Discovery, Optimization, and Evaluation of Novel N-(Benzimidazol-5-yl)-1,3,4-thiadiazol-2-amine Analogues as Potent STAT3 Inhibitors for Cancer Treatment.

Signal transducer and activator of transcription 3 (STAT3) is an attractive target for cancer therapy. However, identifying potent and selective STAT3 small-molecule inhibitors with drug-like properties remains challenging. Based on a scaffold combination strategy, compounds with a novel N-(benzimidazol-5-yl)-1,3,4-thiadiazol-2-amine scaffold were designed and their inhibition of the interleukin-6 (IL-6)/JAK/STAT3 pathway was tested in HEK-Blue IL-6 reporter cells. After optimization of lead compound 12, compound 40 was identified as a selective STAT3 inhibitor that directly binds the SH2 domain to inhibit STAT3 phosphorylation, translocation, and downstream gene transcription. Compound 40 exhibited antiproliferative activities against STAT3-overactivated DU145 (IC50 value = 2.97 µM) and MDA-MB-231 (IC50 value = 3.26 µM) cancer cells and induced cell cycle arrest and apoptosis. In the DU145 xenograft model, compound 40 showed in vivo antitumor efficacy following intraperitoneal administration, with a tumor growth inhibition rate of 65.3% at 50 mg/kg, indicating promise for further development.

Neuroprotective effect of salidroside on hippocampal neurons in diabetic mice via PI3K/Akt/GSK-3ß signaling pathway.

BACKGROUND: Diabetic encephalopathy is manifested by cognitive dysfunction. Salidroside, a nature compound isolated from Rhodiola rosea L, has the effects of anti-inflammatory and antioxidant, hypoglycemic and lipid-lowering, improving insulin resistance, inhibiting cell apoptosis, and protecting neurons. However, the mechanism by which salidroside alleviates neuronal degeneration and improves learning and memory impairment in diabetic mice remains unclear. OBJECTIVE: To investigate the effects and mechanisms of salidroside on hippocampal neurons in streptozotocin-induced diabetic mice. MATERIALS AND METHODS: C57BL/6 mice were randomly divided into 4 groups to receive either sham (control group (CON)), diabetes mellitus (diabetes group (DM)), diabetes mellitus + salidroside (salidroside group (DM + SAL)), and diabetes mellitus + salidroside + phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 (diabetes mellitus + salidroside + LY294002 group (DM + SAL + LY294002)). After 12 weeks of diabetes onset, the cognitive behaviors were tested using Morris water maze. The number of hippocampal neurons was detected by Nissl staining. The expressions of PI3K, p-PI3K, Akt, p-Akt, GSK-3ß, p-GSK-3ß, cleaved caspase-3, caspase-3, Bax, Bcl-2, MAP2, and SYN in the hippocampus were detected by Western blot. Moreover, the expression of MAP2 and SYN in the hippocampus was further confirmed by immunofluorescence staining. RESULTS: Salidroside increased the time of diabetic mice in the platform quadrant and reduced the escape latency of diabetic mice. Salidroside also increased the expression of p-PI3K, p-Akt, p-GSK-3ß, MAP2, SYN, Bcl-2, while suppressed the expression of cleaved caspase-3, caspase3, and Bax in the DM + SAL group compared with the DM group (P < 0.05). The Nissl staining showed that the number of hippocampus neurons in the DM + SAL group was increased with the intact, compact, and regular arrangement, compared with the DM groups (P < 0.05). Interestingly, the protective effects of salidroside on diabetic cognitive dysfunction, hippocampal morphological alterations, and protein expressions were abolished by inhibition of PI3K with LY294002. CONCLUSIONS: Salidroside exerts neuroprotective properties in diabetic cognitive dysfunction partly via activating the PI3K/Akt/GSK-3ß signaling pathway.

Laparoendoscopic single-site radical nephrectomy for localized renal cancer: a descriptive research study with at least a 10-year follow-up.

Background: Laparoendoscopic single-site (LESS) surgery is performed to further narrow the incisions and reduce tissue injury. It has been more than10 years since the surgery was first described. However, there is still no report on the results of 10-year follow-up. This study evaluated the use of long-term oncology and the renal outcomes of LESS radical nephrectomy (LESS-RN) in the treatment of localized renal cancer. Methods: We retrospectively analyzed the clinical data of patients treated with LESS-RN at Changhai Hospital from 2009 to 2012. Patients with localized kidney cancer who were followed-up for at least 10 years were included in the study. The baseline data and major perioperative outcome variables were analyzed. Overall survival (OS) and cancer-specific survival (CSS) were calculated using the Kaplan-Meier method. Results: A total of 48 patients were included in the study, which had a median follow-up of 11 years (interquartile range, 10.7-11.8 years). The 10-year OS and CSS rates were 87.5% [42/48; 95% confidence interval (CI): 0.778-0.972] and 97.9% (47/48; 95% CI: 0.937-1.021), respectively. At the most recent follow-up, there were 5 patients with a chronic kidney disease stage ≥3. Among these 5 patients, 3 developed uremia and required continuous dialysis. Conclusions: For localized renal cancer, LESS-RN is safe and effective with excellent long-term oncology controllability and good functional outcomes. Prospective studies with large sample sizes need to be conducted to validate our results.

Benzobis(imidazole) derivatives as STAT3 signal inhibitors with antitumor activity.

Polycyclic aromatic systems have been considered good biological probes, but some may also be good scaffolds for drug development. In this study, a series of benzobis(imidazole) derivatives were identified as STAT3 signal inhibitors, among which compound 24 showed significant inhibition of IL-6 induced JAK/STAT3 signalling pathway activation. Moreover, 24 inhibited cancer cell growth and migration, and induced cell apoptosis as well as cycle arrest in human hepatocellular carcinoma cells (HepG2) and oesophageal carcinoma cells (EC109). Compound 24 also displayed obvious antitumor activity in a mouse HepG2 cell xenograft tumor model without affecting the body weight. These results confirmed that 24 was a potential STAT3 signal inhibitor with certain antitumor activity.

[A comparative study of two ventilation modes in the weaning phase of preterm infants with respiratory distress syndrome].

OBJECTIVE: To compare the efficacy between synchronized intermittent mandatory ventilation (SIMV) and pressure support ventilation with volume guarantee (PSV+VG) in the weaning phase of preterm infants with respiratory distress syndrome (RDS). METHODS: Forty preterm infants with RDS who were admitted to the neonatal intensive care unit between March 2016 and May 2017 were enrolled as subjects. All infants were born at less than 32 weeks' gestation and received mechanical ventilation. These patients were randomly and equally divided into SIMV group and PSV+VG group in the weaning phase. Ventilator parameters, arterial blood gas, weaning duration (from onset of weaning to extubation), duration of nasal continuous positive airway pressure (NCPAP) after extubation, extubation failure rate, the incidence rates of pneumothorax, patent ductus arteriosus (PDA) and bronchopulmonary dysplasia (BPD), and the mortality rate were compared between the two groups. RESULTS: The PSV+VG group had significantly decreased mean airway pressure, weaning duration, duration of NCPAP after extubation, and extubation failure rate compared with the SIMV group (P<0.05). There were no significant differences in arterial blood gas, mortality, or incidence rates of pneumothorax, PDA and BPD between the two groups (P>0.05). CONCLUSIONS: For preterm infants with RDS, the PSV+VG mode may be a relatively safe and effective mode in the weaning phase. However, multi-center clinical trials with large sample sizes are needed to confirm the conclusion.

Tracking Co(I) Intermediate in Operando in Photocatalytic Hydrogen Evolution by X-ray Transient Absorption Spectroscopy and DFT Calculation.

X-ray transient absorption spectroscopy (XTA) and optical transient spectroscopy (OTA) were used to probe the Co(I) intermediate generated in situ from an aqueous photocatalytic hydrogen evolution system, with [RuII(bpy)3]Cl2·6H2O as the photosensitizer, ascorbic acid/ascorbate as the electron donor, and the Co-polypyridyl complex ([CoII(DPA-Bpy)Cl]Cl) as the precatalyst. Upon exposure to light, the XTA measured at Co K-edge visualizes the grow and decay of the Co(I) intermediate, and reveals its Co-N bond contraction of 0.09 ± 0.03 Å. Density functional theory (DFT) calculations support the bond contraction and illustrate that the metal-to-ligand π back-bonding greatly stabilizes the penta-coordinated Co(I) intermediate, which provides easy photon access. To the best of our knowledge, this is the first example of capturing the penta-coordinated Co(I) intermediate in operando with bond contraction by XTA, thereby providing new insights for fundamental understanding of structure-function relationship of cobalt-based molecular catalysts.

Reconstruction of damaged corneal epithelium using Venus-labeled limbal epithelial stem cells and tracking of surviving donor cells.

Limbal epithelial stem cells are responsible for the self-renewal and replenishment of the corneal epithelium. Although it is possible to repair the ocular surface using limbal stem cell transplantation, the mechanisms behind this therapy are unclear. To investigate the distribution of surviving donor cells in a reconstructed corneal epithelium, we screened a Venus-labeled limbal stem cell strain in goats. Cells were cultivated on denuded human amniotic membrane for 21 days to produce Venus-labeled corneal epithelial sheets. The Venus-labeled corneal epithelial sheets were transplanted to goat models of limbal stem cell deficiency. At 3 months post-surgery, the damaged corneal epithelia were obviously improved in the transplanted group compared with the non-transplanted control, with the donor cells still residing in the reconstructed ocular surface epithelium. Using Venus as a marker, our results indicated that the location and survival of donor cells varied, depending on the corneal epithelial region. Additionally, immunofluorescent staining of the reconstructed corneal epithelium demonstrated that many P63(+) cells were unevenly distributed among basal and suprabasal epithelial layers. Our study provides a new model, and reveals some of the mechanisms involved in corneal epithelial cell regeneration research.