Recently, there has been an increasing consumption of fossil fuels such as oil and natural gas in both industrial production and daily life. This high demand for non-renewable energy sources has prompted researchers to investigate sustainable and renewable energy alternatives. The development and production of nanogenerators provide a promising solution to address the energy crisis. Triboelectric nanogenerators, in particular, have attracted significant attention due to their portability, stability, high energy conversion efficiency, and compatibility with a wide range of materials. Triboelectric nanogenerators (TENGs) have many potential applications in various fields, such as artificial intelligence (AI) and the Internet of Things (IoT). Additionally, by virtue of their remarkable physical and chemical properties, two-dimensional (2D) materials, such as graphene, transition metal dichalcogenides (TMDs), hexagonal boron nitride (h-BN), MXenes, and layered double hydroxides (LDHs), have played a crucial role in the advancement of TENGs. This review summarizes recent research progress on TENGs based on 2D materials, from materials to their practical applications, and provides suggestions and prospects for future research. The growing use of fossil fuels such as oil, natural gas, and other non-renewable energy sources in both industrial and daily activities has raised significant concerns regarding the energy crisis ,3,4,5,6.In 2006, the first piezoelectric nanogenerator (PENG) was manufactured , and latTENGs are based on the triboelectric principle. However, due to the negative effects of triboelectricity in industrial production and daily life, such as the accumulation of friction charges on industrial equipment that can detonate surrounding flammable gases  and the TENGs operate in a variety of modes, including contact–separation mode , lateralAs the key to output performance, the choice of triboelectric material is very important. A range of materials in the triboelectric series have been proposed, including organic polymers, metals, inorganic materials, etc. . BecauseThis review summarizes the exploration and development of 2D materials in the field of TENGs, including the advantages and output properties of different kinds of 2D materials in TENGs. Subsequently, the application of TENGs based on 2D materials in energy harvesting, self-powered monitoring, tribotronic transistors, and other scenarios is also outlined, as shown in Since their discovery, 2D materials have been of great interest to researchers. Researchers have attempted to use mechanical stripping, chemical vapor deposition (CVD), the hydrothermal method, etc., to prepare large areas of materials . The var2 configuration; it is thin, strong, and flexible, with an ultrahigh electron mobility of 200,000 cm2 V−1 s−1, excellent optical transparency of 97%, and good biocompatibility . T. T47]. Tice life . They em2 TENG has a 9.3 V output voltage. Furthermore, TENGs an operate in hybrid compressive and stretching modes, revealing their tolerance to practical tensile and twist motions. It has also been reported that the folding degree can control the output performance by controlling the work function of CG . T. T−2. DuIn conclusion, graphene is widely used in the electrodes and friction layers of TENGs due to its extremely high electron mobility, flexibility, and transparency, and its derivatives also play an important role in regulating the output properties of TENGs. In addition to being a 2D film, graphene has the advantages of good electronic/mechanical properties and can be subjectively synthesized into other macroscopic forms  graphene quantum dots, 1D graphene fibers, and 3D graphene foam) ,59,60. I2 to fabricate hybrid structures and prepared a MoS2-hBN composite film by pulsed-laser deposition . T. T86]. T3C2Tx MXene nanosheets into the hydrogel 2]x+[Ax/nn−]x−·mH2O, where M2+ is the divalent metal oxygen ion , M3+ is a substituted trivalent metal cation , and An− is the interlayer anion  . . 107]. U−1, and a wide pressure detection range spanning from 0 to 120 kPa. These remarkable attributes enable the generation of high-quality output signals, which facilitate the accurate detection of various finger movements. To achieve excellent flexibility and wearability of the sensor, a glove skeleton was created using 3D printing technology and flexible TPU material, while the fingers were made into a ring structure  for self-powered human–machine interactions . MXene/Etructure d. This d3C2Tx MXene/amino-functionalized multiwalled carbon nanotubes (MXene/NH2-MWCNTs) as the friction layer and electrode , a low detection limit (10 ppb), and a fast response/recovery time (51/57 s) as a self-powered formaldehyde sensor.In addition to monitoring pressure and physical activity, TENGs can also be applied for the detection of respiratory behavior and gases. Wang et al. developed a TENG-based sensor using Tilectrode e 109]. . 3C2Tx M of 100% e. AdditiThe potential generated by friction in TENGs can also provide an external power source for two-dimensional transistors. Since 2014, when electrostatic potential generated by TENG was used as gate voltage to regulate the electron transport characteristics in a transistor for the first time, the research and application of tribotronic transistor have been continuously deepened . The int2 FET [2. The contact–separation with the Al electrode is equivalent to generating a negative voltage on the FET gate, thereby reducing the concentration of charge carriers (electrons) in MoS2 and the corresponding source-drain current. Meanwhile, with the increase in the separation distance, the negative voltage increases, and the source-drain current continues to decline. When the separation distance increases from 0 to 30 mm, the source-drain current changes by 10 times. In addition, the prepared tribotronic transistor was is used as a smart tactile switch to control the trigger of the transistor through finger contact–separation. The switching ratio can reach 16, which can be used to control the switching state of an LED. Later, Li et al. used InSe as channel material and deposited an In layer on the top of InSe for doping to prepare a tactile switch with higher sensitivity [Vds of 0.1 V, the switching ratio reaches 106, meeting the requirements of high signal resolution and low power consumption. This can be used to trigger LEDs or demonstrate Morse code.Taking basic tactile switches as an example, Wang et al. designed a novel electronic transistor based on a single-motor mode of vertical coupling of a TENG and a MoS2 FET  for the sitivity   and covalent organic frameworks (COFs) ,116,117.3C2Tx) are also necessary to improve the performance of TENGs. Overall, there remains a need for further research into the properties and production of 2D materials to fully unlock their potential.Although two decades have passed since the first successful stripping of 2D materials, the remarkable magnetic, thermal, piezoelectric, triboelectric, and other properties exhibited by atomic-layer thick materials have not yet been fully explained ,119. ThiUpon review of the preceding summary, it is evident that 2D materials have the potential to serve as modified constituents that can be incorporated into base materials to form composite materials. For instance, they can enhance the dielectric properties of materials, regulate the work function, and facilitate charge capture and interface lubrication. While these benefits have yielded positive results in TENGs, they are macroscopic effects ascertained by various testing instruments, and a robust microscopic mechanism model to explain them is still lacking. Therefore, the establishment of a stable theoretical model for analysis of 2D materials and their interaction with functionalization and base materials is essential to enhance the performance of TENGs.In terms of applications, the soft, transparent, and ultra-thin properties of 2D materials make them ideal for the preparation of flexible TENGs. However, with the rapid development of IoT technology and the growing demand for wearable devices, there is an increasing need for more flexible, miniaturized, self-powered, and wirelessly transmitted devices. Consequently, TENGs must be designed with clever stacking structures and integrated with more signal processing and transmission units in order to meet specialized requirements such as biological compatibility and environmental stability. Furthermore, the development of hybrid energy harvesters that utilize both triboelectric effects and other effects is necessary to enable signal multimode sensing and to broaden the application field of TENGs based on 2D materials .With regard to the field of TENGs, there is no standardized evaluation system to describe its output performance. Various test factors, such as different test environments, applied loads, contact areas, and device structural parameters, can lead to different results in terms of general test results such as open-circuit voltage, short-circuit current, power density, energy conversion efficiency, etc. ,122. ConThis review provides a comprehensive summary of recent research progress on the TENGs based on 2D materials. From a materials perspective, we reviewed the various roles that 2D materials, including graphene and its derivatives, h-BN, TMDs, and MXene, can play in TENGs, such as serving as electrodes, friction layers, or doping modifications. The applications of TENGs in energy harvesting, self-powered sensing, and human–computer interaction were also discussed. Finally, the challenges and future prospects for the development of TENGs were identified. In conclusion, the successful use of 2D materials in TENGs provides new possibilities to enhance their performance and promote practical applications, thereby advancing the field of self-powered sensing and wearable technology. Further progress towards higher-quality TENGs requires a more substantial theoretical foundation, the development of novel materials, and innovative structural designs.


Aspergillus, lipids carry population density-mediated stresses, and their oxidative metabolite oxylipins act as signaling to transmit information inside cells to regulate fungal development in a synchronized way. In this study, we investigated the regulation of density-dependent lipid metabolism in the toxigenic fungi Aspergillus ochraceus by the oxidative lipid metabolomics in conjunction with transcriptomics. In addition to proven hydroxyoctadecadienoic acids (HODEs), prostaglandins (PGs) also appear to have the properties of QSM. As a class of signaling molecule, oxylipins regulate the fungal morphology, secondary metabolism, and host infection through the G protein signaling pathway. The results of combined omics lay a foundation for further verification of oxylipin function, which is expected to elucidate the complex adaptability mechanism in Aspergillus and realize fungal utilization and damage control.Quorum sensing (QS) is a cellular strategy of communication between intra- and inter-specific microorganisms, characterized by the release of quorum sensing molecules (QSMs) that achieve coordination to adaptation to the environment. In  Aspergillus is a genus of filamentous saprophytic fungi which contains four subgenera, 27 sections, and 339 species, and ubiquitously distributed in natural habitats [Aspergillus species, such as A. nidulans, A. niger, A. oryzae, A. terreus and A. sojae, are generally recognized as safe (GRAS) by the Food and Drug Administration (FDA), as eukaryotic cell factories used in food, medicine and other fields of industrialization fermentation and biotechnology. However, some Aspergillus species are terrible food spoilage fungi and/or opportunistic human pathogens which can produce harmful secondary metabolite mycotoxins and pose a serious threat to animal and human health [A. ochraceus is the representative species and a model mycotoxin-producing strain in Aspergillus section Circumdati, which widely contaminates raw materials and processed foods, spatiotemporally involving plant, harvest, process, storage and sale, causing foods' sensory quality reduction, physical damage and chemical composition destruction [A. ochraceus can cause onychomycosis [A. ochraceus from sorghum grain and found that the toxicity of moldy grains was caused by a new toxic metabolite—Ochratoxin A (OTA) [habitats . Some Astruction . On the omycosis , allergiomycosis , COVID-1omycosis , and its A (OTA) , which h A (OTA) , and it  A (OTA) .Candida albicans [The reproduction of toxigenic fungi and the biosynthesis of mycotoxins at different stages are significantly influenced by external environmental factors, signaling molecules, and trans-kingdom communication. With the increase of population density in a limited living space, resource shortages will cause inter- and intra-specific competition for nutrients, oxygen etc.; on the other hand, single cells will communicate and cooperate in a more “holistic” form, such as a biofilm, in order to protect individuals against environmental pressures. This perception of a population signal was first defined as quorum sensing (QS) in 1994 , and is albicans , and curalbicans .A. parasiticus [Oxylipin is a broad family of enzymatic or non-enzymatic oxidation secondary metabolites of monounsaturated fatty acids (MUFAs) and/or polyunsaturated fatty acids (PUFAs). Free fatty acids (FFAs) are cleaved from FAs and diversified by length and degree of unsaturation, which may be incorporated into complex membrane lipids , and provide the substrate to oxylipin synthesis: oleic acid (OA), linoleic acid (LA), α-linolenic acid (ALA), dihomo-γ-linolenic acid (DGLA), arachidonic acid (ARA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) . The stuasiticus , and theasiticus . The enzasiticus ,21,22. Aasiticus .Aspergillus has great changes in morphological switch, reproduction, secondary metabolism, etc. under different population densities, which was related to the diversified types and quantities of QSMs under different degrees of environmental pressures, and this was also confirmed by exogenous addition experiments. For example, hydroxyoctadecadienoic acids (HODEs) are produced by the hydroxylation of carbon atoms at different sites of linoleic acid catalyzed by different LOXs; 9-HODE and 13-HODE alter reproductive formation and secondary metabolism in A. parasiticus, A. nidulans and A. flavus [A. ochraceus at low density, there are fewer conidia but more OTA and the 9-HODE/13-HODE ratio is higher than high density. The addition of 9-HODE inhibited conidiospores formation and promoted OTA synthesis, while 13-HODE had the complete opposite effect [Aspergillus, which via the intracellular cAMP effector influence the conversion between sexual and asexual, vegetative growth, secondary metabolism, pathogenicity, infectivity, and resistance [Aspergillus, but its precise mechanism remains to be further elucidated [Interspecific coexistent oxylipins have similar structures and functions, which can transmit extracellular information between cells by binding to membrane receptors such as G-protein coupled receptors (GPCRs), and through intracellular effectors such as second messenger to modify transcription factors. The expression of related genes will then be regulated and ultimately affect fungal behaviors ,24. Aspe. flavus ,26,27. Ie effect . HODEs wucidated .A. ochraceus growth and OTA biosynthesis is crucial, and there have been studies on the QS mechanism and G-protein signaling pathway in Aspergillus. However, no density-dependent analysis of the oxidized lipidomics of A. ochraceus has been conducted, and no definitive QSM has been identified.Due to the necessity of fungal pollution prevention and control, understanding the influence factors and regulation of A. ochraceus and screened the different metabolites affected by population density. Transcriptomics was used to enrich differentially expressed genes (DEGs) into specific pathways and combined with functional annotations of differential lipid metabolites to explore the causes of fungal behavior changes related to oxylipins, in addition to the mechanism of density-mediated stress that affects fungal behaviors. This work is expected to provide the A. ochraceus model for studies on the mechanism of Aspergillus quorum sensing, which reflects the comprehensive environmental stress caused by density. In addition, it will analyse the metabolism of oxylipins, which is expected to contribute to the prevention and control of fungal contamination by interrupting the cell communication.In our study, we first qualitatively and quantitatively identified the oxidized lipid metabolites in typical high and low densities of Aspergillus ochraceus strain  was purchased from the Institute of Microbiology of the Chinese Academy of Sciences and preserved in glycerol at −80 °C in the lab. Aspergillus spp. strains were activated on a potato dextrose agar (PDA) medium  at 28 °C for 7 days in the dark and the process was repeated three times.The A. ochraceus that grows in PDA medium for 5 days will produce enough spores to cover the plates, which is suitable for scraping and preparing spore suspensions. We used a sterilized hole punch to gently take a 1 cm diameter PDA medium with spores, and placed it in a centrifuge tube containing 1 mL of sterile saline that contained 0.05% Tween 80, then shaking it vigorously for 30 s to resuspend the spores. The spore concentration was counted using a haemacytometer, and each count was repeated three times in parallel, with the final concentration of the spore suspension being adjusted as needed. Based on the previous series of density gradient (101–107 spores/mL) experiments and the OTA yield that was used as the selection index, the 103 spores/mL group with the most OTA production were used as the representative of low population density, while the 106 spores/mL group with the least OTA production was used as the representative of high population density.In general, Each strain was cultured on five plates as technical replicates, and each experiment was repeated three times as biological replicates.Oxidized lipid metabolite extraction and mass spectrometry detection were undertaken using an ultra-high performance liquid chromatography-mass spectrometer (UHPLC-MS) from Biomarker Technologies . Each sample was accurately determined, and at least 100 mg (dry weight after freeze-drying) was homogenized in 1.2 mL of 70% methanol extracting solution with a ball mill. It was then spiked with 20 µL of 1 µmol/L internal standard mixture to each sample and vortexed for 10 min, centrifuged at 5000 rpm for 10 min at 4 °C, and the extraction was repeated and the supernatants were combined. The oxylipins in the supernatants were extracted using Poly-Sery MAX SPE columns , the loading solution volume was 3 mL, and they were then rinsed with 2 mL of 20% methanol and finally eluted with 1 mL of 2% acetonitrile formate.v/v) for UHPLC/MS/MS analysis, and was eluted through an Agilent SB-C18 column  . The solvent system was 0.1% formic acid aqueous solution (A), 0.1% formic acid acetonitrile (B). The injection volume was 4 µL and the gradient was 0~9.0 min from 5% to 95% (B) and maintained for 1 min; 10.0~11.0 min reduced to 5% (B) and equilibrated at 5% to 14 min. The flow rate was 0.35 mL/min and the temperature was 40 °C.The eluent was dried under vacuum and re-dissolved in 100μL of methanol/water . To enhance accurate mass measurement for the ion, a reference solution was vaporised in continuum in the spray chamber. The resulting data were converted to a mass centroid from which the accurate m/z value was measured.Accurate mass measurements of oxylipin compounds were conducted with a triple quadrupole-linear ion trap mass spectrometer (QTRAP) system equipped with an electrospray ionization (ESI) Turbo Ion-Spray interface, operating in the positive and negative ion mode. The ESI source temperature was 500 °C, the ion spray voltage (IS) was 5500 V (positive) and −4500 V (negative), the ion source gas I (GSI), gas II (GSII), and curtain gas (CUR) were set at 55, 60, and 25.0 psi, respectively, and the collision gas (CAD) was high. Instrument tuning and mass calibration were performed with 10 and 100 µmol/L polypropylene glycol solutions in the QQQ and LIT modes, respectively. All metabolites were analyzed using scheduled multiple reaction monitoring (MRM), and a specific set of MRM transitions were monitored for each period according to the metabolites eluted within this period. The MRM data acquisition and processing were done by using Analyst Workstation Software . The scan mode time of flight (TOF) mass spectra were acquired in negative ion mode by using the TOF at 10,000 mass resolving power for scans over the range from The absolute concentration of each oxylipin was calculated by comparison to the standard curves generated through the mass spectrometry measure of series dilutions of all 141 oxylipin standards. Only the oxylipins with a signal to noise ratio greater than 10 (S/N > 10) and the concentration located in the range of the standard curves were considered as absolutely quantified. The accuracy and precision of the current method was validated for the linearity of the standard curve, analyte recovery rate, and relative standard deviation (RSD).t-test was used to calculate the difference significance pvalue of each compound. The R language package ropls was used to perform OPLS-DA modeling, and 200 times permutation tests were performed to verify the reliability of the model. At the same time, theoretical fragment identification and mass deviation were within 100 ppm, and the oxylipins with Variable Importance in Projection (VIP) > 0.00, Fold Change (FC) > 1, and p-value < 1 were considered as significantly changed. The difference metabolites of KEGG pathway enrichment significance were calculated using a hypergeometric distribution test. All data processing and analysis was performed on the biomarker cloud platform (http://www.biocloud.net (accessed on 11 January 2023)).The raw data collected using MassLynx V4.2 was processed by Progenesis QI software for peak extraction, peak alignment and other data processing operations based on the Progenesis QI software online METLIN database and Biomark’s self-built library for identification. After normalizing the original peak area information with the total peak area, principal component analysis and Spearman's correlation analysis were used to judge the repeatability of the samples within group and in addition to the quantity control samples. The identified compounds were searched for classification and pathway information in the KEGG, HMDB, and the LIPID MAPS databases. According to the grouping information, we calculated and compared the difference multiples, and a ®Ultra™ RNA Library Prep Kit for Illumina® . The sequences were further processed with a bioinformatic pipeline tool, the BMKCloud (www.biocloud.net (accessed on 11 January 2023)) online platform. Transcriptome assembly was accomplished using Trinity with min_kmer_cov set to 2 by default, and all other parameters were set to default. Gene expression levels were estimated by cDNA fragments per kilobase of transcript per million fragments mapped. The differential expression analysis of the two groups was performed using DESeq2. The resulting p values were adjusted using Benjamini and Hochberg’s approach for controlling the false discovery rate. Genes with an adjusted p-value < 0.05 found by DESeq2 were assigned as differentially expressed. The cluster analysis was conducted by blasting with gene ontology (GO) [Total RNAs of high/low representative density samples were extracted with a TransZol Up Plus RNA Kit . RNA concentration and purity was measured using a NanoDrop 2000 . RNA integrity was assessed using the RNA Nano 6000 Assay Kit of the Agilent Bioanalyzer 2100 system . Sequencing libraries were generated using the NEBNextogy (GO)  and the ogy (GO) . A functogy (GO)  softwarep < 0.05). All assays were replicated in triplicate.Data were expressed as mean ± standard deviation of three independent experiments. All data analyses were performed using the SPSS statistical package (SPSS Version 20.0). A one-way ANOVA with Duncan’s multiple comparison test were used for the analysis of parametric data. Data with different lowercase letters were considered to be significantly different  with low OTA production was selected as the control, while the low-density group (103 spores/mL) was the experimental group, and the qualitative and quantitative analysis of oxylipins was conducted between groups. The oxidized lipid library in this experiment included 141 lipids.As a class of lipid secondary metabolites, oxylipins can reflect the diversified information of cell communication and also perform important functions with regard to fungal activities. In order to analyze the effect of population density-mediated environmental changes on er index , the hig−1 μmol/g” in both the high-density and low-density groups, followed by ALA, which reached “102 nmol/g” in each group. ARA, DGLA and DHA reached “10−1 nmol/g” in the high-density group, while less in the low-density group. EPA reached “10−2 nmol/g” while the low density group was higher than the high-density group. GLA was the least detectable. Overall, with the increase of carbon chain length and unsaturation, the detection amount decreased. Lipid metabolites with a relatively large amount (at least “nmol/g”) are shown in Among PUFAs, LA was the most detected, and reached the level of “10It is interesting to note that the shorter the carbon chain length of the PUFA substrate, the greater the production of derived oxylipins. In addition, the amount of oxylipins catalyzed by LOX was greater than CYP and greater than COX. It is speculated that short-chain and low-saturated PUFAs are the substrate of long-chain and high-saturated PUFAs, such as LA is the substrate of ARA, the base amount in cells accounts for the main reason, and the potential energy required for LOX hydroxylation is lower than that of epoxy and double oxygenation.A. ochraceus, oxidized lipid metabolomics was performed. Among 141 oxidized lipids, 66 differential metabolites were detected, of which 25 were up-regulated and 41 were down-regulated under the low-density group compared with the high-density control group. The hierarchical clustering of all differential metabolites screened out will cluster with the same or similar attributes in different samples, as has been displayed in the heat maps , TxB3 , and (±)14(15)-DiHET . It can be seen that the difference of long-chain PUFA oxides is more significant, which seems to be related to the complex metabolic processes in the cell, and this also implies a small amount but the efficient utility of complex oxidized lipids in organism activities which are perhaps related to the cascade amplification process.To decipher the cell communication mechanism mediated by population density, and if oxylipin acts as QSM to regulate the development in eat maps a. The voeat maps b. The to5 , 15-keto-PGF1α and PGD1 , HDoHE , PGE2 and PGJ2 , 15(S)-HETrE . Significantly down-regulated metabolic lipids included ARA, LtE4 and LxB4 , TxB3 , 13(S)-HpODE , and PGB2 . The Z-score is converted from the quantitative value and is used to measure the deviation of the experimental group from the control group, which is another way to visualize the relative content of oxidized lipids  was performed. The annotation results of the DEGs were classified according to the pathway type in KEGG .In the lipid metabolism class, the fatty acid degradation (ko00071), fatty acid biosynthesis (ko00061), and fatty acid elongation (ko00062) pathways all showed differences between the high and low density groups. The glycerophospholipid metabolism (ko00564) pathway enriched the most DEGs, followed by steroid biosynthesis (ko00100) and glycerolipid metabolism (ko00561), which are two other complex lipids composed of FFAs. Glycerophospholipid, as the basic composition of the cell membrane, is involved in the membrane flow that is responsible for maintaining cell homeostasis and signal transmission. At the same time, the ABC transporters (ko02010) pathway of the membrane transport class and the MAPK signaling pathway (ko04011) of the signal transduction class in the KEGG Environmental Information Processing term had significant differences, which indicate that it is most affected by density-mediated cell communication. Glycerophospholipid releasing FFAs act as raw materials for oxylipins through phospholipase action , but theThere were four differentially expressed genes in the biosynthesis of the unsaturated fatty acids pathway (ko01040), accounting for 1.38%, but except for the alpha-linolenic acid metabolism pathway (ko00592) enrichment to two DEGs, most genes in the arachidonic acid metabolism (ko00590) and the linoleic acid metabolism (ko00591) pathway were not affected by density  in various pathways a. UnsatuCombined with the transcriptomic analysis, the biosynthesis of the unsaturated fatty acids (ko01040) pathway was greatly affected by the fungi density, and the expression of related genes was significantly up-regulated in the low-density group. The amounts of ALA, EPA and DHA increased, while LA, DGLA and ARA decreased significantly . There aThe linoleic acid metabolism pathway was significantly down-regulated, and 13(S)-HPODE and 13(S)-HODE, which have been verified as QSM, and their derivatives were significantly reduced in the low-density group, while the other QSM, 9-HODE, had no significant change, but its derivatives were significantly reduced . Curious2 and PGD2,which are substrates of the prostaglandin D2 receptor (PTGDR) and prostaglandin E2 receptor (PTGER) in the neuroactive ligand-receptor interaction (ko04080) pathway  in the alpha-linolenic acid metabolism was upregulated, but seems to be unassociated with the increased production of 9(S)-HpOTrE and 13(S)-HpOTrE . The ARA pathway , increasA. ochraceus.This shows that under the influence of population density, firstly, the metabolism of various PUFAs are affected, and the synthesis mechanisms of oxylipins are difficult to speculate upon. Furthermore, whether single specific or multiple substances play the role of QSM needs further research. Third, it is worth exploring at which level and what role other pathways are affected by density in Aspergillus, the PUFAs and their catalytic products can regulate the morphological transformation and secondary metabolism to affect their environmental adaptability and infectivity to the host [A. ochraceus.Fungi have strong adaptability and exhibit rapid aggregation growth under appropriate conditions, while producing secondary metabolites that are beneficial or harmful, and how microorganisms survive the environmental pressure caused by population density is a comprehensive mechanism. The fatty acids' oxidative products not only regulate fungi intraspecific communication, but it was further found that the production and function of oxylipins are interoperable in the interaction between fungi and hosts. That is, oxylipins are a class of widespread signaling molecules among animals, plants, and microorganisms . Althougthe host . Based oA. fumigatus development is only “nmol” level, while HODEs reached the “mmol” level [Fatty acids play an extremely important role in cellular life activities and also serve as substrates for complex biomacromolecules, such as existing in the cell membrane in the esterified form, maintaining cell structure, and coordinating the transport of intracellular and extracellular substances, or being further processed into various derivatives. The metabolism of FAs starts from de novo synthesis with acetyl-CoA as the raw material, while also including elongation and degradation, which is comprehensively regulated by various factors . In addil” level , so the ppoA in A. nidulans reduced the ratio of asexual to sexual reproduction, the ΔppoC of A. fumigatus decreased the spore germination rate, but the size of the spore enlarged, double the ∆ppoAC and triple the ∆ppoABC mutants of A.nidulans delayed and reduced conidiospores development and turned to a premature increase in ascospore production. LOXs catalyze the oxidation of LA to produce HpODEs, which are quickly hydroxylated to HODEs, both of which can affect vegetative growth, morphological transformation, and mycotoxin synthesis through GPCRs, which then activate the cAMP-PKA pathway and regulate the expression of genes. For example, In A. nidulans, A. fumigatus and A. flavus, 5,8-diHODE and 7,8-diHODE induce cell differentiation and lateral branching, and also regulate sexual development and sporulation [ppoA, ppoB, ppoC and ppoD) and one lipoxygenase gene (loxA) in A.flavus destroyed its density-sensing ability, produced high levels of aflatoxin (AF) at any density, as well as during infestation with corn and peanut, and shifting from asexual to sexual development [A. ochraceus, the Δlox mutant that the 13-HODE synthesis inhibited, OTA production decreased and conidia production increased [A. ochraceus inhibited the sporogenesis and promoted OTA synthesis, which indicated the state of low population density, while the effect of 13-HODE was the opposite, and this revealed the effect of HODEs as QSM [Psi catalyzed by PPOs are divided into PsiA, PsiB, and PsiC according to the positioning of the hydroxy groups. PsiAα enhances asexual reproduction, while PsiBα and PsiCα stimulate sexual reproduction, and the ratio of PsiAα to PsiBα and PsiCα determines the form of fungi reproduction ,38,39. Trulation ,35,40. Telopment . In A. oncreased . The adds as QSM .A. nidulans, the addition of 9- and 13-HODE in wild-type induced cAMP surged, but the ΔgprC and ΔgprD mutants remained unchanged [gpr gene mutations were constructed in A. flavus, while with the addition of LA, the raw material of HODEs, only the ΔgprD mutant showed phenotypic differences from the wild type, but the added13-HODE had nine GPCRs deletion mutant strains, including ΔgprD, that did not show the same increase in spore production as WT [Aspergillus with oxylipins as ligands, and the identification of receptors requires specific structures. A bioinformatics analysis of GPCRs was also carried out in A. ochraceus, and a sequence comparison identified GPCR receptors that may be bound by oxylipins [A. ochraceus to environmental signals was comprehensively regulated by multiple intracellular effectors [However, the quantitative analysis results in this experiment showed that, compared with the high-density group, the detection of 9-HODE and 13-HODE in the low-density group were both reduced, and the previous experiments also showed that a relatively larger ratio of 9-HODE was produced in a low population density . It is hnchanged . A libraon as WT . Additioon as WT ,45. Thesxylipins , which cffectors .Aspergillus ΔppoA and ΔppoC mutants [lox knockout that lost the ability to produce oxylipins, such as JA and its derivatives, were more susceptible to A. flavus and A. nidulans, which produced more spores and mycotoxins [A. fumigatus and A. nidulans can transform ARA into PGE2, PGF2α, 6-keto-PGF1α, isoprostanes, and TxB2, which is similar to mammal hosts, but the pathways for the synthesis of these compounds are different [Aspergillus, perhaps because PGs are tiny, have a short half-life, and are unstable, and the measured amount in this experiment is only 10−2 times that of the HODEs. However, it should be noted that the detected amount of PGs was significantly up-regulated at low density, considering that PGs is an important class of GPCR ligand in the mammal, and the scope of QSM in Aspergillus can be expanded to PGs and other ARA derivatives in the future [In the process of fungal infection, both the fungus and the hosts are under stress and coercion brought by each other, and their respective defense systems are activated through oxylipins ,48. Oxid mutants . In addi mutants . Convers mutants ,52. Maizcotoxins ,54. Humaifferent ,55. There future . In concA. ochraceus under low- and high-densities, and explored the underlying QS mechanism of Aspergillus to population stresses. Under low-density, A. ochraceus produced fewer conidia and more mycotoxin OTA, while under high density, which involved resource stress and high pressure, OTA synthesis decreased and there was sexual switching to asexual reproduction. Population density mainly affects the lipid metabolism and environmental information processing in A. ochraceus. The G protein signaling pathway and the cAMP pathway showed significant differences, which are related to the regulation of fungal morphology and the secondary metabolism. Differential lipid metabolites, including the elucidated HODEs and novel potential PGs, may perform the function of QSM. However, in addition to being catalyzed by LOX, COX, CYP, and other enzymes, the synthesis of oxylipins also appears to be non-enzymatic due to oxidative stress caused by high population density. The series of oxylipins produced are recognized by different receptors based on structural differences, and regulate the fungal development and the interaction with the plant and animal hosts in the form of signaling molecules, constituting a complete QS communication mechanism. Subsequently, the effect of HODEs or PGs on fungal sporulation and mycotoxin biosynthesis can be verified by additional experiments, which is likely to lead to new biological methods of fungal damage control. Even further verification of key links such as oxidases, GPCRs, and cAMP effectors is required at the gene level in order to complete the mysterious and complex intraspecific and interspecific communication mechanisms.This paper focused on the lipid metabolomics combined with transcriptomic profiles in


Neopterin is a biomarker of the activation of cellular immunity. The purpose of this review is to summarise neopterin metabolism, methods of its detection, and its role in inflammation, focusing on periodontal inflammatory diseases. This derivative of guanosine is a non-enzymatic product of 7,8-dihydroneopterin oxidation caused by free radicals which protect activated macrophages from oxidative stress. Various methods, usually based on enzyme-linked immunosorbent essay, high-performance liquid chromatography, or radioimmunoassay were developed for the isolation of neopterin. A wide spectrum of diseases and conditions are known to affect neopterin levels, including cardiovascular, bacterial, viral, and degenerative diseases, as well as malignant tumours. Neopterin levels were found to increase in subjects with periodontitis, especially when the oral fluid and gingival crevicular fluid were evaluated. These findings confirm the role of activated macrophages and cellular immunity in periodontal inflammatory diseases. The gingival crevicular fluid and the oral fluid appear to be the most valuable biologic fluids for the evaluation of neopterin levels in periodontitis. For gingival crevicular fluid, neopterin can be determined as the concentration or the so-called total amount. Nonsurgical periodontal treatment was associated with a decrease in neopterin levels, but an increase was also reported, suggesting the possible role of macrophages in the resolution of the periodontal lesion. Neopterin (Np) is a biomarker of the cell-mediated immune response ,2. Np, wThis review focuses on the relation between Np levels and periodontitis. The role of Np in immune response is discussed on molecular level as well. The nonspecificity of Np as a cell-mediated immune response is described in a wide variety of diseases and conditions. The articles included in Part 6 were selected by searching “neopterin” and “periodontitis” in the PubMed and Scopus databases. Searching the PubMed database revealed 27 articles. The Scopus database showed 222 positive results between the years 1997–2022. After consideration of inclusion criteria and of the similar results in both databases, 16 articles were included in this review in Part 6. The inclusion criteria were the full texts of the articles available in English that focus on Np levels in different biological fluids in subjects with periodontitis or in other conditions where periodontitis was evaluated by standard periodontal examination/indexes. When the effect of periodontal therapy was evaluated, only studies that evaluated nonsurgical periodontal therapy were included.Np is a metabolite of guanosine triphosphate (GTP) that is transformed to 7,8-dihydroneopterin via cyclohydrolase I. 7,8-dihydroneopterin is subsequently converted to tetrahyrobiopterin by a combined enzymatic reaction with 6-pyruvoyltetrahydropterin synthase followed by sepiapterin reductase . The firA study in human umbilical vein endothelial cells revealed that transcription of GTP cyclohydrolase I is driven by activation of the Janus kinase 2/signal transducer and the activator of the transcription proteins (JAK2/STAT) pathway after IFN-γ stimulation and by activation of the nuclear factor kappa B (NF-κB) pathway after TNF-α stimulation .7,8-dihydroneopterin is a strong reducing agent, free radical scavenger, and chain-breaking antioxidant . It was 7,8-dihydroneopterin was found to be effective in preventing lipid peroxidation and protein hydroperoxide formation ,24. ProtLipids containing double carbon–carbon double bond(s), especially polyunsaturated fatty acids, are attacked by free radicals or non-radical species, and a hydrogen is abstracted from a carbon and oxygen is inserted ,29. ExteNp was suggested to inhibit the formation of superoxide mediated by nicotinamide adenine dinucleotide phosphate in rat peritoneal macrophages  as a pos2+ ions in vitro [Antioxidant properties were also studied at the molecular level to prevent the oxidation of low density lipoprotein (LDL) ,31,32. Lin vitro . The addin vitro . Np formin vitro . The addin vitro . CD 36 iGiven the potent free radical scavenging of 7,8-dihydroneopterin, it was suggested that the purpose of 7,8-dihydronepterin is to protect activated macrophages against oxidative stress  and cellNp is considered a biomarker of IFN-γ synthesis ,38, macrGenerally, pterins have a low brain–blood barrier permeability, so it is unlikely that Np is passively transferred from blood . The estNeopterin was evaluated in various body fluids, including ,51, urinSerum neopterin levels were not found to be sex dependent. In most scientific studies, Np concentrations below the cut-off value of 10 nmol/L are considered normal . SeveralIn urinary samples, Np is expressed in a ratio with creatinine. These values were found to be higher in women and also decreased in childhood and increased in older individuals ,45. A ci2/10.8% KI in 1 M HCl) [In clinical research, Np levels are usually measured alone. 7,8-dihydroneopterin is not usually assessed in large sample series due to its low stability. The samples must be protected from UV light and stored on ice . In an a1 M HCl) . Subsequ1 M HCl) . For ser1 M HCl) . Given t1 M HCl) . Np and 1 M HCl) .2 = 0.96 for the IBL International ELISA kit  and R2 = 0.48 for the Neopterin ELISA kit  compared to the HPLC method [For the determination of Np, various methods were employed. Several high-performance liquid chromatography (HPLC) methods have been developed. HPLC was proposed as a gold standard for Np determination . CommercC method . It was C method . RadioimC method , but lowC method ,70. PolaC method .Oral fluid neopterin can be detected by commercially available ELISA kits ,72,73,74Np in gingival crevicular fluid was also detected by commercially available ELISA kits. Only one HPLC method has been developed for the simultaneous analysis of Np in conjunction with creatinine, kynurenine, and tryptophan .Neopterin levels were found to be affected by a wide variety of diseases and conditions. In coronary artery diseases and peripheral artery diseases, Np is considered an etiologic and prognostic factor due to the bioavailability of the regulation of nitric oxide (NO) ,77. IncrFor bacterial diseases, Np was proposed to predict complicated cholecystitis. A 3.34 times higher risk of complications was reported in subjects with Np levels that exceeded the cut-off limit (>14.69 nmol/L) . Np is aCellular immunity plays an essential role in viral infection . For exaNp levels in cerebrospinal fluid were affected by neurodegenerative diseases such as multiple sclerosis, neuromyelitis optica, and myelin oligodendrocyte glycoprotein antibody-associated disease and were reported to be useful in differential diagnosis and activity monitoring of these diseases . An assoMacrophages can play a dual role in cancer control. They represent potent effectors of antitumour immunity. On the other hand, they can contribute to tumour growth and progression ,110. TumThe ultramarathon race also caused systemic inflammation and higher Np serum levels and was associated with decreased antioxidant capacity ,120. ThePeriodontitis is a chronic inflammatory disease of periodontal tissues that leads to their destruction and, when untreated, to tooth loss . PeriodoDysregulation of the innate and adaptive immune systems can play an important role in the aetiology of periodontal disease . It was Macrophages were found to polarise into M1 and M2 phenotypes. M1 macrophages, induced via IFN-γ, are considered proinflammatory immune cells. They secrete a wide variety of hydrolytic enzymes, matrix metalloproteinases, to degrade the different compounds of connective tissue. The M1 macrophages phenotype is associated with the production of matrix metalloproteinase 8, 9 and 12 ,126,127.Searching PubMed database and Scopus database revealed 16 studies related to periodontitis impact on Np levels, see For evaluation of the immune response in periodontitis, gingival crevicular fluid (GCF) is essential. This biologic fluid is secreted by the gingival crevice  or the periodontal pocket . Therefore, secretions at the site of inflammation provide the best information on current disease activity. Neopterin GCF concentrations were found to be significantly higher in subjects with periodontitis compared to healthy controls in several studies ,133,135.For the evaluation of cytokines GCF, the so-called total amount (TA) was also used. TA means the weight or amount of the substance in the whole collected GCF sample. The reason for the evaluation of TA is the increased GCF production in inflamed periodontal tissue caused by increased vascular permeability, which can lead to biomarker dilution. Np TA was proposed to be more valuable to Np concentrations by Ozmeric et al. , who fouAfter nonsurgical periodontal therapy, both Np GCF concentrations ,135 and Oral fluid is a mixture of saliva, gingival crevicular fluid, and nasopharyngeal secretions . It alsoThe source of Np in oral fluid is not clear. Ozmeric et al.  stated tNo study showed significant differences in serum/plasma Np levels between subjects with periodontitis and healthy controls ,135. A sOnly two studies ,44 foundAs Np is a very sensitive and nonspecific biomarker of cellular immune system activation, Np reliability may be significantly influenced by concomitant diseases. This was published by Abdel-Haq et al. , who fouMost studies concluded that neopterin levels are involved in periodontitis ,134,135.


Infertility is a well-recognized multifactorial problem affecting the majority of people who struggle with infertility issues. In recent times, among infertility cases, the male factor has acquired importance, and now it contributes to approximately half of the infertility cases because of different abnormalities. In the current study, we used natural phytochemicals as potential drug-lead compounds to target different receptor proteins that are involved in the onset of male infertility. A set of 210 plant phytochemicals were docked counter to active site residues of sex hormone-binding globulin, a disintegrin and metalloproteinase 17, and DNase I as receptor proteins. On the basis of binding scores and molecular dynamics simulation, the phytochemicals tricin, quercetin, malvidin, rhamnetin, isorhamnetin, gallic acid, kaempferol, esculin, robinetin, and okanin were found to be the potential drug candidates to treat male infertility. Molecular dynamics simulation showed tricin as a strong inhibitor of all selected receptor proteins because the ligand–protein complexes remained stabilized during the entire simulation time of 100 ns. Further, an in vivo study was designed to evaluate the effect of tricin in male rats with nicotine-induced infertility. It was explored that a high dose of tricin significantly reduced the levels of alanine transaminase, aspartate transaminase, urea, creatinine, cholesterol, triglyceride, and low-density lipoprotein and raised the level of high-density lipoprotein in intoxicated male rats. A high dose of tricin also increased the reproductive hormones  and reduced the level of DHEA-SO4. The phytochemical  also showed significant improvement in the histo-architecture after nicotine intoxication in rats. From the current study, it is concluded that the phytochemical tricin could serve as a potential drug candidate to cure male infertility. Male infertility is a global health issue that affects about 7% of the male population . VariousSex hormone-binding globulin (SHBG) is a multifunctional glycoprotein that is synthesized by the liver, and it binds to steroid hormones and mediates hormonal signaling. The genetic mutations in SHBG genes, more specifically mutated rs6259 and rs727428 loci, are involved in male infertility [A disintegrin and metalloproteinase 17 (ADAM17)  is a membrane-bound protein and is involved in the regulation of shedding of the ectodomain, which inhibits or activates cellular signaling associated with various inflammatory disorders. The expression of ADAM17 is mandatory for the induction of apoptosis in germ cells. Clinically, ADAM17 has been targeted to prevent apoptosis in germ cells with testicular torsion. Testicular torsion is the most common urological illness among young adults, which further prolongs testicular damage in males. Testicular torsion disrupts normal blood flow in testicular tissues, which leads to severe ischemia . DeoxyriDespite much advancement in the medical field, about 50% of infertility cases are still accountable as idiopathic. Due to a variety of mutations and up- and down-regulation of different proteins in infertility cases, it is still difficult to navigate the exact problem behind every clinical case. The literature provides some of the most reported genes, which, when expressed into proteins, lead to their critical roles in idiopathic infertility in males. Despite the fact that the precise causes are yet not fully understood, genetic, developmental, physical, environmental, and lifestyle variables could all be causal links between infertility and normal health. It has been demonstrated that several genetic variants in infertile males with idiopathic oligoasthenoteratozoospermia are connected to poor spermatogenesis. In the current study, we, therefore, targeted the three most reported proteins because the impaired nature of these proteins plays a crucial role in progressing defective spermatogenesis. Despite the existence of synthetic drugs, we have explored the positive side of natural phytochemicals as natural fighters counter to SHBG, ADAM17, and DNase I as receptor proteins in this study.A total of 210 phytochemicals from different plant sources were docked counter to three receptor proteins . The top five ligands against each receptor protein were selected on the basis of ligand–protein interactions through active amino acids of the catalytic pockets and minimum energy structures .Against sex hormone-binding globulin (SHBG), the phytochemical tricin with a docking score of −11.09 kcal/mol showed strong interactions with amino acids  of the binding pocket a. The liThe third protein, ADAM1 , showed interactions with a selected library of ligands. Among the docked compounds, tricin was found to be the best one, with a docking score of −13.15 kcal/mol . Tricin For the next protein, deoxyribonuclease I (DNase 1), rosavin was revealed as the best candidate to interact with active site residues  of the binding pocket of DNase I with docking score of −9.46 kcal/mol . Among tSwissADME tool is used to reveal the most suitable drug compounds that follow Lipinski’s rule of five (Ro5), which states that the molecular mass should be <500 Dalton, the hydrogen bond donor should be ≤5, the hydrogen bond acceptor should be ≤10, molar refractive index should be in the range of 40–130, and partition coefficient (LogP) should be ≤5. The purpose of these parameters is to distinguish the drug-like candidates that are suitable to be recommended as leading drug candidates. Among the best-selected phytochemicals against three receptor proteins, myricetin, callistephin, and rosavin violated only one rule. Based on other parameters, the compounds that violate no or one rule can be accepted as drug candidates because of their nontoxic behavior. Moronic acid violated two rules of Ro5, and naringin violated four of Lipinski’s rules, and, therefore, they were excluded from further assessment .For further evaluation, all the best-selected phytochemicals were subjected to ADMET  profiling to confirm the bioavailability and non-toxicity of these drug candidates using ADMETlab 2.0, an online platform. On the basis of best docking scores and ADMET parameters, most of the phytochemicals revealed strong binding interactions with the receptor proteins, good absorption, and no toxicity. The ADMET profiling of the best-selected phytochemicals is given in The ADMET profiling of the best-selected phytochemicals were also performed using another online tool, pkCSM, and the results are given in Based on the results of molecular docking and druggability analyses, the best phytochemicals were further selected for molecular dynamics simulation study. The phytochemicals quercetin, malvidin, rhamnetin, isorhamnetin, gallic acid, kaempferol, esculin, robinetin, and okanin showed strong binding interactions with the receptor proteins and did not violate any rule of Ro5. The phytochemical tricin was found to be involved in sufficiently strong binding interactions with all selected receptor proteins, and, therefore, it was selected for MD simulation studies. The MD simulation was performed to determine the binding properties of these ligands inside the binding pockets of target proteins in the dynamic state. Schrodinger’s Desmond Module was used to perform MD simulation to reveal the stability of the protein–ligand complex.The tricin–SHBG protein complex showed stability via MD simulation. Initially, some minor fluctuations in the protein RMSD were observed, and the value was increased from 1 Å to 2 Å, but the average P-RMSD change was ~1 Å, and the protein was found to be stable throughout the simulation time of 100 ns. The ligand tricin was stabilized after 4 ns and remained firmly attached to the protein SHBG. A mode shift was observed at 40 ns; the ligand again stabilized until the end of the simulation time of 100 ns a. The avThe hydrogen bond interaction stability or the consistency of important amino acids of each receptor protein with the best-selected phytochemical as the ligand throughout molecular dynamics simulation revealed that the ligand complexed with selected respective proteins are stable and could be used as potential candidates in drug designing to cure male infertility . The RooThe Protein–Ligand Interaction Fingerprints (PLIF) of the SHBG protein complexed with tricin before and after MD simulation showed that the amino acids Ser42, Asp65, Trp66, and Asn82 are important in stabilizing the complex in drug designing because the residues are involved in making hydrogen bonds with the ligand. The amino acids Phe67, Leu80, Val105, Met107, Val112, Val127, Leu131, Lys134, Met139, and Leu171 were found to be involved in hydrophobic interactions with ligand a. From tFor molecular dynamics simulation, the Molecular Mechanics Generalized Born Surface Area (MM-GBSA) was also calculated using the module of Prime MMGBSA v3.000 . Solvatip < 0.01) in male rats, i.e., 113.8 ± 5.38A from the range of normal in the control rat group as 46.2 ± 4.11D. At the same time, ALT levels reverted to normal following administration of a high dosage of phytochemical tricin (10 mg/kg b.w.) in groups of male rats at 35 ± 3.27E, respectively. A significant (p < 0.01) difference in ALT level was revealed in the plant phytochemical treatment group compared to the control group of female rats. Significantly (p < 0.05) elevation in AST, urea, and creatinine levels were reported in intoxicated groups, i.e., 125.8 ± 6.55A, 54 ± 4.90A, and 1.3 ± 0.08A compared to their respective control group rats. At the same time, there was a significant difference in all of the phytochemical-treated groups of rats , i.e., 26 ± 3.27E, 17 ± 0.82DE, and 0.8 ± 0.13BC, significant (p < 0.01).A ‘liver function test’ is a measurement of the liver’s proper functioning and an increase in blood aminotransferases such as ALT and AST, urea, and creatinine activity, indicating dysfunctional liver cells. Elevated ALT and AST values in the blood suggest impaired hepatocyte damage . The resValues are mean ± SE (standard error) of the study groups. Different letters (A–F) in superscripts in the same row indicate significant mean differences according to Tukey’s pairwise comparison. The values that do not share a letter (superscript) are significantly different.In the context of lipid profile, the cholesterol level was also raised in the intoxicated group to 198 ± 9.80A compared to the normal level in the control group . A high dose of tricin significantly reduced the level of cholesterol by about (138 ± 4.90F) even compared to the positive control group in which the testosterone drug was used. In comparison, the level of TG and LDL were raised to 221 ± 16.33A and 87 ± 2.45A in the nicotine-administrated group, but tricin-treated rats significantly reduced this level to 137 ± 5.32DE and 78 ± 2.53F. HDL cholesterol is also called good cholesterol. Tricin phytochemicals increased the level of HDL, i.e., 42 ± 2.45ABC from 35 ± 2.45F, which was analyzed in the intoxicated group in which nicotine was used for intoxication.p < 0.01).Testosterone and its potent metabolite dihydrotestosterone (DHT) are the major circulating androgens, mainly in males. The effect of tricin and control treatments on the reproductive hormones of male rats is given in The histological examination of liver tissues , ADAM17, and DNase I as receptor proteins to manage male infertility due to the involvement of these proteins in male infertility events. Ramgir et al.  suggesteFrom the current docking study, the phytochemical tricin with a docking score of −11.09 displayed significant binding interactions with Ser42, Phe56, Asp65, Phe67, Leu80, Asn82, Met107, Val127, Leu131, Lys134, Ile141, and Leu171 residues of the active binding pocket of SHBG protein. The other compounds, myricetin, quercetin, malvidin, and rhamnetin, also displayed good binding scores, displaying strong interactions with SHBG protein. The drug assessment of all these predicted candidates fully favored the potential of these phytochemicals as drug candidates. In a study, Esther et al.  docked 4A disintegrin and metalloproteinase 17 (ADAM17) serves as a metalloprotease that plays a crucial role in a number of cellular signaling pathways. In the current study, we also targeted ADAM 17 active catalytic sites. The phytochemical tricin with a docking score of −13.15 kcal/mol showed strong interactions with Leu348, Gly349, Leu401, Val402, His405, His415, Val434, Pro437, Ala439, and Val440 residues of the binding pocket. The other compounds  also interacted with Ala439 and Val440 as common residues of the active site. This suggested the potential of natural bioactive compounds as leading candidates for targeting the ADAM17 protein to cure male infertility. In a study, Mohamed et al. [DNase1, being an endonuclease, regulates the induced apoptotic-based DNA fragmentation. The percentage of damaged DNA is more common in infertile men compared to fertile ones. The DNase1-assisted DNA damage of sperm is the main cause of a defective male reproductive system . In the The drug scanning and ADMET profiling of all the best-selected compounds displayed the maximum potential of these compounds as drug candidates. Almost all selected top ligands followed all five of Lipinski’s rules (Ro5), except naringin, which violated four rules of the Ro5, and moronic acid, which violated two rules of the Ro5. The ADMET scanning further proved the potential of these compounds because they were found to be nontoxic and possessed good bioavailability. The molecular docking, druggability analyses, and molecular dynamics simulation studies revealed tricin, quercetin, malvidin, rhamnetin, isorhamnetin, gallic acid, kaempferol, esculin, robinetin, and okanin phytochemicals as potential drug candidates for the management of male infertility. These phytochemicals also followed all druggability parameters for being good or potential drug candidates. These ligands displayed no Ames toxicity and carcinogenicity. On the basis of the SA score, Lipinski’s rule, Pfizer rule, GSK rule, and the Golden Triangle, the medical biochemistry profiling of the best-selected phytochemicals  also confirmed that these could be used as drug candidates in drug discovery processes against male infertility.4-induced liver toxicity was examined by Shakya et al. [p < 0.05) by CCl4 exposure; however, these variables were all reduced by the application of MD and SD. According to Uemura et al. [In order to investigate the therapeutic effects of phytochemical tricin on the reproductive hormones employing male albino rats as experimental animals, the present investigation was carried out. Increased serum liver enzyme concentrations in blood flow can be caused by the degradation of toxic phytoconstituents found in plants and byproducts, which are expelled by the liver and may alter the normal functioning of the liver . A livera et al. . The exca et al. , dyslipip < 0.01) increased the level of male reproductive hormones. The phytochemical composition, antioxidant activity, and androgenic effects associated with four South African herbal products were studied by Masuku et al. [T. sambesiaca methanol extract possessed the greatest amount of testosterone production capacity, while P. africanum and T. sambesiaca acetone extracts had significantly higher testosterone production at different doses, respectively. In individuals with metabolic syndrome, Usharani et al. [Phyllanthus emblica fruit on lipid profile and oxidative stress. It was concluded that after 12 weeks, there was a significant (p < 0.001) mean percentage change for HDL-C , TC , TG , and LDL-C , respectively, which are in accordance with our results of this study.The main hormones impacting erectile functions in men and regulating libido in women include gonadotrophins (FSH and LH), testosterone, and prolactin . By screu et al. . When coi et al.  assessed4 administration caused testicular toxicity in rats and described how it led to germinal layer degeneration, decreased serum levels of LH and FSH and testosterone in male rats. The reduction in testosterone secretion may be caused by nicotine’s direct effect on Leydig cells, which renders them insensitive to LH and FSH and impairs the production of male reproductive hormones. In a different study, Kubba et al. [Borago officinalis methanolic extract on albino male mice testes and spleen either separately or following the combination of both extracts of plants with CCL4. The findings showed that ameliorative consequences were achieved by increasing luminal and interstitial space, recovering the structure of seminiferous tubules and spermatozoa, and increasing the total number of spermatocytes and spermatids in comparison with the administered groups.Male erections are influenced by reproductive hormones, such as testosterone, gonadotrophins, and prolactin . The hypa et al.  exploredThis current study demonstrated the beneficial effects of tricin phytochemicals on the structural makeup as well as endocrine functions of the male reproductive system. The specialized phytochemical tricin  not only provides stress tolerance in plants but is also involved in defense responses. It has a wide range of pharmaceutical applications, such as anti-inflammatory, anticancer, antioxidant, antiviral, and antihistaminic properties, and, therefore, is a promising nutraceutical ,30.An extensive literature survey was performed to collect phytochemicals from different medicinal plants. In total, 210 phytochemicals were taken as ligands, and their chemical structures were downloaded from the PubChem database in SDF format . Using tA total of three proteins were used in this study as receptor or target proteins. The three-dimensional (3D) structures of sex hormone-binding globulin (PDB ID: 6PYF), A disintegrin and metalloproteinase 17 (PDB ID: 2I47), and deoxyribonuclease I (PDB ID: 4AWN) were retrieved from the Protein Data Bank . The recThe molecular docking analysis was conducted between plant-derived phytochemicals and three different receptor proteins. The PyRx software was employed to conduct a molecular docking study. The prepared structures of receptor proteins were imported into PyRx and converted into a pdbqt format. A default exhaustiveness value of 8 was used to maximize the ligand–protein binding conformational investigations. The docked conformations with the lowest docking score and root mean square deviation (RMSD) were selected as the best ones . FinallyThe online tool SwissADME  was usedThe molecular dynamics (MD) simulation study was employed for the verification of the stability of docked complexes . In this study, complexes were selected for MD simulation on the basis of their minimum docking score, lowest RMSD, minimum violations of Lipinski’s Ro5 , and druggability analysis. To perform MD simulations, the Schrodinger’s Desmond Module was used . For makThe animal experiment was reviewed and approved by the Ethics Committee of the Government College University, Faisalabad . No human participants and/or tissues were involved in this study. The in vivo study was comprised of male albino rats . A normal husbandry environment was provided to the study animals. The animals were given a normal diet and a 12 h light and dark cycle. The animals used in the study were brought from the Department of Physiology, Government College University Faisalabad, and placed in an ordinary husbandry setting. Five groups of animals were set, with four animals in each group. Group 1 was the healthy control (not any drug administered); Group 2 was the intoxicated control (administered with nicotine 2 mg/kg body weight (b.w.) orally for 15 days before the hormone levels were analyzed—when the level of reproductive hormone was decreased, one group was administered with testosterone as a positive control by injection 10 mg/kg body weight (b.w.) intramuscular (i.m.) (positive control group and Group 3)), and the remaining two groups (namely Group 4 and Group 5) were administered with an aqueous solution of tricin phytochemicals (1% stock solution) and administered in two different doses  and 10 mg/kg (b.w.) to intoxicated male groups for 42 days (7 weeks). Tricin in a pure powdered form was purchased from Sigma Aldrich . A normal husbandry environment was provided to all the study animals. For six weeks, the animals were provided a normal diet as well as 12 h of light and dark cycle in the animal house.The following parameters were determined in blood samples collected from study subjects. Liver enzymes, such as transaminases  and aspartate transaminase (AST)) , creatinFollicle-stimulating hormone (FSH) (to check for menopause), testosterone (to check the deficiency in men), luteinizing hormone (LH), progesterone, prolactin, and dehydroepiandrosterone (DHEA)-SO4 were determined using ELISA kit .The animals were dissected for histological examination, and the tissue samples were collected in a buffered formalin  container. Sections were stored in labeled tissue cassettes. The method described by Bancroft and Gamble  was adopThe acquired data were reported as Mean ± SD and analyzed statistically using a one-way ANOVA test , and theMale infertility is a global problem that is related to multiple complications of the male reproductive system, including genetic and physical complications along with environmental factors. Despite much improvement in the medical field, there is still a concept of idiopathic infertility. There is a lack of clinical knowledge of infertility cases, which is the main reason for the low amount of scientific work in this domain. In the current study, three different receptor proteins were targeted, which are directly linked to male infertility events. Out of 210 docked phytochemicals, 15 were selected as top-hit compounds on the basis of their good docking scores and binding interactions with the active site amino acids of three selected receptor proteins . Molecular dynamics simulation revealed the stability of tricin as a ligand in complexes with selected receptor proteins. Further, the drug scanning and ADMET profiling showed the potential of top-selected phytochemicals as leading drug candidates with good efficacy, no carcinogenicity, and cardiotoxicity. Therefore, in the future, these compounds could be used as potential drug candidates against selected receptor proteins involved in male infertility. The in vivo study revealed that herbal plants are comprised of a variety of phytochemicals, and these constituents had significant antioxidant properties both in vitro and in vivo, as well as the ability to significantly restore male reproductive hormones in albino rats as a result of the treatment corresponding to amounts of tricin administered.


Background and Objectives: The anterior-based muscle-sparing (ABMS) approach, which utilizes the interval between the tensor fasciae latae posteriorly, offers several advantages, such as the reduced risk of nerve injury and the freedom to choose various implants. Herein, we aimed to compare the outcome of ABMS to the direct anterior (DA) approach using pairwise meta-analysis techniques. Materials and Methods: A systematic search of the MEDLINE (PUBMED), Embase, and Cochrane Library databases was performed for studies published up to 7 June 2023, which compared the ABMS approach with the DA approach for hip arthroplasty. We compared (1) perioperative outcomes  score, total opioid consumption, length of hospital stay (LOS), and the number of patients discharged to their homes); (2) postoperative complications ; and (3) implant position . Results: Ten studies were eligible for meta-analysis, including 1737 patients who underwent hip arthroplasty with the ABMS approach and 1979 with the DA approach. The pooled analysis showed no differences in all outcome variables, including perioperative outcomes, postoperative complications, and the implant position between the two surgical approaches. Conclusions: In current meta-analysis, the ABMS approach demonstrated comparable results to the conventional DA approach in terms of both clinical and radiologic outcomes as well as postoperative complications. Furthermore, the ABMS approach has the advantage of a broader indication and fewer limitations in terms of the surgical position compared to the DA approach. Therefore, the ABMS approach can be even more beneficial as an option within MSA, surpassing the utility of the DA approach. Hip arthroplasty (HA) is one of the oldest and most renowned surgeries in the field of orthopedics, often referred to as the “operation of the century,” with a history spanning over 100 years . This suIn recent decades, a multitude of surgical approaches have been introduced and refined with the aim of improving surgical outcomes following HA. The emphasis has been directed towards the mitigation of postoperative pain, reduction in postoperative rehabilitation durations, and attainment of heightened functional recuperation. Consequently, in recent years, there has been a growing interest in less invasive muscle-sparing approaches (MSAs), particularly in the field of adult hip reconstruction .The MSA to access the hip joint is not a recent development. It has roots in some of the oldest approaches to the hip joint, namely the Smith-Petersen and Watson-Jones approaches. The direct anterior (DA) approach for HA, one of the most commonly used MSAs today, was first introduced by Judet in 1947 . HoweverAmong the various MSAs, the DA approach, based on the Smith-Petersen approach and utilizing Heuter’s interval for access , has gaiThe anterior-based muscle-sparing (ABMS) approach, also called the anterolateral (AL) approach, abductor sparing/muscle sparing/mini AL approach, or ABLE approach, represents an alternative MSA that addresses some of the drawbacks associated with the DA approach . It utilDespite its potential advantages, there is a paucity of research on the specific benefits and drawbacks of the ABMS approach, as well as a lack of comparative analysis regarding the outcomes of the ABMS approach compared to the DA approach . TherefoOur hypothesis is that the ABMS approach will be comparable to the DA approach in terms of clinical outcomes, postoperative complications, and radiologic outcomes. Additionally, we believe that the ABMS approach offers the advantages of a short learning curve, greater surgical freedom in positioning, and more flexibility in implant selection compared to the DA approach. Therefore, overall, the ABMS approach could be deemed a more advantageous alternative for surgeons who are less familiar with the DA approach.The present study was conducted in accordance with the Revised Assessment of Multiple Systematic Reviews (AMSTAR) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines ,13. WhilFollowing the referenced guidelines, we systematically searched MEDLINE, Embase, and the Cochrane Library for studies comparing the ABMS approach with the DA approach in hip arthroplasty. Using an a priori search strategy, we identified articles published up to 7 June 2023, without any language or publication year restrictions. The search terms included synonyms and terms related to hip replacement, the ABMS approach, and the DA approach. The full search strategies and results for all databases are presented in Two board-certified orthopedic surgeons (J.S.C. and C-H.K.) who worked as faculty members at an academic medical center independently selected the articles for a full-text review based on the titles and abstracts of the studies. In cases where the abstracts provided insufficient information, the full article was reviewed.This meta-analysis was designed as a pairwise meta-analysis. Studies were included based on the “Population, Intervention, Comparator, Outcome, Study design” (PICOS) criteria : (1) patCareful consideration was given to excluding studies with inaccurate definitions of the term “ABMS.” While most papers correctly used the term “anterolateral (AL) approach” as a synonym for ABMS, some inaccurately defined the AL approach as the transgluteal/direct lateral approach. Studies on revision hip arthroplasty, non-original articles, unrelated papers, and duplicates from the same investigation group were also excluded. In cases of overlapping study populations, the publication with the largest sample size was selected for the meta-analysis.Inter-reviewer agreement was assessed at each stage of article selection using κ-values, with predefined categories for agreement strength . We considered the κ-values ≥ 0.6 as acceptable agreement. Disagreements at each stage were resolved through a discussion between the two investigators to reach a consensus. In cases where a consensus could not be reached, a third investigator was involved in the discussion to facilitate resolution.For qualitative data synthesis, standardized forms were used to extract relevant information: (1) study design, (2) country of investigation, (3) mean patient age, (4) sex, (5) type of hip surgery, (6) number of patients in the ABMS and DA approach groups, (7) patient position, (8) type of DA approach, and (9) the outcomes investigated.For the meta-analyses, data extraction focused on (1) perioperative outcomes  score, total opioid consumption, length of hospital stay (LOS), and the number of patients discharged to their homes); (2) postoperative complications , intraoperative fracture, and reoperation rate); and (3) implant position . When there were missing data among the variables for the intended meta-analysis, we contacted the authors directly to obtain the original data for statistical analysis.The methodological quality of the included studies was assessed using the Methodological Index for Non-randomized Studies (MINORS) , a valid2 statistic, with low, moderate, and high heterogeneity defined at 25%, 50%, and 75%, respectively. Forest plots were utilized to present the outcomes, pooled estimates of effects, and overall summary effects of each study. Statistical significance was set at p < 0.05. Data were pooled using a random-effects model that has been recommended previously to avoid overestimating the study results, especially in the medical field [Standard mean differences (SMDs) with 95% confidence intervals (CIs) were used for continuous data, while odds ratios (ORs) with 95% CIs were calculated for dichotomous data. Heterogeneity was assessed using the Ial field . A test al field . All staDetails of the study identification and selection processes are summarized in Of the 10 studies, 7 studies ,22,26,27The MINORS score for assessing the methodological quality had a mean score of 17.5 out of 24 (range: 16–20) . When cop = 0.10). The heterogeneity was high (I2 = 98%).Three studies ,20,25 cop = 0.08 and day-3: SMD, −0.20; 95% CI = −0.59~0.19; p = 0.31, respectively). The heterogeneity was low in the postoperative day-1 data (I2 = 0%) but moderate in the day-3 data (I2 = 68%).Data for the meta-analysis about postoperative day-1 and day-3 VAS scores were extracted from two studies ,25. In ap = 0.43). The heterogeneity was moderate (I2 = 60%). Total opioid consumption in the overall postoperative period was compared in two studies ,20. In tp = 0.43). The heterogeneity was low (I2 = 0%).The length of hospital stay was investigated in four studies ,20,24,25p = 0.24; I2 = 0%).We could extract the data of several patients discharged to their homes from two studies ,24. In aA forest plot and further details about perioperative surgical outcomes are shown in p = 0.14), but the heterogeneity was high (I2 = 79%).Four studies ,22,25,27p = 0.41). The heterogeneity was low to moderate (I2 = 32%).The postoperative dislocation rate was reported in a total of seven studies ,24,25,27p = 0.32; I2 = 0%).Data on SSIs were reported in a total of seven studies. In the ABMS group, there were 17 cases (out of 1446 cases) of SSIs, whereas 16 cases (out of 1689) of SSIs were reported in the DA group. There was no difference in the SSI rate between the two surgical approaches. Heterogeneity was low .The incidence of intraoperative femoral fractures, including trochanteric fractures and calcar fractures, was compared between the two surgical approaches in three studies ,23,25. Tp = 0.16). The heterogeneity was low (I2 = 0%). Three studies reported the rate of reoperation. In the ABMS group, 30 patients (out of 706 patients) of reoperation were reported while 35 (out of 1062 patients) were reported in the DA group. There was no difference in the reoperation rate between the two surgical approaches . A forest plot and further details are shown in Three studies compared the postoperative cup position between two surgical approaches. We could extract the data on the rate of neutral stem alignment from two studies. In a pooled analysis, there were no differences between the ABMS group and DA group in terms of cup inclination, cup anteversion, and the rate of stem neutral alignment (cup inclination: SMD, 0.25; 95% CI = −0.07~0.57; This study demonstrated that the ABMS approach yields comparable results to the DA approach in terms of surgical outcomes, complications, and implant position in all aspects.In recent years, there has been a substantial increase in research focused on the anterior-based approach, with a clear predominance towards the DA approach ,28. A PuHowever, the DA approach has notable disadvantages, including a steep learning curve, concerns about increased complications during the learning period, the risk of lateral femoral cutaneous nerve injury, limitations in implant selection, and difficulties in applying the technique to obese patients . In thisOur study findings revealed no statistically significant differences in perioperative surgical outcomes between the ABMS approach and the DA approach. When compared to the traditional PL approach, which is currently the most widely used approach for HA surgery , the DA In terms of postoperative complications, no statistically significant differences were observed between the ABMS approach and the DA approach. A study by Zuskov et al. published in 2022  reportedMoreover, no differences were observed between the ABMS and DA approaches in terms of the implant position, including the cup and stem. Fundamentally, both approaches are muscle-sparing. The difference lies in whether the approach is medial or lateral to the tensor fasciae latae. However, below this layer, there is no major difference in the two approaches, leading to the conclusion that after an adequate learning curve, there is no significant difference in the implant position between the two approaches, yielding favorable results. Our study had several limitations. First, we were unable to perform various types of subgroup analyses due to the limited number of eligible papers for inclusion. For example, the ABMS approach has the advantage of being applicable in both supine and lateral positions; however, these positions could not be compared separately. Additionally, the DA approach also has different variations, such as the conventional DA approach, performed on a regular table, and the tabled DA approach, performed on a fracture table, but we could not distinguish between them. Second, some of the results of these meta-analyses showed high heterogeneity. This could potentially introduce biases when interpreting the results. Third, a large number of studies included in the research have a retrospective nature. Fourth, the possibility of publication biases should be mentioned. According to the Cochrane guidelines , conductIn current meta-analysis, the ABMS approach demonstrated comparable results to the conventional DA approach in terms of both clinical and radiologic outcomes as well as postoperative complications. Furthermore, the ABMS approach has the advantage of a broader indication and fewer limitations in terms of the surgical position compared to the DA approach. Therefore, the ABMS approach can be even more beneficial as an option within MSAs, surpassing the utility of the DA approach.