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.

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.

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.

Synthesis and evaluation of the HIF-1α inhibitory activities of novel ursolic acid tetrazole derivatives.

The hypoxia-inducible factor-1α (HIF-1α) pathway has been implicated in tumor angiogenesis, growth, and metastasis. Therefore, the inhibition of this pathway is an important therapeutic target for the treatment of various types of cancers. Here, we designed and synthesized 31 ursolic acid (UA) derivatives containing a tetrazole moiety and evaluated them for their potential anti-tumor activities as HIF-1α transcriptional inhibitors. Of these, compound 14d (IC50 0.8 ±â€¯0.2 µM) displayed the most potent activity and compounds 14a (IC50 4.7 ±â€¯0.2 µM) exhibited the most promising biological profile. Analysis of the structure-activity relationships of these compounds with HIF-1α suggested that the presence of a tetrazole group located at C-28 of the UA derivatives was critical for their inhibitory activities.

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.

Risk factors for overt hepatic encephalopathy after transjugular intrahepatic portosystemic shunt creation in patients with liver cirrhosis.

OBJECTIVE: This study aimed to determine the risk factors and establish a risk score for post-transjugular intrahepatic portosystemic shunt (TIPS) overt hepatic encephalopathy (OHE). METHODS: Altogether 299 and 62 cirrhotic patients receiving TIPS from January 2015 to March 2018 were divided into the derivation and validation cohorts, respectively. The data of the derivation cohort were analyzed for risk factors of post-TIPS OHE. A risk score was established from the derivation cohort and verified by the validation cohort. RESULTS: During a median follow-up of 112.6 weeks, 52 (17.4%) patients in the derivation cohort experienced post-TIPS OHE. Logistic regression showed that alcoholic cirrhosis (odds ratio [OR] 3.068, 95% confidence interval [CI] 1.423-6.613, P = 0.004), stent diameter of 10 mm (OR 12.046 [95% CI 2.308-62.862], P = 0.003), portal pressure gradient (PPG) decrement ≥60% (OR 3.548 [95% CI 1.741-7.230], P < 0.001), model for end-stage liver disease (MELD) score ≥10 (OR 2.695 [95% CI 1.203-6.035], P = 0.016), blood ammonia (OR 1.009 [95% CI 1.000-1.018], P = 0.043) and notable hydrothorax (OR 4.393 [95% CI 1.554-12.415], P = 0.005) were associated with an increased risk of post-TIPS OHE. The risk score reached a promising risk evaluation of post-TIPS OHE when verified by the validation cohort (sensitivity 71.4%, specificity 70.7%, accuracy 71.0%). CONCLUSIONS: Alcoholic cirrhosis and notable hydrothorax are independent risk factors for post-TIPS OHE in liver cirrhosis, together with the stent diameter of 10 mm, PPG decrement ≥60%, MELD score ≥10 and blood ammonia. The established risk score is reliable to identify high-risk individuals of developing post-TIPS OHE.

Suppressing growth and invasion of human hepatocellular carcinoma cells by celecoxib through inhibition of cyclooxygenase-2.

Purpose: Biomarkers are lacking in hepatocellular carcinoma (HCC). Cyclooxygenase-2 (COX-2) and its metabolites play crucial roles in the process of inflammation-tumor transformation. This study was aimed to detect COX-2 expression in HCC tissues and evaluate the effects of a COX-2 inhibitor, celecoxib, on biological behaviors of HCC cell lines in vitro. Methods: COX-2 expression was detected by immunohistochemistry on a human HCC tissue microarray. The correlations of COX-2 expression with tumor clinicopathological variables and overall survival were analyzed. The proliferation, apoptosis, cell cycle distribution, invasion capacity, and related signaling molecules of HCC cells after incubated with COX-2 inhibitor celecoxib were evaluated in vitro. Results: Expression levels of COX-2 in HCC tissues were significantly higher than those in paracancerous tissues. The TNM stage III-IV, tumor size >5 cm, lymphovascular invasion and distant metastasis was higher in high COX-2 expression group compared with that in low COX-2 expression group. Patients with low COX-2 expression achieved better 5-year overall survival than those with high COX-2 expression. Treatment with celecoxib was sufficient to inhibit cell proliferation, promote apoptosis, and induce G0/G1 cell cycle arrest in HCC cells with concentration- and time-dependent manners. Celecoxib up-regulated E-cadherin protein through inhibiting COX-2-prostaglandin E2 (PGE2)-PGE2 receptor 2 (EP2)-p-Akt/p-ERK signaling pathway to suppress HCC cells migration and invasion. Conclusion: High COX-2 expression was associated with advanced TNM stage, larger tumor size, increased lymphovascular invasion and short survival. Targeting inhibition of COX-2 by celecoxib exhibited anti-tumor activities by suppressing proliferation, promoting apoptosis, and inhibiting the aggressive properties of HCC cells.

High HIF-1α expression predicts poor prognosis of patients with colon adenocarcinoma.

Hypoxia inducible factor 1 alpha subunit (HIF-1α) is induced in hypoxic conditions and plays a crucial role in the neoangiogenesis and metastasis of cancer. In this study, we aimed to evaluate the expression of HIF-1α in colon adenocarcinoma and to explore its clinicopathological characteristics and prognosis. A tissue microarray involving colon adenocarcinoma tissues and their corresponding paracancerous tissues from 92 patients was utilized to detect HIF-1α. The expression of HIF-1α in colon adenocarcinoma tissues was significantly higher than it was in the corresponding paracancerous tissues (P < 0.001). Furthermore, similar results were observed in HCT116 and RKO human colon adenocarcinoma xenografts in node mice (P < 0.05). Additionally, augmented HIF-1α expression was positively associated with TNM stage III-IV (P = 0.025), the presence of distant metastasis and vascular invasion (P = 0.048), and the presence of positive lymph nodes (P = 0.041). A Kaplan-Meier survival analysis showed that up-regulation of HIF-1α was associated with poor 5-year or 10-year survival (P < 0.05). A multivariable Cox regression analysis also found HIF-1α was an independent risk factor for poor prognosis in colon adenocarcinoma. Thus, targeting HIF-1α might be a viable strategy to treat patients with colon adenocarcinoma.

Adjuvant celecoxib and lanreotide following transarterial chemoembolisation for unresectable hepatocellular carcinoma: a randomized pilot study.

Recurrence of hepatocellular carcinoma (HCC) after transarterial chemoembolisation (TACE) is common due to neoangiogenesis. Cyclooxygenase-2 inhibitors and somatostatin analogues were reported to inhibit tumour angiogenesis. The pilot randomized controlled trial was aimed to prospectively evaluate the protocol of TACE combined with celecoxib and lanreotide (TACE+C+L) in patients with unresectable and advanced HCC. A total of 71 patients with HCC were enrolled and randomly assigned to either TACE (n=35) or TACE+C+L (n=36) group. Overall survival, disease control rate (DCR), and adverse events were assessed during a 3-year follow-up period. The median overall survival of the TACE+C+L group (15.0 months) was doubled compared to that of TACE group (7.5 months), p = 0.012. DCR of the TACE+C+L group was significantly higher than that of the TACE group either at 6 months (72.2% vs 42.9%, p = 0.012) or at 12 months (61.1% vs 28.6%, p = 0.006). The median overall survivals (13 months vs 4.5 months, p = 0.013) and DCR at 12 months (50% vs 13.6%, p = 0.008) of patients with advanced HCC in TACE+C+L groups were significantly higher than those in TACE group. No significant difference of adverse events was observed between the two groups. The occurrence of post-embolisation syndrome in TACE+C+L group was significantly lower than that in TACE group (16.7% vs 60.0%, p = 0.001). In conclusion, the regimen of TACE+C+L prolonged overall survival, enhanced tumour response, reduced post-embolisation syndrome and was well-tolerable in the patients with unresectable HCC. It may be more beneficial for advanced HCC.

Carbohydrate antigen 125 and carcinoembryonic antigen in the differentiation of tuberculous peritonitis and peritonitis carcinomatosa.

Tumor markers could increase in both tuberculous peritonitis and peritonitis carcinomatosa, confusing the differentiation of these diseases. This study aimed to better understand the extent of elevation and diagnostic efficacies of carbohydrate antigen 125 (CA 125), carcinoembryonic antigen (CEA) and combinative use of them in tuberculous peritonitis and peritonitis carcinomatosa. Of 2998 patients reviewed, 101, 120 and 71 patients were assigned to TBP group (tuberculous peritonitis), non-OCA group (non-ovarian carcinoma-related peritonitis carcinomatosa) and OCA group (ovarian carcinoma-related peritonitis carcinomatosa), respectively. The composite index was calculated by CA 125 multiplying CEA. Receiver operator characteristic curves for CA 125, CEA and composite index were acquired. As a result, CA 125 value in OCA group was higher than other two groups (serum CA 125: P < 0.001; ascites CA 125: P < 0.001). On the other hand, non-OCA group had the highest CEA value among three groups (serum CEA: P < 0.001; ascites CEA: P < 0.001). Area under curves of serum/ascites composite index and serum/ascites CEA were larger than those of serum/ascites CA 125. Furthermore, ascites and serum composite index displayed the best sensitivity (0.907) and specificity (0.989), respectively. In conclusion, CA 125 increases in tuberculous peritonitis and non-ovarian carcinoma-related peritonitis carcinomatosa, but it elevates more in ovarian carcinoma-related peritonitis carcinomatosa. CEA is found to increase more significantly in non-ovarian carcinoma-related peritonitis carcinomatosa. CEA and composite index are helpful in distinguishing peritonitis carcinomatosa from tuberculous peritonitis, but composite index is slightly superior to CEA in the differential diagnosis.

Collapsed Reticular Network and its Possible Mechanism during the Initiation and/or Progression of Hepatic Fibrosis.

Among the researches on hepatic fibrosis, great attention was paid to both hepatocytes and extracellular matrix (ECM). However, little focus was drawn on reticular fibrous network, which is important for demarcation and support of hepatocytes. The aim of this study was to investigate the change pattern of reticular fibers in hepatic fibrosis/cirrhosis and its underlying mechanism. In this study, thioacetamide (TAA) and bile duct ligation (BDL) were utilized to induce rat hepatic fibrosis respectively, and Human liver cirrhotic microassay was analyzed with IHC to confirm the results in animal experiment and to detect the metalloproteinases (MMPs) expressions. As a result, the reticular fibers decreased markedly after 1 week in TAA and 1 day in BDL treated rats. Multiple representative regulators of MMPs and MMPs increased significantly in their expressions and activities. Further more, in human liver cirrhotic microassay, MMPs expressions also showed similar patterns as that of animal experiment. In Conclusions: Degradation or collapse of reticular fibers in hepatic sinusoid can be considered as a pathological feature during the initiation and/or progression of hepatic fibrosis. Moreover, such degradation is associated with and probably caused by the over/dysregulated expression of MMPs.