Ilicicolin C suppresses the progression of prostate cancer by inhibiting PI3K/AKT/mTOR pathway.

Aberrant activation of the PI3K/AKT pathway is a driving factor in the development of prostate cancer. Therefore, inhibiting the function of the PI3K/AKT signaling pathway is a strategy for the treatment of prostate cancer. Ilicicolin C is an ascochlorin derivative isolated from the coral-derived fungus Acremonium sclerotigenum GXIMD 02501. Which has anti-inflammatory activity, but its activity against prostate cancer has not yet been elucidated. MTT assay, plate clone-formation assay, flow cytometry and real-time cell analysis technology were used to detect the effects of ilicicolin C on cell viability, proliferation, apoptosis and migration of prostate cancer cells. Molecular docking software and surface plasmon resonance technology were used to analyze the interaction between ilicicolin C and PI3K/AKT proteins. Western blot assay was performed to examine the changes in protein expression. Finally, QikProp software was used to simulate the process of ilicicolin C in vivo, and a zebrafish xenograft model was used to further verify the anti-prostate cancer activity of ilicicolin C in vivo. Ilicicolin C showed cytotoxic effects on prostate cancer cells, with the most significant effect on PC-3 cells. Ilicicolin C inhibited proliferation and migration of PC-3 cells. It could also block the cell cycle and induce apoptosis in PC-3 cells. In addition, ilicicolin C could bind to PI3K/AKT proteins. Furthermore, ilicicolin C inhibited the expression of PI3K, AKT and mTOR proteins and could also regulate the expression of downstream proteins in the PI3K/AKT/mTOR signaling pathway. Moreover, the calculations speculated that ilicicolin C was well absorbed orally, and the zebrafish xenograft model confirmed the in vivo anti-prostate cancer effect of ilicicolin C. Ilicicolin C emerges as a promising marine compound capable of inducing apoptosis of prostate cancer cells by counteracting the aberrant activation of PI3K/AKT/mTOR, suggesting that ilicicolin C may be a viable candidate for anti-prostate cancer drug development. These findings highlight the potential of ilicicolin C against prostate cancer and shed light on its mechanism of action.

A novel four-gene signature for predicting the prognosis of hepatocellular carcinoma.

OBJECTIVE: To identify and utilize gene signatures for the prognostic evaluation of postoperative patients with hepatocellular carcinoma (HCC). METHODS: The gene mRNA expression profiles and corresponding clinicopathological data of postoperative patients with HCC were downloaded from The Cancer Genome Atlas (TCGA) database. Highly differentially expressed genes (DEGs) in tumor tissues compared to adjacent tissues were identified, and their associations with the overall survival (OS) of HCC patients were analyzed. The strongly associated genes were used to develop a prognostic score for the survival stratification of HCC, and the underlying mechanisms were analyzed using bioinformatics. RESULTS: A total of 376 DEGs were identified and four DEGs (ADH4, COL15A1, RET and KCNJ16) were independently associated with OS. A prognostic score derived from the four genes could effectively stratify HCC patients with different OS outcomes, independent of clinical parameters. Patients with high scores exhibited poorer OS than patients with low scores (HR 5.526, 95% CI: 2.451-12.461, p < .001). The four genes were involved in cancer-related biological processes and were independent of each other in bioinformatics analyses. CONCLUSION: Four genes strongly associated with the prognosis of postoperative patients with HCC were identified, and the derived prognostic score was simple and valuable for overall survival prediction.

New Chlorinated Metabolites and Antiproliferative Polyketone from the Mangrove Sediments-Derived Fungus Mollisia sp. SCSIO41409.

Two new chlorinated metabolites, 8-chlorine-5-hydroxy-2,3-dimethyl-7-methoxychromone (1) and 3,4-dichloro-1H-pyrrole-2,5-dione (3), and eight known compounds (2 and 4-9) were isolated from the mangrove sediments-derived fungus Mollisia sp. SCSIO41409. Their structures were elucidated by physicochemical properties and extensive spectroscopic analysis. The absolute configuration of stemphone C (4) was established for the first time by the X-ray crystallographic analysis. Compounds 3 and 4 showed different intensity of antimicrobial activities against several pathogenic fungi and bacteria, and antiproliferative activities against two human prostate cancer cell lines (IC50 values 2.77 to 9.60 µM). Further, stemphone C (4) showed a reducing PC-3 cell colony formation, inducing apoptosis and blocking the cell cycle at S-phase in a dose-dependent manner; thus, it could be considered as a potential antiproliferative agent and a promising anti-prostate cancer lead compound.

Insights into Aptamer-Drug Delivery Systems against Prostate Cancer.

Prostate cancer is a common cancer in elderly males. Significant progress has been made in the drug therapies for prostate cancer in recent years. However, side effects are still problems that have not been overcome by the currently used anti-prostate cancer drugs. Novel technologies can be applied to reduce or even eliminate the side effects of drugs. An aptamer may be a sequence of nucleic acids or peptides that can specifically recognize proteins or cells. Taking advantage of this feature, scientists have designed aptamer-drug delivery systems for the development of anti-prostate cancer agents. Theoretically, these aptamer-drug delivery systems can specifically recognize prostate cancer cells and then induce cell death without attacking normal cells. We collected the relevant literature in this field and found that at least nine compounds have been prepared as aptamer-drug delivery systems to evaluate their precise anti-prostate cancer effects. However, the currently studied aptamer-drug delivery systems have not yet entered the market due to defects. Here, we analyze the published data, summarize the characteristics of these delivery systems, and propose ways to promote their application, thus promoting the development of the aptamer-drug delivery systems against prostate cancer.

Blood-derived molecular signatures as biomarker panels for the early detection of colorectal cancer.

Colorectal cancer (CRC) is one of the leading causes of tumor morbidity and mortality worldwide. Endoscopy is currently the main screening method, but the invasiveness and high cost hamper the application of endoscopy in asymptomatic patients with a risk of CRC and lead to a low diagnostic rate for early CRC. In recent years, the progress of transcriptomics, epigenetics, immunomics and metabolomics has greatly contributed to the identification of novel molecular markers for the noninvasive screening of CRC, and many molecules in various biological processes have been identified and evaluated for CRC detection. However, individual molecules always have insufficient diagnostic performance as biomarkers for the detection of CRC; therefore, a frequent strategy to overcome this deficiency is the use of molecule signatures as biomarker panels to improve the diagnostic power. Here, we reviewed the diagnostic performance of blood-derived molecular signatures (mRNAs, microRNAs, autoantibodies, and metabolites) as biomarker panels for CRC detection, particularly for early detection, and discussed their limitations and prospects.

Discovery and Synthesis of a Novel Series of Liver X Receptor Antagonists.

Fourteen novel compounds were prepared and their antagonistic activities against liver X receptors (LXR) α/ß were tested in vitro. Compound 26 had an IC50 value of 6.4 µM against LXRα and an IC50 value of 5.6 µM against LXRß. Docking studies and the results of structure-activity relationships support the further development of this chemical series as LXRα/ß antagonists.

Targeting androgen receptor in glioblastoma.

Glioblastomas are primary brain tumors that originate from glial stem cells or progenitor cells. There is a large difference in the incidence of glioblastoma between males and females. Studies revealed that the gender differences in the tumor may be attributable to the androgen receptor signaling axis. The incidence rate of glioblastoma in men is higher than that in women. Aberrant activation of the androgen receptor signaling pathway, or interactions between the androgen receptor signaling axis and other signaling axes promote the development of glioblastoma. Therefore, targeting the androgen receptor holds promise as a therapeutic approach for glioblastoma. This review investigates the dynamics of drug research into the treatment of glioblastoma by targeting the androgen receptor. The first finding in line with expectations is that androgen receptor antagonists, represented by enzalutamide, have been studied and shown to have anti-glioblastoma effects. In addition, it was found that the combination of 5-alpha reductase inhibitors and androgen receptor antagonists resulted in better therapeutic outcomes than each of them alone. Similar results were obtained with the combination of an epidermal growth factor receptor inhibitor and an androgen receptor antagonist. In addition, four small molecule compounds have been shown to exert significant anti-glioblastoma effects by directly or indirectly targeting the androgen receptor. Expectantly, one of these small molecules, seviteronel, progressed to the phase II clinical trial stage. These findings suggest that targeting the androgen receptor for glioblastoma may be a promising therapeutic option.

Dankasterone A induces prostate cancer cell death by inducing oxidative stress.

Oxidative stress plays a dual role in tumor survival, either promoting tumor development or killing tumor cells under different conditions. Dankasterone A is a secondary metabolite derived from the fungus Talaromyces purpurogenu. It showed good potential in a screen for anti-prostate cancer compounds. In this study, MTT results showed dankasterone A was cytotoxic to prostate cancer cells, with an IC50 of 5.10 µM for PC-3 cells and 3.41 µM for 22Rv1 cells. Further studies, plate cloning assays and real-time cell analysis monitoring showed that dankasterone A significantly inhibited clonal colony formation and cell migration in 22Rv1 and PC-3 cells. In addition, flow cytometry results showed that dankasterone A induced apoptosis in prostate cancer cells while having no impact on cell cycle distribution. At the molecular level, Protein microarray experiments and western blot assays revealed that dankasterone A specifically and dramatically upregulated HO-1 protein expression; and the results of cell fluorescence staining showed that dankasterone A induced overexpression of reactive oxygen species in 22Rv1 and PC-3 cells. Taken together, dankasterone A induced prostate cancer cells to undergo intense oxidative stress, which resulted in the production of large amounts of HO-1 and the release of large amounts of reactive oxygen species, leading to apoptosis of prostate cancer cells, ultimately resulting in the inhibition of both cell proliferation and migration. We also validated the anti-prostate cancer effects of dankasterone A in vivo in a zebrafish xenograft tumor model. In conclusion, dankasterone A has the potential to be developed as an anti-prostate cancer drug.

Pharmacological Small Molecules against Prostate Cancer by Enhancing Function of Death Receptor 5.

Death receptor 5 (DR5) is a membrane protein that mediates exogenous apoptosis. Based on its function, it is considered to be a target for the treatment of cancers including prostate cancer. It is encouraging to note that a number of drugs targeting DR5 are now progressing to different stages of clinical trial studies. We collected 38 active compounds that could produce anti-prostate-cancer effects by modulating DR5, 28 of which were natural compounds and 10 of which were synthetic compounds. In addition, 6 clinically used chemotherapeutic agents have also been shown to promote DR5 expression and thus exert apoptosis-inducing effects in prostate cancer cells. These compounds promote the expression of DR5, thereby enhancing its function in inducing apoptosis. When these compounds were used in combination with the natural ligand of DR5, the number of apoptotic cells was significantly increased. These compounds are all promising for development as anti-prostate-cancer drugs, while most of these compounds are currently being evaluated for their anti-prostate-cancer effects at the cellular level and in animal studies. A great deal of more in-depth research is needed to evaluate whether they can be developed as drugs. We collected literature reports on small molecules against prostate cancer through modulation of DR5 to understand the current dynamics in this field and to evaluate the prospects of small molecules against prostate cancer through modulation of DR5.

α-Terthienyl induces prostate cancer cell death through inhibiting androgen receptor expression.

Prostate cancer is a disease that often occurs in elderly men. Androgen receptor signaling pathway runs through the occurrence and development of prostate cancer. Thereby, targeting androgen receptor is a crucial strategy for the treatment of prostate cancer. α-Terthienyl, which has been used as photosensitive activator and insecticide, is a natural compound rich in marigold. In the present study, we found α- terthienyl could inhibit the cell viability of four prostate cancer cell lines, especially on LNCaP and 22Rv1 cells which endogenously express androgen receptor. Then we proved that it could inhibit the proliferation of prostate cancer cells and induce apoptosis of prostate cancer cells by plate clone formation assay and flow cytometry respectively. Furthermore, we found α-terthienyl could inhibit androgen receptor nuclear translocation, reduce androgen receptor expression, reduce the mRNA and protein expression of androgen receptor target genes (KLK3, TMPRSS2, PCA3) and nuclear proliferation antigen Ki67 and PCNA. In addition, it inhibited the expression and phosphorylation of Akt protein while increasing the expression of tumor suppressor p27. Besides, we constructed a mouse xenograft prostate cancer model and confirmed that α-terthienyl also inhibited the growth of prostate cancer in vivo. In conclusively, α-terthienyl played an anti-prostate cancer role by inhibiting both the expression of androgen receptor and the transduction of its signal pathway, suggesting that it is a promising natural small molecule for the treatment of prostate cancer.

Analysis of regulating activities of 5'-epiequisetin on proliferation, apoptosis, and migration of prostate cancer cells in vitro and in vivo.

Advanced prostate cancer has a poor prognosis, and it is urgent to develop new effective drugs. 5'-Epiequisetin is a tetramic acid derivative which was isolated from a marine sponge-derived fungus Fusarium equiseti in our previous study. In this study, 5'-epiequisetin showed cytotoxicity against four prostate cancer cell lines, namely, LNCaP, 22Rv1, DU145, and PC-3 cells, with the lowest IC50 value of 4.43 ± 0.24 µM in PC-3 cells. Further studies showed that it could dramatically regulate the clonal colony formation, apoptosis, and migration of PC-3 cells. In addition, flow cytometry data showed that 5'-epiequisetin could block the cell cycle at the G1 phase. Proteome profiler array and Western blot revealed that 5'-epiequisetin could regulate the expression of proteins responsible for cell proliferation, apoptosis, and migration. 5'-Epiequisetin regulated the expression of PI3K, Akt, phosphorylated Akt, and proteins which control the cell cycle. Meanwhile, 5'-epiequisetin upregulated expression of DR5 and cleave-caspase 3, which play important roles in the process of apoptosis. Moreover, when DR5 was silenced by small interfering RNA, the proportion of apoptotic cells induced by 5'-epiequisetin remarkably declined. In addition, 5'-epiequisetin downregulated the expression of survivin which plays a key role in the process of survival and apoptosis. 5'-Epiequisetin also impacted beta-catenin and cadherins, which were associated with cell migration. In addition, 5'-Epiequisetin significantly inhibited the progression of prostate cancer in mice, accompanied by regulating the protein expression of DR5, caspase 8, survivin, and cadherins in vivo. Taken together, these findings indicated that 5'-epiequisetin showed an anti-prostate cancer effect by inducing apoptosis and inhibiting cell proliferation and migration both in vitro and in vivo, suggesting a promising lead compound for the pharmacotherapy of prostate cancer.

Cytoskeleton-associated membrane protein 4 is upregulated in tumor tissues and is associated with clinicopathological characteristics and prognosis in hepatocellular carcinoma.

The role of cytoskeleton-associated membrane protein 4 (CKAP4) in hepatocellular carcinoma (HCC) is controversial. The present study aimed to investigate the association between tumor CKAP4 mRNA expression and clinicopathological characteristics and prognosis in patients with HCC. Data relating to CKAP4 mRNA expression in HCC tumor and normal adjacent liver tissues, and clinicopathological characteristics, were downloaded from the Gene Expression Omnibus and The Cancer Genome Atlas databases. The CKAP4 mRNA levels in tumor tissues were compared with those in normal adjacent liver tissues, their association with clinicopathological parameters was analyzed, and diagnostic and prognostic values were evaluated in patients with HCC. In all 4 datasets (total samples, n=693), CKAP4 mRNA levels were significantly higher in tumor tissues compared with adjacent tissues (all P<0.001), with the area under the receiver operating characteristic curve ranging from 0.799-0.898 for HCC diagnosis. In patients with HCC with available clinical data (n=361), the low-level CKAP4 mRNA group exhibited a lower body mass index (P=0.005), higher α-fetoprotein level (P<0.001), more frequent adjacent liver tissue inflammation (P<0.001), poorer tumor histological grade (P<0.001), higher Ishak fibrosis score (P=0.035) and a more advanced tumor node metastasis (TNM) stage (P=0.014) compared with the high-level CKAP4 mRNA group. Patients stratified by all the above parameters, except for TNM stage, exhibited significantly different expression of tissue CKAP4 mRNA (P<0.05-0.001). Furthermore, higher CKAP4 mRNA levels were observed in patients who died within one year following diagnosis compared with those who survived >3 years (P=0.003). The high-level CKAP4 mRNA group also exhibited lower overall survival (OS) and disease-free survival (DFS) rates compared with the low-level group [hazard ratio (HR)=1.494; 95% confidence interval (CI), 1.044-2.138; P=0.028] for OS and (HR=1.616; 95% CI, 1.022-2.555; P=0.040) for DFS. The results of the present study suggest that CKAP4 mRNA is upregulated in HCC tumor tissues compared with normal adjacent tissues, and is associated with poor clinical prognosis, pathological features and survival in patients with HCC. Thus, CKAP4 is a potential biomarker for HCC diagnosis and prognosis.

[Observation of therapeutic effects on cervical vertigo treated with different methods].

OBJECTIVE: To compare the therapeutic effects of routine acupuncture, the electroacupuncture and the combined therapy of electroacupuncture and acupoint injection. METHODS: Ninety-one cases were randomly divided into a routine acupuncture group (30 cases), an electroacupuncture group (31 cases), and a combined therapy of electroacupuncture and acupoint injection group (30 cases). Zusanli (ST 36), Fengchi (GB 20), Anmian (Extra), Taiyang (EX-HN 5), Hegu (LI 4), Yintang (EX-HN 3), Baihui (GV 20) and Sishengcong (EX-HN 1) were selected among 3 groups. Even manipulation was applied in routine acupuncture group; G 6805 electroacupuncture apparatus was added in electroacupuncture group; in combined therapy of electroacupuncture and acupoint injection group, electroacupuncture was applied, besides, Vitamin B12 0.5 mg and 0.2%/ Lidocaine 2 mL were injected at Fengchi (GB 20) and Anmian (Extra). Twenty treatments were given in 4 weeks. The changes of average blood flow of vertebral artery and basilar artery before and after treatment were observed and graded by the cervical vertigo syndrome and function score; the therapeutic effects were evaluated as well. RESULTS: The average blood flow of vertebral artery and basilar artery, and the cervical vertigo syndrome and function score were improved in 3 groups (all P < 0.01), in which, it was more obvious in combined therapy of electroacupuncture and acupoint injection group than in others (P < 0.05, P < 0.01), and it in electroacupuncture group was superior to that in routine acupuncture group (P < 0.05). The effective rate was 63.3% (19/30) in routine acupuncture group, 80.6% (25/31) in electroacupuncture group and 90.3% (28/30) in combined therapy of electroacupuncture and acupoint injection group, indicating the significant differences among them (P < 0.05, P < 0.01). CONCLUSION: The routine acupuncture, electroacupuncture, and combined therapy of electroacupuncture and acupoint injection are effective for cervical vertigo; the combined therapy is the best, and electroacupuncture comes second. It illustrates that the routine acupuncture, electroacupuncture, and combined therapy of electroacupuncture and acupoint injection have additive effects on treatment of cervical vertigo.

[Clinical observation on distinctive water-medicine cup therapy for treatment of cervical spondylopathy of cervical type].

OBJECTIVE: To use distinctive water-medicine cup therapy for treatment of cervical spondylopathy of cervical type as a sample to provide a more effective cupping method for clinic. METHODS: One hundred and forty cases were randomly divided into a medicine cup group (n = 47), a water cup group (n = 47) and a empty cup group (n = 46). The medicine cup group were treated by cupping therapy with a self-made medicine cup with 45 degrees C Chinese herb solution; the water cup group were treated with a cup with 45 degrees C water, and the empty cup group with a cup with nothing. Clinical symptoms and signs were observed for comparison of therapeutic effects. RESULTS: Clinically cured was 39 cases, and markedly effective was 8 cases in the medicine cup group; 20 cases were clinically cured, 22 cases were markedly effective and 5 cases were effective in the water cup group; 12 cases were clinically cured, 19 cases were markedly effective and 15 cases were effective in the empty cup group. There were significant differences in the ratio of cases of different therapeutic effects and the difference of pain score before and after treatment between the medicine cup group and the water cup group (P < 0.05), between the water cup group and the empty cup group (P < 0.05), and between the medicine cup group and the empty cup group (P < 0.01). CONCLUSION: The therapeutic effect of the distinctive medicine cup is better than the water cup group, and the water cup group is better than the empty cup group.

[Clinical study on moxibustion for treatment of abnormal blood lipids].

OBJECTIVE: To observe clinical therapeutic effect of moxibustion on abnormal blood lipids. METHODS: The patients who did not take the medicine for regulating blood lipids and had still abnormal blood lipids after diet therapy for 3 months, were divided into 4 groups according to different types of abnormal blood lipids. Forty cases selected in each group were again divided randomly into a treatment group and a control group. The treatment group were treated with moxibustion at Shousanli (LI 10), Zusanli (ST 36) and Shenque (CV 3) on the basis of diet therapy, and the control group only with the diet therapy. Their therapeutic effects were observed and compared after treatment of 90 days. RESULTS: There were significant differences between the treatment group and the control group in various groups of different types of abnormal blood lipids (P < 0.05). CONCLUSION: Moxibustion at Shousanli (LI 10), Zusanli (ST 36) and Shenque (CV 3) has a better therapeutic effect on abnormal blood lipids.