CS2164, a novel multi-target inhibitor against tumor angiogenesis, mitosis and chronic inflammation with anti-tumor potency.

Although inhibitors targeting tumor angiogenic pathway have provided improvement for clinical treatment in patients with various solid tumors, the still very limited anti-cancer efficacy and acquired drug resistance demand new agents that may offer better clinical benefits. In the effort to find a small molecule potentially targeting several key pathways for tumor development, we designed, discovered and evaluated a novel multi-kinase inhibitor, CS2164. CS2164 inhibited the angiogenesis-related kinases (VEGFR2, VEGFR1, VEGFR3, PDGFRα and c-Kit), mitosis-related kinase Aurora B and chronic inflammation-related kinase CSF-1R in a high potency manner with the IC50 at a single-digit nanomolar range. Consequently, CS2164 displayed anti-angiogenic activities through suppression of VEGFR/PDGFR phosphorylation, inhibition of ligand-dependent cell proliferation and capillary tube formation, and prevention of vasculature formation in tumor tissues. CS2164 also showed induction of G2/M cell cycle arrest and suppression of cell proliferation in tumor tissues through the inhibition of Aurora B-mediated H3 phosphorylation. Furthermore, CS2164 demonstrated the inhibitory effect on CSF-1R phosphorylation that led to the suppression of ligand-stimulated monocyte-to-macrophage differentiation and reduced CSF-1R+ cells in tumor tissues. The in vivo animal efficacy studies revealed that CS2164 induced remarkable regression or complete inhibition of tumor growth at well-tolerated oral doses in several human tumor xenograft models. Collectively, these results indicate that CS2164 is a highly selective multi-kinase inhibitor with potent anti-tumor activities against tumor angiogenesis, mitosis and chronic inflammation, which may provide the rationale for further clinical assessment of CS2164 as a therapeutic agent in the treatment of cancer.

Advances in targeting histone deacetylase for treatment of solid tumors.

Histone deacetylase (HDAC) serves as a critical molecular regulator in the pathobiology of various malignancies and have garnered attention as a viable target for therapeutic intervention. A variety of HDAC inhibitors (HDACis) have been developed to target HDACs. Many preclinical studies have conclusively demonstrated the antitumor effects of HDACis, whether used as monotherapy or in combination treatments. On this basis, researchers have conducted various clinical studies to evaluate the potential of selective and pan-HDACis in clinical settings. In our work, we extensively summarized and organized current clinical trials, providing a comprehensive overview of the current clinical advancements in targeting HDAC therapy. Furthermore, we engaged in discussions about several clinical trials that did not yield positive outcomes, analyzing the factors that led to their lack of anticipated therapeutic effectiveness. Apart from the experimental design factors, issues such as toxicological side effects, tumor heterogeneity, and unexpected off-target effects also contributed to these less-than-expected results. These challenges have naturally become significant barriers to the application of HDACis. Despite these challenges, we believe that advancements in HDACi research and improvements in combination therapies will pave the way or lead to a broad and hopeful future in the treatment of solid tumors.

Relationship between cerebral hypoxic tissue volume and prognosis after stroke.

BACKGROUND/AIMS: Between 50 and 70% of stroke survivors suffer from severe disabilities such as paralysis and aphasia. Poor stroke outcome is a reflection of our incomplete understanding of the underlying mechanisms, and hence the capacity to implement appropriate treatment(s). We evaluated hypoxic tissue after stroke and patient condition severity and prognosis. METHODS: Hypoxic tissue volume was quantified within 14 days after stroke. Patients were classified as hypoxic positive or negative. Patients were evaluated at imaging and 21 days later. Prognosis was assessed at 30 and 90 days. RESULTS: Significant improvement was shown in hypoxia-positive (vs. hypoxia-negative) patients (p < 0.05). There were significant positive relationships between the volume of hypoxic tissue and the improvement in specialized test scores at 90 days (p < 0.05 for both). Presence of hypoxic tissue within 14 days after cerebral stroke was related to recovery at 3 weeks and prognosis at 90 days. CONCLUSIONS: The assessment of hypoxic tissue volume after stroke may be useful in predicting patient recovery.

Naringenin and hesperetin, two flavonoids derived from Citrus aurantium up-regulate transcription of adiponectin.

The dried, immature fruit of Citrus aurantium L., 'Zhiqiao' in Chinese, has been used to treat cardiovascular diseases in traditional Chinese medicine for centuries. Naringenin and hesperetin and their glycosides present in considerable amounts (about 10 approximately 15%) in the herb. The aim of this study is to test whether naringenin and hesperetin influence adiponectin expression, which plays an important role in glucose and lipid metabolism with antiatherogenic and anti-inflammatory properties. Treatment with naringenin and hesperetin enhanced adiponectin transcription in differentiated 3T3-L1 cells. Both naringenin and hesperetin induced peroxisome proliferator-activated receptor (PPAR)gamma-controlled luciferase expression in a dose-dependent manner (20-160 microM), whereas only naringenin possessed significant activity to activate PPARalpha. These results suggested the two flavonoids might exert antiatherogenic effects partly through activating PPAR and up-regulating adiponectin expression in adipocytes. Our findings give new insight for the molecular explanations for the therapeutic effects of Zhiqiao.

[Preliminary study on the value of 99Tc(m)-HL91 imaging in predicting sensitivity to radiotherapy in patients with nasopharyngeal carcinoma].

OBJECTIVE: To investigate the feasibility of 9Tc(m)-HL91 imaging in prediction of 34 radiotherapy sensitivity of naqsopharyngeal cancer( NPC) and its relationship with prognosis. METHODS: patients with NPC confirmed by pathology, staging from II-IVa, underwent 99Tc(m)-HL91 SPECT imaging one week before radiotherapy. 18 of them received adjuvant chemotherapy. The hypoxia in primary nasopharyngeal lesions and cervical lymph node metastases were calculated semi-quantitatively, and compared with clinical findings in medium-term therapy at 4 months and 1 year post therapy. RESULTS: (1) There was no significant relationship between the total preliminary curative effect of adjuvant chemotherapy and the degree of nasopharyngeal lesion hypoxia (T/Mu, gamma = -0.394, P = 0.145; T/ Ce gamma = -0.510, P = 0.052). But there was a significant difference between the partial curative effect group and significant curative effect group. (2) The degree of NPC regression in the medium-term radiotherapy group was negatively correlated with the degree of hypoxia (T/Mu, gamma = -0.602; T/Ce, gamma = -0.643, P < 0.01). (3) 23 patients had good local control except one case with lung and bone metastasis 4 months post-therapy. The lesions disappeared or not developed in 6 patients (T/Mu 1.30 +/- 0.23, T/Ce 3.61 +/- 0.84). Two patients at stage III and IVa relapsed (T/Mu were 1.40 and 1.27, respectively; T/Ce were 4.10 and 3.85, respectively), there was no significant difference. (4) The degree of lymph node hypoxia had no correlation with the curative effect on medium-term radiotherapy. CONCLUSION: 99 Tc(m)-HL91 hypoxia imaging may predict sensitivity to radiotherapy in patients with NPC, with a potential help to carry out individual therapy. However, further investigation is needed to ascertain whether it could predict the long-time curative effect on NPC radiotherapy.

Chiglitazar Preferentially Regulates Gene Expression via Configuration-Restricted Binding and Phosphorylation Inhibition of PPARγ.

Type 2 diabetes mellitus is often treated with insulin-sensitizing drugs called thiazolidinediones (TZD), which improve insulin resistance and glycemic control. Despite their effectiveness in treating diabetes, these drugs provide little protection from eminent cardiovascular disease associated with diabetes. Here we demonstrate how chiglitazar, a configuration-restricted non-TZD peroxisome proliferator-activated receptor (PPAR) pan agonist with moderate transcription activity, preferentially regulates ANGPTL4 and PDK4, which are involved in glucose and lipid metabolism. CDK5-mediated phosphorylation at serine 273 (S273) is a unique regulatory mechanism reserved for PPARγ, and this event is linked to insulin resistance in type 2 diabetes mellitus. Our data demonstrates that chiglitazar modulates gene expression differently from two TZDs, rosiglitazone and pioglitazone, via its configuration-restricted binding and phosphorylation inhibition of PPARγ. Chiglitazar induced significantly greater expression of ANGPTL4 and PDK4 than rosiglitazone and pioglitazone in different cell models. These increased expressions were dependent on the phosphorylation status of PPARγ at S273. Furthermore, ChIP and AlphaScreen assays showed that phosphorylation at S273 inhibited promoter binding and cofactor recruitment by PPARγ. Based on these results, activities from pan agonist chiglitazar can be an effective part of a long-term therapeutic strategy for treating type 2 diabetes in a more balanced action among its targeted organs.

Peroxisome proliferator-activated receptor-gamma transcriptionally up-regulates hormone-sensitive lipase via the involvement of specificity protein-1.

Both peroxisome proliferator-activated receptor (PPAR)-gamma and hormone-sensitive lipase (HSL) play important roles in lipid metabolism and insulin sensitivity. We demonstrate that expression of the HSL gene is up-regulated by PPARgamma and PPARgamma agonists (rosiglitazone and pioglitazone) in the cultured hepatic cells and differentiating preadipocytes. Rosiglitazone treatment also results in up-regulation of the HSL gene in liver and skeleton muscle from an experimental obese rat model, accompanied by the decreased triglyceride content in these tissues. The proximal promoter (-87 bp of the human HSL gene) was found to be essential for PPARgamma-mediated transactivating activity. This important promoter region contains two GC-boxes and binds the transcription factor specificity protein-1 (Sp1) but not PPARgamma. The Sp1-promoter binding activity can be endogenously enhanced by PPARgamma and rosiglitazone, as demonstrated by analysis of EMSA and chromatin immunoprecipitation assay. Mutations in the GC-box sequences reduce the promoter binding activity of Sp1 and the transactivating activity of PPARgamma. In addition, mithramycin A, the specific inhibitor for Sp1-DNA binding activity, abolishes the PPARgamma-mediated up-regulation of HSL. These results indicate that PPARgamma positively regulates the HSL gene expression, and up-regulation of HSL by PPARgamma requires the involvement of Sp1. Taken together, this study suggests that HSL may be a newly identified PPARgamma target gene, and up-regulation of HSL may be an important mechanism involved in action of PPARgamma agonists in type 2 diabetes.

The PPARalpha/gamma dual agonist chiglitazar improves insulin resistance and dyslipidemia in MSG obese rats.

1. The aim of this study was to investigate the capacity of chiglitazar to improve insulin resistance and dyslipidemia in monosodium L-glutamate (MSG) obese rats and to determine whether its lipid-lowering effect is mediated through its activation of PPARalpha. 2. Chiglitazar is a PPARalpha/gamma dual agonist. 3. The compound improved impaired insulin and glucose tolerance; decreased plasma insulin level and increased the insulin sensitivity index and decreased HOMA index. Euglycemic hyperinsulinemic clamp studies showed chiglitazar increased the glucose infusion rate in MSG obese rats. 4. Chiglitazar inhibited alanine gluconeogenesis, lowered the hepatic glycogen level in MSG obese rats. Like rosiglitazone, chiglitazar promoted the differentiation of adipocytes and decreased the maximal diameter of adipocytes. In addition, chiglitazar decreased the fibrosis and lipid accumulation in the islets and increased the size of islets. 5. Chiglitazar reduced plasma triglyceride, total cholesterol (TCHO), nonesterified fatty acids (NEFA) and low density lipoprotein-cholesterol levels; lowered hepatic triglyceride and TCHO contents; decreased muscular NEFA level. Unlike rosiglitazone, chiglitazar showed significant increase of mRNA expression of PPARalpha, CPT1, BIFEZ, ACO and CYP4A10 in the liver of MSG obese rats. 6. These data suggest that PPARalpha/gamma coagonist, such as chiglitazar, affect lipid homeostasis with different mechanisms from rosiglitazone, chiglitazar may have better effects on lipid homeostasis in diabetic patients than selective PPARgamma agonists.

Follow-up and evaluation of the pregnancy outcome in women of reproductive age with Graves' disease after 131Iodine treatment.

The aims of the present study were to analyze the outcomes of pregnancy, after 131I treatment, in patients of reproductive age with Graves' hyperthyroidism and to investigate the effects, if any, of the 131I treatment on the mothers and newborns. From 2009 to 2014, 257 pregnant female patients with Graves' hyperthyroidism in the outpatients at the Department of Nuclear Medicine and 166 healthy pregnant women from the Department of Obstetrics at Sun Yat-Sen Memorial Hospital were included in our study. They were divided into a 131I therapy group (n = 130) and an anti-thyroid drug (ATD) group (n = 127) according to their therapy before conception. The neonatal gender, rate of preterm birth, body weight ratio and occurrence of low birth weight [except for higher rates of abortion (odds ratio; OR = 2.023) and cesarean delivery (OR = 1.552) in patients with Graves' hyperthyroidism] showed no statistically significant differences from those of the healthy group (P > 0.05). The level of intrauterine growth restriction did not differ between the Graves' hyperthyroidism group and the healthy group (8 vs 2, 3.0% vs 1.2%). The outcomes of pregnancy among the 131I therapy group, ATD group and healthy group also showed no significant differences. Of the patients treated with 131I, no significant differences were observed in the outcomes of their pregnancies, whether they received propylthiouracil (PTU), levothyroxine or no additional drug treatment during pregnancy. Women with hyperthyroidism who were treated with 131I therapy could have normal delivery if they ceased 131I treatment for at least six months prior to conception and if their thyroid function was reasonably controlled and maintained using the medication: anti-thyroid drug and levothyroxine before and during pregnancy.

Construction of a virtual combinatorial library using SMILES strings to discover potential structure-diverse PPAR modulators.

Based on the structural characters of PPAR modulators, a virtual combinatorial library containing 1226,625 compounds was constructed using SMILES strings. Selected ADME filters were employed to compel compounds having poor drug-like properties from this library. This library was converted to sdf and mol2 files by CONCORD 4.0, and was then docked to PPARgamma by DOCK 4.0 to identify new chemical entities that may be potential drug leads against type 2 diabetes and other metabolic diseases. The method to construct virtual combinatorial library using SMILES strings was further visualized by Visual Basic.net that can facilitate the needs of generating other type virtual combinatorial libraries.