Active Molecules Research Articles

A very promising antibiofilm activity against Candida albicans from an in vitro screening for antimicrobial, antibiofilm and antiproliferative activity of new synthesized 4-cinnamamido- and 2-phenoxyacedamido-1H-pyrazol-5-yl)benzamides

AbstractSeveral new synthesized 4-cinnamamido- and 2-phenoxyacedamido-(1H-pyrazol-5-yl)benzamides were obtained by two multi step different synthetic routes in order to maximize their yield. The new derivatives were screened to determine the antiproliferative, antimicrobial and antibiofilm activity. The biological results showed how, respect to the antiproliferative and antimicrobial activities, the compounds have a low to missing activity. Different are the results obtained concerning the antibiofilm activity, especially towards Candida albicans. Most of the synthesized compounds showed a good percentage inhibition of biofilm formation ranging from 60 to 73% with a Biofilm Inhibition Concentration 50% (BIC50) from 0.13 to 0.01 µM. Among the synthesized compounds the ethyl 5-(4-(2-(4-chlorophenoxy)acetamido)benzamido)-1-methyl-1H-pyrazole-4-carboxylate (27c) resulted the most active molecule with a BIC50 of 0.01 µM. According to the results obtained, such compound could be considered a lead subject of further studies to obtain novel and more effective antibiofilm agents against C. albicans.

Identifying the Potential Apoptotic Metabolites in Postmortem Beef Muscle by Targeted Metabolomics.

Apoptotic cells may release specific metabolites to act as messengers during the apoptotic process. This study represents the first attempt to identify potential apoptotic metabolites in postmortem muscle. Ninety potential apoptotic metabolites in beef were selected and analyzed through targeted metabolomics, with 84 of them exhibiting significant differences over the postmortem time. Following the addition of the mitochondria-targeted antiapoptotic agent mitoquinone to postmortem muscle, metabolomic analysis revealed that 73 apoptotic metabolites still underwent significant changes, even against the backdrop of altered apoptosis. Of these 73 apoptotic metabolites, 54 exhibited similar trends at various treatment times with adding mitoquinone, including lipids (6), amino acids (27), nucleosides (11), and carbohydrate and energy metabolism (10). Mitoquinone significantly reduced the levels of most apoptotic metabolites, and inhibition of apoptosis resulted in a significant decrease in the levels of numerous apoptotic metabolites. Consequently, these apoptotic metabolites are considered complementary to apoptosis in postmortem muscle, with their increased levels potentially promoting apoptosis. Noteworthy apoptotic metabolites, such as glycerol 3-phosphate, serine, AMP, ATP, GMP, and creatine, were identified as active signaling molecules that attract and recruit phagocytes during apoptosis, assisting in recognizing apoptotic cells by phagocytes. This study provides, for the first time, insights into potential apoptotic metabolites in postmortem muscle, contributing to a better understanding of meat biochemistry.

The Emerging Role of Silk Fibroin for the Development of Novel Drug Delivery Systems

In order to reduce the toxicological impact on healthy cells and to improve the therapeutic response, many drug delivery systems have been fabricated and analysed, involving the use of different natural and synthetic materials at macro-, micro- and nanoscales. Among the natural materials which have demonstrated a huge potential for the development of effective drug delivery systems, silk fibroin has emerged for its excellent biological properties and for the possibility to be processed in a wide range of forms, which can be compliant with multiple active molecules and pharmaceutical ingredients for the treatment of various diseases. This review aims at presenting silk fibroin as an interesting biopolymer for applications in drug delivery systems, exploring the results obtained in recent works in terms of technological progress and effectiveness in vitro and in vivo.

Single-cell sequencing of tumour infiltrating T cells efficiently identifies tumour-specific T cell receptors based on the T cell activation score

Adoptively transferred T cell receptor-engineered T cells are a promising cancer treatment strategy, and the identification of tumour-specific TCRs is essential. Previous studies reported that tumour-reactive T cells and TCRs could be isolated based on the expression of activation markers. However, since T cells with different cell states could not respond uniformly to activation but show a heterogeneous expression profile of activation and effector molecules, isolation of tumour-reactive T cells based on single activation or effector molecules could result in the absence of tumour-reactive T cells; thus, combinations of multiple activation and effector molecules could improve the efficiency of isolating tumour-specific TCRs. We enrolled two patients with lung adenocarcinoma and obtained their tumour infiltrating lymphocytes (TILs) and autologous tumour cells (ATCs). TILs were cocultured with the corresponding ATCs for 12 h and subjected to single-cell RNA sequencing. First, we identified three TCRs with the highest expression levels of IFNG and TNFRSF9 mRNA for each patient, yet only the top one or two recognized the corresponding ATCs in each patient. Next, we defined the activation score based on normalized expression levels of IFNG, IL2, TNF, IL2RA, CD69, TNFRSF9, GZMB, GZMA, GZMK, and PRF1 mRNA for each T cell and then identified three TCRs with the highest activation score for each patient. We found that all three TCRs in each patient could specifically identify corresponding ATCs. In conclusion, we established an efficient approach to isolate tumour-reactive TCRs based on combinations of multiple activation and effector molecules through single-cell RNA sequencing.

Meteorin-like protein/METRNL/Interleukin-41 ameliorates atopic dermatitis-like inflammation.

Meteorin-like protein (METRNL)/Interleukin-41 (IL-41) is a novel immune-secreted cytokine/myokine involved in several inflammatory diseases. However, how METRNL exerts its regulatory properties on skin inflammation remains elusive. This study aims to elucidate the functionality and regulatory mechanism of METRNL in atopic dermatitis (AD). METRNL levels were determined in skin and serum samples from patients with AD and subsequently verified in the vitamin D3 analogue MC903-induced AD-like mice model. The cellular target of METRNL activity was identified by multiplex immunostaining, single-cell RNA-seq and RNA-seq. METRNL was significantly upregulated in lesions and serum of patients with dermatitis compared to healthy controls (p <.05). Following repeated MC903 exposure, AD model mice displayed elevated levels of METRNL in both ears and serum. Administration of recombinant murine METRNL protein (rmMETRNL) ameliorated allergic skin inflammation and hallmarks of AD in mice, whereas blocking of METRNL signaling led to the opposite. METRNL enhanced β-Catenin activation, limited the expression of Th2-related molecules that attract the accumulation of Arginase-1 (Arg1)hi macrophages, dendritic cells, and activated mast cells. METRNL can bind to KIT receptor and subsequently alleviate the allergic inflammation of AD by inhibiting the expansion of immune cells, and downregulating inflammatory gene expression by regulating the level of active WNT pathway molecule β-Catenin.

ИЗУЧЕНИЕ ПРОЦЕССОВ КОМПЛЕКСООБРАЗОВАНИЯ В ПОЛИМЕРНЫХ БИОДЕГРАДИРУЕМЫХ КОМПОЗИЦИЯХ

One of the possible directions of the development of targeted substance delivery systems is the creation and introduction of biodegradable polymers into production. Their distinctive feature is that they are capable of spontaneously gradually degradation in the body due to natural biochemical processes. There is an increasing spread pharmaceutical form, which use similar excipients in their technology – medicinal ocular insert. Modified cellulose, gums and rare-cross-linked acrylic polymers are used to create a biodegradable matrix base. In terms of development approach, ocular inserts can be divided into two groups according to the principle of matrix biodegradation. In non-biodegradable composites, the effect of prolongation of the therapeutic effect is observed due to the release of the active substance from the non-decomposing matrix. This fact can be confirmed by both pharmacopoeial and non-pharmacopoeial methods. The classic tests regulated by the Pharmacopoeia of the XV edition include the "Dissolution" test (GPM.1.4.2.0014 "Dissolution of solid pharmaceutical dose forms"), and for non–pharmacopoeial ones – dialysis through a semipermeable membrane according to Kruvchinsky or using Franz's dialysis cells. The analysis of the kinetics of dissolution helps to determine and select the most suitable matrix-forming agent to be used in the composition with other substances in the composition of ocular insert. Ocular inserts with a biodegradable matrix have a second factor that affects the release of active substances – the formation of complexes or associates between parts of the matrix and the active ingredient molecules. These intermolecular compounds can indirectly prolong the effect of the drug. All features must be taken into account in the development of ocular inserts, since they, among other things, help to model fundamentally new ways of targeted delivery of substances. In this case, it is necessary to develop a test for the second modified release factor, which would reliably determine the presence of complexation processes within the selected ocular inserts model.

Asymmetric Synthesis of SCF3‐Substituted Alkylboronates by Copper‐Catalyzed Hydroboration of 1‐Trifluoromethylthioalkenes

AbstractA synthetic method for preparation of optically active trifluoromethylthio (SCF3) compounds by a copper‐catalyzed regio‐ and enantioselective hydroboration of 1‐trifluoromethylthioalkenes with H‐Bpin has been developed. The enantioselective hydrocupration of an in situ generated CuH species and subsequent boration reaction generate a chiral SCF3‐containing alkylboronate, of which Bpin moiety can be further transformed to deliver various optically active SCF3 molecules. Computational studies suggest that the SCF3 group successfully controls the regioselectivity in the reaction.

Beyond BCMA: the next wave of CAR T cell therapy in multiple myeloma

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment landscape of relapsed/refractory multiple myeloma. The current Food and Drug Administration approved CAR T cell therapies idecabtagene vicleucel and ciltacabtagene autoleucel both target B cell maturation antigen (BCMA), which is expressed on the surface of malignant plasma cells. Despite deep initial responses in most patients, relapse after anti-BCMA CAR T cell therapy is common. Investigations of acquired resistance to anti-BCMA CAR T cell therapy are underway. Meanwhile, other viable antigenic targets are being pursued, including G protein-coupled receptor class C group 5 member D (GPRC5D), signaling lymphocytic activation molecule family member 7 (SLAMF7), and CD38, among others. CAR T cells targeting these antigens, alone or in combination with anti-BCMA approaches, appear to be highly promising as they move from preclinical studies to early phase clinical trials. This review summarizes the current data with novel CAR T cell targets beyond BCMA that have the potential to enter the treatment landscape in the near future.

Testing the predictive power of reverse screening to infer drug targets, with the help of machine learning

Estimating protein targets of compounds based on the similarity principle—similar molecules are likely to show comparable bioactivity—is a long-standing strategy in drug research. Having previously quantified this principle, we present here a large-scale evaluation of its predictive power for inferring macromolecular targets by reverse screening an unprecedented vast external test set of more than 300,000 active small molecules against another bioactivity set of more than 500,000 compounds. We show that machine-learning can predict the correct targets, with the highest probability among 2069 proteins, for more than 51% of the external molecules. The strong enrichment thus obtained demonstrates its usefulness in supporting phenotypic screens, polypharmacology, or repurposing. Moreover, we quantified the impact of the bioactivity knowledge available for proteins in terms of number and diversity of actives. Finally, we advise that developers of such approaches follow an application-oriented benchmarking strategy and use large, high-quality, non-overlapping datasets as provided here.

Understanding Coenzyme Q.

Coenzyme Q (CoQ), also known as ubiquinone, comprises a benzoquinone head group and a long isoprenoid sidechain. It is thus extremely hydrophobic and resides in membranes. It is best known for its complex function as an electron transporter in the mitochondrial electron transport chain (ETC) and in several other cellular processes. In fact, CoQ appears to be central to the redox balance of the cell. Remarkably, its structure and properties have not changed from bacteria to vertebrates. In metazoans, it is synthesized in all cells and is found in most, and maybe all, biological membranes. CoQ is also known as a nutritional supplement, mostly because of its involvement with antioxidant defenses. However, whether there is any health benefit from oral consumption of CoQ is not well established. Here we review the function of CoQ as a redox active molecule in the ETC and other enzymatic systems, its role as a pro-oxidant in reactive oxygen species generation, and its separate involvement in antioxidant mechanisms. We also review CoQ biosynthesis, which is particularly complex because of its extreme hydrophobicity, as well as the biological consequences of primary and secondary CoQ deficiency, including in human patients. Primary CoQ deficiency is a rare inborn condition due to mutation in CoQ biosynthetic genes. Secondary CoQ deficiency is much more common as it accompanies a variety of pathological conditions, including mitochondrial disorders as well as aging. In this context, we discuss the importance, but also the great difficulty, of alleviating CoQ deficiency by CoQ supplementation.

Identifying Substructures That Facilitate Compounds to Penetrate the Blood-Brain Barrier via Passive Transport Using Machine Learning Explainer Models.

The local interpretable model-agnostic explanation (LIME) method was used to interpret two machine learning models of compounds penetrating the blood-brain barrier. The classification models, Random Forest, ExtraTrees, and Deep Residual Network, were trained and validated using the blood-brain barrier penetration dataset, which shows the penetrability of compounds in the blood-brain barrier. LIME was able to create explanations for such penetrability, highlighting the most important substructures of molecules that affect drug penetration in the barrier. The simple and intuitive outputs prove the applicability of this explainable model to interpreting the permeability of compounds across the blood-brain barrier in terms of molecular features. LIME explanations were filtered with a weight equal to or greater than 0.1 to obtain only the most relevant explanations. The results showed several structures that are important for blood-brain barrier penetration. In general, it was found that some compounds with nitrogenous substructures are more likely to permeate the blood-brain barrier. The application of these structural explanations may help the pharmaceutical industry and potential drug synthesis research groups to synthesize active molecules more rationally.

The Complete Assessment of Small Molecule and Peptidomimetic Inhibitors of Sortase A Towards Antivirulence Treatment.

This review covers the most recent advances in the development of inhibitors for the bacterial enzyme sortase A (SrtA). Sortase A (SrtA) is a critical virulence factor present ubiquitously in Gram-positive bacteria of which many are considered pathogenic. Sortases are key enzymes regulating bacterial adherence to host cells, by anchoring extracellular matrix-binding proteins to the bacterial outer cell wall. By targeting virulence factors, effective treatment can be achieved, without inducing antibiotic resistance to the treatment. All in all, this would lead to a more sustainable, long-term approach to treating bacterial infections, including ones that display multiple resistance to current therapeutics. Currently, it appears there are many promising approaches available that have the potential to advance into further clinical development, with peptidomimetic and in vivo active small molecules among the most promising. There are currently no approved drugs on the market targeting SrtA, despite its promise, adding to the relevance of this review article, as it extends to the pharmaceutical industry additionally to academic researchers.

SLAMF8 as a potential biomarker for rheumatoid arthritis identified by comparing peripheral blood mononuclear cells, fibroblast‐like synoviocytes, and synovial tissue using bioinformatics analysis

AbstractBackgroundRheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease. Its pathogenesis is not fully understood, and early diagnosis is challenging owing to the lack of effective biomarkers. This study aimed to analyze different samples to identify potential biomarkers and therapeutic targets.MethodsMicroarray datasets of RA, osteoarthritis (OA), and healthy control (HC) were downloaded from the Gene Expression Omnibus database. R software was used to identify differentially expressed genes (DEGs), which were visualized using volcano and heat maps. Venn diagrams, principal component analysis, gene set enrichment analysis, gene ontology, and Kyoto Encyclopedia of genes and genomes were used to analyze the data. A protein–protein interaction network was constructed, and synovial tissues from patients with RA and OA were collected for verification using the collagen‐induced arthritis mouse model.ResultsMore DEGs were found in synovial tissues than in peripheral blood mononuclear cells or fibroblast‐like synoviocytes. Principal component analysis revealed significant differences between the RA and OA samples, highlighting the unique advantages of synovial tissue. Enrichment analysis revealed that metabolic and cytokine signaling pathways play crucial roles in the development of RA. Further analysis of the four synovial datasets identified 54 DEGs, of which signaling lymphocytic activation molecule family (SLAMF) 8 was identified as the key molecule. SLAMF8 levels were increased in the synovial tissue of patients with RA compared to those of patients with OA (0.38 ± 0.19 vs. 12.40 ± 1.66), and SLAMF8 levels were similarly elevated in collagen‐induced arthritis model mice compared with those in the healthy mice (1.13 ± 0.47 vs. 9.05 ± 2.5).ConclusionsThis study established the unique advantages of synovial tissue for RA research and identified metabolic and cytokine signaling pathways as important for RA development. Thus, SLAMF8 may be a potential therapeutic target for RA.

Synthesis and characterization of UV organic light-emitting electrochemical cells (OLECs) using phenanthrene fluorene derivatives for flexible applications

This paper details how two new small molecules, based on phenanthrene, were developed, and tailored for light-emitting device applications. An account is provided of both the compound synthesis and the methodologies employed in device fabrication. The ink formulation was improved by the use of triflate counterions. Standard bottom emitting devices were constructed on ITO glass along with top emitting devices on a sputter coated silver on glass substrate. Both structures exhibit UV emissions from the synthesized molecules. Successful EL emission within the UV spectrum range has been achieved by spray coating these active molecules onto glass slides. The optimized solution-processed devices produce UV emission using a semi-transparent silver nanowire top electrode. This results in electroluminescence (EL) peaking at 398 nm, with a maximum EL emission intensity of 20.5 μW/cm2.

Current progress in the synthesis of imidazoles and their derivatives via the use of green tools

Abstract Imidazoles have a unique position in heterocyclic chemistry as these constitute the basic framework of several bio-molecules. Thus, increasing research is being carried out on the synthesis of imidazoles and their derivatives, mainly because of the application of imidazoles in pharmaceutical and medicinal research. Keeping sustainability in mind, researchers are developing synthetic pathways for the synthesis of imidazoles and their derivatives by employing techniques involving green tools, thus leading to sustainable pathways. In this review, we aim to compile such synthetic methodologies involving green tools for the synthesis of imidazoles. The review will cover the synthetic reactions that involve green tools such as microwave irradiation, ultrasound irradiation, and ball milling. We aim to highlight the scope and relevance of such green tools in today’s synthetic research. Through this review, we wish to contribute towards the synthesis of imidazoles that serve as a useful class of heterocyclic compounds involved in the development of pharmaceutically active molecules. We sincerely hope that this review will serve as a relevant guide for future sustainable research in the synthesis of imidazoles and their derivatives.

Repellent activity of essential oils to the Lone Star tick, Amblyomma americanum

BackgroundThe Lone Star tick, Amblyomma americanum is important to human health because of a variety of pathogenic organisms transmitted to humans during feeding events, which underscores the need to identify novel approaches to prevent tick bites. Thus, the goal of this study was to test natural and synthetic molecules for repellent activity against ticks in spatial, contact and human fingertip bioassays.MethodsThe efficacy of essential oils and naturally derived compounds as repellents to Am. americanum nymphs was compared in three different bioassays: contact, spatial and fingertip repellent bioassays.ResultsConcentration response curves after contact exposure to 1R-trans-chrysanthemic acid (TCA) indicated a 5.6 μg/cm2 concentration required to repel 50% of ticks (RC50), which was five- and sevenfold more active than DEET and nootkatone, respectively. For contact repellency, the rank order of repellency at 50 μg/cm2 for natural oils was clove > geranium > oregano > cedarwood > thyme > amyris > patchouli > citronella > juniper berry > peppermint > cassia. For spatial bioassays, TCA was approximately twofold more active than DEET and nootkatone at 50 μg/cm2 but was not significantly different at 10 μg/cm2. In spatial assays, thyme and cassia were the most active compounds tested with 100% and 80% ticks repelled within 15 min of exposure respectively and was approximately twofold more effective than DEET at the same concentration. To translate these non-host assays to efficacy when used on the human host, we quantified repellency using a finger-climbing assay. TCA, nootkatone and DEET were equally effective in the fingertip assay, and patchouli oil was the only natural oil that significantly repelled ticks.ConclusionsThe differences in repellent potency based on the assay type suggests that the ability to discover active tick repellents suitable for development may be more complicated than with other arthropod species; furthermore, the field delivery mechanism must be considered early in development to ensure translation to field efficacy. TCA, which is naturally derived, is a promising candidate for a tick repellent that has comparable repellency to commercialized tick repellents.Graphical

Modulating solvated structure of Zn2+ and inducing surface crystallography by a simple organic molecule with abundant polar functional groups to synergistically stabilize zinc metal anodes for long-life aqueous zinc-ion batteries

Aqueous zinc-ion batteries (AZIBs) have attracted significant attention owing to their inherent security, low cost, abundant zinc (Zn) resources and high energy density. Nevertheless, the growth of zinc dendrites and side reactions on the surface of Zn anodes during repeatedly plating/stripping shorten the cycle life of AZIBs. Herein, a simple organic molecule with abundant polar functional groups, 2,2,2-trifluoroether formate (TF), has been proposed as a high-efficient additive in the ZnSO4 electrolyte to suppress the growth of Zn dendrites and side reaction during cycling. It is found that TF molecules can infiltrate the solvated sheath layer of the hydrated Zn2+ to reduce the number of highly chemically active H2O molecules owing to their strong binding energy with Zn2+. Simultaneously, TF molecules can preferentially adsorb onto the Zn surface, guiding the uniform deposition of Zn2+ along the crystalline surface of Zn(002). This dual action significantly inhibits the formation of Zn dendrites and side reactions, thus greatly extending the cycling life of the batteries. Accordingly, the Zn//Cu asymmetric cell with 2 % TF exhibits stable cycling for more than 3,800 cycles, achieving an excellent average Columbic efficiency (CE) of 99.81 % at 2 mA cm−2/1 mAh cm−2. Meanwhile, the Zn||Zn symmetric cell with 2 % TF demonstrates a superlong cycle life exceeding 3,800 h and 2,400 h at 2 mA cm−2/1 mAh cm−2 and 5 mA cm−2/2.5 mAh cm−2, respectively. Simultaneously, the Zn//VO2 full cell with 2 % TF possesses high initial capacity (276.8 mAh/g) and capacity retention (72.5 %) at 5 A/g after 500 cycles. This investigation provides new insights into stabilizing Zn metal anodes for AZIBs through the co-regulation of Zn2+ solvated structure and surface crystallography.

Mast cells and wound healing: Still an open question.

Mast cells, which originate from the bone marrow, possess the ability to secrete a diverse array of active molecules. These molecules include mediators (histamine, heparin), which have been identified for decades and are stored in specific granules, as well as small molecules generated instantaneously in response to stimulation (membrane lipid derivatives, nitric oxide), and a multitude of multifunctional cytokines that are secreted constitutively. Activated mast cells participate in the regulation of the local immune response and exert control over critical events of inflammation and healing with the assistance of a vast array of mediators. The involvement of these cell types in inflammatory states suggests that mast cells may function as sentinels that activate local immune processes in response to various types of stimuli and the entry of antigens. Moreover, due to their proximity to nerve fibers and reactivity to a variety of neurotransmitters, mast cells are among the cells that may facilitate local neuroimmune interactions. With this in mind, it is necessary to consider their participation in the repair of injuries in both acute and chronic conditions.

ß‐Phenethylamine Synthesis via Latent Dual Electrophilicity of N‐Pyridinium Aziridines

ß‐Phenethylamines are widely represented in biologically and pharmacologically active organic small molecules. Here, we introduce N‐pyridinium aziridines as latent dual electrophiles for the synthesis of ß‐phenethylamines. Bromide‐promoted ring opening generates ß‐halopyridinium amines. Selective Ni‐catalyzed C–C cross‐coupling between organozinc nucleophiles and the benzylic C–Br electrophile affords a diverse family of ß‐functionalized phenethylaminopyridinium salts, and coupling is stereoconvergent in the presence of chiral ligands. Subsequent Ni‐catalyzed reductive N–N bond activation within the b‐functionalized phenethylamino‐pyridinium salts furnishes the products of formal olefin carboamination. Other reductive N–N cleavage reactions are demonstrated to provide access to free primary amines, alkylated amines, heterocycles, and products derived from N‐centered radical chemistry. The developed reaction sequence can be implemented in the context of complex molecules and natural product derivatives. Together, the described results provide a general and modular synthesis of ß‐phenethylamines and significantly expand the utility of N‐pyridinium aziridines as linchpins in chemical synthesis

Zinc-Ion Anchor Induced Highly Reversible Zn Anodes for High Performance Zn-Ion Batteries.

Unstable Zn interface with serious detrimental parasitic side-reactions and uncontrollable Zn dendrites severely plagues the practical application of aqueous zinc-ion batteries. The interface stability was closely related to the electrolyte configuration and Zn2+ depositional behavior. In this work, a unique Zn-ion anchoring strategy is originally proposed to manipulate the coordination structure of solvated Zn-ions and guide the Zn-ion depositional behavior. Specifically, the amphoteric charged ion additives (denoted as DM), which act as zinc-ion anchors, can tightly absorb on the Zn surface to guide the uniform zinc-ion distribution by using its positively charged -NR4 + groups. While the negatively charged -SO3 - groups of DM on the other hand, reduces the active water molecules within solvation sheaths of Zn-ions. Benefiting from the special synergistic effect, Zn metal exhibits highly ordered and compact (002) Zn deposition and negligible side-reactions. As a result, the advanced Zn||Zn symmetric cell delivers extraordinarily 7000 hours long lifespan (0.25 mA cm-2, 0.25 mAh cm-2). Additionally, based on this strategy, the NH4V4O10||Zn pouch-cell with low negative/positive capacity ratio (N/P ratio=2.98) maintains 80.4 % capacity retention for 180 cycles. A more practical 4 cm*4 cm sized pouch-cell could be steadily cycled in a high output capacity of 37.0 mAh over 50 cycles.