Engineering natural molecule-triggered genetic control systems for tunable gene-and cell-based therapies

The ability to precisely control activities of engineered designer cells provides a novel strategy for modern precision medicine.Dynamically adjustable gene-and cell-based precision therapies are recognized as next generation medicines.However,the translation of these controllable therapeutics into clinical practice is severely hampered by the lack of safe and highly specific genetic switches controlled by triggers that are nontoxic and side-effect free.Recently,natural products derived from plants have been extensively explored as trigger molecules to control genetic switches and synthetic gene networks for multiple applications.These controlled genetic switches could be further introduced into mammalian cells to obtain synthetic designer cells for adjustable and fine tunable cell-based precision therapy.In this review,we introduce various available natural molecules that were engineered to control genetic switches for controllable transgene expression,complex logic computation,and therapeutic drug delivery to achieve precision therapy.We also discuss current challenges and prospects in translating these natural molecule-controlled genetic switches developed for biomedical applications from the laboratory to the clinic.

Antiviral effects of natural small molecules on aquatic rhabdovirus by interfering with early viral replication

Spring viremia of carp virus(SVCV)is globally widespread and poses a serious threat to aquatic ecology and aquaculture due to its broad host range.To develop effective agents to control SVCV infection,we selected 16 naturally active small molecules to assess their anti-SVCV activity.Notably,dihydroartemisinin(DHA)(100μmol/L)and(S,S)-(+)-tetrandrine(TET)(16μmol/L)exhibited high antiviral effects in epithelioma papulosum cyprinid(EPC)cells,with inhibitory rates of 70.11%and 73.54%,respectively.The possible antiviral mechanisms were determined as follows:1.Preincubation with DHA and TET decreased viral particle infectivity in fish cells,suggesting that horizontal transmission of SVCV in the aquatic environment was disrupted;2.Although neither had an effect on viral adhesion,TET(but not DHA)interfered with SVCV entry into host cells(>80%),suggesting that TET may have an antiviral function in early viral replication.For in vivo study,both agents enhanced the survival rate of SVCV-infected zebrafish by 53.3%,significantly decreased viral load,and modulated the expression of antiviralrelated genes,indicating that DHA and TET may stimulate the host innate immune response to prevent viral infection.Overall,our findings indicated that DHA and TET had positive effects on suppressing SVCV infection by affecting early-stage viral replication,thus holding great potential as immunostimulants to reduce the risk of aquatic rhabdovirus disease outbreaks.

Potential therapeutic effects of polyphenols in Parkinson's disease:in vivo and in vitro pre-clinical studies

Parkinson's disease is a neurodegenerative disorder characterized by a combination of severe motor and non-motor symptoms.Over the years,several factors have been discovered to play a role in the pathogenesis of this disease,in particular,neuroinflammation and oxidative stress.To date,the pharmacological treatments used in Parkinson's disease are exclusively symptomatic.For this reason,in recent years,the research has been directed towards the discovery and study of new natural molecules to develop potential neuroprotective therapies against Parkinson's disease.In this context,natural polyphenols have raised much attention for their important anti-inflammatory and antioxidant properties,but also for their ability to modulate protein misfolding.In this review,we propose to summarize the relevant in vivo and in vitro studies concerning the potential therapeutic role of natural polyphenols in Parkinson's disease.

Recovery of natural active molecules using aqueous two-phase systems comprising of ionic liquids/deep eutectic solvents

Due to environmental protection requirements,extraction of bioactive compounds from plant materials using environment-friendly green solvents has always been a research hotspot.And great efforts of scholars have been made in this direction,as well as environment-friendly solvents have been used to develop many innovative extraction techniques.Ionic liquids(ILs)and deep eutectic solvents(DESs)are two kinds of typical designable green solvents,which are potential replacements for traditional volatile organic solvents used for extracting.Under the substances action of inorganic salts or polymers,ILs/DESs can form an aqueous two-phase system(ATPS),which has obvious advantages for separating natural products.This paper discussed the phase separation principle of ILs/DESs-based ATPSs and reviewed the applications in the extraction of natural active molecules in recent years,as well as to promote the development of separation of the active constituents in Chinese materia medica.

Natural compounds in the regulation of proteostatic pathways: An invincible artillery against stress, ageing, and diseases

Cells have different sets of molecules for performing an array of physiological functions.Nucleic acids have stored and carried the information throughout evolution,whereas proteins have been attributed to performing most of the cellular functions.To perform these functions,proteins need to have a unique conformation and a definite lifespan.These attributes are achieved by a highly coordinated protein quality control(PQC)system comprising chaperones to fold the proteins in a proper threedimensional structure,ubiquitin-proteasome system for selective degradation of proteins,and autophagy for bulk clearance of cell debris.Many kinds of stresses and perturbations may lead to the weakening of these protective cellular machinery,leading to the unfolding and aggregation of cellular proteins and the occurrence of numerous pathological conditions.However,modulating the expression and functional efficiency of molecular chaperones,E3 ubiquitin ligases,and autophagic proteins may diminish cellular proteotoxic load and mitigate various pathological effects.Natural medicine and small molecule-based therapies have been well-documented for their effectiveness in modulating these pathways and reestablishing the lost proteostasis inside the cells to combat disease conditions.The present article summarizes various similar reports and highlights the importance of the molecules obtained from natural sources in disease therapeutics.

Photosensitive pro-drug nanoassemblies harboring a chemotherapeutic dormancy function potentiates cancer immunotherapy

Immunotherapy combined with effective therapeutics such as chemotherapy and photodynamic therapy have been shown to be a successful strategy to activate anti-tumor immune responses for improved anticancer treatment.However,developing multifunctional biodegradable,biocompatible,low-toxic but highly efficient,and clinically available transformed nano-immunostimulants remains a challenge and is in great demand.Herein,we report and design of a novel carrier-free photo-chemotherapeutic nano-prodrug COS-BA/Ce6 NPs by combining three multifunctional components-a self-assembled natural small molecule betulinic acid(BA),a water-soluble chitosan oligosaccharide(COS),and a low toxic photosensitizer chlorin e6(Ce6)-to augment the antitumor efficacy of the immune adjuvant anti-PD-L1-mediated cancer immunotherapy.We show that the designed nanodrugs harbored a smart and distinctive“dormancy”characteristic in chemotherapeutic effect with desired lower cytotoxicity,and multiple favorable therapeutic features including improved^(1)O_(2)generation induced by the reduced energy gap of Ce6,pH-responsiveness,good biodegradability,and biocompatibility,ensuring a highly efficient,synergistic photochemotherapy.Moreover,when combined with anti-PD-L1 therapy,both nano-coassembly based chemotherapy and chemotherapy/photodynamic therapy(PDT)could effectively activate antitumor immunity when treating primary or distant tumors,opening up potentially attractive possibilities for clinical immunotherapy.