DNA G-Quadruplexes as Targets for Natural Product Drug Discovery

DNA guanine(G)-quadruplexes(G4s)are unique secondary structures formed by two or more stacked Gtetrads in G-rich DNA sequences.These structures have been found to play a crucial role in highly transcribed genes,especially in cancer-related oncogenes,making them attractive targets for cancer therapeutics.Significantly,targeting oncogene promoter G4 structures has emerged as a promising strategy to address the challenge of undruggable and drug-resistant proteins,such as MYC,BCL2,KRAS,and EGFR.Natural products have long been an important source of drug discovery,particularly in the fields of cancer and infectious diseases.Noteworthy progress has recently been made in the discovery of naturally occurring DNA G4-targeting drugs.Numerous DNA G4s,such as MYC-G4,BCL2-G4,KRAS-G4,PDGFR-b-G4,VEGF-G4,and telomeric-G4,have been identified as potential targets of natural products,including berberine,telomestatin,quindoline,sanguinarine,isaindigotone,and many others.Herein,we summarize and evaluate recent advancements in natural and nature-derived DNA G4 binders,focusing on understanding the structural recognition of DNA G4s by small molecules derived from nature.We also discuss the challenges and opportunities associated with developing drugs that target DNA G4s.

Simultaneous purification of minor components in natural products using twin-column recycling chromatography with a step solvent gradient

The isolation of minor components from complex natural product matrices presents a significant challenge in the field of purification science due to their low concentrations and the presence of structurally similar compounds.This study introduces an optimized twin-column recycling chromatography method for the efficient and simultaneous purification of these elusive constituents.By introducing water at a small flowing rate between the twin columns,a step solvent gradient is created,by which the leading edge of concentration band would migrate at a slower rate than the trailing edge as it flowing from the upstream to downstream column.Hence,the band broadening is counterbalanced,resulting in an enrichment effect for those minor components in separation process.Herein,two target substances,which showed similar peak position in high performance liquid chromatography(HPLC)and did not exceed 1.8%in crude paclitaxel were selected as target compounds for separation.By using the twin-column recycling chromatography with a step solvent gradient,a successful purification was achieved in getting the two with the purity almost 100%.We suggest this method is suitable for the separation of most components in natural produces,which shows higher precision and recovery rate compared with the common lab-operated separation ways for natural products(thin-layer chromatography and prep-HPLC).

Natural Products Improve Organ Microcirculation Dysfunction Following Ischemia/Reperfusion-and Lipopolysaccharide-Induced Disturbances:Mechanistic and Therapeutic Views

Microcirculatory disturbances are complex processes caused by many factors,including abnormal vasomotor responses,decreased blood flow velocity,vascular endothelial cell injury,altered leukocyte and endothelial cell interactions,plasma albumin leakage,microvascular hemorrhage,and thrombosis.These disturbances involve multiple mechanisms and interactions among mechanisms that can include energy metabolism,the mitochondrial respiratory chain,oxidative stress,inflammatory factors,adhesion molecules,the cytoskeleton,vascular endothelial cells,caveolae,cell junctions,the vascular basement membrane,neutrophils,monocytes,and platelets.In clinical practice,aside from drugs that target abnormal vasomotor responses and platelet adhesion,there continues to be a lack of multi-target drugs that can regulate the complex mechanistic links and interactions underlying microcirculatory disturbances.Natural products have demonstrated obvious positive therapeutic effects in treating ischemia/reperfusion(I/R)-and lipopolysaccharide(LPS)-induced microcirculatory disturbances.In recent years,numerous research papers on the improvement of microcirculatory function by natural products have been published in international journals.In 2008 and 2017,the first listed author of this review was invited to publish reviews in the journal of Pharmacology&Therapeutics on the improvement of microcirculatory disturbances and organ injury induced by I/R using Salvia miltiorrhiza ingredients and other natural components of compounded Chinese medicine,respectively.This review systematically summarizes the effects,targets of action,and mechanisms of natural products regarding improving I/R-and LPSinduced microcirculatory disturbances and tissue injury.Based on this summary,scientific proposals are suggested for the discovery of new drugs to improve microcirculatory disturbances in disease.

Recent Advances of Bioactive Marine Natural Products in Drug Discovery

Marine natural products(MNPs)are valuable resources for drug development.To date,17 drugs from marine sources are in clinical use,and 33 pharmaceutical compounds are in clinical trials.Presently the success of drug development from the marine resources is higher than the industry average.It is a feasible strategy to conduct the discovery of druglead compounds based on marine chemical ecology by fully exploiting the pharmacological potential of marine chemical defense matters.In the search for bioactive MNPs,our group has constructed a biological resources library including more than 1500 strains of fungi.Focusing on the strategy of Blue Drug Library,we have discovered a series of novel MNPs with abundant biological functions.Highly efficient and scalable total synthesis of(+)-aniduquinolone A(44)and pesimquinolone I(48)have been completed,which will facilitate access to sufficient quantities of candidates for in vivo pharmacological and toxicological studies.As a nucleoprotein(NP)inhibitor,QLA(75)possesses significant anti-influenza A virus(IAV)activities both in vitro and in vivo.CHNQD-00803(76)is a potent and selective AMP-activated kinase(AMPK)activator that can effectively inhibit metabolic disorders and metabolic dysfunction-associated steatohepatitis(MASH)progression.Moreover,we identified two new candidate molecules with potent anti-hepatocellular carcinoma effects.Particularly,as a natural guanine-nucleotide exchange factors for ADP-ribosylation factor GTPases(Arf-GEFs)inhibitor prodrug,CHNQD-01255(78)is qualified to be developed as a targeted candidate anticancer drug,which may be promising to apply for cancer immunotherapy.Hence,it is evident that MNPs play an important role in drug development.

Research progress on natural products against hepatocellular carcinoma

Hepatocellular carcinoma(HCC)remains a prevalent and challenging malignancy globally,characterized by its numerous causal factors and generally unfavorable prognosis.In the relentless pursuit of effective treatment modalities,natural products have emerged as a promising and relatively non-toxic alternative,garnering significant interest.The integration of natural products with contemporary medical research has yielded encouraging therapeutic outcomes in the management of HCC.This review offers a comprehensive overview of the causal factors underlying HCC,and the diverse treatment options available,and highlights the advancements made by natural products in anti-HCC research.Particularly,we provide an outline of the various types of natural products,their corresponding nomenclature,target molecules,and mechanisms of action that exhibit anti-HCC activities.Natural products are anticipated to play a pivotal role in future comprehensive treatment plans for liver cancer,potentially offering patients improved survival rates and an enhanced quality of life.

Natural product-based treatment potential for type 2 diabetes mellitus and cardiovascular disease

BACKGROUND Type 2 diabetes(T2D)is a metabolic disease of impaired glucose utilization and a major cause of cardiovascular disease(CVD).The pathogenesis of both diseases shares common risk factors and mechanisms,and both are significant contributors to global morbidity and mortality.Supplements of natural products for T2D mellitus(T2DM)and CVD can be seen as a potential preventive and effective therapeutic strategy.AIM To critically evaluate the therapeutic potential of natural products in T2D and coronary artery disease(CAD).METHODS By using specific keywords,we strategically searched the PubMed database.Randomized controlled trials(RCTs)were searched as the primary focus that examined the effect of natural products on glycemic control,oxidative stress,and antioxidant levels.We focused on outcomes such as low blood glucose levels,adjustment on markers of oxidative stress and antioxidants.After screening fulllength papers,we included 9 RCTs in our review that met our inclusion criteria.RESULTS In the literature search on the database,we found that various natural products like plant secondary metabolites play a diverse role in the management of CAD.American ginseng,sesame oil and cocoa flavanols proved effective in lowering blood glucose levels and controlling blood pressure,which are key factors in managing T2DM and CVD.In diabetic patients Melissa officinalis effectively reduce inflammation and shows diabetes prevention.Both fish oil and flaxseed oil reduced insulin levels and inflammatory markers,suggesting benefits for both conditions.The lipid profile and endothelial function were enhanced by Nigella sativa oil and Terminalia chebula,which is significant for the management of cardiovascular risk factors in T2DM.Additionally Bilberry extract also showed promise for improving glycemic control in patients with T2DM.CONCLUSION The high level of antioxidant,anti-inflammatory,and anti-angiogenic properties found in natural products makes them promising therapeutic options for the management of CAD,with the potential benefit of lowering the risk of CAD.

Targeting oxidative stress with natural products: A novel strategy for esophageal cancer therapy

Esophageal cancer(ESC)is a malignant tumor that originates from the mucosal epithelium of the esophagus and is part of the digestive tract.Although the exact pathogenesis of ESC has not been fully elucidated,excessive oxidative stress is an important characteristic that leads to the development of many cancers.Abnormal expression of several proteins and transcription factors contributes to oxidative stress in ESCs,which alters the growth and proliferation of ESCs and promotes their metastasis.Natural compounds,including alkaloids,terpenes,polyphenols,and xanthine compounds,can inhibit reactive oxygen species production in ESCs.These compounds reduce oxidative stress levels and subsequently inhibit the oc-currence and progression of ESC through the regulation of targets and pathways such as the cytokine interleukins 6 and 10,superoxide dismutase,the NF-+ACY-kappa+ADs-B/MAPK pathway,and the mammalian Nrf2/ARE target pathway.Thus,targeting tumor oxidative stress has become a key focus in anti-ESC therapy.This review discusses the potential of Natural products(NPs)for treating ESCs and summarizes the application prospects of oxidative stress as a new target for ESC treatment.The findings of this review provide a reference for drug development targeting ESCs.Nonetheless,further high-quality studies will be necessary to determine the clinical efficacy of these various NPs.

Natural product-induced oxidative stress-synergistic anti-tumor effects of chemotherapeutic agents

Reactive oxygen species are closely related to tumor development.In recent years,reactive oxygen species has become a hot spot in tumor therapy,and many natural substances in nature contain compound components with anti-tumor effects.However,there is a lack of discussion on the synergistic anti-tumor effects of natural products in combination with chemotherapeutic drugs through reactive oxygen species.The terms“natural products”,“reactive oxygen species”,“anti-tumor”,and“chemotherapy”were used to identify the synergistic effects of natural products.We conducted a systematic literature search in PubMed and Web of Science databases for relevant research articles and reviews published in recent years.We systematically summarized the studies related to anti-tumor active ingredients in natural compounds in the field of reactive oxygen species in recent years.A total of 77 relevant literatures were included.Among them,45 literatures containing various natural products such as terpenoids,flavonoids,alkaloids,etc.exert anti-tumor effects by regulating reactive oxygen species levels,and 32 literatures regarding adjunctive role of natural products in anti-tumor therapy.In this study,we found that natural products exert anti-tumor effects by elevating reactive oxygen species levels.It provides strong theoretical support for future clinical studies.

Current therapeutic modalities and chemopreventive role of natural products in liver cancer:Progress and promise

Liver cancer is a severe concern for public health officials since the clinical cases are increasing each year,with an estimated 5-year survival rate of 30%–35%after diagnosis.Hepatocellular carcinoma(HCC)constitutes a significant subtype of liver cancer(approximate75%)and is considered primary liver cancer.Treatment for liver cancer mainly depends on the stage of its progression,where surgery including,hepatectomy and liver transplantation,and ablation and radiotherapy are the prime choice.For advanced liver cancer,various drugs and immunotherapy are used as first-line treatment,whereas second-line treatment includes chemotherapeutic drugs from natural and synthetic origins.Sorafenib and lenvatinib are first-line therapies,while regorafenib and ramucirumab are secondline therapy.Various metabolic and signaling pathways such as Notch,JAK/STAT,Hippo,TGF-β,and Wnt have played a critical role during HCC progression.Dysbiosis has also been implicated in liver cancer.Drug-induced toxicity is a key obstacle in the treatment of liver cancer,necessitating the development of effective and safe medications,with natural compounds such as resveratrol,curcumin,diallyl sulfide,and others emerging as promising anticancer agents.This review highlights the current status of liver cancer research,signaling pathways,therapeutic targets,current treatment strategies and the chemopreventive role of various natural products in managing liver cancer.

Role of natural products and intestinal flora on type 2 diabetes mellitus treatment

Diabetes mellitus(DM)is a complicated,globally expanding disease that is influenced by hereditary and environmental variables.Changes in modern society’s food choices,physical inactivity,and obesity are significant factors in the development of type 2 DM(T2DM).The association between changes in intestinal flora and numerous disorders,including obesity,diabetes,and cardiovascular diseases,has been studied in recent years.The purpose of this review is to analyze the mechanisms underlying the alteration of the diabetic patients’intestinal flora,as well as their therapeutic choices.Also included is a summary of the antidiabetic benefits of natural compounds demonstrated by studies.The short-chain fatty acids theory,the bile acid theory,and the endotoxin theory are all potential methods by which intestinal flora contributes to the establishment and progression of T2DM.Due to an intestinal flora imbalance,abnormalities in shortchain fatty acids and secondary bile acids have been found in diabetic patients.Additionally,metabolic endotoxemia with altering flora induces a systemic inflammatory response by stimulating the immune system via bacterial translocation.The agenda for diabetes treatment includes the use of short-chain fatty acids,probiotics,prebiotics in the diet,fecal bacteria transplantation,and antibiotics.Animal studies have proven the antidiabetic benefits of numerous bioactive substances,including Flavonoids,Alkaloids,Saponin,and Allicin.However,further research is required to contribute to the treatment of diabetes.

Marine natural product lepadin A as a novel inducer of immunogenic cell death via CD91-dependent pathway

Immunogenic Cell Death(ICD)represents a mechanism of enhancing T cell-driven response against tumor cells.The process is enabled by release of damage-associated molecular patterns(DAMPs)and cytokines by dying cells.Based on molecular studies and clinical marker assessment,ICD can be a new target for cancer chemotherapy hitherto restricted to a few conventional anticancer drugs.In view of the development of small molecules in targeted cancer therapy,we reported the preliminary evidence on the role of the natural product lepadin A(1)as a novel ICD inducer.Here we describe the ICD mechanism of lepadin A(1)by proving the translocation of the protein calreticulin(CRT)to the plasma membrane of human A2058 melanoma cells.CRT exposure is an ICD marker in clinical studies and was associated with the activation of the intrinsic apoptotic pathway in A2058 cells with lepadin A(1).After the treatment,the tumour cells acquired the ability to activate dendritic cells(DCs)with cytokine release and costimulatory molecule expression that is consistent with a phenotypic profile committed to priming T lymphocytes via a CD91-dependent mechanism.The effect of lepadin A(1)was dose-dependent and comparable to the response of the chemotherapy drug doxorubicin(2),a well-established ICD inducer.

Natural products and extracts from plants as natural UV filters for sunscreens:A review

Although solar exposure is necessary for human health,phototoxicology induced by excessive UVB and UVA radiation,which involves sunburns,skin aging and even tu-morigenesis,has been widely researched.Sunscreen is one of the most important ways to protect skin from UV phototoxic damage.As well as inorganic and organic UV filters,some natural products or plant extracts with aromatic rings in their structures,such as flavonoids or polyphenols,can absorb UV to reduce sunburn,acting as a natu-ral UV filter;they also show antioxidant or/and anti-inflammatory activity.This could explain why,although there are no officially approval natural commercial sun-filters,more and more commercial sunscreen products containing plant extracts are avail-able on the market.Here we summarize articles focusing on natural UV filters from plant published in the last 6 years,selecting the most significant data in order to better understand the photoprotective activity of natural products and extracts from plants,including their major constituents and main biological effects,methods for evaluating UV radiation resistance,anti-UV radiation experimental models and anti-UV radiation mechanisms.

Mechanisms of action of natural products on type 2 diabetes

Over the past several decades,type 2 diabetes mellitus(T2DM)has been considered a global public health concern.Currently,various therapeutic modalities are available for T2DM management,including dietary modifications,moderate exercise,and use of hypoglycemic agents and lipid-lowering medications.Although the curative effect of most drugs on T2DM is significant,they also exert some adverse side effects.Biologically active substances found in natural medicines are important for T2DM treatment.Several recent studies have reported that active ingredients derived from traditional medicines or foods exert a therapeutic effect on T2DM.This review compiled important articles regarding the therapeutic effects of natural products and their active ingredients on isletβcell function,adipose tissue inflammation,and insulin resistance.Additionally,this review provided an in-depth understanding of the multiple regulatory effects on different targets and signaling pathways of natural medicines in the treatment of T2DM as well as a theoretical basis for clinical effective application.

Prioritised identification of structural classes of natural products from higher plants in the expedition of antimalarial drug discovery

The emergence and spread of drug-recalcitrant Plasmodium falciparum parasites threaten to reverse the gains made in the fight against malaria.Urgent measures need to be taken to curb this impending challenge.The higher plant-derived sesquiterpene,quinoline alkaloids,and naphthoquinone natural product classes of compounds have previously served as phenomenal chemical scaffolds from which integral antimalarial drugs were developed.Historical successes serve as an inspiration for the continued investigation of plant-derived natural products compounds in search of novel molecular templates from which new antimalarial drugs could be developed.The aim of this study was to identify potential chemical scaffolds for malaria drug discovery following analysis of historical data on phytochemicals screened in vitro against P.falciparum.To identify these novel scaffolds,we queried an in-house manually curated database of plant-derived natural product compounds and their in vitro biological data.Natural products were assigned to different structural classes using NPClassifier.To identify the most promising chemical scaffolds,we then correlated natural compound class with bioactivity and other data,namely(i)potency,(ii)resistance index,(iii)selectivity index and(iv)physicochemical properties.We used an unbiased scoring system to rank the different natural product classes based on the assessment of their bioactivity data.From this analysis we identified the top-ranked natural product pathway as the alkaloids.The top three ranked super classes identified were(i)pseudoalkaloids,(ii)naphthalenes and(iii)tyrosine alkaloids and the top five ranked classes(i)quassinoids(of super class triterpenoids),(ii)steroidal alkaloids(of super class pseudoalkaloids)(iii)cycloeudesmane sesquiterpenoids(of super class triterpenoids)(iv)isoquinoline alkaloids(of super class tyrosine alkaloids)and(v)naphthoquinones(of super class naphthalenes).Launched chemical space of these identified classes of compounds was,by and large,distinct from that of‘legacy’antimalarial drugs.Our study was able to identify chemical scaffolds with acceptable biological properties that are structurally different from current and previously used antimalarial drugs.These molecules have the potential to be developed into new antimalarial drugs.

Natural product rhynchophylline prevents stress-induced hair graying by preserving melanocyte stem cells via theβ2 adrenergic pathway suppression

Norepinephrine(NA),a stress hormone,can accelerate hair graying by binding toβ2 adrenergic receptors(β_(2)AR)on melanocyte stem cells(McSCs).From this,NA-β_(2)AR axis could be a potential target for preventing the stress effect.However,identifying selective blockers forβ_(2)AR has been a key challenge.Therefore,in this study,advanced computer-aided drug design(CADD)techniques were harnessed to screen natural molecules,leading to the discovery of rhynchophylline as a promising compound.Rhynchophylline exhibited strong and stable binding within the active site ofβ_(2)AR,as verified by molecular docking and dynamic simulation assays.When administered to cells,rhyncho-phylline effectively inhibited NA-β_(2)AR signaling.This intervention resulted in a significant reduction of hair graying in a stress-induced mouse model,from 28.5%to 8.2%.To gain a deeper understanding of the underlying mechanisms,transcriptome sequencing was employed,which revealed that NA might disrupt melanogenesis by affecting intracellular calcium balance and promoting cell apoptosis.Importantly,rhynchophylline acted as a potent inhibitor of these downstream pathways.In conclusion,the study demonstrated that rhynchophylline has the potential to mitigate the negative impact of NA on melanogenesis by targetingβ_(2)AR,thus offering a promising solution for preventing stress-induced hair graying.

Occurrence of D-amino acids in natural products

Since the identified standard genetic code contains 61 triplet codons of three bases for the 20 L-proteinogenic amino acids(AAs),no D-AA should be found in natural products.This is not what is observed in the living world.D-AAs are found in numerous natural compounds produced by bacteria,algae,fungi,or marine animals,and even vertebrates.A review of the literature indicated the existence of at least 132 peptide natural compounds in which D-AAs are an essential part of their structure.All compounds are listed,numbered and described herein.The two biosynthetic routes leading to the presence of D-AA in natural products are:non-ribosomal peptide synthesis(NRPS),and ribosomally synthesized and post-translationally modified peptide(RiPP)synthesis which are described.The methods used to identify the AA chirality within naturally occurring peptides are briefly discussed.The biological activity of an all-L synthetic peptide is most often completely different from that of the D-containing natural compounds.Analyzing the selected natural compounds showed that D-Ala,D-Val,D-Leu and D-Ser are the most commonly encountered D-AAs closely followed by the non-proteinogenic D-allo-Thr.D-Lys and D-Met were the least prevalent D-AAs in natu-rally occurring compounds.

Acute kidney injury:microRNAs and new therapeutic opportunities for natural products

In the past few decades,acute kidney injury(AKI),characterized by an abrupt decrease in kidney filtration rate,has become a public health issue affecting between 1%and 15%of the population,which causes high morbidity and death.There is mounting evidence that miRNAs are noncoding single-stranded RNAs with a short length of about 20 nucleotides and have been highly conserved through evolution.Through targeting mRNAs,miRNA may mediate intercellular communication during AKI’s physiological and pathological processes.It is interesting to note that natural products can improve AKI by regulating miRNA expression,which might represent a potentially innovative therapeutic strategy.This review aims at providing an overview of the new data obtained on miRNAs in the treatment and diagnosis of AKI,summarizing studies on natural products improving AKI through regulating miRNAs’expression;in the same time,it will shed new light on AKI risk biomarkers and therapeutic intervention as well.We summarized the roles of miRNAs involved in AKI progression or protection against renal injury in 32 articles;we found five natural products can improve AKI by regulating miRNA expression,which will potentially provide a reference for clinical treatment.Natural products might represent a potentially innovative therapeutic strategy;in the same time,miRNAs will shed new light on AKI risk biomarkers and therapeutic intervention.

Research progress of natural products in treating polycystic ovary syndrome

Polycystic ovary syndrome(PCOS)is a common metabolic disorder reproductive endocrine disease in puberty and women of childbearing age.At present,metformin is mainly used in clinical to treat PCOS.From recent researches,many natural products,such as flavonoids,alkaloids,cumarins,etc,showed curing effects on PCOS.These have been attracting more and more attention.By searching the researches from database of CNKI,PubMed etc,this paper aims at providing a reference for PCOS drug research and development.

A Review of Textile Fabrication Using Bioactive Compounds Derived from Natural Products

Antimicrobial-treated textiles should exhibit efficacy against a broad spectrum of bacterial and fungal species,all while maintaining user safety with a non-toxic profile.Natural antimicrobial compounds play a vital role in textile finishing processes.The proliferation of synthetic antimicrobial agents introduces environmental and consumer safety concerns.Given these potential hazards associated with synthetic agents,the utilization of natural antimicrobial agents is gaining traction,as they tend to have fewer adverse effects on users and are more environmentally sustainable.Numerous natural antimicrobial compounds,sourced from plants such as neem,basil,turmeric,aloe vera,and clove oil,have been developed,showcasing inherent antimicrobial properties.This review article highlights the importance of incorporating bioactive components in the creation of antibacterial textile fabrics.

Exploring the efficacy of natural products in alleviating Alzheimer’s disease

Alzheimer’s disease(hereafter AD) is a progressive neurodegenerative disorder that affects the central nervous system. There are multiple factors that cause AD, viz., accumulation of extracellular Amyloid-beta 42 plaques, intracellular hyper-phosphorylated Tau tangles, generation of reactive oxygen species due to mitochondrial dysfunction and genetic mutations. The plaques and tau tangles trigger aberrant signaling, which eventually cause cell death of the neurons. As a result, there is shrinkage of brain, cognitive defects, behavioral and psychological problems. To date, there is no direct cure for AD. Thus, scientists have been testing various strategies like screening for the small inhibitor molecule library or natural products that may block or prevent onset of AD. Historically, natural products have been used in many cultures for the treatment of various diseases. The research on natural products have gained importance as the active compounds extracted from them have medicinal values with reduced side effects, and they are bioavailable. The natural products may target the proteins or members of signaling pathways that get altered in specific diseases. Many natural products are being tested in various animal model systems for their role as a potential therapeutic target for AD, and to address questions about how these natural products can rescue AD or other neurodegenerative disorders. Some of these products are in clinical trials and results are promising because of their neuroprotective, anti-inflammatory, antioxidant, anti-amyloidogenic, anticholinesterase activities and easy availability. This review summarizes the use of animal model systems to identify natural products, which may serve as potential therapeutic targets for AD.