Minimal Toxic Side Effects Research Articles

Discovery of novel quinazoline derivatives as tubulin polymerization inhibitors targeting the colchicine binding site with potential anti-colon cancer effects

Tubulin is a critical target for cancer therapy, with colchicine binding site inhibitors (CBSIs) being the most extensively researched. A series of quinazoline derivatives designed to target the colchicine binding site of tubulin were synthesized and evaluated for their biological activities. The antiproliferative effects of these compounds were tested against six human cancer cell lines, and compound Q19 demonstrated potent antiproliferative activity against the HT-29 cell line, with an IC50 value of 51 nM. Additionally, further investigation revealed that Q19 effectively inhibited microtubule polymerization by binding to the colchicine binding site on tubulin. Furthermore, compound Q19 arrested the HT-29 cell cycle at the G2/M phase, induced apoptosis in these cells, and disrupted angiogenesis. Finally, compound Q19 exhibited potent inhibitory effects on tumor growth in HT-29 xenografted mice while demonstrating minimal toxic side effects and acceptable pharmacokinetic properties. These findings suggested that Q19 hold promise as a potential candidate for colon cancer therapy targeting tubulin.

Discovery of Positive Allosteric Modulators of α 7 nAChR by an Ensemble-based Virtual Screening Method, Molecular Dynamics Simulation, and in vitro Biological Activity Testing

The [Formula: see text]7 nicotinic acetylcholine receptor (nAChR) is a neurotransmitter receptor and a promising therapeutic target for neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. In this study, we used deep learning-based classification modeling, molecular docking, and intracellular calcium signal detection experiments to identify positive allosteric modulators (PAMs) of the [Formula: see text]7 nAChR from natural tobacco products. First, we used a classification prediction model based on the direct message-passing neural network (D-MPNN) and molecular docking to predict potential [Formula: see text]7 PAMs. Subsequently, absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions were performed to determine its pharmacological properties and minimal toxic side effects, leading to the selection of three natural compounds for in vitro activity validation. Calcium signaling assay experiments revealed that diosmetin can enhance nicotine-induced calcium ion signaling. 100 ns molecular dynamics (MD) simulations indicated that diosmetin can form a dense and stable complex with [Formula: see text]7 nAChR. This study provides valuable insights for the design of more effective and selective ligands for the [Formula: see text]7 nAChR.

Gypenoside L inhibits hepatocellular carcinoma by targeting the SREBP2-HMGCS1 axis and enhancing immune response

Hepatocellular carcinoma (HCC) is a malignant tumor that occurs in the liver, with a high degree of malignancy and relatively poor prognosis. Gypenoside L has inhibitory effects on liver cancer cells. However, its mechanism of action is still unclear. This study aims to investigate the inhibitory effects of gypenoside L on HCC in vitro and in vivo, and explore its potential mechanisms. The results showed that gypenoside L reduced the cholesterol and triglyceride content in HepG2 and Huh-7 cells, inhibited cell proliferation, invasion and metastasis, arrested cell cycle at G0/G1 phase, promoted cell apoptosis. Mechanistically, it targeted the transcription factor SREPB2 to inhibit the expression of HMGCS1 protein and inhibited the downstream proteins HMGCR and MVK, thereby regulating the mevalonate (MVA) pathway. Overexpression HMGCS1 led to significant alterations in the cholesterol metabolism pathway of HCC, which mediated HCC cell proliferation and conferred resistance to the therapeutic effect of gypenoside L. In vivo, gypenoside L effectively suppressed HCC growth in tumor-bearing mice by reducing cholesterol production, exhibiting favorable safety profiles and minimal toxic side effects. Gypenoside L modulated cholesterol homeostasis, enhanced expression of inflammatory factors by regulating MHC I pathway-related proteins to augment anticancer immune responses. Clinical samples from HCC patients also exhibited high expression levels of MVA pathway-related genes in tumor tissues. These findings highlight gypenoside L as a promising agent for targeting cholesterol metabolism in HCC while emphasizing the effectiveness of regulating the SREBP2-HMGCS1 axis as a therapeutic strategy.

A Review on Investigating the Interactions between Nanoparticles and the Pulmonary Surfactant Monolayer with Coarse-Grained Molecular Dynamics Method.

Pulmonary drug delivery has garnered significant attention due to its targeted local lung action, minimal toxic side effects, and high drug utilization. However, the physicochemical properties of inhaled nanoparticles (NPs) used as drug carriers can influence their interactions with the pulmonary surfactant (PS) monolayer, potentially altering the fate of the NPs and impairing the biophysical function of the PS monolayer. Thus, the objective of this review is to summarize how the physicochemical properties of NPs affect their interactions with the PS monolayer. Initially, the definition and properties of NPs, as well as the composition and characteristics of the PS monolayer, are introduced. Subsequently, the coarse-grained molecular dynamics (CGMD) simulation method for studying the interactions between NPs and the PS monolayer is presented. Finally, the implications of the hydrophobicity, size, shape, surface charge, surface modification, and aggregation of NPs on their interactions with the PS monolayer and on the composition of biomolecular corona are discussed. In conclusion, gaining a deeper understanding of the effects of the physicochemical properties of NPs on their interactions with the PS monolayer will contribute to the development of safer and more effective nanomedicines for pulmonary drug delivery.

Synthesis and application of multifunctional magnetic mesoporous nanomaterials with redox reaction and NIR response in tumor treatment

In recent years, the novel minimally invasive combination therapy for tumors has garnered widespread attention due to its controllable therapeutic target, effective combination therapy outcome, and minimal toxic side effects. This study integrated inorganic nanospheres of ferric oxide (Fe3O4) with mesoporous silica nanoparticles (MSN), along with polymeric organic polymers—polyaniline (PANI) and hyaluronic acid (HA)—to create a multifunctional tumor treatment platform (Fe3O4@MSN@PANI@HA), aiming to enhance the efficacy of therapies that have monotherapy limitations. The Fe2+ within the Fe3O4@MSN@PANI@HA nanoparticles can react with the unique hydrogen peroxide present in the tumor microenvironment to generate hydroxyl radicals (·OH), which possess cytotoxic properties that can selectively eradicate tumor cells, thereby facilitating chemodynamic therapy (CDT). Moreover, Fe3O4@MSN@PANI@HA nanoparticles, when loaded with the chemotherapy drug doxorubicin hydrochloride (DOX), yield Fe3O4@MSN@PANI@HA-DOX nanoparticles. It has been demonstrated that these nanoparticles exhibit commendable drug-loading efficiency and controlled drug-release capabilities, contributing to the chemotherapy of tumors. The inclusion of PANI in the Fe3O4@MSN@PANI@HA nanoparticles endows them with an exceptional photothermal conversion capability. Upon exposure to an 808-nm near-infrared laser (NIR), the photothermal conversion efficiency of the composite nanomaterials reaches 42.76 %, thereby enabling photothermal therapy (PTT) through the thermal ablation of tumor cells. The HA component of the composite nanoparticles provides excellent biocompatibility and a sustained drug-release effect. Simultaneously, it could target tumor cells by recognizing specific receptors that are overexpressed on the cell surfaces, directing the transport of the composite nanoparticles to the tumor site, and selectively destroying tumor cells. This paper confirms the potent therapeutic impact of composite nanoparticles on tumors and offers a novel perspective for designing multifunctional composite nanomaterials.

Current status, mechanism and research progress of major sedative-hypnotic drugs for the treatment of insomnia

Insomnia, a widespread condition in modern society, has seen a rise in its affected population in recent years. Prolonged insomnia not only causes anxiety and depression but also impairs individuals’ work and study efficiency while posing a threat to their physical health. Drug therapy is the predominant treatment for insomnia, encompassing drugs such as barbiturates, benzodiazepines, novel non-benzodiazepines, melatonin receptor agonists, melatonin, and orexin receptor antagonists. However, concerns arise due to the significant side effects, ease of tolerance development, dependency issues, and rebound phenomena upon drug discontinuation for some of these medications. Hence, there’s an urgent need for the research and development of novel hypnotic-sedative drugs that offer minimal toxic side effects, excellent tolerance, and reduced dependency. This paper presents a review of the mechanisms and research advancements of key sedative-hypnotic drugs in recent years. Furthermore, based on conformational relationships, we aim to predict the structure of these novel drugs, providing a valuable reference for drug research and development, while offering diverse drug options tailored to different patient needs.

Self-assembled nanoparticle-mediated cascade chemotherapy and chemodynamic therapy for enhanced tumor therapy

Chemodynamic therapy (CDT) is a non-invasive treatment strategy that aims to combat tumor growth by efficiently generating reactive oxygen species (ROS). However, the effectiveness of CDT can be limited by factors such as the availability of endogenous hydrogen peroxide (H2O2). Here, we established an intelligent nano-based drug delivery system responsive to the tumor microenvironment by self-assembling Cu2+, cisplatin, and L-histidine to form nanoparticles (Pt/CuH NPs), which can achieve the therapeutic effect of specific tumor killing by cascading chemotherapy with CDT. The Pt/CuH NPs are triggered by the acidic conditions and high glutathione (GSH) levels present in the tumor microenvironment, leading to the release of cisplatin and Cu2+. Cisplatin facilitates the production of H2O2 through a two-step enzymatic reaction, subsequently triggering ROS cascade that is amplified by CDT. Concurrently, Cu2+ consumes GSH and is reduced to Cu+, which reacts with H2O2 in an efficient Fenton-like reaction, amplifying oxidative stress and ultimately enhancing the anti-tumor therapeutic efficacy. Pt/CuH NPs demonstrated a significant cytotoxic effect on tumor cells in vitro. In vivo studies in mice indicated minimal toxic side effects at the tested dosages. The Pt/CuH NPs effectively combine chemotherapy and CDT strategies, showcasing the potential of a chemotherapy-cascading CDT approach for anti-tumor treatment.

Cannabidiol Inhibits Epithelial Ovarian Cancer: Role of Gut Microbiome.

Epithelial ovarian cancer is among the deadliest gynecological tumors worldwide. Clinical treatment usually consists of surgery and adjuvant chemo- and radiotherapies. Due to the high rate of recurrence and rapid development of drug resistance, the current focus of research is on finding effective natural products with minimal toxic side effects for treating epithelial ovarian tumors. Cannabidiol is among the most abundant cannabinoids and has a non-psychoactive effect compared to tetrahydrocannabinol, which is a key advantage for clinical application. Studies have shown that cannabidiol has antiproliferative, pro-apoptotic, cytotoxic, antiangiogenic, anti-inflammatory, and immunomodulatory properties. However, its therapeutic value for epithelial ovarian tumors remains unclear. This study aims to investigate the effects of cannabidiol on epithelial ovarian tumors and to elucidate the underlying mechanisms. The results showed that cannabidiol has a significant inhibitory effect on epithelial ovarian tumors. In vivo experiments demonstrated that cannabidiol could inhibit tumor growth by modulating the intestinal microbiome and increasing the abundance of beneficial bacteria. Western blot assays showed that cannabidiol bound to EGFR/AKT/MMPs proteins and suppressed EGFR/AKT/MMPs expression in a dose-dependent manner. Network pharmacology and molecular docking results suggested that cannabidiol could affect the EGFR/AKT/MMPs signaling pathway.

Discovery of non-sulfonamide carbonic anhydrase IX inhibitors through structure-based virtual screening.

Carbonic anhydrase IX (CA IX) is a subtype of the human carbonic anhydrase (hCA) family and exhibits high expression in various solid tumors, rendering it a promising target for tumor therapy. Currently, marketed carbonic anhydrase inhibitors (CAIs) are primarily composed of sulfonamides derivatives, which may have impeded their potential for further expansion. Therefore, we have developed a structure-based virtual screening approach to explore novel CAIs exhibiting distinctive structures and anti-tumor potential in the FDA database. In vitro experiments demonstrated that 3-pyridinemethanol (0.42 μM), procodazole (8.35 μM) and pamidronic acid (8.51 μM) exhibited inhibitory effects on CA IX activity. The binding stability and interaction mode between the CA IX and the hit compounds are further investigated through molecular dynamics simulations and binding free energy calculations. Furthermore, the ADME/Tox prediction results indicated that these compounds exhibited favorable pharmacological properties and minimal toxic side effects. Our study successfully applied computational strategies to discover three non-sulfonamide inhibitors of carbonic anhydrase IX (CA IX) that demonstrate inhibitory activity in vitro. These findings have significant implications for the development of CA IX inhibitors and anti-tumor drugs, contributing to their progress in the field.

Stimulus-Responsive Nano-Prodrug Strategies for Cancer Therapy: A Focus on Camptothecin Delivery.

Camptothecin (CPT) is a highly cytotoxic molecule with excellent antitumor activity against various cancers. However, its clinical application is severely limited by poor water solubility, easy inactivation, and severe toxicity. Structural modifications and nanoformulations represent two crucial avenues for camptothecin's development. However, the potential for further structural modifications is limited, and camptothecin nanoparticles fabricated via physical loading have the drawbacks of low drug loading and leakage. Prodrug-based CPT nanoformulations have shown unique advantages, including increased drug loading, reduced burst release, improved bioavailability, and minimal toxic side effects. Stimulus-responsive CPT nano-prodrugs that respond to various endogenous or exogenous stimuli by introducing various activatable linkers to achieve spatiotemporally responsive drug release at the tumor site. This review comprehensively summarizes the latest research advances in stimulus-responsive CPT nano-prodrugs, including preparation strategies, responsive release mechanisms, and their applications in cancer therapy. Special focus is placed on the release mechanisms and characteristics of various stimulus-responsive CPT nano-prodrugs and their application in cancer treatment. Furthermore, clinical applications of CPT prodrugs are discussed. Finally, challenges and future research directions for CPT nano-prodrugs are discussed. This review to be valuable to readers engaged in prodrug research is expected.

Insights into the removal of endocrine disruptor, bisphenol A (BPA) from aqueous solution using Fc-rGO/nZVI nanocomposite system

The most prevalent phenolic compound discovered in the environment is bisphenol A (BPA). It is a common endocrine disruptor and the chemical used in the manufacture of polycarbonate and synthetic resins. In the current research, a nanocomposite composed of a 3D framework of reduced graphene oxide and nano-zero-valent iron (nZVI) is developed by the sol-gel technique. Through a green synthesis procedure that uses an in-situ reduction technique with Punica granatum rind extract, the Fc-rGO is embedded with nZVI. The Fc-rGO/nZVI nanocomposite was tested for the removal of BPA and achieved 94.40 ± 1.3% removal efficiency in 180 min. The pseudo-first-order kinetic adsorption model showed the best fit with an R2 value of 0.99. Additionally, the impact of different dissolved substances, including electrolytes and organic matter found naturally in water systems, on the removal efficiency of Fc-rGO/nZVI was investigated. The inhibition effects of dissolved electrolytes followed the order of CO32−> NO3−> Na+. The residual toxicity test of treated BPA using A. cepa as the model organism showed increased cell viability. This research reveals that the nanocomposite developed is simple to fabricate, highly stable with minimal toxic side effects, effective in the removal of BPA, and reusable. The nanocomposite is appropriate for practical use in water systems given that it is economical and environmentally friendly.

Immobilization of horseradish peroxidase on metal-organic framework to improve enzyme activity for enhanced chemodynamic therapy

Bio-enzymes have the advantages of strong substrate specificity, high catalytic efficiency, and minimal toxic side effects, making them promising drugs in cancer therapy. However, the poor stability and cellular penetrability of uncoated protein in the physiological environment severely restricts the direct application of Bio-enzyme. To address it, we report a metal-organic framework (MOF), Hf-DBA (H2DBA, biphenyl carboxylic acid ligands). The morphology of the Hf-DBA was revealed by TEM and the diameter was in the range of 200 to 350 nm. Hf-DBA acted a carrier for intracellular delivery and protection of horseradish peroxidase (HRP). The prepared HRP@Hf-DBA can catalyze the excess H2O2 in the tumor cells to generation of •OH for chemodynamic therapy (CDT). Compared with free HRP, the catalytic activity of HRP@Hf-DBA is significantly improved, and the optimal catalytic conditions are explored. The catalytic stability of HRP@Hf-DBA remained above 70% after 12 cycles of catalysis. After treatment with HRP@Hf-DBA, the apoptosis rates of A549 and Hela cells was 71.64%, and 76.86%. The results in vitro show that HRP@Hf-DBA can effectively inhibit the growth of tumor cells through enhanced CDT.

A targeted drug delivery system based on E. coli ghost for inhibiting non-Hodgkin’s lymphoma

Doxorubicin (DOX) is extensively utilized in the treatment of aggressive lymphomas, while its significant toxic side effects hamper its clinical application. Hence, there is an urgent need for a safe and effective antilymphoma drug delivery system at this stage. This study successfully developed an optimal drug delivery system (R-PEG@BGs-DOX) to safe and efficient delivery of DOX to non-Hodgkin's lymphoma site. The R-PEG@BGs-DOX was prepared by modifying polyethylene glycol (PEG) and Rituximab (R) onto the surface of bacterial ghosts (BGs), which were obtained through NaOH treatment of E. coli BL21 with modulation to achieve target structures. The prepared R-PEG@BGs exhibited efficient loading of DOX, demonstrating excellent targeting properties. The R-PEG@BGs-DOX can significantly inhibit the growth of non-Hodgkin's lymphoma cells while showing minimal toxic side effects on normal tissues. These results strongly suggest that R-PEG@BGs-DOX holds great promise as an intelligent, safe, and effective drug delivery system for anti-lymphoma treatment.

PH-responsive resveratrol-loaded ZIF-8 nanoparticles modified with tannic acid for promoting colon cancer cell apoptosis.

Resveratrol (Res) is known for its potential in treating various types of cancers, with a particular advantage of causing minimal toxic side effects. However, its clinical application is constrained by challenges such as poor bioavailability, low water solubility, and chemical instability in neutral and alkaline environments. In light of these limitations, we have developed a pH-responsive drug delivery nanoplatform, Res@ZIF-8/TA NPs, which exhibits good biocompatibility and shows promise for in vitro cancer therapy. Benefiting from the mild reaction conditions provided by zeolitic imidazolate frameworks (ZIFs), a "one-pot method" was used for drug synthesis and loading, resulting in a satisfactory loading capacity. Notably, Res@ZIF-8/TA NPs respond to acidic environments, leading to an improved drug release profile with a controlled release effect. Our cell-based experiments indicated that tannic acid (TA) modification enhances the biocompatibility of ZIFs. 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide (MTT assay), Hoechst 33342/PI staining, cell scratch assay, Transwell and Reverse Transcription quantitative PCR (RT-qPCR) assays further demonstrated that Res@ZIF-8/TA NPs inhibited colon cancer cell migration and invasion, and promoted apoptosis of colon cancer cells, suggesting a therapeutic potential and demonstrating anti-cancer properties. In conclusion, the Res@ZIF-8/TA NPs pH-responsive drug delivery systems we developed may offer a promising avenue for cancer therapy. By addressing some of the challenges associated with Res-based treatments, this system could contribute to advancements in cancer therapeutics.

Mesoporous Titanium Dioxide Nanoparticles-Poly(N-isopropylacrylamide) Hydrogel Prepared by Electron Beam Irradiation Inhibits the Proliferation and Migration of Oral Squamous Cell Carcinoma Cells.

An urgently needed approach for the treatment of oral squamous cell carcinoma (OSCC) is the development of novel drug delivery systems that offer targeted specificity and minimal toxic side effects. In this study, we developed an injectable and temperature-sensitive composite hydrogel by combining mesoporous titanium dioxide nanoparticles (MTNs) with Poly(N-isopropylacrylamide) (PNIPAAM) hydrogel to serve as carriers for the model drug Astragalus polysaccharide (APS) using electron beam irradiation. The characteristics of MTNs, including specific surface area and pore size distribution, were analyzed, and the characteristics of MTNs-APS@Hyaluronic acid (HA), such as microscopic morphology, molecular structure, crystal structure, and loading efficiency, were examined. Additionally, the swelling ratio, gel fraction, and microscopic morphology of the composite hydrogel were observed. The in vitro cumulative release curve was plotted to investigate the sustained release of APS in the composite hydrogels. The effects on the proliferation, migration, and mitochondrial membrane potential of CAL-27 cells were evaluated using MTT assay, scratch test, and JC-1 staining. The results indicated successful preparation of MTNs with a specific surface area of 147.059 m2/g and an average pore diameter of 3.256 nm. The composite hydrogel displayed temperature-sensitive and porous characteristics, allowing for slow release of APS. Furthermore, it effectively suppressed CAL-27 cells proliferation, migration, and induced changes in mitochondrial membrane potential. The addition of autophagy inhibitors chloroquine (CQ) and 3-methyladenine (3-MA) attenuated the migration inhibition (p < 0.05).

Photothermal-triggered release of alkyl radicals and cascade generation of hydroxyl radicals via a versatile hybrid nanocatalyst for hypoxia-irrelevant synergistic antibiofilm therapy

Well-designed nanocatalysts capable of generating free radicals have recently shown promising potential for treating bacterial biofilm infections. However, the biofilm microenvironments such as hypoxia and over-expressed glutathione (GSH) seriously limit their biomedical applications. To address these issues, we herein construct a dual free radical nanogenerator (MnO2/GOx/AIBI) by loading glucose oxidase (GOx) and thermal-labile azo initiator (AIBI) onto the flower-like MnO2 with high loading capacity for the hypoxia-irrelevant treatment of biofilm-associated bacterial infections. On the one hand, MnO2/GOx/AIBI nanocomposites can generate hydroxyl radicals by glucose-fueled cascade catalytic reactions between GOx and MnO2 for efficient O2– and H2O2-self-supplying chemodynamic therapy (CDT). On the other hand, MnO2 can provide local photonic hyperpyrexia, which not only triggers the O2-independent generation of alkyl radicals for photothermal dynamic therapy (PTDT), but also enhances the CDT efficacy by accelerating the release of Fenton-type Mn2+. Besides, MnO2 can degrade GSH over-expressed in the infection sites, improving the synergistic CDT/PTDT therapeutic effectiveness by redox dyshomeobasis. The hybrid MnO2/GOx/AIBI nanocatalysts exhibit satisfactory in vitro and in vivo antibacterial and antibiofilm performances with minimal toxic side effects. Taken together, the developed hypoxia-irrelevant dual-mode synergistic antibacterial nanoplatform can effectively overcome the interferences of biofilm microenvironments, showing a promising potential for future biomedical applications.

Performance of a novel, eco‐friendly, cellulose‐based superabsorbent polymer (Cellulo‐SAP): Absorbency, stability, reusability, and biodegradability

AbstractSuperabsorbent polymers (SAPs) have attracted tremendous attention recently, with researchers noting that their high water absorbability is valuable for various applications, especially in agricultural contexts. Two types of materials can be used to produce SAPs: Fossil‐based (which are harmful to the environment) and bio‐based (which are significantly more environmentally friendly, given their biodegradability and minimal toxic side effects). Although bio‐based SAPs are preferable for environmental reasons, their synthesis tends to be time consuming and labour intensive, while their absorption capacity (AC) can be far below expectations. To address these problems, a novel, eco‐friendly, cellulose‐based superabsorbent polymer (Cellulo‐SAP) was developed in this study through facile preparation via free radical synthesis using modified cellulose. Then, the absorbency, thermal/pH stability, reusability, and biodegradability of Cellulo‐SAP were evaluated. This new polymer demonstrated reusability as a water reservoir, in addition to high thermal and pH stability. More importantly, Cellulo‐SAP achieved an AC of 475 g/g and exhibited superior biodegradability compared to a commercial, fossil‐based SAP. Accordingly, these results prove that Cellulo‐SAP can be used in agriculture as an effective alternative to fossil‐based SAPs.

Croconaine-based nanoparticles enable efficient optoacoustic imaging of murine brain tumors

Contrast enhancement in optoacoustic (photoacoustic) imaging can be achieved with agents that exhibit high absorption cross-sections, high photostability, low quantum yield, low toxicity, and preferential bio-distribution and clearance profiles. Based on advantageous photophysical properties of croconaine dyes, we explored croconaine-based nanoparticles (CR780RGD-NPs) as highly efficient contrast agents for targeted optoacoustic imaging of challenging preclinical tumor targets. Initial characterization of the CR780 dye was followed by modifications using polyethylene glycol and the cancer-targeting c(RGDyC) peptide, resulting in self-assembled ultrasmall particles with long circulation time and active tumor targeting. Preferential bio-distribution was demonstrated in orthotopic mouse brain tumor models by multispectral optoacoustic tomography (MSOT) imaging and histological analysis. Our findings showcase particle accumulation in brain tumors with sustainable strong optoacoustic signals and minimal toxic side effects. This work points to CR780RGD-NPs as a promising optoacoustic contrast agent for potential use in the diagnosis and image-guided resection of brain tumors.

Targeting the DEAD-Box RNA Helicase eIF4A with Rocaglates-A Pan-Antiviral Strategy for Minimizing the Impact of Future RNA Virus Pandemics.

The increase in pandemics caused by RNA viruses of zoonotic origin highlights the urgent need for broad-spectrum antivirals against novel and re-emerging RNA viruses. Broad-spectrum antivirals could be deployed as first-line interventions during an outbreak while virus-specific drugs and vaccines are developed and rolled out. Viruses depend on the host’s protein synthesis machinery for replication. Several natural compounds that target the cellular DEAD-box RNA helicase eIF4A, a key component of the eukaryotic translation initiation complex eIF4F, have emerged as potential broad-spectrum antivirals. Rocaglates, a group of flavaglines of plant origin that clamp mRNAs with highly structured 5′ untranslated regions (5′UTRs) onto the surface of eIF4A through specific stacking interactions, exhibit the largest selectivity and potential therapeutic indices among all known eIF4A inhibitors. Their unique mechanism of action limits the inhibitory effect of rocaglates to the translation of eIF4A-dependent viral mRNAs and a minor fraction of host mRNAs exhibiting stable RNA secondary structures and/or polypurine sequence stretches in their 5′UTRs, resulting in minimal potential toxic side effects. Maintaining a favorable safety profile while inducing efficient inhibition of a broad spectrum of RNA viruses makes rocaglates into primary candidates for further development as pan-antiviral therapeutics.

Neuroprotective mechanisms of mangiferin in neurodegenerative diseases.

The central nervous system (CNS) regulates and coordinates an extensive array of complex processes requiring harmonious regulation of specific genes. CNS disorders represent a large burden on society and cause enormous disability and economic losses. Traditional Chinese medicine (TCM) has been used for many years in the treatment of neurological illnesses, such as Alzheimer's disease, Parkinson's disease, stroke, and depression, as the combination of TCM and Western medicine has superior therapeutic efficacy and minimal toxic side effects. Mangiferin (MGF) is an active compound of the traditional Chinese herb rhizome anemarrhenae, which has antioxidant, anti-inflammation, anti-lipid peroxidation, immunomodulatory, and anti-apoptotic functions in the CNS. MGF has been demonstrated to have therapeutic effects in CNS diseases through a multitude of mechanisms. This review outlines the latest research on the neuroprotective ability of MGF and the diverse molecular mechanisms involved.