A Review on The Pathogenesis of Cardiovascular Disease of Flaviviridea Viruses Infection.

Members of the Flaviviridae family, encompassing the Flavivirus and Hepacivirus genera, are implicated in a spectrum of severe human pathologies. These diseases span a diverse spectrum, including hepatitis, vascular shock syndrome, encephalitis, acute flaccid paralysis, and adverse fetal outcomes, such as congenital heart defects and increased mortality rates. Notably, infections by Flaviviridae viruses have been associated with substantial cardiovascular compromise, yet the exploration into the attendant cardiovascular sequelae and underlying mechanisms remains relatively underexplored. This review aims to explore the epidemiology of Flaviviridae virus infections and synthesize their cardiovascular morbidities. Leveraging current research trajectories and our investigative contributions, we aspire to construct a cogent theoretical framework elucidating the pathogenesis of Flaviviridae-induced cardiovascular injury and illuminate prospective therapeutic avenues.

Analysis of the differential expression and prognostic relationship of DEGs in AML based on TCGA database.

BACKGROUND: Acute myeloid leukemia (AML) is a common and lethal hematological malignant hyperplastic disease originating from hematopoietic stem cells. The purpose of this study is to obtain the key differentially expressed gene (DEG) related to the survival of AML by The Cancer Genome Atlas (TCGA) database and to verify these genes by a clinical follow-up investigation, in order to identify valuable predictive and prognostic biomarkers for early diagnosis of AML and predict the survival rates. METHODS: The RNA sequencing (RNA-Seq) data and clinical information of TCGA-LAML were downloaded from the TCGA database. After that we (1) screened the survival-related DEGs by Cox regression analysis, (2) selected the cytogenetics risk-related DEGs by DESeq2 R package, and (3) filtrated the genes in the top10 pathways of up-regulated and down-regulated of Normalization Enrichment Score (NES) by Gene Set Enrichment Analysis (GSEA). Finally, we focused the intersectional genes of above three parts as the key gene of the present study. The following Multivariate.

Indocyanine green derived carbon dots with significantly enhanced properties for efficient photothermal therapy.

A simple yet effective strategy to enhance the properties of traditional dye indocyanine green (ICG) in all aspects was proposed and demonstrated. Specifically, indocyanine green-derived carbon dots (ICGCDs) were synthesized from ICG via a simple hydrothermal treatment. The ICGCDs exhibited significantly enhanced thermal stability and anti-photobleaching compared to ICG. Furthermore, their photothermal properties were also notably strengthened, in which a wider functional pH range, 50% improvement in photothermal conversion efficiency and superior photothermal cyclability were achieved. Thanks to these superior properties, ICGCDs were demonstrated as efficient NIR bioimaging and photothermal agents in both in vitro and in vivo experiments. Most excitingly, the strategy demonstrated in this study is likely to have broad applications in other systems.

Inhibiting cardiac autophagy suppresses Zika virus replication.

Zika Virus (ZIKV) infection is a global threat. Other than the congenital neurological disorders it causes, ZIKV infection has been reported to induce cardiac complications. However, the precise treatment plans are unclear. Thus, illustrating the pathogenic mechanism of ZIKV in the heart is critical to providing effective prevention and treatment of ZIKV infection. The mechanism of autophagy has been reported recently in Dengue virus infection. Whether or not autophagy participates in ZIKV infection and its role remains unrevealed. This study successfully established the in vitro cardiomyocytes and in vivo mouse models of ZIKV infection to investigate the involvement of autophagy in ZIKV infection. The results showed that ZIKV infection is both time and gradient-dependent. The key autophagy protein, LC3B, increased remarkably after ZIKV infection. Meanwhile, autophagic flux was detected by immunofluorescence. Applying autophagy inhibitors decreased the LC3B levels. Furthermore, the number of viral copies was quantified to evaluate the influence of autophagy during infection. We found that autophagy was actively involved in the ZIKV infection and the inhibition of autophagy could effectively reduce the viral copies, suggesting a potential intervention strategy for reducing ZIKV infection and the undesired complications caused by ZIKV.

Current Progress of EMT: A New Direction of Targeted Therapy for Colorectal Cancer with Invasion and Metastasis.

Colorectal cancer (CRC) is a common malignant tumor with a high frequency of recurrence and metastasis, which are the major causes of death in patients. The prerequisite for the invasion and metastasis is the strong mobility of CRC cells to transport far away from the original site to the distant organs and tissues, where they settle down and proliferate. It was reported that the epithelial-mesenchymal transition (EMT) is involved in the occurrence and development of various tumors in the entire process of tumor invasion and metastasis. Therefore, as a vital factor for the biological characteristics of tumor cells, EMT markers may serve as prognostic predictors and potential therapeutic targets in CRC. This article mainly reviews the current status of CRC with metastasis, the studies of EMT, the possible relationship of EMT with CRC, as well as the potential targeted therapy.

Gibberellin derivative GA-13315 overcomes multidrug resistance in breast cancer by up-regulating BMP6 expression.

Chemoresistance represents a major obstacle in breast cancer treatment. Bone morphogenetic protein 6 (BMP6) was reported to participate in the occurrence and development of various tumors. In the present study, the results of transcriptome sequencing, qRT-PCR and western blot analysis revealed that BMP6 was down-regulated in multidrug resistant MCF-7/Adr breast cancer cells and BMP6 overexpression sensitized MCF-7/Adr cells to chemotherapeutic drugs, indicating that BMP6 downregulation was involved in the mechanisms of multidrug resistance (MDR) of MCF-7/Adr breast cancer cells. GA-13315 (GA5) is a new tetracyclic diterpenoid selected from a series of gibberellin derivatives. Here, we found that GA5 exhibited more potent anti-tumor activity in multidrug resistant MCF-7/Adr breast cancer cells and xenografts, indicating that GA5 could overcome MDR. Mechanistically, GA5 increased BMP6 expression, and BPM6 knockdown partially reversed the inhibitory effect of GA5 on cell proliferation. Furthermore, we found that ERK phosphorylation and P-gp expression were increased in MCF-7/Adr cells when compared with MCF-7 cells. Either overexpression of BMP6 or treatment the cells with GA5 significantly decreased ERK phosphorylation and P-gp expression, indicating that GA5 reversed MDR of MCF-7/Adr cells by upregulating BMP6, thereby inhibiting the activation of ERK signaling pathway and reducing P-gp expression. Collectively, our present study demonstrated that the MDR of MCF-7/Adr cells was closely related to the low expression of BMP6, and revealed the molecular mechanisms by which GA5 overcame MDR in breast cancer, providing evidence in supporting the development of GA5 to be a promising agent for overcoming MDR in clinical cancer therapy in the future.

Current progress of ferroptosis study in ovarian cancer.

Tumors are the leading cause of death all over the world, among which ovarian cancer ranks the third in gynecological malignancies. The current treatment for ovarian cancer is liable to develop chemotherapy resistance and high recurrence rate, in which a new strategy is demanded. Ferroptosis, a newly discovered manner of regulatory cell death, is shown to be induced by massive iron-dependent accumulation of lipid reactive oxygen species. With the in-depth study of ferroptosis, its associated mechanism with various tumors is gradually elucidated, including ovarian tumor, which probably promotes the application of ferroptosis in treating ovarian cancer. To this end, this review will focus on the history and current research progress of ferroptosis, especially its regulation mechanism, and its potential application as a novel treatment strategy for ovarian cancer.

Carbon dot composites for bioapplications: a review.

Carbon dots (CDs) have received extensive attention in the last decade for their excellent optical, chemical and biological properties. In recent years, CD composites have also received significant attention due to their ability to improve the intrinsic properties and expand the application scope of CDs. In this article, the synthesis processes of four types of CD composites (metal-CD, nonmetallic inorganics-CD, and organics-CD as well as multi-components-CD composites) are systematically summarized first. Then the recent advancements in the bioapplications (bioimaging, drug delivery and biosensing) of these composites are also highlighted and discussed. Last, the current challenges and future trends of CD composites in biomedical fields are discussed.

Possibility of inducing tumor cell senescence during therapy.

The treatment options for cancer include surgery, radiotherapy and chemotherapy. However, the traditional approach of high-dose chemotherapy brings tremendous toxic side effects to patients, as well as potentially causing drug resistance. Drug resistance affects cell proliferation, cell senescence and apoptosis. Cellular senescence refers to the process in which cells change from an active proliferative status to a growth-arrested status. There are multiple factors that regulate this process and cellular senescence is activated by various pathways. Senescent cells present specific characteristics, such as an increased cell volume, flattened cell body morphology, ceased cell division and the expression of ß-galactosidase. Tumor senescence can be categorized into replicative senescence and premature senescence. Cellular senescence may inhibit the occurrence and development of tumors, serving as an innovative strategy for the treatment of cancer. The present review mainly focuses on senescent biomarkers, methods for the induction of cellular senescence and its possible application in the treatment of cancer.

Investigation into the Biological Impact of Block Size on Cathepsin S-Degradable HPMA Copolymers.

N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymers have been studied as an efficient carrier for drug delivery and tumor imaging. However, as with many macromolecular platforms, the substantial accumulation of HPMA copolymer by the mononuclear phagocyte system (MPS)-associated tissues, such as the blood, liver, and spleen, has inhibited its clinical translation. Our laboratory is pursuing approaches to improve the diagnostic and radiotherapeutic effectiveness of HPMA copolymers by reducing the nontarget accumulation. Specifically, we have been investigating the use of a cathepsin S (Cat S)-cleavable peptidic linkers to degrade multiblock HPMA copolymers to increase MPS-associated tissue clearance. In this study, we further our investigation into this area by exploring the impact of copolymer block size on the biological performance of Cat S-degradable HPMA copolymers. Using a variety of in vitro and in vivo techniques, including dual labeling of the copolymer and peptide components, we investigated the constructs using HPAC pancreatic ductal adenocarcinoma models. The smaller copolymer block size (S-CMP) demonstrated significantly faster Cat S cleavage kinetics relative to the larger system (L-CMP). Confocal microscopy demonstrated that both constructs could be much more efficiently internalized by human monocyte-differentiated macrophage (hMDM) compared to HPAC cells. In the biodistribution studies, the multiblock copolymers with a smaller block size exhibited faster clearance and lower nontarget retention while still achieving good tumor targeting and retention. Based on the radioisotopic ratios, fragmentation and clearance of the copolymer constructs were higher in the liver compared to the spleen and tumor. Overall, these results indicate that block size plays an important role in the biological performance of Cat S-degradable polymeric constructs.

Investigation of the Biological Impact of Charge Distribution on a NTR1-Targeted Peptide.

The neurotensin receptor 1 (NTR1) has been shown to be a promising target, due to its increased level of expression relative to normal tissue, for pancreatic and colon cancers. This has prompted the development of a variety of NTR1-targeted radiopharmaceuticals, based on the neurotensin (NT) peptide, for diagnostic and radiotherapeutic applications. A major obstacle for the clinical translation of NTR1-targeted radiotherapeutics would likely be nephrotoxicity due to the high levels of kidney retention. It is well-known that for many peptide-based agents, renal uptake is influenced by the overall molecular charge. Herein, we investigated the effect of charge distribution on receptor binding and kidney retention. Using the [(N-α-Me)Arg8,Dmt11,Tle12]NT(6-13) targeting vector, three peptides (177Lu-K2, 177Lu-K4, and 177Lu-K6), with the Lys moved closer (K6) or further away (K2) from the pharmacophore, were synthesized. In vitro competitive binding, internalization and efflux, and confocal microscopy studies were conducted using the NTR1-positive HT-29, human colon cancer cell line. The 177/natLu-K6 demonstrated the highest binding affinity (21.8 ± 1.2 nM) and the highest level of internalization (4.06% ± 0.20% of the total added amount). In vivo biodistribution, autoradiography, and metabolic studies of 177Lu-radiolabeled K2, K4, and K6 were examined using CF-1 mice. 177Lu-K4 and 177Lu-K6 gave the highest levels of in vivo uptake in NTR1-positive tissues, whereas 177Lu-K2 yielded nearly 2-fold higher renal uptake relative to the other radioconjugates. In conclusion, the position of the Lys (positively charged amino acid) influences the receptor binding, internalization, in vivo NTR1-targeting efficacy, and kidney retention profile of the radioconjugates. In addition, we have found that hydrophobicity likely play a role in the unique biodistribution profiles of these agents.

Cathepsin S-cleavable, multi-block HPMA copolymers for improved SPECT/CT imaging of pancreatic cancer.

This work continues our efforts to improve the diagnostic and radiotherapeutic effectiveness of nanomedicine platforms by developing approaches to reduce the non-target accumulation of these agents. Herein, we developed multi-block HPMA copolymers with backbones that are susceptible to cleavage by cathepsin S, a protease that is abundantly expressed in tissues of the mononuclear phagocyte system (MPS). Specifically, a bis-thiol terminated HPMA telechelic copolymer containing 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. Three maleimide modified linkers with different sequences, including cathepsin S degradable oligopeptide, scramble oligopeptide and oligo ethylene glycol, were subsequently synthesized and used for the extension of the HPMA copolymers by thiol-maleimide click chemistry. All multi-block HPMA copolymers could be labeled by (177)Lu with high labeling efficiency and exhibited high serum stability. In vitro cleavage studies demonstrated highly selective and efficient cathepsin S mediated cleavage of the cathepsin S-susceptible multi-block HPMA copolymer. A modified multi-block HPMA copolymer series capable of Förster Resonance Energy Transfer (FRET) was utilized to investigate the rate of cleavage of the multi-block HPMA copolymers in monocyte-derived macrophages. Confocal imaging and flow cytometry studies revealed substantially higher rates of cleavage for the multi-block HPMA copolymers containing the cathepsin S-susceptible linker. The efficacy of the cathepsin S-cleavable multi-block HPMA copolymer was further examined using an in vivo model of pancreatic ductal adenocarcinoma. Based on the biodistribution and SPECT/CT studies, the copolymer extended with the cathepsin S susceptible linker exhibited significantly faster clearance and lower non-target retention without compromising tumor targeting. Overall, these results indicate that exploitation of the cathepsin S activity in MPS tissues can be utilized to substantially lower non-target accumulation, suggesting this is a promising approach for the development of diagnostic and radiotherapeutic nanomedicine platforms.

Evaluation of DOTA-chelated neurotensin analogs with spacer-enhanced biological performance for neurotensin-receptor-1-positive tumor targeting.

INTRODUCTION: Neurotensin receptor 1 (NTR1) is overexpressed in many cancer types. Neurotensin (NT), a 13 amino acid peptide, is the native ligand for NTR1 and exhibits high (nM) affinity to the receptor. Many laboratories have been investigating the development of diagnostic and therapeutic radiopharmaceuticals for NTR1-positive cancers based on the NT peptide. To improve the biological performance for targeting NTR1, we proposed NT analogs with a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelation system and different lengths of spacers. METHODS: We synthesized four NTR1-targeted conjugates with spacer lengths from 0 to 9 atoms (null (N0), ß-Ala-OH (N1), 5-Ava-OH (N2), and 8-Aoc-OH (N3)) between the DOTA and the pharmacophore. In vitro competitive binding, internalization and efflux studies were performed on all four NT analogs. Based on these findings, metabolism studies were carried out on our best performing conjugate, (177)Lu-N1. Lastly, in vivo biodistribution and SPECT/CT imaging studies were performed using (177)Lu-N1 in an HT-29 xenograft mouse model. RESULTS: As shown in the competitive binding assays, the NT analogs with different spacers (N1, N2 and N3) exhibited lower IC50 values than the NT analog without a spacer (N0). Furthermore, N1 revealed higher retention in HT-29 cells with more rapid internalization and slower efflux than the other NT analogs. In vivo biodistribution and SPECT/CT imaging studies of (177)Lu-N1 demonstrated excellent accumulation (3.1 ± 0.4%ID/g) in the NTR1-positive tumors at 4h post-administration. CONCLUSIONS: The DOTA chelation system demonstrated some modest steric inhibition of the pharmacophore. However, the insertion of a 4-atom hydrocarbon spacer group restored optimal binding affinity of the analog. The in vivo assays indicated that (177)Lu-N1 could be used for imaging and radiotherapy of NTR1-positive tumors.

The influence of linker length on the properties of cathepsin S cleavable (177)Lu-labeled HPMA copolymers for pancreatic cancer imaging.

N-(2-hydroxypropyl)-methacrylamide (HPMA) copolymers have shown promise for application in the detection and staging of cancer. However, non-target accumulation, particularly in the liver and spleen, hinders the detection of resident or nearby metastatic lesions thereby decreasing diagnostic effectiveness. Our laboratory has pursued the development of cathepsin S susceptible linkers (CSLs) to reduce the non-target accumulation of diagnostic/radiotherapeutic HPMA copolymers. In this study, we ascertain if the length of the linking group impacts the cleavage and clearance kinetics, relative to each other and a non-cleavable control, due to a reduction in steric inhibition. Three different CSLs with linking groups of various lengths (0, 6 and 13 atoms) were conjugated to HPMA copolymers. In vitro cleavage studies revealed that the longest linking group (13 atoms) led to more rapid cleavage when challenged with cathepsin S. The CSL incorporated HPMA copolymers demonstrated significantly higher levels of excretion and a significant decrease in long-term hepatic and splenic retention relative to the non-cleavable control. Contrary to in vitro observations, the length of the linking group did not substantially impact the non-target in vivo clearance. In the case of HPAC tumor retention, the CSL with the null (0 atom) linker demonstrated significantly higher levels of retention relative to the other CSLs. Given these results, we find that the length of the linking group of the CSLs did not substantially impact non-target clearance, but did influence tumor retention. Overall, these results demonstrate that the CSLs can substantially improve the non-target clearance of HPMA copolymers thereby enhancing clinical potential.

Synthesis and in vitro and in vivo evaluation of hypoxia-enhanced 111In-bombesin conjugates for prostate cancer imaging.

UNLABELLED: Receptor-targeted agents, such as gastrin-releasing peptide receptor (BB2r)-targeted peptides, have been investigated extensively in preclinical and clinical studies. In an attempt to increase the effectiveness of diagnostic or radiotherapeutic agents, we have begun to explore the incorporation of the hypoxia-selective prodrug 2-nitroimidazole into receptor-targeted peptides. Hypoxia is a well-known characteristic of many solid tumors, including breast, prostate, and pancreatic cancers. The aim of this approach is to use the hypoxia-trapping capability of 2-nitroimidazoles to increase the retention of the agent in hypoxic, BB2r-positive tumors. We have demonstrated that incorporation of one or more 2-nitroimidazoles into the BB2r-targeted peptide significantly increases the in vitro retention of the agent in hypoxic prostate cancer cells. The study described herein represents our first investigation of the in vivo properties of these hypoxia-enhanced BB2r-targeted agents in a PC-3 xenograft mouse model. METHODS: Four (111)In-labeled BB2r-targeted conjugates--(111) IN-1, (111) IN-2, (111) IN-3, and (111) IN-4, composed of 2-nitroimidazole moieties of 0, 1, 2, and 3, respectively--were synthesized, labeled, and purified. The BB2r binding affinities, externalization, and protein-association properties of these radioconjugates were assessed using the BB2r-positive PC-3 human prostate cancer cell line under hypoxic and normoxic environments. The in vivo biodistribution and micro-SPECT/CT imaging of the (111) IN-1, (111) IN-2, and (111) IN-4 radioconjugates were investigated in PC-3 tumor-bearing severely combined immunodeficient mice. RESULTS: All conjugates and (nat)In-conjugates demonstrated nanomolar binding affinities. (111) IN-1, (111) IN-2, (111) IN-3, and (111) IN-4 demonstrated 41.4%, 60.7%, 69.1%, and 69.4% retention, correspondingly, of internalized radioactivity under hypoxic conditions relative to 34.8%, 35.3%, 33.2%, and 29.7% retention, respectively, under normoxic conditions. Protein-association studies showed significantly higher levels of association under hypoxic conditions for 2-nitroimidazole-containing BB2r-targeted radioconjugates than for controls. On the basis of the initial 1-h uptake in the PC-3 tumors, (111) IN-1, (111) IN-2, and (111) IN-4 demonstrated tumor retentions of 1.5%, 6.7%, and 21.0%, respectively, by 72 h after injection. Micro-SPECT/CT imaging studies of (111) IN-1, (111) IN-2, and (111) IN-4 radioconjugates resulted in clear delineation of the tumors. CONCLUSION: On the basis of the in vitro and in vivo studies, the BB2r-targeted agents that incorporated 2-nitroimidazole moieties demonstrated improved retention. These results indicate that further exploration into the potential of hypoxia-selective trapping agents for BB2r-targeted agents, as well as other targeted compounds, is warranted.

Nitrendipine nanocrystals: its preparation, characterization, and in vitro-in vivo evaluation.

The present investigation was undertaken with the objective of developing a solid formulation containing nitrendipine nanocrystals for oral delivery. Nitrendipine nanocrystals were prepared using a tandem precipitation-homogenization process. Then, spray drying, a cost-effective method very popular in industrial situations, was employed to convert the nanocrystals into a solid form. The parameters of the preparation process were investigated and optimized. The optimal process was as follows: firstly, nitrendipine/acetone solution (100 mg/ml) was added to a polyvinyl alcohol solution (1 mg/ml) at 10°C, then the pre-suspension was homogenized for 20 cycles at 1,000 bar. Both differential scanning calorimetry and X-ray diffraction analysis indicated that nitrendipine was present in crystalline form. The in vitro dissolution rate of the nanocrystals was significantly increased compared with the physical mixture and commercial tablet. The in vivo testing demonstrated that the C(max) of the nanocrystals was approximately 15-fold and 10-fold greater than that of physical mixture and commercial tablet, respectively. In addition, the AUC(0→24) of the nanocrystals was approximately 41-fold and 10-fold greater than that of physical mixture and commercial tablet, respectively.