Exploring the mechanism of action of Sparganii Rhizoma-Curcumae Rhizoma for in treating castration-resistant prostate cancer: a network-based pharmacology and experimental validation study.

Sparganii Rhizoma-Curcumae Rhizoma (SR-CR) is a classic drug pair for the treatment of castration-resistant prostate cancer (CRPC), but its mechanism has not been clarified. The study aims to elucidate the potential mechanism of SR-CR in the management of CRPC. The present study employed the TCMSP as well as the SwissTargetPrediction platform to retrieve the chemical composition and targets of SR-CR. The therapeutic targets of CRPC were identified through screening the GeneCards, Disgenet, and OMIM databases. Subsequently, the Venny online platform was utilized to identify the shared targets between the SR-CR and CRPC. The shared targets were enrichment analysis using the Bioconductor and Kyoto encyclopedia of genes and genomes (KEGG) databases. The active ingredients and core targets were verified through molecular docking and were validated using PC3 cells in the experimental validation phase. A total of 7 active ingredients and 1126 disease targets were screened from SR-CR, leading to a total of 59 shared targets. Gene Ontology (GO) analysis resulted in 1309 GO entries. KEGG pathways analysis yielded 121 pathways, primarily involving cancer-related signaling pathways. The results from molecular docking revealed stable binding interactions between the core ingredients and the core targets. In vitro cellular assays further demonstrated that SR-CR effectively suppressed the activation of the Prostate cancer signaling pathway in PC3 cells, leading to the inhibition of cell proliferation and promotion of apoptosis. The SR-CR exert therapeutic effects on CRPC by inhibiting cell proliferation and promoting apoptosis through the Prostate cancer signaling pathway.

Oxygen-independent alkyl radical nanogenerator enhances breast cancer therapy.

The hypoxic microenvironment of breast cancer substantially reduces oxygen-dependent free radical generation. Overexpression of glutathione (GSH) in tumor cells mitigates the impact of free radical generation. In this study, we designed and developed an oxygen-independent alkyl radical nanogenerator (copper monosulfide/2,2'-azabis(2-imidazoline) dihydrochloride@bovine serum albumin; CuS/AIPH@BSA) with spatiotemporally controlled properties and GSH consumption to enhance breast cancer therapy. We encapsulated the alkyl radical initiator, AIPH, in hollow mesoporous CuS nanoparticles with photothermal conversion effect and enveloped them in BSA. AIPH was released and decomposed to generate alkyl radicals in hypoxic breast cancer with the photothermal conversion effect of CuS under near-infrared laser irradiation. CuS consumed high GSH levels in tumor cells because it could form complex with GSH and thereby enhanced free radical treatment. In vivo and in vitro assays demonstrated the anti-tumor efficacy of the rationally designed free-radical nanogenerator in hypoxic microenvironment of breast cancer without showing systemic toxicity.

Green Synthesis of Nano-Zero Valence Iron with Green Tea and It's Implication in Lead Removal.

The nano-zero valence iron (nZVI) via green synthesis for heavy metal remediation has attracted many attentions due to its low-cost, environmental-safety, relative reproductivity, and high stability. However, influence of synthesis conditions on the physiochemical properties of nZVI via green tea extracts and the responding suspensibility, which is required for high reactivity, has not been fully elucidated. In this study, we investigated the zeta potentials, sedimentation and lead (Pb2+) removal capacity of various nZVIs synthesized using green tea extracts. The results showed that the tea extracts extracted at 80oC presented an excellent activity, which contributed to the outstanding suspensibility and reaction activity of nZVI synthesized in a volume ratio of 1:1 (tea extraction versus Fe2+ solution). Thus, the optimized nZVI was successfully prepared with a Pb2+ removal capacity (377.3 mg/g), which was seven times stronger than 50.31 mg/g of traditional chemical synthesized nZVI.

Facile preparation of indocyanine green and tiny gold nanoclusters co-loaded nanocapsules for targeted synergistic sono-/photo-therapy.

Photothermal therapy (PTT) and sono-photodynamic therapy (SPDT) are fast growing local treatment modalities with minimal invasiveness and high safety. Gold nanoparticles and indocyanine green (ICG) have been used as sensitizers for PTT and SPDT. However, long resident time of gold nanoparticles in tissues and fast elimination of ICG hampered their further clinical applications. Herein, we developed nanocapsules formed by hyaluronic acid and chitosan loading with ICG and tiny gold nanoclusters (TAuNCs) to overcome the shortcomings of gold nanoparticles and ICG for combined PTT and SPDT. The nanocapsules exhibited good biological stability, favorable photothermal effects, and ultrasound/near-infrared light (NIR)-responsive release behaviors. The hyaluronic acid could mediate the specific delivery of cargos to CD44 protein over-expressing cancer cells. The in vitro and in vivo results showed that TAuNCs and ICG could act synergistically to obtain satisfactory anticancer effects under NIR laser and/or ultrasound exposure induced by thermal ablation and reactive oxygen species (ROS) generation. Biodistribution and excretion studies showed that the nanocapsules had longer ICG retention time in tumor and most of the TAuNCs could be effectively excreted from the body within one month. This study thus provides a facile strategy for the development of a safe and high-performance nanoplatform for synergistic PTT/SPDT.

A new biflavonoids from Aster tataricus induced non-apoptotic cell death in A549 cells.

A new biflavonoids, (2R,2''R)-7-O-methyl-2,3,2'',3''-tetrahydrorobustaflavone (1), along with five known flavonoids (2-6) were isolated from the MeOH extract of Aster tataricus. Among them, compounds 1-2 were the C-3'-C-6'' type biflavonoids obtained from the genus Aster for the first time. The structures and absolute configurations of compound 1 was confirmed based on extensive spectroscopic and circular dichroism analyses. Compound 1 exhibited moderate cytotoxicity against seven human cancer A549, HepG2, PC3, DU145, MCF-7, LOVO and NCI-H1975 cell lines. Compound 1 remarkably inhibited the proliferation of A549 cancer cells with IC50 value of 5.4 µM. Further preliminary pharmacological study, 1 induces A549 cell death by non-apoptotic forms through flow cytometry and cell scratch assay data.

A nanosensitizer self-assembled from oleanolic acid and chlorin e6 for synergistic chemo/sono-photodynamic cancer therapy.

BACKGROUND: Sono-photodynamic therapy (SPDT) which is the combination of photodynamic therapy (PDT) and sonodynamic therapy (SDT), could exert much better anti-cancer effects than monotherapy. The combination of chemotherapy and PDT or SDT has shown great potential for cancer treatment. However, the combination of SPDT and chemotherapy for cancer treatment is rarely explored. PURPOSE: We utilized a natural hydrophobic anti-cancer drug oleanolic acid (OA) and a photosensitizer chlorin e6 (Ce6) through self-assembly technology to form a carrier-free nanosensitizer OC for combined chemotherapy and SPDT for cancer treatment. No studies involving using carrier-free nanomedicine for combined chemotherapy/SPDT have been reported yet. STUDY DESIGN: After fully characterization of OC, the in vitro and in vivo anti-cancer activities of OC were investigated and the mechanisms of the synergistic therapeutic effects were studied. METHODS: OC were synthesized through self-assembly technology and characterized by dynamic light scattering (DLS) and an atomic force microscope (AFM). Confocal microscope was used to investigate the intracellular uptake efficiency and the penetration ability of OC. The cell viability of PC9 and 4T1 cells treated with OC under laser and ultrasound (US) irradiation was determined by MTT assay. Furthermore, flow cytometry was performed to detect the reactive oxygen species (ROS) generation, loss of mitochondrial membrane potential (MMP), cell apoptosis and cell cycle arrest. Finally, the anti-tumor therapeutic efficacy of OC was investigated in orthotopic 4T1 breast tumor-bearing mouse model. RESULTS: OC showed an average particle size of around 100 nm with excellent light stability. OC increased more than 23 times accumulation of Ce6 in cancer cells and had strong tumor penetration ability in three-dimensional (3D) multicellular tumor spheroids (MCTSs). Compared with other therapeutic options, OC showed obvious synergistic inhibitory effects under light and US irradiation in PC9 and 4T1 cells with a significant decrease in IC50 values. Mechanism studies showed that OC could generate high ROS, induce MMP loss, and cause apoptosis and cell cycle arrest. In vivo studies also approved the synergistic therapeutic effects of OC in 4T1 mouse models. CONCLUSION: Self-assembled carrier-free nanosensitizer OC could be a promising therapeutic agent for synergistic chemo/sono-photodynamic therapy for cancer treatment.

Electrospun composite nanofibers with all-trans retinoic acid and MWCNTs-OH against cancer stem cells.

AIMS: Cancer stem cells (CSCs) are the source of tumors and play a key role in the resistance of cancer to therapies. To improve the current therapies against CSCs, in this work we developed a novel system of electrospun polycaprolactone (PCL) nanofibers containing hydroxylated multi-walled carbon nanotubes (MWCNTs-OH) and all-trans retinoic acid (ATRA). MATERIALS AND METHODS: The nanofiber membranes were forged by electrospinning, and the physical and chemical properties of the nanofiber membranes were evaluated by scanning electron microscopy, XRD and Raman etc. The photothermal properties of nanofiber membranes and their effects on CSCs differentiation and cytotoxicity were investigated. Finally, the anti-tumor effect of nanofiber membranes in vivo was evaluated. KEY FINDINGS: The nanofibers formed under optimal conditions were smooth without beads. The nanofibrous membranes with MWCNTs-OH could increase temperature of the medium under near-infrared (NIR) illumination to suppress the viability of glioma stem cells (GSCs). Meanwhile, the added ATRA could further induce the differentiation of GSCs to destroy their stemness and reduce their resistance to heat treatment. Compared with no NIR irradiation, after 2min NIR irradiation, the membranes reduced the in-vitro viability of GSCs by 13.41%, 14.83%, and 26.71% after 1, 2, and 3 days, respectively. After 3 min daily illumination for 3 days, the viability of GSCs was only 22.75%, and similar results were observed in vivo. SIGNIFICANCE: These results showed efficiently cytotoxicity to CSCs by combining heat therapy and differentiation therapy. The nanofiber membranes if inserted at the site after surgical tumor removal, may hinder tumor recurrence.

Systematic investigation of the mechanism of Cichorium glandulosum on type 2 diabetes mellitus accompanied with non-alcoholic fatty liver rats.

Cichorium glandulosum(CG) can treat various diseases with multiple targets effectively. It has been widely used in folk medicine to treat nonalcoholic fatty liver disease (NAFLD) as well as type 2 diabetes mellitus (T2DM). However, the active compounds and underlying mechanisms of CG on T2DM accompanied with NAFLD (T2DM-NAFLD) remain unclear. In this study, a systems pharmacology method was used to explain the pharmacology mechanism of CG for treatment of T2DM-NAFLD. Twenty four main compounds were detected by UPLC-Q-TOF-MS, of which 13 showed favorable pharmacokinetic profiles. We demonstrated with target fishing and pathway analysis that CG has protective effects on T2DM-NAFLD, probably through the regulation of 88 targets and 86 pathways. Forty nine targets were related to T2DM, and 39 were related to NAFLD, while 27 targets, primarily involved in insulin resistance and inflammation were common to T2DM and NAFLD related pathways. A NF-κB signaling pathway was chosen to validate the impacts of CG on T2DM-NAFLD because CG can ameliorate T2DM-NAFLD by regulating the NF-κB signaling pathway according to animal experiments. These findings systematically interpreted the active compounds and mechanism of the efficiency of CG for treating T2DM-NAFLD. This study not only laid a basis for understanding the active compounds and action mechanism of CG, but also provides a reference for a study of the mechanism of a herbal medicine for the treatment of multiple diseases.

Melatonin Enhances Proliferation and Modulates Differentiation of Neural Stem Cells Via Autophagy in Hyperglycemia.

Dysfunction of neural stem cells (NSCs) has been linked to fetal neuropathy, one of the most devastating complications of gestational diabetes. Several studies have demonstrated that melatonin (Mel) exerted neuroprotective actions in various stresses. However, the role of autophagy and the involvement of Mel in NSCs in hyperglycemia (HG) have not yet been fully established. Here, we found that HG increased autophagy and autophagic flux of NSCs as evidenced by increasing LC3B II/I ratio, Beclin-1 expression, and autophagosomes. Moreover, Mel enhanced NSCs proliferation and self-renewal in HG with decreasing autophagy and activated mTOR signaling. Consistently, inhibition of autophagy by 3-Methyladenine (3-Ma) could assist Mel effects above, and induction of autophagy by Rapamycin (Rapa) could diminish Mel effects. Remarkably, HG induced premature differentiation of NSCs into neurons (Map2 positive cells) and astrocytes (GFAP positive cells). Furthermore, Mel diminished HG-induced premature differentiation and assisted NSCs in HG differentiation as that in normal condition. Coincidentally, inhibiting of NSCs autophagy by 3-Ma assisted Mel to modulate differentiation. However, increasing NSCs autophagy by Rapa disturbed the Mel effects and retarded NSCs differentiation. These findings suggested that Mel supplementation could contribute to mimicking normal NSCs proliferation and differentiation in fetal central nervous system by inhibiting autophagy in the context of gestational diabetes. Stem Cells 2019;37:504-515.

Synthesis and biological characterization of novel rose bengal derivatives with improved amphiphilicity for sono-photodynamic therapy.

Sono-Photodynamic therapy (SPDT) utilizing ultrasound and light has been demonstrated that this novel approach can lower dosage resulting in reduction of the potential side effects caused by sensitizers. Recently, a new formulation of rose bengal (RB) as an intralesional injection has completed clinical trials phase II for PDT treatment of melanoma cancer. However, the inherent unfavorable pharmacological properties of RB hindered its extensive clinical development. With the aim to identify new RB derivatives (RBDs) with enhanced photodynamic and sonodynamic anticancer efficiency, a series of amphiphilic RBDs have been designed, synthesized and biological characterized. Among them, RBD4 significantly improved cellular uptake and enhanced intracellular ROS generation efficiency upon light and ultrasound irradiation, resulting in dramatically improved anticancer potency. Notably, RBD4 has a relative potency similar to sinoporphyrin sodium (DVDMS), indicating its further potential application for SPDT.

Monascus Pigment Rubropunctatin: A Potential Dual Agent for Cancer Chemotherapy and Phototherapy.

The Monascus pigment, rubropunctatin, was extracted and purified from red mold rice (RMR), and its cytotoxic activities against human cervical carcinoma HeLa cells were studied under the conditions with or without light irradiation. The IC50 value of rubropunctatin against HeLa cells in the dark was 93.71 ± 1.96 µM (24 h), while the cytotoxic activity was enhanced more than 3 times (IC50 = 24.02 ± 2.17 µM) under light irradiation (halogen lamp, 500 W; wavelength, 597-622 nm; and fluence rate, 15 mW cm(-2), for 30 min). However, the IC50 value of rubropunctatin against the immortalized human cervical epithelial H8 cells was more than 300 µM, even under light irradiation, indicating that rubropunctatin has a favorable selectivity index (SI). Treatment of HeLa cells with rubropunctatin in the dark or under light irradiation resulted in a dose-dependent apoptosis, as validated by the increase in the percentage of cells in the sub-G1 phase and phosphatidylserine externalization, and the inductive effect on HeLa cell apoptosis was boosted by the light irradiation. In addition, treatment with rubropunctatin alone or under light irradiation was found to induce apoptosis in HeLa cells via the mitochondrial pathway, including loss of mitochondrial membrane potential, activation of caspase-3, caspase-8, and caspase-9, and increase of the level of intracellular reactive oxygen species (ROS). It was suggested that rubropunctatin could be a promising natural dual anticancer agent for photodynamic therapy and chemotherapy.

Dendrimeric anticancer prodrugs for targeted delivery of ursolic acid to folate receptor-expressing cancer cells: synthesis and biological evaluation.

The anticancer efficacy of ursolic acid (UA) was limited by poor water solubility, non-specific tumor distribution, and low bioavailability. To overcome this problem, polyamidoamine (PAMAM) conjugated with UA and folic acid (FA) as novel dendrimeric prodrugs were designed and successfully synthesized by a concise one-pot synthetic approach. Both FA and UA were covalently conjugated to the surface of PAMAM through acid-labile ester bonds and the covalently linked UA could be hydrolysed either in acidic (pH 5.4) or in neutral (pH 7.4) PBS solution. The cellular uptake study indicated that the presence of FA enhanced uptake of the dendrimeric prodrugs in folate receptor (FR) over-expressing Hela cells. The enhanced cellular uptake could be due to the electrostatic absorptive endocytosis and FR-mediated endocytosis. In contrast, for HepG2 cells, a FR-negative cell line, FA conjugation on the surface of the dendrimer showed no effect on the cellular uptake. In MTT assay and cell cycle analysis, FA-modified dendrimeric prodrugs showed significantly enhanced toxicity than non-FA-modified ones in Hela cells. These results suggested that FA-modified dendrimeric UA prodrugs have the potential for targeted delivery of UA into cancer cells to improve its anti-tumor efficacy.

Evolution in medicinal chemistry of ursolic acid derivatives as anticancer agents.

Currently, there is a renewed interest in common dietaries and plant-based traditional medicines for the prevention and treatment of cancer. In the search for potential anticancer agents from natural sources, ursolic acid (UA), a pentacyclic triterpenoid widely found in various medicinal herbs and fruits, exhibits powerful biological effects including its attractive anticancer activity against various types of cancer cells. However, the limited solubility, rapid metabolism and poor bioavailability of UA restricted its further clinical applications. In the past decade, with substantial progress toward the development of new chemical entities for the treatment of cancer, numerous UA derivatives have been designed and prepared to overcome its disadvantages. Despite extensive effort, discovery of effective UA derivatives has so far met with only limited success. This review summarizes the current status of the structural diversity and evolution in medicinal chemistry of UA analogues and provides a detailed discussion of future direction for further research in the chemical modifications of UA.

Preparation and sonodynamic activities of water-soluble tetra-α-(3-carboxyphenoxyl) zinc(II) phthalocyanine and its bovine serum albumin conjugate.

Sonodynamic therapy (SDT) is a new approach for cancer treatment, involving the synergistic effect of ultrasound and certain chemical compounds termed as sonosensitizers. A water-soluble phthalocyanine, namely tetra-α-(3-carboxyphenoxyl) zinc(II) phthalocyanine (ZnPcC4), has been prepared and characterized. The interactions between ZnPcC4 and bovine serum albumin (BSA) were also investigated by absorption and fluorescence spectroscopy. It was found that there were strong interactions between ZnPcC4 and BSA with a binding constant of 6.83×10(7)M(-1). A non-covalent BSA conjugate of ZnPcC4 (ZnPcC4-BSA) was prepared. Both ZnPcC4 and ZnPcC4-BSA exhibited efficient sonodynamic activities against HepG2 human hepatocarcinoma cells. Compared with ZnPcC4, conjugate ZnPcC4-BSA showed a higher sonodynamic activity with an IC50 value of 7.5µM. Upon illumination with ultrasound, ZnPcC4-BSA can induce an increase of intracellular reactive oxygen species (ROS) level, resulting in cellular apoptosis. The results suggest that the albumin conjugates of zinc(II) phthalocyanines functionalized with carboxyls can serve as promising sonosensitizers for sonodynamic therapy.

Exploring therapeutic potentials of baicalin and its aglycone baicalein for hematological malignancies.

Despite tremendous advances in the targeted therapy for various types of hematological malignancies with successful improvements in the survival rates, emerging resistance issues are startlingly high and novel therapeutic strategies are urgently needed. In addition, chemoprevention is currently becoming an elusive goal. Plant-derived natural products have garnered considerable attention in recent years due to the potential dual functions as chemotherapeutics and dietary chemoprevention. One of the particularly ubiquitous families is the polyphenolic flavonoids. Among them, baicalin and its aglycone baicalein have been widely investigated in hematological malignancies because both of them exhibit remarkable pharmacological properties. This review focuses on the recent achievements in drug discovery research associated with baicalin and baicalein for hematological malignancy therapies. The promising anticancer activities of these two flavonoids targeting diverse signaling pathways and their potential biological mechanisms in different types of hematological malignancies, as well as the combination strategy with baicalin or baicalein as chemotherapeutic adjuvants for recent therapies in these intractable diseases are discussed. Meanwhile, the biotransformation of baicalin and baicalein and the relevant approaches to improve their bioavailability are also summarized.