Agrochemicals, whichare crucial to meet the world food qualitativeand quantitative demand, are compounds used to kill pests . Regrettably, there are some importantissues associated with their widespread and extensive use ; thus, a reducedand more controlled use of agrochemicals and thorough detection infood, water, soil, and fields are necessary. In this regard, the developmentof new functional materials for the efficient application, detection,and removal of agrochemicals is a priority. Metal–organic frameworks(MOFs) with exceptional sorptive, recognition capabilities, and catalyticalproperties have very recently shown their potential in agriculture.This Review emphasizes the recent advances in the use of MOFs in agriculturethrough three main views: environmental remediation, controlled agrochemicalrelease, and detection of agrochemicals. Agrochemicals canbe classified on the basis of various principles, such as toxicity,target, chemical composition and formula, mode of entry or action,and source. Here, we will classify them according to their mode ofaction, although their toxicity, target, and origin will also be discussed.Thus, agrochemicals can be divided into pesticides , fertilizers , soil conditioners , liming (Ca and Mg) and acidifying agents, andplant growth regulators .1 the intensive use of agrochemicals has deterioratedthe quality of ecosystems  byimpacting human health and, in recent years, leading to the developmentof pesticide-resistant strains.4 Over the period of 2011–2018,pesticide sales were around 360,000 tons per year only in the EuropeanUnion (EU) with the major groups sold being fungicides, herbicides,and bactericides. This is particularly crucial since, according tothe Food and Agriculture Organization (FAO) of the United Nations,agriculture occupies about 38% of Earth’s terrestrial surface.5 High and repeated doses of hazardous agrochemicalsare routinely used to protect crops against pests  and boost food productivity .With a global population projected to rise above 9.7 billion by 2050,food security is of increasing importance. Herbicides are the mostwidely used pesticides, comprising >40% of total use, while insecticidesand fungicides constitute approximately 30% and 20%, respectively.Pesticide/fertilizer pollution patterns are well-established witha major pollution peak taking place a few days or weeks after agrochemicalapplication.6 Ideally, their toxic effectshould be limited to both the target area and organisms. However,the lack of specificity of agrochemicals and their widespread use7 allow them to leach out of the soil and entersurface water and groundwater; therefore, they are even present indrinking water.8Witha dramatic increase after the second World War,10 resultingin frequent contamination of terrestrial and aquatic environments.11 The EU Drinking Water Directive sets the general drinking waterquality standard for added concentrations of pesticides and theirmetabolites to be less than 0.5 μg·L–1. Remarkably, most of the studies in this field report that ∼80%of the studied pesticides are found in concentrations much higherthan the EU water quality standard  in the area of Zurich, Switzerland,13 40-, 25-, and 20-fold higher concentrationsof amitrole, diuron, and terbuthylazine in the Arc River in France,respectively,14 and 8-, 12-, 16-, and 25-foldhigher concentrations of oxadiazon, pretilachlor, bentazone, and 2-methyl-4-chlorophenoxyaceticacid (MCPA) in the Rhône River in France, respectively,15 among others).On the basis oftheir application methods, between 10% and 75%of the pesticides do not reach their targets,16 However, the vastmajority of these countries lack the capacity to handle chemical managementissues and, furthermore, they still need to develop legislation, institutions,and general awareness. Therefore, this should be considered a globalenvironmental problem. In terms of acute toxicity to humans, manyagrochemicals manifest their toxicity through biochemical and functionalactions in the central and peripheral nervous system. Also, althoughnot always easy to identify, there is evidence that links long-termexposure to some pesticides with chronic illnesses, including dermal,respiratory, liver, and kidney disorders,17 fertility difficulties,19 postponed neuropathy,20 and cancer .21 In this sense, it is likely that the scale and outcome of pesticide-associatedchronic effects are underestimated as the symptoms of such poisoningsmay be incorrectly attributed to other affects. Aside from toxicityto humans, in terms of environmental costs, the unsystematic use ofagrochemicals increases pest and disease resistance, diminishes nitrogenfixation and soil biodiversity, and increases the bioaccumulationof pesticides.22 Finally, the loss of livestockto resistant bacterial diseases also represents a considerable wasteof water and energy investment as well as capital.Despite the strict EU regulation,pesticides continue enter thefood chain through water and food. Regarding other regions, the problemis magnified. For example, it is predicted that in 2050 the majorpart of global chemical sales will take place in Asia. During thelast two decades, South-East Asian countries have shown a strong industrialgrowth in agriculture.23 However,as for pesticides, the use of chemical fertilizers is limited by theirpoor specificity, increasing both the environmental and productioncosts .26 Further, inefficiencies in the production of food are further intensifiedby food waste .27 The actual scenario of the inefficient use offertilizers and intensive irrigation, biocides, and processed foodis stressing ecosystems and leading to significant environmental collateralinjuries .5 All theabove suggests that water, food, nature, and animal and human healthare inextricably linked to the agri-food systems.Apart frompesticides, fertilizers are among the major contributorsto raise crop yield, and therefore, their use has been exponentiallyenhanced over the past decades .229 nanopesticidesand nanofertilizers have been proposed as a novel class of plant protectionand growth products that promise a number of benefits to agriculture,the environment and, finally, human health. One of their key driversis the important reduction in the quantity of agrochemicals necessaryto guarantee crop protection and growth, which may be achieved bydifferent ways, such as (i) improved apparent solubility and stabilityof photo- and thermolabile agrochemicals or active ingredients (AIs),(ii) controlled release and targeted delivery of AIs, and (iii) enhancedbioavailability and adhesion  or by reducing losses of mobile nutrients to other naturalenvironments (nitrate). However, long-term instability, subsequentburst agrochemical release, and associated toxicity are some of themajor drawbacks that need to be addressed.The increase of society’s concern regardingthe potentialdamage of agrochemical application in agricultural production haschallenged industry and researchers to search for new efficient andsafer methods against insect pests, infections, and unwanted plantsor weeds. In this sense, nanotechnology research has recently receivedan increasing attention in agriculture. With the general aim of developingdelivery nanosystems for agrochemicals,adhesion 1. Nanoca340 MOFs have been proposed for many societal andindustrially relevant applications, such as adsorption,41 separation,42 magnetism,43 luminescence,44 conductivity,45 sensing,43 catalysis,46 energy,47 drug delivery,48 etc. In particular, MOFs are promising materialsin agriculture due to their interesting properties: (i) versatilehybrid compositions, which allow a huge variety of combinations, (ii)large specific surface areas and pore volumes, related to exceptionalsorption capacities, (iii) simply functionalizable cavities, wherespecific host–guest interactions may occur, (iv) synthesisat large scale , and (v)an adequate stability profile, so they are stable enough to accomplishtheir function and, after being degraded, prevent associated toxicityin animals/plants due to their accumulation.Among the novel technologies proposedin agriculture, metal–organicframeworks (MOFs) have gained a significant role in the fields ofthe elimination of agrochemicals (adsorption and/or photodegradation)and sensing. MOFs are considered to be a remarkable class of highlyporous coordination polymers, containing inorganic nodes  and organic linkers , that assemble into multidimensional periodic lattices.53 or their potential in the detection and quantification of thesepotentially toxic molecules,55 the use of MOFs as agrochemical delivery systems is a very recentresearch field, initiated in 2015.56 Groupedby their function, this Review will discuss the MOFs and MOF-basedcomposites that have been investigated to date in the agriculturaldomain. In order to give a broad spectrum of benefits and drawbacksof the use of each material, particular features of each structureand its properties are also included. In the text, the most original,interesting, and promising MOFs in agriculture will be highlighted,although all the reports currently found in the literature are summarizedin Different strategieshave been reported in the use of MOF-typematerials in agriculture. In particular, related to agrochemicals,MOFs have been proposed (i) in water remediation through the elimination(adsorption/degradation) of agrochemicals or derived products, (ii)as carriers for the controlled release of agrochemicals, and (iii)as sensors for the determination of these molecules in water or food2. While 4herbicides: alachlor, atrazine (ATZ), bentazon, chipton, clopyralid,2,4-dichlorophenoxyacetic acid , diuron (DUR), glufosinate(GLU), glyphosate (GLY), gramoxone, isoproturon (IPU), mecoprop, paraquat,quizalofop-P-ethyl (QPE), and tebuthiuron; (ii) fungicides: propiconazole and thifluzamide (THI); (iii) insecticides: chlorantraniliprole, chlorpyrifos, cyhalothrin, diazinon, dichlorvos,dimethoate, ethion, fenamiphos, fenitrothion, malathion methyl, metrifonate,nitenpyram (NIT), paraoxon, parathion methyl, prothiofos, thiamethoxam,several neonicotinoids , and organophosphoruspesticides . In recent years, MOFs have exponentiallybeen investigated forthe removal (mainly adsorption or degradation processes) of differentcontaminants from water. Originally, this field was focused on theremoval of organic dyes, although recently, agrochemicals have alsobeen included as target contaminants due to their increasing presencein natural waters and their severe toxicity to living beings. Thus,an increase in the number of reports dealing with the eliminationof different agrochemicals using MOFs has been reported 3, includ4.12BDC: benzene-1,4-dicarboxylic acid, poresize of ∼8 Å).57 MIL-53(Cr)exhibited an efficient and fast adsorption (556 mg·g–1 in 1 h) with an adsorption capacity much higher than that of activatedcarbon (286 mg·g–1) or zeolite (256 mg·g–1). Importantly, the adsorption of 2,4-D at a verylow concentration is 5-fold greater that of activated carbon at aplateau concentration, demonstrating the utility of MIL-53(Cr) incommercial uses for consumed water with low 2,4-D levels. Finally,the recyclability of MIL-53(Cr), after washing the MOF with a mixtureof water/ethanol, was also noticeable after 3 cycles, suggesting thepotential application of this MOF on the herbicide’s removal.In a more recent work, a series of furan-thiophene derived from Cr-MOFMIL-101(Cr) ([Cr3(O)X-(BDC)3(H2O)2], X = OH or F; Brunauer–Emmett–Teller surfacearea (SBET) ∼ 4100 m2 g–1; pore volume (Vp) = 2.02 cm3 g–1; pore size of 11.7and 16 Å) was achieved via visible-light-mediated C–Cbond-forming catalysis within photosensitizing porous materials.58 The process of trapping the guest molecule wasaccomplished under metal-free and very mild conditions, leading tonovel functionalized MOFs with more π–π stacking,H bonding properties, and outstanding adsorption capacity to eliminateherbicides from the aqueous solutions. The synthesized MOFs removedup to 96.9% of the tested herbicides from the aqueous solutions evenat initially very low herbicide concentrations (30 ppm). Particularly,the Br derivative MIL-101(Cr)-C5 inhibited the maximum adsorbed capacitiesfor DUR, alachlor, and tebuthiuron with adsorption capacities of 186.4,150.2, and 95.2 mg·g–1, respectively. Veryrecently, a composite based on Zr-MOF UiO-66-NH2 ([Zr6O4(OH)4(BDC-NH2)6]·nH2O; SBET ∼ 950 m2 g–1; pore size of ∼11and 8 Å; H2BDC-NH2: 2-aminoterephthalicacid) was described for the removal of herbicides in water.59 UiO-66-NH2 was loaded on the carbonnanotube aerogels (MPCAs) by the in situ nucleationand growth of the UiO-66-NH2 NPs onto the carbon nanotubes(UiO-66-NH2@MPCA). The study on the adsorption of chiptonand alachlor demonstrated that the adsorption capacity of UiO-66-NH2@MPCA was improved with respect the single MOF NPs, whichis indicative of a synergistic effect between the MOF and MPCA . Further, rice was used to assess the biosecurityof the composite. Remarkably, UiO-66-NH2@MPCA could reducethe accumulation of Zr4+ in the roots and leaves of ricein comparison with the UiO-66-NH2 NPs, demonstrating thatMPCA can diminish the potential environmental risk of the MOF materials.Lastly, the authors demonstrated the reusability of the compositeup to 5 times without decreasing its adsorption capacity. Finally,we want to highlight two reports utilizing the water stable Zr-basedMOF NU-1000 ([Zr6(μ3-O)4(μ3–OH)4(−OH)4(−OH2)4(PyTBA)2]; PyTBA: 4,4′,4″,4‴-tetrabenzoate; SBET ∼ 2100 m2·g–1; pore size of ∼12 and 30 Å). In the first study, reportedby Pankajakshan et al.,60 NU-1000 was describedfor the efficient elimination of GLY from aqueous media. NU-1000 comprises[Zr6(μ3-O)4(μ3-OH)4(H2O)4(OH)4] assecondary building units, acting as Lewis acid nodes that can reactwith the Lewis base phosphate group of GLY. Theoretical calculationsdemonstrated that the interaction energy of GLY with the NU-1000 nodeswas −37.63 KJ·mol–1. NU-1000 was synthesizedin different particle size scales (100–2000 nm), reducing theequilibrium times with smaller MOF sizes and achieving a total GLYloading of 1516.02 mg·g–1 (or 8.97 mg·g–1) in only 20 min. In the second work, the same authorsthoroughly investigated the mechanism governing ATZ adsorption onZr6-based MOFs  by investigatingthe impact of MOF used linkers and topology on ATZ uptake capacityand kinetics.61 Among all the tested Zr-MOFs,it was found that the mesopores of NU-1000 facilitate the rapid ATZuptake, saturating in less than 5 min. Excluding the pyrene-basedlinker, NU-1008 ([Zr6(μ-O)4(μ-OH)4(HCOO)(H2O)3(OH)3(TCPB)2]; TCPB: 1,2,4,5-tetrakis(4-carboxyphenyl)benzene; SBET ∼ 1400 m2·g–1; pore size of ∼14 and 30 Å) removed <20% of the exposedATZ. The pyrene-based linker seems to offer enough sites for π–πinteractions with ATZ as revealed by the near 100% uptake  material([Cr(OH)(BDC)]; H% uptake 4. These 4.26(TCPP)1.5]; H2TCPP:tetrakis(4-carboxyphenyl)porphyric; SBET = 2600 m2·g–1; Vp = 0.95 cm3·g–1; poresize = 1.9 nm) as both the sensor for the recognition of trace NITand the photocatalyst to enable the pesticide degradation.62 The intense fluorescence of the probe was quenchedby NIT, leading to a sensing range from 0.05 to 10.0 μg·mL–1. The potentiality of PCN-224 in the degradation ofNIT was further identified. The photodegradative effectiveness wasup to 95% after only 20 min of laser irradiation, whereas no significantNIT degradation was detected under darkness, regardless of the PCN-224presence. Therefore, this material could be established as an all-in-onenanoplatform for pesticide sensing, detection, and posterior photodegradationin agricultural farmland and other environments. Among other MOF-basedcomposites, metallic NP composites are the most employed. The MIL-53(Fe)@AgIO3 composite was successfully applied in the decomposition oftwo organophosphate pesticides under sunlight irradiation.63 After 1 hof solar light irradiation, 78–90% of both pesticides was individuallydegraded in tap and distilled water. In binary mixtures (both composites),70% of mineralization is achieved after 3 h. Another example of metallicNPs@MOF composites is magnetic α-Fe2O3@MIL-101(Cr)@TiO2 for the degradation of paraquat herbicidefrom aqueous solution.64 A maximum photocatalyticdegradation was achieved at optimal conditions  and HRP@H-MOF(Zr)composites were applied in the treatment of wastewater containingIPU and 2,4-D, achieving a complete and very fast (15 min) degradation.Finally, we want to highlight the fabrication of purified esteraseembedded in zeolitic imidazolate frameworks (ZIFs) for the degradationof pesticides.66 Particularly, in thiswork, aryloxyphenoxypropionate herbicide-hydrolyzing enzyme, QpeH,was embedded into ZIF-10 ([Zn(Im)2]; Im: imidazonate) andZIF-8 ([Zn(Hmim)2]; Hmim: 2-methylimidazole; SBET ∼ 1260 m2 g–1, Vp ∼ 0.6 cm3 g–1, pore size of ∼3.4 and 11.4 Å) and tested in the degradationof quizalofop-P-ethyl in a watermelon field. Remarkably, the QpeH@ZIF-10composite showed a slightly improved degradation efficiency comparedto QpeH@ZIF-8 (88% vs 84%). Unfortunately, no ZIF degradation studieswere performed in this research in an attempt to rationalize the differentbehaviors of both ZIF composites and their potential application inreal water treatments. It should be noted that the QpeH@ZIF compositeswere demonstrated to affect the recovery of the bacterial communityin soil.MOFs have also been used as supportfor the stabilization of enzymes able to degrade agrochemicals inwastewater and soil. Gao et al. described the preparation of a hierarchicallyporous MOF (H-MOF(Zr)) as support of the chloroperoxidase (CPO) andhorseradish peroxidase (HRP) enzymes, leading to the CPO/HRP@H-MOF(Zr)composite.5herbicides, cis-1,3-dichloropropene  and ortho-disulfides;(ii) fungicides, diniconazole, prochloraz, tebuconazole,and zoxystrobin; (iii) insecticides, chlorantraniliprole,λ-cyhalothrin, dinotefuran, imidacloprid, and thiamethoxam;(iv) fertilizers: urea; (v) plant grow regulators: gibberellin. The first MOF described as a delivery agent of agrochemicalswas OPA-MOF . In 2015,Anstoetz et al. described the use of an OPA-MOF as a microbially inducedslow-release N and P fertilizer.56 In thisresearch, the capacity of the urea-templated OPA-MOF as a new fertilizerwith a slow release was investigated and compared with a standardP (triple superphosphate) and N (urea) fertilizer . Theauthors hypothesize that the OPA-MOF is a gradual-release fertilizerfor crops grown on acidic soils, where microbial consumption of theoxalate linker gives rise to the degradation of the framework structure,thereby releasing Fe phosphate. While in the OPA-MOF treatment thehydrolysis of urea was fast, the conversion of the ammonium to nitratewas significantly diminished in comparison with the urea treatment. However, P uptake and yield in OPA-MOF was considerablylower than in conventionally fertilized plants. OPA-MOF was provento have potential as an enhanced efficiency N fertilizer but not inP bioavailability. A year later, two novel OPA-MOFs were hydrothermallysynthesized and fully characterized to be used again as slow-releasefertilizers.104 The framework backboneis robust and based on FeO6 units with bidentate oxalatebridges joining adjacent Fe centers. PO4 units have corner-sharingfor all of their oxygens with the FeO6 units. The authorsstudied the release of oxalate, setting it high enough to permit oxalateconcentrations in the soil solution to achieve 1 mg·L–1 but also low enough to avoid fast and purely chemically driven compounddegradation. The results show that, from the two synthesized materials,OPA-MOF-I has a slow solubility with an oxalate concentration of ca.5 mg·L–1 at high loading and seems to be compatiblewith trials as a fertilizer in future works.The recent enthusiasm around the use of MOFs as agrochemical deliveryagents is highlighted in cis-1,3-dichlorophropene.105 The MOF [Ca14(l-lactate)20(acetate)8X] , constructedfrom Ca2+ ions and l-lactate, presents aperturesand an internal diameter of 7.8 and 9.6 Å, respectively, anda permanent porosity of 430 m2·g–1. MOF-1201 can efficiently encapsulate the 1,3-DCPP agrochemicalwith a total pesticide loading of 1.4 mmol·g–1 (13 wt %). Originally, the fumigant release study was performedusing an air flow, demonstrating a slow release when purging samplesof the 1,3-DCPP loaded MOF  in an air flow of 1.0cm3·min–1. The loaded 1,3-DCPP@MOF-1201showed a 100 times slower release compared to that of the liquid 1,3-DCPP,achieving 80% of the total release in 100 000 min·g–1. Porphyrinic MOFs have also been described as promisingcarriers of fungicides.106 Particularly,PCN-224 was loaded (30 wt %) with tebuconazole and constructed layerby layer with chitosan and pectin to get tebuconazole microcapsules.The synthesized microcapsules (Tebuc@PCN@P@C) had a dual-microbialeffect on plant bacterial and fungal diseases (1O2) wasreleased from the organic linker porphyrin when the MOF NPs were exposedto light after the formation of pectin to inhibit the pathogens. Thesynthesized compound displayed excellent double activities of havingphotodynamic therapy and being microbicidal against the bacteria X. campestris pv campestris  and P. syringae pv tomato  and the fungi A. alternate (68.0%).Finally, the authors studied the safety of this compound against Chinesecabbage (Brassica rapa pekinensis) in a greenhouseenvironment. The results demonstrated that the synthesized microcapsulesdo not have a major effect on both the fresh weight and the soil plantanalysis development (SPAD) value of the tested plant leaf, so theTebuc@PCN@P@C microcapsules can be considered safe.In2017, Yaghi and co-workers described a naturally degradableMOF as a carrier of the important fumigant diseases 5. First,III-tannic acid (TA) networks.107 The FeIII-TA complexes are able to absorb UV–vis near-infrared(NIR) lights. The design of MIL-101(Fe)-TA NPs enables the releaseof the tebuconazole cargo (24.1 wt %) in response to 7 stimuli ,phosphate, ethylenediaminetetraacetate (EDTA), and sunlight) to meetthe diverse controlled release of the encapsulated cargo . Thisis important since, in various parts of the plants themselves or causedby pest and pathogens, there are different pH values. Further, whencrop plants suffer from biotic or abiotic stress, H2O2 is rapidly produced in cells. On the basis of the Fentonreaction between H2O2 and FeII/FeIII, the release of the cargo will be induced by the degradationof MIL-101(Fe). GSH, normally found in plants and animals, is ableto reduce FeIII to FeII, causing the degradationof MIL-101(Fe) and, then, promoting the release of the encapsulatedpesticide. Additionally, phosphates can induce MIL-101(Fe) degradationby competitive coordination with FeIII, and finally, theFeIII-TA networks on MIL-101(Fe) will stimulate the controlledrelease of the pesticide via the photothermal effect of the NIR lightof sunlight. Lastly, this system demonstrated high fungicidal activitiesagainst R. solani  and F. gaminearum ; good safety in seed germination, seedling emergence,and plant height of wheat by seed dressing; satisfactory control efficacieson wheat powdery mildew caused by B. graminis.A very recent and complete study described a further example ofa tebuconazole loaded MOF, the MIL-101(Fe) gated with Feed cargo 6. Tebucop-toluenesulfonate) (TMPyP) as a photosensitizer(PS) in the cage of HKUST-1 2(H2O)3])  to efficiently produce singlet oxygen to inactivate plant pathogensunder light irradiation.108 The preparedPS@HKUST-1 loaded about 12 wt % of PS, exhibiting an excellent andbroad-spectrum photodynamic antimicrobial activity in vitro against three plant pathogenic fungi  and two pathogenicbacteria (P. syringae pv lachrymans and C. michiganense subsp. Michiganense). Besides, Allium cepa chromosome aberration assaysconfirmed that PS@HKUST-1 showed no genotoxicity and safety to thegrowth of cucumber and Chinese cabbage.Finally, we want to mention a report on the construction of a porphyrinMOF nanocomposite constructed by incorporating 5,10,15,20-tetrakis(1-methyl-4-pyridinio)porphyrintetra phosphate, butachlor,carbaryl, chlorimuron ethyl, 2,4-dichlorophenol, 4-chlorophenoxyaceticacid (4-CPA), chlortoluron, 2,4-D, dicamba, desmetryn,2-propionicacid (2-DPP), chlorotoluron, dipropetryn, epoxide, fenuron, fluometuron,glufosinate, GLY, heptachlor prometryn, MCPA, (2-methyl-4-chlorophenoxy)butyric acid (MCPB), (2-methyl-4-chlorophenoxy) propionic acid (MCPP),metsulfuron methyl, monuron, nicosulfuron, metazachlor, molinate,nitrofen, paraquat, pretilachlor, prometon, propanil, pyrazosulfuronethyl, secbumeton, simazine, sulfometuron methyl, sulfosulfuron, terbumeton,terbuthylazine, thifensulfuron methyl, trietazine, and trifluralin;(ii) fungicides: bromuconazole, carbendazim, chlorothalonil,2,6-dichloro-4-nitroaniline , difenoconazole, diniconazole,epoxiconazole, fenbuconazole, flusilazole, flutriafol, hexachlorobenzene,hexaconazole, iprodione, myclobutanil, penconazole, prochloraz, propiconazole,pyraclostrobin, pyrimethanil, tebuconazole, thiabendazole, thiophanatemethyl, and triadimefon; (iii) insecticides: aldrin,avermectin, azinphos methyl, bifenthrin, bromopropylate, carbofuran,chlordane, chlorfluazuron, chlorpyrifos, clethodim, clofentezine,coumaphos, β-cyfluthrin, cyhalothrin, cyphenothrin, deltamethrin,diazinon, o,p′- and p,p′-1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), p,p′-1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene, dichlorvos, dieldrin,difenoxuron, diflubenzuron, dimethoate, diniconazole, dinotefuran,α- and β-endosulfan, fenitrothion, fenpropathrin, fenthion,fenvalerate, flufenoxuron flumetralin, α-, β-, γ-,and δ-hexachlorocyclohexane (HCH), hexaflumuron, imidacloprid,isocarbophos, lufenuron, malathion , monocrotophos,NIT, nitenpyram, p-nitrophenyl phosphate, matrine,methamidophos, paraoxon, paraoxon ethyl, parathion, parathion methyl,penfluoron, permethrin, phosalone, pirimiphos, procymidone, profenofos,pyridaben, pyrimicarb, quinalphos, teflubenzuron, triazophos, thiamethoxam,tribenuron methyl, trichlorfon, o,p′- and p,p′-1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethylene (DDT), 1,1,1-trichloro-2,2-bis(4chlorophenyl)ethane,triflumuron, and thiacloprid; (iv) plant growth hormones: forchlorfenuron, 6-benzylaminopurin, indole-3-acetic acid, 3-indolebutyricacid, and indolepropionic acid.Considering the important detrimental effect of pesticides on humanhealth, researchers have extensively studied and discussed the pretreatment,extraction, detection, and determination of agrochemical residuesin water, fruits, and vegetables. These data have been valuable tofood analysts and regulatory authorities for monitoring the qualityand safety of fresh food products, among others. As would be expected,MOFs and MOF composites have been extensively proposed for the extractionand determination of these dangerous substances in food and water.Many different agrochemicals have been analyzed using MOFs: (i) 2)]n , that wasthermally stable and luminescent was prepared via a hydrothermal reaction.122 This material was tested as a solid-phase extraction(SPE) material for the detection of trace levels of organophosphatepesticide (OP) via stripping voltametric analysis. The determinationof parathion methyl as a model included two main steps: parathionmethyl adsorption and electrochemical stripping detection of adsorbedpesticide. The MOF modified glass carbon electrode was immersed intoa sample solution containing the desired parathion methyl concentration,and the peak currents increased rapidly with the immersion time, upto 12 min, which indicated the saturation. The calculated limit ofdetection (LOD: 0.0006 μg·mL–1) is comparablewith that of 0.0048 μg·mL–1 at a hangingmercury drop electrode, suggesting that the reported MOF is reliablefor the determination of OPs in water. The same year, Barreto et al.reported the evaluation a new adsorbent 3D MOF [(La0.9Eu0.1)2(DPA)3(H2O)3]  for the determinationof pesticides from four chemical classes, namely, organochlorine (endosulfan),organophosphate , dicarboximide (procymidone),and carbamate (pirimicarb) in fresh lettuce (Lactuca sativa) by matrix solid-phase dispersion (MSPD) and gas chromatography–massspectrometry (GC/MS).123 The recoveriesobtained ranged from 78% to 107% with relative standard deviation(RSD) values between 1.6% and 8.0%. The LOD and limit of quantification(LOQ) ranged from 0.02 to 0.05 mg·kg–1 andfrom 0.05 to 0.1 mg·kg–1, respectively, forthe different pesticides studied. Importantly, the comparison witha conventional sorbent (silica gel) showed better performance of theMOF sorbent for all tested pesticides. However, the reasons of thisimprovement are not investigated or discussed by authors. Later on,in 2017, Tao et al.124 originally synthesizeda tetraphenylethene-based ligand (BPyTPE: (E)-1,2-diphenyl-1,2-bis(4-(pyridin-4-yl)phenyl)ethene)with a trans conformation and prominent AIE properties.On the basis of BPyTPE, a novel 2D pillared-layered LMOF [Zn2(bpdc)2(BPyTPE)]  was developed showing a 3-fold interpenetration structure. Theactivated material (without solve) exhibits a strong blue-green emissionat 498 nm with an important φF of 99%. The emissionof the MOF without solvent can be quenched selectively and effectivelyby 2,6-DN. Thus, the authors established a method to quantitativelyand sensitivity detect trace 2,6-DN with a linear range of 0.94–16.92ppm and a low detection limit of 0.13 ppm.In 2010, Wen et al. reportedone of the first works about the applicationof MOFs in the efficient detection of agrochemicals. In this study,a new MOF, named [Cd4(μ3-OH)412+] bridged by TCPB4– linkers in a scu topology benzene; SBET: 1450 m2·g–1; rhombic channels of ∼10 × 5.3 and ∼3.5 ×2.4 Å2, in situ detection of OP pesticides.125 Along the 22 pesticides tested, the synthesized CAU-24quickly absorbs trace amounts of OP parathion methyl and indicatesits presence. It has a low LOD of 0.115 μg·kg–1 (0.438 nM) with a wide linear range from 70 μg·kg–1 to 5.0 mg·kg–1. The waterstability of this Zr-MOF was investigated by suspending it in waterfor 24 h and monitoring by powder X-ray diffraction (PXRD), adsorption/desorptionisotherms, and pore distribution. The crystalline structure and porosityof the Zr-MOF was kept in water after 24 h. Finally, the Zr-MOF wasused to mimic rapid in situ imaging detection ofpesticide residues on surface vegetables (lettuce and cowpea); visualsignals appeared under UV light within 5 min. Therefore, this MOFhas the possibility for low-cost, rapid, and in situ imaging detection of OP contamination via easy-to-read visual signals.When one considersthese outstanding original works, MOFs haveopened a new opportunity for the development of efficient techniquesto detect agrochemicals. However, most of these materials are moreor less sensitive to moisture or water and can be degraded throughhydrolysis. Only few MOFs can maintain their stability in water ora moist environment. One example is the previously reported luminescentZr-MOF CAU-24, based on the C-centered orthorhombic arrangement cluster[Zr126 In thiswork, MIL-101(Fe) was modified as a model with superparamagnetic qualitiesusing Fe3O4 to form a homogeneous magnetic product(Fe3O4/MIL-101 composite). The Fe3O4/MIL-101 composite was investigated for the magneticsolid-phase extraction of six OPs from human hair and urine samplesfollowed by gas chromatography analysis. Under optimized conditions, thismethod showed low LOD (0.21–228 ng·mL–1), wide linearity, and good precision . The adequate recoveries of the spikedsamples were 76.8–94.5% and 74.9–92.1% for hair andurine, respectively, suggesting that the Fe3O4/MIL-101 sorbent is feasible for the analysis of trace OPs in biologicalsamples. Other Fe3O4-MOF-based composites haverecently been reported for the efficient determination of differentagrochemicals, for example, the magnetic solid-phase extraction methodbased on the attapulgite-modified MOF (ATP@Fe3O4@ZIF-8) in the determination of bezoylureas  of benzoylureas prior to high-performance liquidchromatography (HPLC) determination (–1 withsatisfactory recovery of 88.29–95.99%) and precision . Moreover, after 5 cycles, therewas hardly any noticeable loss of the extraction efficiency. Finally,this method was effectively used in the determination of 6 benzoylureasin different tea infusions; the determined relative recoveries rangedfrom 78.8% to 114.3%.MOF composites have also beenused in the determination of agrochemicals.In 2014, a MOF with an iron oxide enclosure was reported for the determinationof OPs in biological samples.mination 8. The es3O4@ZIF-8-based composites is the work reportedby Senosy et al. on the basis of the synthesis of Fe3O4@APTES-GO/ZIF-8 (APTES: (3-aminopropyl)triethoxysilane; GO:graphene oxide) and its evaluation as an adsorbent for the determinationof triazole fungicides in water, honey, and fruit juices.128 Here, GO sheets were used to improve the dispersionof the adsorbent in aqueous solutions and, again, ZIF-8 to ensureenough surface area and active sites. Under the optimum conditions, the obtained linearityof this method ranged from 1 to 1000 μg·L–1 for all analytes. The LODs and LOQs of four triazole fungicidesranged from 0.014 to 0.109 μg L–1 and from0.047 to 0.365 μg L–1, respectively. Moreover,this adsorbent could be reused without significant loss of its extractionrecoveries. When compared with the outcomes from other studies, Fe3O4@APTES-GO/ZIF-8-MSPE could provide a higher performanceand achieve satisfactory results for the analysis of trace triazolefungicides in complex matrices. Another composite, based on a nanoarchitectureof Mxene/carbon nanohorns/β-cyclodextrin-MOF (MXene/CNHs/β-CD-MOFs),was utilized as an electrochemical sensing platform for the determinationof carbendazim pesticide.129 β-CD-MOFscombined the properties of the host–guest recognition of β-CDand porous structure, high porosity, and pore volume of MOFs, whichare fundamental in achieving a high adsorption capacity of carbendazim.MXene/CNHs possess a large specific surface area, accessible activesites, and high conductivity, which allowed more mass transport channelsand enhanced the mass transfer capacity and catalysis of carbendazim.128 With the collaborative effectof both (β-CD-MOFs and MXene/CNHs), the electrode extended awide linear range from 3.0 nM to 10.0 μM and a low LOD of 1.0nM. Additionally, this sensor also showed high selectivity, reproducibility,and long-term stability as well as satisfactory application in tomatosamples.Another example of magnetic solid-phase extraction using Fe7Asa novel class of materials, MOFs exhibit a great potential inagroindustry, either to detect or eliminate agrochemicals or to achievetheir sustained and controlled release. In all these scenarios, theaim is to reach the rational and environmentally friendly use of agrochemicals.Despite the novelty of MOFs in agriculture, the experience acquiredin other areas  allowus to identify precise challenges related to their use in agriculture.First, MOF stability under the working conditions is of crucialrelevance. However, from the wide number of MOFs and MOF-based compositesreported in environmental remediation (water and soil), only few discussthis critical point and mostly under conditions far from real waterstreams or fields. In this sense, many of these materials are builtup from toxic metals  and/or harmful organic moieties, which can be released upon the MOF degradation.The selection of safe and stable MOFs is therefore mandatory for theiruse in agroindustry . Further, it is essential to investigate the performanceof MOFs under real conditions using complex water and soil compositionsand/or vegetables or plants , considering concentration ranges foundin nature, different temperatures, humidity, sunlight hours, soilcomposition, or pH in different parts of plants, among others.218 To further progress through the application, specific manufacturingand devices should be considered ,and one needs to take into account the potential decrease in the MOFperformance.Second, the cost of MOFs is of particular importance for agroindustryapplications. When one takes into account that vegetables and fruitsare normally popular and affordable, it is necessary to use a low-costand long-lifetime material. Nontoxic and abundant safe precursorstogether with simple synthetic routes with a high space time yield need to be put in placefor the most promising candidates. Note here that few MOFs have beenproduced so far at the ton scale by different companies, and thus,they are not currently commercially available.Finally, understanding the interaction of the agrochemicalsandMOFs might help one further improve the resulting performances atthe detection, removal, or progressive release stages. Also, researchcould be focused on multifunctional MOFs and MOF composites that combine,for instance, the extraction with the detection of pesticides in foodmatrices or the simultaneous elimination of different agrochemicals.Although there are challenges to the use of MOFs in agriculture,this new domain in the application of MOFs will continue, and it isexpected that novel knowledge and development will soon be the outcome.This Review opens fascinating perspectives for the safe and efficientMOF application in agriculture.


Actin-related protein 2/3 complex subunit 1B (ARPC1B) deficiency is a recently described inborn error of immunity (IEI) presenting with combined immunodeficiency and characterized by recurrent infections and thrombocytopenia. Manifestations of immune dysregulation, including colitis, vasculitis, and severe dermatitis, associated with eosinophilia, hyper-IgA, and hyper-IgE are also described in ARPC1B-deficient patients. To date, hematopoietic stem cell transplantation seems to be the only curative option for patients. ARPC1B is part of the actin-related protein 2/3 complex (Arp2/3) and cooperates with the Wiskott–Aldrich syndrome protein (WASp) in the regulation of the actin cytoskeleton remodeling and in driving double-strand break clustering for homology-directed repair. In this study, we aimed to investigate radiosensitivity (RS) in ARPC1B-deficient patients to assess whether it can be considered an additional disease trait. First, we performed trio-based next-generation-sequencing studies to obtain the ARPC1B molecular diagnosis in our index case characterized by increased RS, and then we confirmed, using three different methods, an increment of radiosensitivity in all enrolled ARPC1B-deficient patients. In particular, higher levels of chromatid-type aberrations and γH2AX foci, with an increased number of cells arrested in the G2/M-phase of the cell cycle, were found in patients’ cells after ionizing radiation exposition and radiomimetic bleomycin treatment. Overall, our data suggest increased radiosensitivity as an additional trait in ARPC1B deficiency and support the necessity to investigate this feature in ARPC1B patients as well as in other IEI with cytoskeleton defects to address specific clinical follow-up and optimize therapeutic interventions. ARPC1B gene presenting with combined immunodeficiency, recurrent infections, thrombocytopenia, immune dysregulation, and increased radiosensitivity.Patient with a homozygous deletion c.212_226del in Radiosensitivity is a new trait of ARPC1B defect.The arrest of damaged cells in the G2/M-phase is suggestive of a defective Arp2/3-ARPC1B complex that is unable to drive DNA double-strand breaks (DSBs) clustering for homology-directed repair (HDR) but also of an impaired Aurora-A activation.To study radiosensitivity in ARPC1B-deficient patients as well as in other IEI with cytoskeleton defects is needed to optimize therapeutic interventions.Actin-related protein 2/3 complex subunit 1B (ARPC1B) deficiency is a recently described autosomal recessive disease characterized by combined immunodeficiency (CID), thrombocytopenia, and immune dysregulation having eczema, allergy, autoimmunity, and inflammatory diseases, in addition to an increased risk of severe infections as common features . ARPC1B In the present study, starting from the characterization of a severe CID patient affected by ARPC1B deficiency presenting with an increased radiosensitivity (RS), we further investigated RS in other ARPC1B patients to assess whether it could be considered a trait of the disease.The case index patient (PtII-1) was enrolled, monitored, and treated during the follow-up at the Children’s Hospital Bambino Gesù (Rome). In addition, three previously molecularly and clinically defined ARPC1B patients , 5 were All procedures performed in the study were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Blood samples, EBVB cell lines, and fibroblast cells were obtained from all enrolled subjects after obtaining informed consent following standard ethical procedures with approval of the Children’s Hospital Bambino Gesù Ethical Committee (1702_OPBG_2018), the Institutional Ethical Committee of San Raffaele Hospital , and Gaslini Hospital.https://www.genewiz.com/en-GB/Public/Services/Next-Generation-Sequencing/). WES and WGS statistics and data output are reported in ARPC1B (NCBI NM_005720.4) and SLC6A19 (NCBI NM_001003841.3) genes .External companies performed whole-exome sequencing (WES) and whole-genome sequencing (WGS) .Epstein–Barr virus B (EBVB) cell lines were exposed at room temperature to 30 cGy X-rays . After 3 h of incubation with 5 × 10EBVB cells were treated with chemical radiomimetic-induced DNA damage bleomycin (BLM)  and analyzed by FACS or IF for γH2AX at different time points of incubation  depending on the type of experiments. DNA damage repair, cell cycle phases, and cell viability were investigated. Details relative to FACS analysis and immunofluorescence/confocal laser microscopy protocols are reported in the Supplementary section.S. aureus sepsis with an abscess in the site of central venous catheter (CVC) insertion. The family history resulted positive for allergy and psoriasis. During the follow-up period, we observed marked improvement in diarrhea and ulcerations, but the persistence of recurrent infections, mostly otitis  and severe psoriatic dermatitis with lymph and monocytic infiltrates (in vitro stimulations (PHA/OKT3/Candid/Tetanus toxoid), an increased memory T cell subset was confirmed over time, and a low memory B-cell subset was found. Additionally, progressive lymphopenia with an increment of CD21low memory cells was observed. Regulatory T cells (CD4+CD25hiCD127lowFoxp3+) were also increased, showing mainly memory phenotype and reduced Helios (IKZF2) co-expression (+CD45RO+CXCR5+ follicular helper T-cell (TFH) frequencies varied accordingly to the therapy received  born from consanguineous parents  (ARPC1B gene (Trio-based WES  234500)  , while both parents’ signatures clustered with those of healthy donors (HDs) (C7<parents< C23) (panel down).In the frame of a study exploring RS in patients affected by CID, immune dysregulation, and/or severe dermatitis, before the identification of the 2AX foci . We foun*0.05 < p-value < ***0.001) at 2 and 4 h after treatment in all ARPC1B patients compared to HDs.Extending the DSB repair analysis to irradiated fibroblasts from two other previously described ARPC1B patients , 5, we d***p < 0.001 vs. ****p < 0.0001), two conditions highly sensitive to ionizing radiation (IR) (***p < 0.001). The mutations found in ARPC1B and WAS patients are reported in Furthermore, as shown in ion (IR) . In addiion (IR) , WAS patTo further confirm our results, RS was explored in ARPC1B and WAS patients’ EBVB cells treated with the radiomimetic DNA-cleaving agent bleomycin (BLM) by assessing γH2AX expression through FACS and immunofluorescence assay (IF). The obtained results showed an increment of the γH2AX level in almost all ARPC1B-deficient patients’ cells following 2 h of treatment, which was more evident in PtII-1, Pt1-ARPC1B, and Pt1-WAS  and Pt3-ARPC1B1 cells (after 8 h)   , 22. In Investigating the fate of damaged cells, we found a similar kinetic profile of cell survival during the 24 h of recovery culture in all tested samples, although with a cell line-specific rate before and after BLM treatment.Of note, although a higher incidence of cancer has not been reported in ARPC1B patients so far, probably due to the early age of patients, our results encourage the need to monitor the disease evolution in these patients as in other defective HDR proteins that, albeit mildly affected, can lead to an increased risk of developing cancers –31.In conclusion, here we described, for the first time, an increased RS as a disease trait in ARPC1B deficiency. This trait can occur at different levels of severity depending on host factors that are still undefined. Further studies are needed to address the clinical relevance to designing specific clinical management and optimizing therapeutic interventions, including the choice of the HSCT conditioning regimen.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/The studies involving human participants were reviewed and approved by number:1702_OPBG_2018 and TIGET06, TIGET09. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.MC, GU, DA, NC, ANA, GD and CC interpreted the results and wrote the manuscript. MC, GU, FB, SP, CRC, MZ, SD, AB, FP, AC, VD’O, J-PV, MT, ANA and GD performed molecular and functional experiments and developed NGS analysis. CRC, AB, FP, AC, MT and GD created gene clusters to filter variants and integrated clinical and bioinformatics analysis of data retrieved by different genetic platforms. DA, NC, SV, IP, CG, EA, BR, LP, PZ, AGF, AD, GP, MG, MEH, AF, PP, PR, AA, and CC provided or referred clinical samples and patient’s clinical data. MC, GU, SV, MT, ANA, GD and CC participate to the study design and data interpretation. MC, GU, DA, NC, SV, MT, J-PV, AA, ANA, GD and CC made substantial contributions to revising the manuscript. ANA, GD, CC supervised the research and manuscript revision. All authors contributed to the article and approved the submitted version of manuscript.This work was funded by the Italian Ministry of Health , the Italian TELETHON Foundation (grant number GGP15109 to AF), Fondazione Bambino Gesù (Vite Coraggiose to MT), and the Italian Ministry of Research (FOE 2019 to MT) 2021_05_INFETT_CANCRINI to CC.The authors acknowledge the Rare Immunodeficiency, AutoInflammatory and AutoImmune Disease (RITA) network. The authors are grateful to patients and their families for participating in this study. We also thank Dr. Paola Ariganello for clinical assistance and our senior nurse Nadia Iavarone. We thank Jennifer Faudella and Patrizia Antimi for administrative assistance.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The reviewer VB declared a shared affiliation with the author J-PV to the handling editor at the time of review.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Liver hepatocellular carcinoma (LIHC) ranks the sixth in global cancer incidence with poor prognosis. Necroptosis is a kind of regulated cell death and has been proved to be of significance in cancer occurrence and progression. However, few studies comprehensively discuss the potential applications of necroptosis-related genes (NRGs) in the prognostic evaluation and immunotherapy of LIHC.  The prognostic signature in the present study was built up using LASSO Cox regression analysis. Integrated bioinformatics tools were utilized to explore the potential mRNA-miRNA-lncRNA regulatory axis in LIHC. Furthermore, qRT-PCR method was used to verify the EZH2 expression in LIHC tissues. Furthermore, prognostic performance of EZH2 in LIHC was assessed by Kaplan-Meier method.  A total of 14 NRGs were differentially expressed in LIHC tissues. The overall genetic mutation status of these NRGs in LIHC was also shown. NRGs were significantly correlated with programmed necrotic cell death, as well as Toll-like receptor signaling pathway in GO and KEGG pathway analysis. Kaplan-Meier analysis revealed that ALDH2, EZH2, NDRG2, PGAM5, RIPK1, and TRAF2 were related to the prognosis. A prognostic signature was constructed by these six genes and showed medium to high accuracy in the prediction of LIHC patients' prognosis. Further analysis revealed that NRGs were correlated with pathological stage, immune infiltration, and drug resistance in LIHC. Moreover, we identified a potential lncRNA TUG1/miR-26b-5p/EZH2 regulatory axis in LIHC, which might affect the progression of LIHC. qRT-PCR suggested a higher mRNA level of EZH2 in LIHC tissues. And a poor overall survival rate was detected in LIHC patients with high EZH2 expression. Moreover, EZH2 expression and cancer stage were identified as the independent risk factors affecting LIHC patients' prognosis.  In the present study, we conducted comprehensive bioinformatic analyses and built up a necroptosis-related prognostic signature containing four genes  for patients with LIHC, and this prognostic signature showed a medium to high predictive accuracy. And our study also identified a lncRNA TUG1/miR-26b-5p/EZH2 regulatory axis, which might be of great significance in LIHC progression. In addition, based on the data from our center, the result of qRT-PCR and survival analysis showed a higher mRNA level of EZH2 in LIHC tissues and an unfavorable prognosis in high EZH2 expression group, respectively. Liver hepatocellular carcinoma (LIHC) ranks the sixth in global cancer incidence and has become the fourth leading cause of cancer death worldwide with 8.2% mortality rate. In 2018, LIHC causes over 700000 cancer-related deaths . In thesNecroptosis is a novel mechanism of regulated cell death mediating by RIP1, RIP3, and MLKL , 5. SomeOwing to the continuous updates and development of bioinformatic technique, using big data to study the molecular mechanisms of diseases and to explore biomarkers for prognosis, diagnosis, and therapy becomes feasible. At present, necroptosis-related prognostic signatures for kidney renal clear cell carcinoma, esophageal adenocarcinoma, and pancreatic adenocarcinoma have been established with high predictive accuracy –13. Howen = 371). The expression data was normalized to transcript per kilobase million (FPKM) values for the further analyses. Meanwhile, standardized copy number variation (CNV) data from TCGA-LIHC dataset was downloaded in UCSC Xena website. R software (version 4.0.5) and several online bioinformatic platforms were used to perform the analyses in the current study.On October 1st, 2021, we downloaded the RNA sequencing data and the corresponding clinical characteristics of LIHC patients from TCGA database (https://metascape.org), a web portal to predict the interactions of gene set, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed to assess the potential biological functions and molecular mechanisms of NRGs in LIHC [p value of 0.01, a minimal overlap of 3, and a minimal enrichment of 1.5.By reviewing the previous literatures, we obtained 17 necroptosis-related genes which are RIPK1, RIPK3, MLKL, TLR2-4, TNFRSF1A, PGAM5, ZBP1, NR2C2, HMGB1, CXCL1, USP22, TRAF2, ALDH2, EZH2, and NDRG2 , 14–21. p values, hazard ratio (HR), and 95% confidence interval (CI). Based on prognostic NRGs, a prognostic signature was built up using LASSO Cox regression model. Riskscore = ∑i=1n(Expi × Coei). Setting the median risk score as the cutoff, patients were divided into low- and high-risk groups. OS curves of the two groups were compared by Kaplan-Meier analysis, and the predictive accuracy of the prognostic model was assessed by time ROC curve. In addition, Spearman's correlation analysis was used to explore the relationship between risk score and infiltrating level of immune cells in LIHC tissues.Kaplan-Meier methods were performed to identify the prognostic NRGs, and log-rank test was applied to calculate the https://cistrome.shinyapps.io/timer) was used to illustrate the association between immune cell infiltration and the expression of NRGs associated with risk score. And the comparison of infiltration levels among LIHC tissues with different somatic copy number alterations (SCNAs) for NRGs associated with risk score were also visualized. Moreover, Pearson's correlation analysis was conducted to show the correlation between NRGs associated with risk score and drug sensitivity data from Genomics of Drug Sensitivity in Cancer (GDSC).The correlation between pathological stage and the expression level of ALDH2, EZH2, NDRG2 and PGAM5 in LIHC tissues was visualized by violin plots. Next, TIMER (http://www.targetscan.org/), miRDB (http://mirdb.org/), and StarBase (http://starbase.sysu.edu.cn/), respectively. The expression level and prognostic performance of the miRNA targets which were included in the intersection among these three databases were shown. According to the above miRNA targets, upstream lncRNA targets binding to miRNAs were explored by StarBase (http://starbase.sysu.edu.cn/) and LncBase (https://carolina.imis.athena-innovation.gr/). Similarly, the most promising lncRNA targets were detected with Student's t-test by TCGA-LIHC dataset.The miRNA targets of NRGs associated with risk score were detected in TargetScan . In addition, the study was approved by the Ethics Committee of the Second Affiliated Hospital of Nanchang University, and each patient provided written informed consent.Forty LIHC tissues and corresponding normal liver tissues from patients without any treatment preoperatively were collected. The expression of EZH2 in LIHC tissues and normal liver tissues was compared by Student's p < 0.05). C>T was the most common SNV class . Area under the curve (AUC) of 1-year, 3-year, and 5-year ROC curve was 0.743, 0.684, and 0.678, respectively , CD4+ T cell , neutrophil , macrophage , and myeloid dendritic cell .Kaplan-Meier survival curves revealed that LIHC patients with high EZH2, PGAM5, RIPK1, and TRAF2 expression showed an unfavorable OS rate, while patients with high ALDH2 and NDRG2 expression were associated with a better OS rate . Next, aectively . The relp = 0.000302) and NDRG2 (p = 0.0321) decreased as the pathological stage increased. However, the expression of EZH2 increased as the pathological stage increase. We then selected EZH2, ALDH2, and NDRG2 to explore their relationship with immune infiltration in LIHC, respectively. The result showed that a positive correlation existed between EZH2 and the immune abundance of B cells , CD8+ T cells , CD4+ T cells , macrophage , neutrophils , and dendritic cells . ALDH2 expression showed negative correlation with B cell , CD8+ T cell , CD4+ T cell , macrophage, neutrophils , and dendritic cells . There was a negative association between infiltration level of B cell  and NDRG2 expression in LIHC tissues (In  tissues . We then tissues . Moreovep = 0.045). Therefore, we selected hsa-miR-26b-5p as the most promising miRNA target of EZH2. The upstream lncRNAs binding to hsa-miR-26b-5p were excavated by LncBase and StarBase. The results advised TUG1, KCNQ1OT1, and GAS5 as the lncRNAs targets (p < 0.0001). Survival analysis suggested high TUG1 expression was linked with unfavorable OS rate in LIHC patients (p = 0.026). Therefore, the potential mRNA-miRNA-lncRNA regulatory axis, lncRNA TUG1/miR-26b-5p/EZH2 regulatory axis, was detected, which might influence the development of LIHC.Previous studies had clearly reported the function of ALDH2 in the occurrence and progression of LIHC . Thus, w targets . Moreovep < 0.0001, p = 0.038). Univariate and multivariate Cox regression analyses suggested that EZH2 expression and nodal metastasis status, cancer stage, gender, and age were the independent risk factors affecting LIHC patients' prognosis .The mRNA level of EZH2 in LIHC tissues and normal liver tissues was analyzed by qRT-PCR, which showed a significant upregulation in LIHC tissues  and the downregulated genes  were selected out for further analyses. Functional enrichment analysis was conducted to confirm whether these differentially expressed NRGs had associations with necroptosis in LIHC, which showed these NRGs were correlated with programmed necrotic cell death, positive regulation of interleukin-8 production, TNF signaling pathway, NF-kappa B signaling pathway, Toll-like receptor signaling pathway, and Herpes simplex infection. The above pathways had correlations with necroptosis and tumor progression, which was proven in previous studies. And NF-kappa B signaling pathway regulated the process of inflammation and cancer progression . TNF sigIn our study, survival analysis suggested that high EZH2, PGAM5, RIPK1, and TRAF2 expressions were related to an unfavorable prognosis in LIHC patients, while high ALDH2 and NDRG2 expressions were linked with a better prognosis. For better predicting LIHC patients' prognosis, the expression profile of these 6 prognostic genes in TCGA-LIHC dataset was used to build up a prognostic signature. Of these 6 genes, only EZH2, ALDH2, NDRG2, and PGAM5 were associated with risk score. In general, our prognostic signature obtained medium to high accuracy in the prediction of LIHC patients' prognosis. Previous studies had reported EZH2 was related to the progression, invasion, and metastasis of the hepatocellular carcinoma –32. HoweAnother significant finding of the current study was that NRGs were significantly correlated with pathological stage, immune infiltration, and drug resistance in LIHC. ALDH2 decreased as the pathological stage increased, indicating that ALDH2 may serve as a tumor suppressor and inhibit LIHC progression. Hou et al. also revealed that ALDH2 opposes hepatocellular carcinoma progression by regulating AMP-activated protein kinase signaling in mice . In our Through mRNA-miRNA-lncRNA network, lncRNA TUG1/miR-26b-5p/EZH2 regulatory axis was identified, which might participate in the occurrence and progression of LIHC. Previous study had reported the expression level of TUG1 was increased in LIHC tissues and the expression of TUG1 promoted LIHC cell proliferation in mouse model . In LIHCThe major findings of the present study were as follow: first, we utilized TCGA-LIHC dataset and bioinformatic methods to construct a necroptosis-related prognostic signature containing four genes , which obtained medium to high predictive accuracy. Second, the current study used ceRNA network to identify a lncRNA TUG1/miR-26b-5p/EZH2 regulatory axis, which might influence the progression of LIHC. In addition, we used the data from our center to perform qRT-PCR and survival analysis, which indicated a higher mRNA level of EZH2 in LIHC tissues and an unfavorable prognosis in high EZH2 expression group, respectively. However, further in vivo and in vitro studies should be conducted to verify these results.


Squalus acanthias). Studies have previously demonstrated that this promoter compound and its derivatives exhibit potent bactericidal activity against Gram-negative, Gram-positive bacteria, and multidrug-resistant bacteria. The antibacterial activity of squalamine was found to correlate with that of other antibiotics, such as colistin and polymyxins. Still, in the field of microbiology, evidence has shown that squalamine and its derivatives have antifungal activity, antiprotozoa effect against a limited list of protozoa, and could exhibit antiviral activity against both RNA- and DNA-enveloped viruses. Furthermore, squalamine and its derivatives have been identified as being antiangiogenic compounds in the case of several types of cancers and induce a potential positive effect in the case of other diseases such as experimental retinopathy and Parkinson’s disease. Given the diverse effects of the squalamine and its derivatives, in this review we provide the different advances in our understanding of the various effects of these promising molecules and try to draw up a non-exhaustive list of the different mechanisms of actions of squalamine and its derivatives on the human organism and on different pathogens.Squalamine is a natural aminosterol that has been discovered in the tissues of the dogfish shark ( Marine ecosystems are extremely rich in bioactive compounds, with a myriad of pharmaceutical properties and characteristics, enabling their use in the prevention and control of major diseases . The greSqualus acanthias. It was discovered in 1993 by Moore et al., after studying the innate immune system of different animals -7-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H cyclopenta[a]phenanthren-17-yl]-2-methylheptan-3-yl] hydrogen sulfate or (3β-N-1-{N-[3-(4-aminobutyl)]-1,3-diaminopropane)-7α, 24R-dihydroxy-5α-cholestane-24-sulfate)   15]. Th. Th34H65sulfate)  9,15]. ,15. 34H6sulfate)  16,17].,17.34H65Escherichia coli (E. coli) (American Type Culture Collection (ATCC) 25922), Pseudomonas aeruginosa (P. aeruginosa) (ATCC 27853), Staphylococcus aureus (S. aureus) (ATCC 25923), and a clinical isolate Streptococcus pneumoniae (S. pneumoniae) (recovered from the sputum of a cystic fibrosis patient), and compared to colistin  and ASD 2 [7β--cholestan-3β-ol)  was inve reduced  19]..E. coli P. aeruginosa DSM 939 (ATCC 15442), S. aureus DSM 799 (ATCC 6538), Candida albicans  German Collection of Microorganisms (DSM) 1386 (ATCC 10231), and Aspergillus niger (A. niger) (ATCC 16404) .,27.15,27stigated . As a reria used . Howeverria used . These dS. aureus. Cutaneous colonization was studied in a mouse model infected by methicillin-susceptible S. aureus (ATCC 25923) and methicillin-resistant S. aureus (MRSA) (Collection de Souches de l’Unité des Rickettsies (CSUR) P102) at 106–108 colony-forming unit/mL (cfu/mL), separately. Squalamine revealed a high degree of viable S. aureus load reduction with bactericidal effect up to 4-log10, during a 2-day experiment. A single dose of squalamine formulated at 1% in a petrolatum-based cream completely eradicated S. aureus , Trichophyton mentagrophytes (T. mentagrophyte), Trichophyton soudanense (T. soudanense), Microsporum canis (M. canis), Microsporum audouinii (M. audouinii), Microsporum persicolor (M. persicolor), Microsporum cookie (M. cookie), and Microsporum gypseum (M. gypseum), with MICs ranging from 4–16 mg/L for squalamine, and from 2–8 mg/L for the synthetic aminosterol derivative , with ED50 (50% effective dose) values close to 1 μM. The symmetrical polyamine spermine analogs of squalamine also showed remarkable activity against Leishmania donovani (an amastigote form cultured in macrophages). In contrast, the aminosterol derivatives tested were not active against Trypanosoma cruzi, even in higher concentrations  human breast cancer cell line and in vivo with HER-2 breast tumor xenografts, where squalamine treatment (at 2 mg/kg daily) reduced the growth of tumors as compared to controls . Thus, tIn the case of ovarian cancer, squalamine is also considered as a natural antiangiogenic sterol which has a potential role in the treatment of ovarian cancers, in the absence of standard chemotherapy treatment. The response of ovarian cancer cells, with or without HER-2 gene overexpression to the squalamine or cisplatin treatment was evaluated in both tumor xenograft models and in tissue culture. For that, mice with tumors were treated with control solution, cisplatin alone (4 mg/kg on day 1), squalamine alone (2 mg/kg on days 1–10), or cisplatin in combination with squalamine (days 1–10). Squalamine elicited a partial reduction in tumor size as compared to controls. More profound tumor growth inhibition (94–95% compared to the controls) was elicited by combining treatment of squalamine with either low or high doses of cisplatin. Moreover, it was revealed that squalamine did not influence tumor-induced VEGF production in these experiments  12]..12].50  close to 5 μM in 24 h and 3 μM in 72 h post-treatment. This squalamine derivative caused cell cycle arrest, specifically in G2/M transition, and apoptosis activation by cleavage and activation of the pro-apoptotic enzymes caspase-8 and PARP-1, and it led to cancer cell detachment by inhibiting the tyrosine-protein phosphatase PTP1B, known for its role in the development of breast cancer  6). Results demonstrate that the response rate of the tumor progression following this treatment concorded with the historical studies of carboplatin and paclitaxel already realized. The authors suggested that further non-invasive imaging studies will allow collecting even more evidences of the beneficial clinical effects of squalamine on blood vessel density, blood flow, or tissue metabolism in the target cancer tissues, and will allow optimizing the dose, the schedule, and the route of administration of squalamine for a maximal clinical benefit . An. An2/dayrelevant  30]. A . A 2/day benefit .2/day, and arthralgia, myalgia, and neutropenia at 400 mg/m2/day . Fu. Fui, anIn animal models and in the context of intestinal pathologies related to neurodegenerative diseases, squalamine and its derivative trodusquemine could have a promotive effect on neurodegenerative disease, especially in cases of Parkinson’s and Alzheimer diseases . SqualamGiven that the antiangiogenic effect of squalamine in tumors has already been demonstrated in various studies, there has been a growing interest in evaluating the effect of this aminosterol in the case of retinopathies ,38,61,62Squalamine, an aminosterol isolated from sharks, known for their unusual immune system and natural resistance to pathogens, has demonstrated its large antimicrobial activity and antitumor effects. In addition, several studies were able to demonstrate the potential activity of squalamine in the rehabilitation of the level of retinopathies and restoring the intestinal activity in patients with Parkinson’s disease. Experimental studies showed that squalamine could exhibit a moderate level of an adverse effect on the eukaryotic cells. It contains a cholesterol core that creates membrane permeabilization to kill pathogens, modifies cell membrane characterization of eukaryote cells, inhibits angiogenesis of tumor cells, and macular edema disease.Squalamine and its derivatives are promising molecules, but further studies and clinical trials are needed to establish routine therapeutic protocols with these compounds. It will be also interesting to broaden the study of the spectrum of the antimicrobial activity of these aminosterols and to carry out more specific clinical studies needed for the validation and the use of squalamine and its derivatives in therapeutic programs.


Plasma metabolomic profile is disturbed in dementia patients, but previous studies have discordant conclusions.Circulating metabolomic data of 110,655 people in the UK Biobank study were measured with nuclear magnetic resonance technique, and incident dementia records were obtained from national health registers. The associations between plasma metabolites and dementia were estimated using Cox proportional hazard models. The 10-fold cross-validation elastic net regression models selected metabolites that predicted incident dementia, and a 10-year prediction model for dementia was constructed by multivariable logistic regression. The predictive values of the conventional risk model, the metabolites model, and the combined model were discriminated by comparison of area under the receiver operating characteristic curves (AUCs). Net reclassification improvement (NRI) was used to estimate the change of reclassification ability when adding metabolites into the conventional prediction model.n=24) to the conventional dementia risk prediction model significantly improved the prediction for incident dementia  and reclassification ability  for identifying high risk groups.Amongst 110,655 participants, the mean (standard deviation) age was 56.5 (8.1) years, and 51 186 (46.3%) were male. A total of 1439 (13.0%) developed dementia during a median follow-up of 12.2 years (interquartile range: 11.5–12.9 years). A total of 38 metabolites, including lipids and lipoproteins, ketone bodies, glycolysis-related metabolites, and amino acids, were found to be significantly associated with incident dementia. Adding selected metabolites (Our analysis identified various metabolomic biomarkers which were significantly associated with incident dementia. Metabolomic profiles also provided opportunities for dementia risk reclassification. These findings may help explain the biological mechanisms underlying dementia and improve dementia prediction.The online version contains supplementary material available at 10.1186/s12916-022-02449-3. Dementia is a leading cause of disability in people over 65 years worldwide . It is eMetabolomics comprehensively analyses small molecular metabolites in targeted tissues or biofluids, to indicate genetic, environmental, and pathological changes during disease development. Previous studies have revealed deranged metabolomic profiles in dementia patients, but further studies have provided conflicting conclusions , 4–6. SuThe UK Biobank Study is a prospective study that measured 249 metabolomic biomarkers in approximately 118,000 EDTA plasma samples using high-throughput nuclear magnetic resonance (NMR). Its large sample size, long-term follow-up, standardized platform of metabolomics profiling, and systematic ascertainment of incident dementia provide a unique opportunity to investigate the metabolomic profile of incident dementia and assess the additive values of metabolites for incident dementia.We studied participants in the prospective UK Biobank Study cohort that met the inclusion criteria of this study. The UK Biobank Study includes over 500,000 people of middle and old age that were recruited from 2006 to 2010 across the UK. Their baseline demographic, phenotypic, and genotypic characteristics were collected in 22 assessment centres at enrolment, and further collections were accumulated after follow-up intervals of 6 months to 3 years. Detailed protocols of the UK Biobank Study are described elsewhere .n = 55,328) and a replication group . The workflow of the analyses is presented in Fig. For the identification of metabolomic biomarkers associated with incident dementia, the present analyses included participants without prior dementia at baseline with available metabolomic data. A total of 110,730 participants had metabolites data, of which 75 participants with a history of dementia were excluded. Finally, 110,655 participants were included in the current analysis. To develop a prediction model for 10-year incident dementia risk, participants were randomly divided into a discovery group  code, including 290.0–290.4, 294.1, 331.0–331.2, and 331.5 in ICD-9 and A81.0, F00, F01, F02, F03, F05.1, F10.6, G30, G31.0, G31.1, and G31.8 in ICD-10, covering Alzheimer's Disease dementia, vascular dementia, and dementias of other causes. The follow-up period was defined from baseline to the earliest one amongst the incident dementia date, lost-of-follow-up date, death date, or the last date of data update, which was April 28, 2021.Age , gender Z-transformed. Our present study included two separate analyses  or less. β coefficients of adjusted hazard ratio (HR), 95% coefficient interval (CI) and P values of all 249 metabolites in the cox model are presented in Additional file Continuous variables were described with mean  or median , and categorical variables were described with number and percentage. The values of all metabolites were first transformed using natural logarithmic transformation (lnx+1]) and then ) and then=55,328) and a testing set  to develop and validate the 10-year incident dementia risk prediction model. We used elastic net regularized logistic regression models to select metabolomic predictors. The elastic net regularized logistic regression model is a straightforward supervised machine learning algorithm combining least absolute shrinkage and selection operator (LASSO) regression and Ridge regression with a good probabilistic interpretation of variables suitable for disease prediction. The LASSO penalty selected variables by reducing the absolute value of weight, while the Ridge penalty further reducing the extremities of weights. Details of the model have been described elsewhere [α  and λ . Of note, α controls the balance between LASSO and Ridge, with α(1) corresponding to the lasso (the default estimator) and α(0) corresponding to ridge regression [λ and β coefficients for elastic net regression models in seek of minimum to minimize cross-validation prediction error, and order to achieve optimal robustness of the model. Each combination of α and λ on a two-dimensional grid underwent 10-fold cross-validation for elastic net logistic regression to compute cross-validation prediction error and assign β coefficient for each metabolite to achieve the minimum cross-validation function. In the final model, α=1 and λ=0.0003648 were selected by cross-validation. Minimum cross-validation mean deviance was 0.0887588. 24 metabolites were given nonzero coefficient  and R .Our analysis included 110,655 participants without dementia at baseline, with an average (SD) age of 56.5 (8.1), of which 59,469 (53.7%) were female. After a median follow-up of 12.2 years (IQR: 11.5–12.9 years), 1439 (1.30%) participants developed dementia. Baseline characteristics of all participants stratified by incident dementia are summarized in Table P=1.52×10−4), three ketone bodies , phospholipids to total lipids ratio in intermediate-density lipoproteins (IDL), small low-density lipoproteins (LDL), and very small very-low-density lipoproteins (VLDL) , and free cholesterol to total lipids ratio in very large VLDL , were positively associated with dementia, while 30 other metabolomic biomarkers from amino acids, fatty acids, lipids and lipoprotein subclasses, were inversely associated with the incident dementia.Amongst the 249 metabolomic biomarkers tested by UK Biobank Study with NMR technique, after controlling for multiple testing, 38 metabolites remained significantly associated with dementia incidence    Fig. . CategorUsing data from over 100,000 plasma samples from UK Biobank, we discovered that 38 serum metabolites including amino acids, ketone bodies, glycolysis metabolites, lipids, and lipoproteins were significantly associated with an increased risk of incident dementia. Our findings suggest the addition of metabolites into dementia risk stratification models could improve its prediction and reclassification for at-risk individuals. These metabolites also further insights to biological mechanisms which may underly dementia, and may assist in the prediction of dementia.Our results showed branched-chain amino acids (BCAAs) are negatively associated with an elevated risk of incident dementia, which is consistent with several previous studies , 30. It Our analysis also implicated ketone bodies and citrate as metabolites positively associated with incident dementia. Elevation of plasma ketone bodies infer a switch from glucose-dependent substrates as energy, which occurs in low carbohydrate diets, disrupted glucose uptake disorders like diabetes, or during long periods of fasting. Ketone bodies have also been implicated in cognitive impairment and Alzheimer’s dementia (AD) brains which were exposed to long-term glucose uptake and utilization disruption , 34. Thiβ deposition and p-tau accumulation, and may protect neurons against oxidation and inflammation, thereby preserving vascular and synaptic function [Strong negative correlations were observed between small high-density lipoproteins (HDL), its lipid constituents  and incident dementia in the present analysis. Similar findings have been replicated by previous studies although an adequate explanation on these observations is yet to be fully realized , 40, 41.function , 43.Total lipids, cholesteryl esters, cholesterol, triglycerides in VLDL and LDL subclasses, and polyunsaturated fatty acids (PUFA) were inversely associated with future risk of dementia, while free cholesterol concentration in very large VLDL was associated with an increased risk of dementia. These findings are aligned with some previous studies , 44, 45,Furthermore, we successfully identified candidate metabolites, whose addition to the conventional model could significantly improve the accuracy of dementia prediction and reclassification of risk group, thus might improve the sensitivity of identifying patients in their prodromal phase. Such findings suggest the potential clinical use of metabolomic biomarkers as complementary information for early and population-based detection of dementia. However, though our model showed statistically significant improvement through the addition of metabolites, caution is still required when interpreting clinical implications as the absolute increase was not substantial. This was possible because conventional risk factors for dementia, e.g., diabetes and hypertension, already accounted for some of the metabolic changes in dementia pathogenesis.Our study had several strengths, including the use of over 100,000 samples over a 14-year follow-up duration, the adjustment for confounding factors, and a homogeneous platform to analyse metabolites using the NMR technique . Some liBy use of a novel study design to investigate a prospective cohort of 110,655 participants over 14 years, several metabolomic biomarkers were found significantly associated with dementia incidence. The metabolites identified in this study may supplement future hypotheses explaining the complex interplay between energy and lipid metabolism, and the development of dementia. These metabolites improved risk stratification when added to conventional risk factor models, and this study provides an opportunity for considering the improvement of screening tools to better identify at-risk populations. Our findings also further discuss biological mechanisms underlying dementia and potentially facilitate the prediction, prevention, and treatment of dementia. Molecular and genetic studies were needed to determine the exact pathways mediating our observed associations, and clinical studies are needed to prove these metabolites can improve screening and prediction of dementia.Additional file 1: Table S1. Baseline characteristics of study participants stratified by discovery or replication dataset. Table S2. β coefficient of adjusted HR (95% CI) and P values of Incident Dementia for All 249 Metabolites in Cox Proportional Hazards Model. Table S3. Coefficients of selected 24 metabolites in elastic net regularized logistic regression model after 10-fold cross validation, their coefficients in e-net regression model in training dataset, and their VIFs in testing dataset.Additional file 2: Table S4. β coefficients (95% CI) and P values of conventional risk factors and metabolites in the multi-variable logistic model for 10-year incident dementia prediction.


C4H, HCT, HQT, C3H, F3H, ANS, MYB1), which might relate to the phytochemical content of those cultivars. The carbohydrates’ content differs among and within cultivars, while the rest of the phytochemicals differ only among cultivars. The cultivars ‘EMI’ and ’Lagkada’ scored higher than the rest in phenolics, anthocyanins, ascorbic acid, caffeoylquinic acid, and antioxidant capacity. Moreover, significant correlations were observed between various ingredients and the antioxidant capacity (FRAP and DPPH). Sequence analysis revealed several SNPs in C4H, HQT, F3H, ANS, and MYB1 among the cultivars studied. According to chi-square and logistic regression analyses, the missense mutation C4H4-108 correlates significantly with flavonoids, anthocyanins, and proteins; the synonymous mutation HQT-105 correlates with anthocyanins and ascorbic acid; the missense mutation HQT-438 correlates with flavonoids and chlorogenic acid, while the missense mutation ANS1-65 correlates with anthocyanins and sugars. These polymorphisms can be potentially utilized as molecular markers in eggplant breeding, while our data also contribute to the study of eggplant’s secondary metabolism and antioxidant properties.Eggplant is a widely consumed vegetable, with significant nutritional value and high antioxidant content, mainly due to its phenolic constituents. Our goal was to determine the levels of carbohydrates, proteins, total phenolics, anthocyanins, flavonoids, chlorogenic acid, and the antioxidant capacity in thirteen eggplant cultivars cultivated in Greece and to identify sequence polymorphisms in key regulating genes of the phenylpropanoid pathway ( Solanum melongena L.) is the fifth most popular vegetable worldwide, with around 56.6 million tons (Mt) of global production. China (36.6 Mt) is the top producer, followed by India (12.7 Mt) and Egypt (1.3 Mt) . The eggplant was introduced in Greece, around the 13th century as an ornamental plant, but now is an important part of the Greek gastronomy and the Mediterranean diet, with many local landraces possessing considerable morphological and genetic diversity  × 100.The antioxidant activity was determined with the 2,2-diphenyl-1-picrylhydrazyl (DPPH) method ,42. For 2]3+ to [Fe(TPTZ)2]2+ and the results were expressed as μmol Fe2+ per 100 g FW. In brief, 80 μL of FRAP reagent  were mixed with 55 μL acetate buffer  and 60 μL of samples (20.0 mg of FW of extract mL−1). Absorbance was measured at 595 nm. Ferrous sulfate heptahydrate  was used for the construction of a standard curve .In addition, we used the ferric reducing antioxidant power (FRAP) method , which mhttp://eggplant.kazusa.or.jp/, accessed on 17 October 2020) [https://www.ncbi.nlm.nih.gov/tools/primer-blast/, accessed on 22 January 2019) and the Oligo Analysis Tool . The exons selected, as well as the primer pair sequences, can be found as Total genomic DNA was extracted by homogenizing 100 mg of young leaf tissue from each accession with liquid nitrogen and following the CTAB protocol , with moer 2020) . Primers2, and approximately 1 ng of DNA template. PCR was performed in a C1000 Touch™ Thermal Cycler (Bio-Rad), Hercules, CA, USA, using different annealing temperatures, depending on the gene amplified , 1.5 mM MgClmplified .HCT3, OP295901-OP295950 for HQT, OP295951-296000 for C4H2, OP296001-OP296050 for C4H4, OP296051-OP296100 for C3H, OP296101-OP296150 for F3H, OP296151-OP296200 for MYB1, OP296201-OP296250 for ANS1.For PCR products’ verification, 5 μL of each PCR product were electrophoresed in 1% agarose gels, along with a 100 bp NEB DNA ladder . Amplified products were purified using the Nucleospin Gel and PCR clean-up kit ; concentration and quality of PCR products were determined using Quawell UV-Vis Q5000 spectrophotometer  and prepared for sequencing. The gene sequences obtained were deposited in GenBank under accession numbers OP295851-OP296250: OP295851-OP295900 for https://web.expasy.org/translate/, accessed on 23 August 2022) and standard genetic code.Exon sequences were manually edited using Finch TV version 1.4.0.  and SeqMan II software . For the enzymes that the whole coding sequence was selected, exon sequences were combined and analyzed as one data set. Multiple sequence alignments were performed with Sequencer Demo 4.8  and Clustal Omega multiple sequence alignment package ,46, usin𝛼 = 0.05). Spearman’s correlation was performed for all variable pairs at a 5% level of significance (𝛼 = 0.05) and estimated values of r > 0.90, r > 0.70, and r > 0.50 are interpreted as very high, high, and moderate, respectively. Heatmapping of the average values of the quality traits for the selected genotypes was performed with the online web tool Heatmapper [Means, standard deviation, and standard error for instrumental measurements were calculated using three replicates from each eggplant variety measurement. Fruits from each variety were subjected to mean comparison by one-way analysis of variance (ANOVA) using Tukey’s test at a 5% level of significance (atmapper .2) was performed to reveal the statistically important correlations. The SNPs significantly correlated were used as independent variables for the logistic regression performed afterward. This way, we tried to examine if the chemical content (dependent variables) correlates with specific mutations (SNPs). Statistical analysis was performed using IBM SPSS Statistics v.27 software.Furthermore, we proceeded to find out if any significant correlation exists between the phytochemicals with molecular data, and we tested if certain SNPs (missense and synonymous) are linked with the concentration levels of total phenolics, flavonoids, anthocyanins, chlorogenic acid, ascorbic acid, proteins, and sugars. For this purpose, the concentrations of each phytochemical were divided into three groups  by calculating their range and appointing two cut points. Cut point 1 ((range/3) + minimum value) indicates the point that divides low from moderate values and cut point 2 ((2*range/3) + minimum value) indicates the point separating moderate from high values. Then a chi-square test (XSolanum melongena L. is one of the main edible species worldwide with high nutritional value due to its plethora of chemical constituents, that are beneficial for human health. Despite its importance, it lacks genetic and genomic tools, compared to other members of the Solanaceae family such as tomato, but recently serious efforts have been made to bridge this gap [this gap ,23. ThisANS1-65 shows potential to be used as a molecular marker since homozygotes tend to have a high content of anthocyanins and sugars, but further study needs to be done. Other SNPs with potential interest are C4H4-108, HQT-105, and HQT-438. Breeding programs increasingly consider the concentration and content of bioactive compounds as a major breeding objective [Differences were observed within and among cultivars both at chemical and molecular levels. Cultivars ‘EMI’ and ‘Lagkada’ scored higher than the rest in phenolics, anthocyanins, ascorbic acid, caffeoylquinic acid, and antioxidant capacity. At the molecular level, out of the sixteen SNPs detected, only SNP bjective . Therefo


Ocimum tenuiflorum, often known as Krishna tulsi, is the most sacred herb in India. It was utilized for a variety of medicinal purposes. Therefore, itis of interest to document the molecular docking analysis data of PARγ modulators from Ocimum tenuiflorum. Four of the twenty substances  have a considerable binding affinity for the PPARγ.These phytochemicals are a source of potential anti-diabetic medicines.The ligand-activated transcription factor peroxisome proliferator-activated receptor (PPAR) has become a major target for type 2 diabetes. It belongs to the nuclear receptor superfamily, which controls the expression of proteins involved in glucosemetabolism, lipid metabolism, adipocyte proliferation and differentiation, and insulin sensitivity.  Diabetes mellitus has been linked to the pathogenesis of long-term consequences such as atherosclerosis, retinopathy, nephropathy, neuropathy, and microangiopathy, which are produced by increased glucose to fat conversion, sorbitol buildup, and proteinglycation ,2. AcarbPeroxisome proliferator-activated receptors (PPARs) are a family of nuclear proteins that regulate cellular differentiation and development, as well as metabolic processes such as glucose, lipid, and protein  andprotOcimum tenuiflorum (Ocimum sanctum) is known as Thulasi/Tulsi and belongs to theLamiaceae family. It is extensively grown throughout the world and is revered as India's sacred plant. Tulsi, also known as Holy Basil, has been used by Vaishnavas for thousands of years. Fresh leaves of this plant are often used to cure coughs, colds,abdominal pain, skin illnesses, arthritis, severe eye conditions, measles, and diarrhea throughout the Indian subcontinent. Preclinical tests on extracts from several sections of O. tenuiflorum revealed anti-fertility, anti-cancer,anti-diabetic, anti-fungal, hepatoprotective, and cardioprotective properties [Ocimum tenuiflorum.PPAR-γ is a master controller of adipocyte separation and appears to be a vital player in the lipid digestion system and glucose homeostasis, as well as controlling cell growth and tweaking the digestion system and aggravation in resistant cells. Itis activated when preadipocytes and adipocytes are separated . Accordioperties . Therefo3D crystal structure of peroxisome proliferator-activated receptor gamma (PPAR-γ) was downloaded from Protein Data Bank (pdb id: 5YCP). Before performing docking studies the protein structure was prepared by removing water molecules present in thecrystal structure and co crystallized ligand.Ocimum tenuiflorum was selected from literature and the 2d structure of these compounds were downloaded from pubchem database in SDF format. By using online smiles translator the 2d sdf was converted into 3d PDB format.The converted pdb format was load to pyrx for docking analysis (Table 1 - see PDF).20 compounds from The procedure of docking of ligands with the receptor has been performed using Autodock version 0.8 of pyrx software . The ligOcimum tenuiflorum as a PPAR- γ agonist.PPAR-γ is a ligand-activated transcription factor that controls a variety of metabolic processes, including lipid and glucose homeostasis ,15. PPARGbind best value was used to rank the docking outcomes (lowest energy). The lower the Gbind energy, the more stable the conformation established, whereas the higher the Gbind energy, the less stable the complex created. Rosmarinic acid, permethrin, luteolin,and isosakuranetin had binding energies of -8.3, -8.3, -7.3, and -7.1 kcal/mol, respectively. This shows that these chemicals have a high affinity for PPARγ.The specificity of ligand binding is largely determined by hydrogen bonds. Their essential contribution is directly incorporated into GRID, a computational approach for detecting energetically favorable ligand binding sites on a target molecule with agiven structure. Because of the great H-bonding capacities of both H-bond donors and H-bond acceptors, H-bonds play a substantial role in binding affinity. Table 1(see PDF) illustrates the protein residues that interact with phytocompounds via hydrogen bonds.The four chemicals that were chosen established more hydrogen bonds with PPAR. Among the four compounds RosmarinicAcid formed the four hydrogen bonds with amino acids residues of SER-289,HIS-323,HIS-449 and TYR-473 with distance of 1.5,2.4,2.2 and 2.4Årespectively. Permethrin also formed the four hydrogen interaction through SER-289,HIS-323,HIS-449 andTYR-473 with distance of 2.3,2.4,2.4 and 2.2Å. The Luteolin formed two hydrogen with ARG-288,SER-289 at distance of 2.1and 1.3Å. Isosakuranetinformed only one hydrogen interaction with ARG-288 at distance of 2.4Å. The hydrogen bond interaction distance of these compounds occurs below 3Å. It indicates that all the compounds formed the stable interaction with PPARγ. As per literaturethese compounds showed the interaction in the Ser289, His323, Tyr473, and His449 residues, which was present in the ligand binding domain. Data shows that selected these compounds may acts as potential drug candidate for diabetics after the experimentallyvalidation .Plant-derived chemicals regulate PPAR activity more strongly than other substances. The potential modulators  revealed a number of molecular interactions with the PPARγ protein's binding sitefor further consideration.


JCI report phenotypes from separate, rare missense mutations of human TRPV1. He, Zambelli, and colleagues investigated TRPV1K710N, which showed reduced functionality, while Katz, Zaguri, and co-authors reported on TRPV1N331K, which led to a complete functional knockout. The findings provide insights that will improve our understanding of the endogenous functions of TRPV1 in humans and may facilitate a rational TRPV1-targeting approach to achieve hyperthermia-free analgesia.Transient receptor potential vanilloid 1 (TRPV1), a receptor for capsaicin and noxious heat, has been one of the most compelling targets for analgesics. However, systemic inhibition of TRPV1 is an impractical approach as a pain killer, since systemic antagonism induces hyperthermia. Two articles in this issue of the  The sensory system detects noxious stimuli and allows us to avoid harmful tissue-damaging injuries , which is beneficial for survival. However, persistent pain from pathological conditions, such as chronic inflammation of knee joints or peripheral nerve damage, has no such protective value and needs to be treated. Current primary therapeutics for chronic pain are often limited in their analgesic efficacy and may produce adverse side effects. High addiction liability is a problem of opioidergic medications. An ideal treatment for chronic pain needs to selectively alleviate persistent pain conditions without influencing the beneficial pain sensation and without producing adverse side effects.SCN9A, a voltage-gated sodium channel gene encoding Nav1.7, revealed its critical role in nociceptors , a receptor for capsaicin . To deveiceptors . While miceptors , our undiceptors , 6. HoweTRPV1 mutation through reverse translation using a mouse line carrying the ortholog missense mutation. Through a clever in silico approach comparing human TRPV1 rare mutations with avian TRPV1 lacking capsaicin sensitivity, the authors attempted to identify a single residue that eliminates capsaicin sensitivity without altering heat sensitivity or thermoregulation. TRPV1K710N is an extremely rare mutation in humans. The mutation induces structural alteration in the TRP domain that is critical in channel gating and multimerization  and ten TAT sequences. The V1-cal peptide reduced capsaicin-induced pain-like behaviors and neurogenic inflammation in vivo. Systemic administration of V1-cal peptide via an osmotic pump reversed neuropathy-induced thermal, mechanical, and cold hyperalgesia. In both Trpv1K710N mice and V1-cal–treated naive mice, body temperature was not affected. Although He, Zambelli, and colleagues were unable to validate these TRPV1K710N phenotypes in humans, preclinical data suggest the potential for a hyperthermia-free analgesic approach using a peptide targeting a narrowly defined region of TRPV1.He, Zambelli, and co-authors  report orization . Cells cin vitro . When thTRPV1N331K), Katz, Zaguri, and co-authors , an agonist of transient receptor potential ankyrin subtype 1 (TRPA1), was increased .Unlike with conventional TRPV1 antagonists, He, Zambelli, and co-authors reported that systemic administration of V1-cal did not produce hyperthermia in mice, suggesting that the region-specific targeting of TRPV1 can lead to potential hyperthermia-free analgesia . Furtherory pain . Any offTRPV1 has been one of the most compelling targets for the development of analgesics. Topical capsaicin, a TRPV1 agonist, is approved for treating chronic neuropathic pain , and it