Sonoinduced Tumor Therapy and Metastasis Inhibition by a Ruthenium Complex with Dual Action: Superoxide Anion Sensitization and Ligand Fracture.

Photoresponsive ruthenium(II) complexes have recently emerged as a promising tool for synergistic photodynamic therapy and chemotherapy in oncology, as well as for antimicrobial applications. However, the limited penetration power of photons prevents the treatment of deep-seated lesions. In this study, we introduce a sonoresponsive ruthenium complex capable of generating superoxide anion (O2•-) via type I process and initiating a ligand fracture process upon ultrasound triggering. Attaching hydroxyflavone (HF) as an "electron reservoir" to the octahedral-polypyridyl-ruthenium complex resulted in decreased highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) energy gaps and triplet-state metal to ligand charge transfer (3MLCT) state energy (0.89 eV). This modification enhanced the generation of O2•- under therapeutic ultrasound irradiation at a frequency of 1 MHz. The produced O2•- rapidly induced an intramolecular cascade reaction and HF ligand fracture. As a proof-of-concept, we engineered the Ru complex into a metallopolymer platform (PolyRuHF), which could be activated by low-power ultrasound (1.5 W cm-2, 1.0 MHz, 50% duty cycle) within a centimeter range of tissue. This activation led to O2•- generation and the release of cytotoxic ruthenium complexes. Consequently, PolyRuHF induced cellular apoptosis and ferroptosis by causing mitochondrial dysfunction and excessive toxic lipid peroxidation. Furthermore, PolyRuHF effectively inhibited subcutaneous and orthotopic breast tumors and prevented lung metastasis by downregulating metastasis-related proteins in mice. This study introduces the first sonoresponsive ruthenium complex for sonodynamic therapy/sonoactivated chemotherapy, offering new avenues for deep tumor treatment.

Disruption of cholangiocyte-B cell crosstalk by blocking the CXCL12-CXCR4 axis alleviates liver fibrosis.

B cells can promote liver fibrosis, but the mechanism of B cell infiltration and therapy against culprit B cells are lacking. We postulated that the disruption of cholangiocyte-B-cell crosstalk could attenuate liver fibrosis by blocking the CXCL12-CXCR4 axis via a cyclooxygenase-2-independent effect of celecoxib. In wild-type mice subjected to thioacetamide, celecoxib ameliorated lymphocytic infiltration and liver fibrosis. By single-cell RNA sequencing and flow cytometry, CXCR4 was established as a marker for profibrotic and liver-homing phenotype of B cells. Celecoxib reduced liver-homing B cells without suppressing CXCR4. Cholangiocytes expressed CXCL12, attracting B cells to fibrotic areas in human and mouse. The proliferation and CXCL12 expression of cholangiocytes were suppressed by celecoxib. In CXCL12-deficient mice, liver fibrosis was also attenuated with less B-cell infiltration. In the intrahepatic biliary epithelial cell line HIBEpiC, bulk RNA sequencing indicated that both celecoxib and 2,5-dimethyl-celecoxib (an analog of celecoxib that does not show a COX-2-dependent effect) regulated the TGF-ß signaling pathway and cell cycle. Moreover, celecoxib and 2,5-dimethyl-celecoxib decreased the proliferation, and expression of collagen I and CXCL12 in HIBEpiC cells stimulated by TGF-ß or EGF. Taken together, liver fibrosis can be ameliorated by disrupting cholangiocyte-B cell crosstalk by blocking the CXCL12-CXCR4 axis with a COX-2-independent effect of celecoxib.

Strengthening through adversity: The hormesis model in developmental psychopathology.

BACKGROUND: Employing a developmental psychopathology framework, we tested the utility of the hormesis model in examining the strengthening of children and youth through limited levels of adversity in relation to internalizing and externalizing outcomes within a brain-by-development context. METHODS: Analyzing data from the Adolescent Brain and Cognitive Development study (N = 11,878), we formed latent factors of threat, deprivation, and unpredictability. We examined linear and nonlinear associations between adversity dimensions and youth psychopathology symptoms and how change of resting-state functional connectivity (rsFC) in the default mode network (DMN) from Time 1 to Time 5 moderates these associations. RESULTS: A cubic association was found between threat and youth internalizing problems; low-to-moderate family conflict levels reduced these problems. Deprivation also displayed a cubic relation with youth externalizing problems, with moderate deprivation levels associated with fewer problems. Unpredictability linearly increased both problem types. Change in DMN rsFC significantly moderated the cubic link between threat levels and internalizing problems, with declining DMN rsFC levels from Time 1 to Time 5 facilitating hormesis. Hormetic effects peaked earlier, emphasizing the importance of sensitive periods and developmental timing of outcomes related to earlier experiences. CONCLUSIONS: Strengthening through limited environmental adversity is crucial for developing human resilience. Understanding this process requires considering both linear and nonlinear adversity-psychopathology associations. Testing individual differences by brain and developmental context will inform preventive intervention programming.

Effects of Phloroglucinol on Embryo Transfer: A Systematic Review and Meta-Analysis.

INTRODUCTION: Phloroglucinol may be able to improve embryo transfer outcomes. We aimed to systematically evaluate the effects of phloroglucinol on embryo transfer outcomes. METHODS: The databases searched were PubMed, Ovid MEDLINE, Web of Science, Wanfang, CQVIP, China National Knowledge Infrastructure, and ClinicalTrials.gov. The last search was on February 7, 2023. The included studies were written in English or Chinese. Randomized controlled trials and cohort studies aiming to assess the effect of phloroglucinol on embryo transfer outcomes were included. The studies reported at least one of the primary outcomes (biochemical pregnancy rate, clinical pregnancy rate, and live birth rate). The odds ratio (OR) and 95% confidence interval (CI) were calculated. A random-effects or fixed model was used where applicable to estimate the results. RESULTS: Seventeen articles reporting 5,953 cycles were included. Biochemical pregnancy rate (OR = 1.58, 95% CI = 1.20-2.08, I2 = 71%), clinical pregnancy rate (OR = 1.69, 95% CI = 1.35-2.10, I2 = 64%), and live birth rate (OR = 1.45, 95% CI = 1.23-1.71, I2 = 36%) were improved by phloroglucinol. Less miscarriage (OR = 0.46, 95% CI = 0.35-0.60, I2 = 0%), less ectopic pregnancy (OR = 0.45, 95% CI = 0.28-0.72, I2 = 0%), higher implantation rate (OR = 1.45, 95% CI = 1.24-1.71, I2 = 62%) but more multiple pregnancy rate (OR = 1.48, 95% CI = 1.13-1.94, I2 = 0%) were induced by phloroglucinol. Endometrial peristaltic waves were improved by phloroglucinol (OR = 22.87, 95% CI = 5.52-94.74, I2 = 72%). CONCLUSION: Phloroglucinol may improve the outcomes of embryo transfer, including biochemical pregnancy, clinical pregnancy, and live birth rates. Further studies are warranted.

COVID-19-related stress exacerbates the effect of child maltreatment on negative affect via increased identity confusion during adolescence.

INTRODUCTION: Exposure to childhood maltreatment may undermine the crucial developmental task of identity formation in adolescence, placing them at risk for developing negative affect. The current study investigated whether COVID-19-related stress intensified the indirect link between child maltreatment and adolescents' negative affect through identity confusion. METHOD: Using multidimensional assessments of child maltreatment (threat vs. deprivation), the study included a sample of 124 adolescents (Mage = 12.89, SD = 0.79; 52% female) assessed before (January 2018 to March 2020) and during the pandemic (May to October 2020) in Georgia, United States. The majority of the participants were European American (78.8%), followed by African American (11.5%), Hispanic (3.8%), Asian/Pacific Islander (1.0%), and other (4.8%). We used structural equation modeling to test (a) the mediating role of identity confusion in the link between childhood maltreatment and negative affect and (b) whether COVID-19-related stress moderated these indirect effects. Simple slopes and Johnson-Neyman plots were generated to probe regions of significant interaction effects. RESULTS: Threat and deprivation predicted an increase in adolescent identity confusion. Additionally, childhood threat and deprivation were indirectly linked to adolescents' negative affect through increased levels of identity confusion. COVID-19-related stress significantly exacerbated the link between identity confusion and negative affect. CONCLUSION: Identity confusion is a mechanism underlying the link between child maltreatment and the development of negative affect in adolescence. Our results inform prevention and intervention programs that aim to reduce negative affect among adolescents who experience threatening and depriving rearing environments.

The Influence of Pubertal Development on Early Adolescent Sleep and Changes in Family Functioning.

Pubertal development has been separately linked to adolescents' sleep problems and larger family functioning, but research connecting these inter-related processes remains sparse. This study aimed to examine how pubertal status and tempo were related to early adolescents' sleep and their family functioning. Using longitudinal data from the Adolescent Brain and Cognitive Development study, the study's sample (N = 4682) was 49.2% female, was an average of 9.94 years old at baseline, and was 60.1% white. Analyses in the current study modeled the indirect associations between pubertal change and changes in family conflict via adolescent sleep duration and variability of duration. The results suggested that pubertal status and tempo predicted shorter adolescent sleep durations and greater variability in those durations, which predicted residual increases in family conflict. The findings highlight the role of adolescents' pubertal changes in their sleep and how such changes can negatively affect family functioning.

CH02 peptide promotes ex vivo expansion of umbilical cord blood-derived CD34 + hematopoietic stem/progenitor cells.

Umbilical cord blood (UCB) is an advantageous source for hematopoietic stem/progenitor cell (HSPC) transplantation, yet the current strategies for large-scale and cost-effective UCB-HSPC preparation are still unavailable. To overcome these obstacles, we systematically evaluate the feasibility of our newly identified CH02 peptide for ex vivo expansion of CD34 + UCB-HSPCs. We herein report that the CH02 peptide is specifically enriched in HSPC proliferation via activating the FLT3 signaling. Notably, the CH02-based cocktails are adequate for boosting 12-fold ex vivo expansion of UCB-HSPCs. Meanwhile, CH02-preconditioned UCB-HSPCs manifest preferable efficacy upon wound healing in diabetic mice via bidirectional orchestration of proinflammatory and anti-inflammatory factors. Together, our data indicate the advantages of the CH02-based strategy for ex vivo expansion of CD34 + UCB-HSPCs, which will provide new strategies for further development of large-scale HSPC preparation for clinical purposes.

Pretreatment of Dienogest for Women with Endometriosis in in vitro Fertilization: A Systematic Review and Meta-Analysis.

INTRODUCTION: Dienogest (DNG) was demonstrated to be comparable to gonadotropin-releasing hormone agonist (GnRH-a) in controlling symptoms of endometriosis. GnRH-a is used before in vitro fertilization (IVF) in women with endometriosis to improve pregnancy outcomes. We aimed to determine the effect of DNG pretreatment on IVF outcomes, including number of mature oocytes, rate of clinical pregnancies, and rate of live births in women with endometriosis. METHODS: All studies involving DNG, IVF, and endometriosis were searched from the PubMed; Ovid/MEDLINE, Wanfang, CQVIP, China National Knowledge Infrastructure databases; and ClinicalTrials.gov. The study population was women with endometriosis in IVF. Randomized controlled trials and cohort studies were included. All included studies comprised a DNG group and a control group. The outcomes were number of mature oocytes, rate of clinical pregnancies, and rate of live births. We calculated the odds ratio or mean difference and 95% confidence interval for each study and used a random-effects model to estimate the results. RESULTS: Five articles were screened by the search strategy. One article without a control group was excluded. Finally, four articles with 422 patients were included. No significant differences in number of mature oocytes (MD = -1.27, 95% CI: -3.63 to 1.09, I2 = 91%), the rate of clinical pregnancies (odds ratio = 1.07, 95% CI: 0.33-3.47, I2 = 84%), or the rate of live births (odds ratio = 1.09, 95% CI: 0.34-3.46, I2 = 84%) were found between the DNG group and the control group. CONCLUSION: Pretreatment with DNG for women with endometriosis who underwent IVF could not improve the number of mature oocytes, the rate of clinical pregnancies, or the rate of live births.

Effects of gonadotropin-releasing hormone agonist pretreatment on frozen embryo transfer outcomes in artificial cycles: a meta-analysis.

PURPOSE: Gonadotropin-releasing hormone agonist (GnRHa) before artificial cycle (AC) is expected to improve pregnancy outcomes in frozen-thawed embryo transfer (FET). Many studies have explored the impact of GnRHa pretreatment of AC in FET, but the results were inconsistent. This meta-analysis was performed to systematically evaluate the effect of GnRHa pretreatment on AC in FET. METHODS: The last search was January 31, 2022. Randomized controlled trials and cohort studies aiming to assess the effect of GnRHa as the pretreatment of AC for endometrial preparation in FET were included. GnRHa was used before AC in the treatment group. In the control group, no pretreatment was used before AC. The eligible studies included at least one of the following outcomes: implantation, clinical pregnancy, and live birth. We calculated the odds ratio (OR) or mean difference (MD) and 95% confidence interval (CI) for each study and used a random-effects or fixed model to estimate the results. RESULTS: 27 articles (10 RCTs and 17 non-RCTs) and 14152 patients were included. AC + GnRHa improved the implantation rate (OR = 1.31, 95% CI 1.03-1.66, I2 = 79%), clinical pregnancy rate (OR = 1.27, 95% CI 1.10-1.45, I2 = 53%), and live birth rate (OR = 1.16, 95% CI 1.05-1.29, I2 = 39%). We also found that AC + GnRHa increased the implantation rate (OR = 1.35, 95% CI 1.07-1.69, I2 = 53%) and clinical pregnancy rate (OR = 1.50, 95% CI 1.12-2.01, I2 = 50%) in repeated implantation failure. In addition, AC + GnRHa was positively associated with preterm birth (OR = 1.5, 95% CI 1.15-1.94, I2 = 0%). CONCLUSIONS: GnRHa pretreatment in FET can improve implantation, clinical pregnancy, and live birth rates, especially in patients with repeated implantation failure. GnRHa pretreatment seems to improve FET outcomes, though with a higher preterm birth rate.

Synthesis and Evaluation of NF-κB Inhibitory Activity of Mollugin Derivatives.

(1) Background: Nuclear factor κB (NF-κB) is an important transcriptional regulator that regulates the inflammatory pathway and plays a key role in cellular inflammatory and immune responses. The presence of a high concentration of NF-κB is positively correlated with the severity of inflammation. Therefore, the inhibition of this pathway is an important therapeutic target for the treatment of various types of inflammation; (2) Methods: we designed and synthesized 23 mollugin derivatives and evaluated their inhibitory activity against NF-κB transcription; (3) Results: Compound 6d exhibited the most promising inhibitory activity (IC50 = 3.81 µM) and did not show any significant cytotoxicity against the tested cell lines. Investigation of the mechanism of action indicated that 6d down-regulated NF-κB expression, possibly by suppressing TNF-α-induced expression of the p65 protein. Most of the compounds exhibited potent anti-inflammatory activity. Compound 4f was the most potent compound with 83.08% inhibition of inflammation after intraperitoneal administration, which was more potent than mollugin and the reference drugs (ibuprofen and mesalazine). ADMET prediction analysis indicated that compounds 6d and 4f had good pharmacokinetics and drug-like behavior; (4) Conclusions: Several series of mollugin derivatives were designed, synthesized, and evaluated for NF-κB inhibitory activity and toxicity. These results provide an initial basis for the development of 4f and 6d as potential anti-inflammatory agents.

Inhibition of cyclooxygenase-2 enhanced intestinal epithelial homeostasis via suppressing ß-catenin signalling pathway in experimental liver fibrosis.

The intestinal barrier dysfunction is crucial for the development of liver fibrosis but can be disturbed by intestinal chronic inflammation characterized with cyclooxygenase-2 (COX-2) expression. This study focused on the unknown mechanism by which COX-2 regulates intestinal epithelial homeostasis in liver fibrosis. The animal models of liver fibrosis induced with TAA were established in rats and in intestinal epithelial-specific COX-2 knockout mice. The impacts of COX-2 on intestinal epithelial homeostasis via suppressing ß-catenin signalling pathway were verified pharmacologically and genetically in vivo. A similar assumption was tested in Ls174T cells with goblet cell phenotype in vitro. Firstly, disruption of intestinal epithelial homeostasis in cirrhotic rats was ameliorated by celecoxib, a selective COX-2 inhibitor. Then, ß-catenin signalling pathway in cirrhotic rats was associated with the activation of COX-2. Furthermore, intestinal epithelial-specific COX-2 knockout could suppress ß-catenin signalling pathway and restore the disruption of ileal epithelial homeostasis in cirrhotic mice. Moreover, the effect of COX-2/PGE2 was dependent on the ß-catenin signalling pathway in Ls174T cells. Therefore, inhibition of COX-2 may enhance intestinal epithelial homeostasis via suppression of the ß-catenin signalling pathway in liver fibrosis.

Celecoxib reduces hepatic vascular resistance in portal hypertension by amelioration of endothelial oxidative stress.

The balance between endothelial nitric oxide (NO) synthase (eNOS) activation and production of reactive oxygen species (ROS) is very important for NO homeostasis in liver sinusoidal endothelial cells (LSECs). Overexpression of cyclooxygenase-2 (COX-2), a major intravascular source of ROS production, has been observed in LSECs of cirrhotic liver. However, the links between low NO bioavailability and COX-2 overexpression in LSECs are unknown. This study has confirmed the link between low NO bioavailability and COX-2 overexpression by COX-2-dependent PGE2-EP2-ERK1/2-NOX1/NOX4 signalling pathway in LSECs in vivo and in vitro. In addition, the regulation of COX-2-independent LKB1-AMPK-NRF2-HO-1 signalling pathway on NO homeostasis in LSECs was also elucidated. The combinative effects of celecoxib on diminishment of ROS via COX-2-dependent and COX-2-independent signalling pathways greatly decreased NO scavenging. As a result, LSECs capillarisation was reduced, and endothelial dysfunction was corrected. Furthermore, portal hypertension of cirrhotic liver was ameliorated with substantial decreasing hepatic vascular resistance and great increase of portal blood flow. With the advance understanding of the mechanisms of LSECs protection, celecoxib may serve as a potential therapeutic candidate for patients with cirrhotic portal hypertension.

Retrospective Comparison of Clinical Outcomes Following Splenic Vein Stenting and Splenic Arterial Embolization in Sinistral Portal Hypertension-Related Gastrointestinal Bleeding.

BACKGROUND. Sinistral portal hypertension (SPH) is caused by an obstruction of the splenic vein and is a potential cause of upper gastrointestinal bleeding. Although splenic arterial embolization (SAE) and splenic vein stenting are accepted treatment options for SPH, their outcomes have not been compared directly. OBJECTIVE. This retrospective study compared the outcomes of splenic vein stenting and SAE for SPH-related gastrointestinal bleeding. METHODS. Data of patients with SPH treated by interventional radiology between January 1, 2013, and June 1, 2019, who had at least 6 months of clinical follow-up were retrospectively identified from the electronic database at our hospital. Patients were divided into the SAE group (SAE alone), splenic vein stenting-SAE group (SAE immediately after splenic vein stenting failure using the same procedure as the SAE group), and splenic vein stenting group (successful treatment with SVS). Patients' baseline characteristics and follow-up data were retrieved, and their clinical outcomes were compared. RESULTS. Thirty-seven patients with SPH were included. We assigned 11, 12, and 14 patients to the SAE, splenic vein stenting-SAE, and splenic vein stenting groups, respectively. Rebleeding (e.g., hematemesis, melena, or both) was significantly less common (p = .01) in the splenic vein stenting group (7.1% [1/14]) than in the SAE and splenic vein stenting-SAE groups combined (47.8% [11/23]). Splenectomy to resolve rebleeding was not significantly different (p = .63) in the splenic vein stenting group (7.1% [1/14]) compared with the SAE and splenic vein stenting-SAE groups combined (17.4% [4/23]). No interventional procedure-related deaths were observed during follow-up in any group. CONCLUSION. When feasible, splenic vein stenting is a safe and effective treatment of SPH-related gastrointestinal bleeding that appears to better prevent rebleeding than SAE. CLINICAL IMPACT. Splenic vein stenting should be recommended over SAE for the treatment of SPH-related upper gastrointestinal bleeding when possible.

Intractable biliary obstruction after TIPS creation treated by magnet-assisted endoscopic biliary-duodenal anastomosis.

BACKGROUND: Though biliary obstruction is a common clinical situation, it is rarely caused by transjugular intrahepatic portosystemic shunt (TIPS) placement. When TIPS-induced intractable biliary obstruction happens, liver transplantation seems to be the only resort to cure this condition. METHODS: Herein, we describe a patient who suffered from intractable biliary obstruction following TIPS placement. RESULTS: The patient was finally cured by magnet-assisted endoscopic biliary-duodenal anastomosis, without further requirement of liver transplantation. After more than 6 months of follow-up, this patient recovered well, and recurrence of biliary obstruction was not observed. CONCLUSION: We showed that magnet-assisted endoscopic biliary-duodenal anastomosis is a safe method, which is easy to perform and worthy of popularizing.

Compromised Ileal Mucus Barrier Due to Impaired Epithelial Homeostasis Caused by Notch1 Signaling in Cirrhotic Rats.

BACKGROUND: In liver cirrhosis, intestinal mucus barrier is rarely studied. AIMS: This study aimed to investigate whether mucus barrier in ileum is altered in cirrhotic rats and its underlying mechanisms. METHODS: Thioacetamide was injected to induce liver cirrhosis in rats. Serum from portal vein blood, and ileum and liver tissues were obtained for further analysis. Goblet cell-like Ls174T cells were cultured for in vitro experiments. RESULTS: The ileal mucus was thin, loose, and porous with small bubbles in cirrhotic rats. mRNA expressions of Muc2 and TFF3 were also down-regulated in cirrhotic rats. Bacteria located near to crypts and LPS were increased in the serum from portal vein in cirrhotic rats. Smaller theca area and few goblet cells were found in cirrhotic rats compared with control. Increased proliferation of ileal epithelia was observed in cirrhotic rats. Notch1, Dll1, and Hes1 expressions were enhanced, and KLF4 expression was suppressed in ileum of cirrhotic rats. In Ls174T cells, EDTA and NICD plasmid induced NICD and Hes1 expression and suppressed KLF4 concomitantly, and mucus expression almost vanished in these cells. NICD plasmid induced more proliferation in Ls174T cells. Oppositely, after DBZ treatment, NICD and Hes1 were inhibited along with augmentation of KLF4 and increased mucous expression in Ls174T cells, while proliferation of the cells was suppressed. CONCLUSIONS: In cirrhotic rats, mucus barrier was impaired. This might be attributed to increased proliferation and decreased differentiation of epithelia, which might be mediated by Notch1-Hes1-KLF4 signaling.

Synthesis and evaluation of HIF-1α inhibitory activities of novel panaxadiol derivatives.

Hypoxia-inducible factor 1α (HIF-1α) is a known regulator of tumor cell proliferation, migration, and angiogenesis. The presence of a high concentration of HIF-1α is positively correlated with the severity of cancer. Therefore, the inhibition of this pathway represents an important therapeutic target for the treatment of various types of cancer. Here, we designed and synthesized 30 panaxadiol (PD) derivatives and evaluated their inhibitory activities against HIF-1α transcription. Of these, compound 3l exhibited the most promising inhibitory activity (IC50 = 3.7 µM) and showed significantly decreased cytotoxicity compared with PD. Compound 9e exhibited the strongest cytotoxic effect and may be considered for further preclinical development.

High expression of long non-coding RNA Linc-A associates with poor survival in patients with colorectal cancer.

Long intergenic non-coding RNA for kinase activation (Linc-A) has been reported to enhance the occurrence and progression of breast cancer. Nevertheless, whether Linc-A is related to the tumorigenesis of colorectal cancer (CRC) remains unknown. In this study, we aimed to evaluate the expression of Linc-A in colon adenocarcinoma and explore the correlation between Linc-A and prognosis of CRC. The expression of Linc-A in human colon tissues was evaluated by qRT-PCR, which contained 15 pairs of human colon adenocarcinoma and paracancerous tissues and other 65 colon adenocarcinoma tissues. A total of 80 patients were divided into low and high expression groups according to the Linc-A levels. The levels of Linc-A in colon adenocarcinoma was higher than that in paracancerous tissues (p = 0.047). Furthermore, high expression of Linc-A was associated with advanced TNM stage (p = 0.013), positive lymph nodes (p = 0.024), low 5-year survival rate (p = 0.024) and even 10-year survival rate (p = 0.007). Besides, Linc-A, advanced age, advanced TNM stage, deep infiltration degree and positive lymph nodes were also found to be positively related to poor overall 5-year survival by Kaplan-Meier survival analysis(p < 0.05). Then, multivariable Cox regression analysis revealed that Linc-A was an independent risk factor for prognosis of colon adenocarcinoma (p = 0.047). In conclusion, high expression of Linc-A is associated with advanced TNM stage, lymphatic metastasis and poor survival in patients with CRC. Linc-A may be served as a candidate prognostic biomarker for CRC.

Evaluation of ursolic acid derivatives with potential anti-Toxoplasma gondii activity.

Toxoplasma gondii is an important pathogen that causes serious public health problems. Currently, therapeutic drugs for toxoplasmosis cause serious side effects, and more effective and novel substances with relatively low toxicity are urgently needed. Ursolic acid (UA) has many properties that can be beneficial to healthcare. In this study, we synthesized eight series of UA derivatives bearing a tetrazole moiety and evaluated their anti-T. gondii activity in vitro using spiramycin as a positive control. Most of the synthesized derivatives exhibited better anti-T. gondii activity in vitro than UA, among which compound 12a exhibited the most potent anti-T. gondii activity. Furthermore, the results of biochemical parameter determination indicated that 12a effectively restored the normal body weight of mice infected with T. gondii, reduced hepatotoxicity, and exerted significant anti-oxidative effects compared with the findings for spiramycin. Additionally, our molecular docking study indicated that the synthesized compounds could act as potential inhibitors of T. gondii calcium-dependent protein kinase 1 (TgCDPK1), with 12a possessing strong affinity for TgCDPK1 via binding to the key amino acids GLU129 and TYR131.

Design, synthesis, and screening of novel ursolic acid derivatives as potential anti-cancer agents that target the HIF-1α pathway.

The transcription factor hypoxia-inducible factor-1α (HIF-1α) plays an important role in tumor angiogenesis, growth, and metastasis and is recognized as an important potential therapeutic target for cancer. Here, we designed and synthesized three novel series of ursolic acid derivatives containing an aminoguanidine moiety and evaluated them as HIF-1α inhibitors and anti-cancer agents using human cancer cell lines. Most of the compounds exhibited significant inhibition of HIF-1α transcriptional activity, as measured using a Hep3B cell-based luciferase reporter assay. Among these compounds, 7b was the most potent inhibitor of HIF-1α expression under hypoxic conditions (IC50 4.0 µM) and did not display significant cytotoxicity against any cell lines tested. The mechanism of action of 7b was investigated, we found that 7b downregulated HIF-1α protein expression, possibly by suppressing its synthesis, reduced production of vascular endothelial growth factor, and inhibited the proliferation of cancer cells.