC cells, suggesting a cytotoxic role of Ziyu II-induced autophagy. Mechanistic studies showed that Ziyu II induced autophagy by inhibiting Akt/mTOR pathway, and Akt reactivation partially reduced Ziyu II-induced autophagy. Notably, Ziyu II improves the sensitivity of CRC cells to the first-line chemotherapeutic drugs 5-fluorouracil. Conclusion and Implications:This study provides new insights into the molecular mechanisms of Ziyu II-mediated CRC suppression involving induction of both apoptosis and autophagy, and establishes potential applications of Ziyu II for clinical CRC treatment.