Small Compounds Research Articles

Direct Injection Electrospray Ionization Mass Spectrometry (ESI‐MS) Analysis of Proteins with High Matrix Content:Utilizing Taylor–Aris Dispersion

AbstractThis is the first work demonstrating the utility of the Taylor–Aris (TA) dispersion in avoiding serious interference issues commonly occurring in the electrospray ionization‐mass spectrometric (ESI‐MS) determination of therapeutic protein pharmaceuticals undergoing no pre‐separation or sample purification. It was also pointed out that the TA dispersion conditions and its analytical utilization for proteomics can be easily accomplished in a commercial CE‐MS instrument. In the proposed Taylor–Aris dispersion‐assisted mass spectrometry (TADA‐MS) analysis 0.5 μL sample is injected into a 65 cm long 50 μm i.d. capillary and pumped with 1 bar toward the MS. The procedure is efficient for the direct injection analysis of components having low diffusion coefficients (proteins) that are present in complex matrices of small organic and inorganic compounds.

GPCRs involved in metabolic diseases: pharmacotherapeutic development updates.

G protein-coupled receptors (GPCRs) are expressed in a variety of cell types and tissues, and activation of GPCRs is involved in enormous metabolic pathways, including nutrient synthesis, transportation, storage or insulin sensitivity, etc. This review intends to summarize the regulation of metabolic homeostasis and mechanisms by a series of GPCRs, such as GPR91, GPR55, GPR119, GPR109a, GPR142, GPR40, GPR41, GPR43 and GPR120. With deep understanding of GPCR's structure and signaling pathways, it is attempting to uncover the role of GPCRs in major metabolic diseases, including metabolic syndrome, diabetes, dyslipidemia and nonalcoholic steatohepatitis, for which the global prevalence has risen during last two decades. An extensive list of agonists and antagonists with their chemical structures in a nature of small molecular compounds for above-mentioned GPCRs is provided as pharmacologic candidates, and their preliminary data of preclinical studies are discussed. Moreover, their beneficial effects in correcting abnormalities of metabolic syndrome, diabetes and dyslipidemia are summarized when clinical trials have been undertaken. Thus, accumulating data suggest that these agonists or antagonists might become as new pharmacotherapeutic candidates for the treatment of metabolic diseases.

Elucidation of the mechanism of action of ailanthone in the treatment of colorectal cancer: integration of network pharmacology, bioinformatics analysis and experimental validation.

Background: Ailanthone, a small compound derived from the bark of Ailanthus altissima (Mill.) Swingle, has several anti-tumour properties. However, the activity and mechanism of ailanthone in colorectal cancer (CRC) remain to be investigated. This study aims to comprehensively investigate the mechanism of ailanthone in the treatment of CRC by employing a combination of network pharmacology, bioinformatics analysis, and molecular biological technique. Methods: The druggability of ailanthone was examined, and its targets were identified using relevant databases. The RNA sequencing data of individuals with CRC obtained from the Cancer Genome Atlas (TCGA) database were analyzed. Utilizing the R programming language, an in-depth investigation of differentially expressed genes was carried out, and the potential target of ailanthone for anti-CRC was found. Through the integration of protein-protein interaction (PPI) network analysis, GO and KEGG enrichment studies to search for the key pathway of the action of Ailanthone. Then, by employing molecular docking verification, flow cytometry, Transwell assays, and Immunofluorescence to corroborate these discoveries. Results: Data regarding pharmacokinetic parameters and 137 target genes for ailanthone were obtained. Leveraging The Cancer Genome Atlas database, information regarding 2,551 differentially expressed genes was extracted. Subsequent analyses, encompassing protein-protein interaction network analysis, survival analysis, functional enrichment analysis, and molecular docking verification, revealed the PI3K/AKT signaling pathway as pivotal mediators of ailanthone against CRC. Additionally, the in vitro experiments indicated that ailanthone substantially affects the cell cycle, induces apoptosis in CRC cells (HCT116 and SW620 cells), and impedes the migration and invasion capabilities of these cells. Immunofluorescence staining showed that ailanthone significantly inhibited the phosphorylation of AKT protein and suppressed the activation of the PI3K/AKT signaling pathway, thereby inhibiting the proliferation and metastasis of CRC cells. Conclusion: Therefore, our findings indicate that Ailanthone exerts anti-CRC effects primarily by inhibiting the activation of the PI3K/AKT pathway. Additionally, we propose that Ailanthone holds potential as a therapeutic agent for the treatment of human CRC.

Evolution of nucleophilic high molecular-weight organic compounds in ambient aerosols: a case study

Abstract. Nucleophilic high molecular-weight organic compounds (HMWOCs) are sensitive to protons (H+) in Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) analysis. A comprehensive evaluation of the diurnal evolution of nucleophilic HMWOCs was performed. HMWOCs aged significantly in daily cycles, accompanied by functionality shifts, particularly oxygenated and reduced nitrogen (CHON and CHN) as well as oxygenated organics. The intensities of high molecular-weight (HMW) oxygenated compounds increased during both daytime and nighttime. The daytime evolution produced more nitrogen-containing compounds with carboxylic group (–COOH) homologues with molecular weights greater than 300, while the nighttime evolution produced mostly small CHON compounds (molecular weights < 300). During evolution, nighttime CHON removals were observed; meanwhile, carboxylation was also identified in CHON groups. The daytime evolution produced significantly more reduced-nitrogen-containing compounds; a day- and nighttime increase in CHN compounds with five members was also observed. This study can provide insights into the aging of less polar organic aerosols.

A novel, small anti-HBV compound reduces HBsAg and HBV-DNA by destabilizing HBV-RNA.

Currently, standard treatments for chronic hepatitis B such as nucleos(t)ide analogs (NAs), effectively reduce hepatitis B virus (HBV) loads but rarely result in a functional cure (defined as sustained HBsAg loss). We report the discovery of a novel, 4-pyridone compound, SAG-524, a potent and orally bioavailable small molecule inhibitor of HBV replication. The antiviral characteristics and selectivity of SAG-524 and its derivative compound against HBV were evaluated in HBV-infection assays and HBV-infected chimeric urokinase-type plasminogen activator/severe combined immunodeficiency mice with humanized livers (PXB mice), alone or in combination with entecavir. Toxicity studies were conducted in mice and monkeys. SAG-524 reduced HBV-DNA (IC50 = 0.92nM) and HBsAg (IC50 = 1.4nM) in the supernatant of the HepG2.2.15 cells. SAG-524 selectively destabilized HBV-RNA via PAPD5, but not GAPDH or albumin mRNA, by shortening the poly(A) tail. PAPD5 may also be involved in HBV regulation via ELAVL1. In a study of HBV-infected PXB mice, SAG-524 produced potent reductions of serum HBsAg and HBcrAg, and the minimum effective dose was estimated to be 6mg/kg/day. The combination therapy with entecavir greatly reduced HBsAg and cccDNA in the liver due to reduction of human hepatocytes with good tolerability. Administration of SAG-524 to monkeys, up to 1000mg/kg/day for two weeks, led to no significant toxicity, as determined by blood tests and pathological images. We have identified SAG-524 as novel and orally bioavailable HBV-RNA destabilizers which can reduce HBsAg and HBV-DNA levels, and possibly contribute a functional cure.

Mass Spectrometry of Putrescine, Spermidine, and Spermine Covalently Attached to Francisella tularensis Universal Stress Protein and Bovine Albumin.

Bacterial and mammalian cells are rich in putrescine, spermidine, and spermine. Polyamines are required for optimum fitness, but the biological function of these small aliphatic compounds has only been partially revealed. Known functions of polyamines include interaction with nucleic acids that alters gene expression and with proteins that modulate activity. Although polyamines can be incorporated into proteins, very few naturally occurring polyaminated proteins have been identified, which is due in part to the difficulty in detecting these adducts. In the current study, bovine albumin and the recombinant universal stress protein from Francisella tularensis were used as models for mass spectrometry analysis of polyaminated proteins. The proteins were covalently bound to putrescine, spermidine, or spermine by the action of carbodiimide or microbial transglutaminase. Tryptic peptides, subjected to liquid chromatography tandem mass spectrometry (LC-MS/MS), were identified using Protein Prospector software. We describe the search parameters for identifying polyaminated peptides and show MS/MS spectra for adducts with putrescine, spermidine, and spermine. Manual evaluation led us to recognize signature ions for polyamine adducts on aspartate, glutamate, and glutamine, as well as neutral loss from putrescine, spermidine, and spermine during the fragmentation process. Mechanisms for the formation of signature ions and neutral loss are presented. Manual evaluation identified a false-positive adduct that had formed during trypsinolysis and resulted in peptide sequence rearrangement. Another false positive initially appeared to be a 71 kDa putrescine adduct on a cysteine residue. However, it was an acrylamide adduct on cysteine for a sample extracted from a polyacrylamide gel. The information presented in this report provides guidance and serves as a model for identifying naturally occurring polyaminated proteins.

Investigating the molecular mechanism of traditional Chinese medicine for the treatment of placental syndromes by influencing inflammatory cytokines using the Mendelian randomization and molecular docking technology.

Placental syndromes, which include pregnancy loss, preterm birth, gestational diabetes mellitus (GDM), and hypertensive disorders in pregnancy (HDP), have a strong association with disorder inflammatory reactions. Nonetheless, the exact causal relationship has not been established. This study aims to investigate the causal relationship between placental syndromes and inflammatory cytokines utilizing Mendelian randomization (MR). Additionally, we examined the interaction between small molecular compounds derived from traditional Chinese medicine and inflammatory cytokines using molecular docking method. After obtaining the data of inflammatory cytokines and placental syndromes, as well as establishing single nucleotide polymorphisms (SNPs), we employed the inverse variance weighted (IVW) method to assess the causal relationship. We also accessed the heterogeneity and the horizontal pleiotropy of these data. The "ClusterProfiler" R package was utilized for Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene Ontology (GO) term analyses. The protein-protein interaction (PPI) network was constructed using STRING database. AutoDock Vina software was used for molecular docking, and Discovery Studio 2019 was used for visualization purposes. We found that the growth regulated oncogene A (GROA) and interleukin-9 (IL-9) were associated with the development of pregnancy hypertension, whereas interleukin-10 (IL-10) and hepatocyte growth factor (HGF) were linked to the occurrence of preeclampsia. Moreover, there were correlations observed between interleukin-18 (IL-18), IL-10, macrophage colony-stimulating factor (MCSF), and platelet-derived growth factor BB (PDGFbb) in cases of chronic hypertension combined with pregnancy (CHP). Additionally, macrophage migration inhibitory factor (MIF) exhibited a connection with GDM, and TNF related apoptosis inducing ligand (TRAIL) demonstrated a causal relationship with preterm birth. It is plausible to suggest that interleukin-1β (IL-1β) might contribute to the promotion of pregnancy loss. All of the binding free energy values of small molecular compounds with inflammatory cytokines were below -5.0 kcal/mol. Furthermore, all of the RMSD values were less than 2. GROA, IL-1β, IL-9, IL-10, IL-18, MIF, MCSF, HGF, PDGFbb and TRAIL were found to be causally associated with placental syndromes. Molecular docking analysis revealed that small molecular compounds, such as puerarin, magnolol, atractylenolide I, paeoniflorin, tumulosic acid and wogonin, are closely bound to these inflammatory cytokines.

Identifying Potent Fat Mass and Obesity-Associated Protein Inhibitors Using Deep Learning-Based Hybrid Procedures

The fat mass and obesity-associated (FTO) protein catalyzes metal-dependent modifications of nucleic acids, namely the demethylation of methyl adenosine inside mRNA molecules. The FTO protein has been identified as a potential target for developing anticancer therapies. Identifying a suitable ligand-targeting FTO protein is crucial to developing chemotherapeutic medicines to combat obesity and cancer. Scientists worldwide have employed many methodologies to discover a potent inhibitor for the FTO protein. This study uses deep learning-based methods and molecular docking techniques to investigate the FTO protein as a target. Our strategy involves systematically screening a database of small chemical compounds. By utilizing the crystal structures of the FTO complexed with ligands, we successfully identified three small-molecule chemical compounds (ZINC000003643476, ZINC000000517415, and ZINC000001562130) as inhibitors of the FTO protein. The identification process was accomplished by employing a combination of screening techniques, specifically deep learning (DeepBindGCN) and Autodock vina, on the ZINC database. These compounds were subjected to comprehensive analysis using 100 nanoseconds of molecular dynamics and binding free energy calculations. The findings of our study indicate the identification of three candidate inhibitors that might effectively target the human fat mass and obesity protein. The results of this study have the potential to facilitate the exploration of other chemicals that can interact with FTO. Conducting biochemical studies to evaluate these compounds’ effectiveness may contribute to improving fat mass and obesity treatment strategies.

A Comprehensive Review on Exosome: Recent Progress and Outlook.

Exosomes are intrinsic membrane-based vesicles that play a key role in both normal and pathological processes. Since their discovery, exosomes have been investigated as viable drug delivery systems and clinical indicators because of their magnitude and effectiveness in delivering biological components to targeted cells. Exosome characteristics are biocompatible, prefer tumor recruitment, have tunable targeting efficiency, and are stable, making them outstanding and eye-catching medication delivery systems for cancer and other disorders. There is great interest in using cell-released tiny vesicles that activate the immune system in the age of the fast development of cancer immunotherapy. Exosomes, which are cell-derived nanovesicles, have a lot of potential for application in cancer immunotherapy due to their immunogenicity and molecular transfer function. More significantly, exosomes can transfer their cargo to specified cells and so affect the phenotypic and immune-regulation capabilities of those cells. In this article, we summarize exosomes' biogenesis, isolation techniques, drug delivery, applications, and recent clinical updates. The use of exosomes as drug-delivery systems for small compounds, macromolecules, and nucleotides has recently advanced. We have tried to give holistic and exhaustive pieces of information showcasing current progress and clinical updates of exosomes.

In silico identification of chikungunya virus replication inhibitor validated using biochemical and cell-based approaches.

Discovering an alternative therapy with a long-lasting effect on symptoms caused by chikungunya virus (CHIKV) infection is prompted by the lack of a vaccine and the absence of safe, effective and non-toxic medications. One potential strategy is synthesizing or identifying small compounds that can specifically target the active site of an essential enzyme and prevent virus replication. Previous site-directed mutagenesis studies have demonstrated the crucial role of the macrodomain, which is a part of non-structural protein 3 (nsP3), in virus replication. Exploiting this fact, the macrodomain can be targeted to discover a natural substance that can inhibit its function and thereby impede virus replication. With this aim, the present study focused on potential CHIKV nsP3 macrodomain (nsP3MD) inhibitors through in silico, in vitro and cell-based methods. Through virtual screening of the natural compound library, nine nsP3MD inhibitors were initially identified. Molecular dynamics (MD) simulations were employed to evaluate these nine compounds based on the stability of their ligand-receptor complexes and energy parameters. Target analysis and ADMET (i.e. absorption, distribution, metabolism, excretion and toxicity) prediction of the selected compounds revealed their drug-like characteristics. Subsequent in vitro investigation allowed us to narrow the selection down to one compound, N-[2-(5-methoxy-1H-indol-3-yl) ethyl]-2-oxo-1,2-dihydroquinoline-4-carboxamide, which exhibited potent inhibition of CHIKV growth. This molecule effectively inhibited CHIKV replication in the stable embryonal rhabdomyosarcoma cell line capable of producing CHIKV. Our findings demonstrate that the selected compound possesses substantial anti-CHIKV nsP3MD activity both in vitro and in vivo. This work provides a promising molecule for further preclinical studies to develop a potential drug against the CHIKV.

An overview of recent advancements in small molecules suppression of oncogenic signaling of K-RAS: an updated review.

RAS (rat sarcoma) oncoproteins are crucial for the growth of some human cancers, including lung, colorectal, and pancreatic adenocarcinomas. The RAS family contains three known human isoforms H(Harvey)-RAS, N(Neuroblastoma)-RAS, and K(Kirsten)-RAS. Mutations in RAS proteins cause up to ~ 30% of cancer cases. For almost 30 years, mutant proteins druggable pockets remained undiscovered, they are nearly identical to their essential, wild-type counterparts and cause cancer. Recent research has increased our knowledge of RAS's structure, processing, and signaling pathways and revealed novel insights into how it works in cancer cells. We highlight several approaches that inhibit RAS activity with small compounds in this review: substances that blocked farnesyltransferase (FTase), isoprenylcysteine carboxyl methyltransferase (Icmt), and RAS-converting enzyme 1 (Rce1) three important enzymes required for RAS localization. Inhibitors block the son of sevenless (SOS) protein's role in nucleotide exchange activity, small molecules that interfered with the phosphodiesterase (PDEδ)-mediated intracellular RAS transport processes, substances that focused on inhibiting RAS-effector interactions. Inhibitors are made to suppress the oncogenic K-RAS G12C mutant only when the nucleophilic cysteine residue at codon 12 is present and many inhibitors with various mechanisms like breaking the organization membrane of K-RAS nano-clustering. So, this is a thorough analysis of the most recent advancements in K-RAS-targeted anticancer techniques, hopefully offering insight into the field's future.

Functional promiscuity of small multidrug resistance transporters from Staphylococcus aureus, Pseudomonas aeruginosa, and Francisella tularensis.

Small multidrug resistance transporters efflux toxic compounds from bacteria and are a minimal system to understand multidrug transport. Most previous studies have focused on EmrE, the model SMR from Escherichia coli, finding that EmrE has a broader substrate profile than previously thought and that EmrE may perform multiple types of transport, resulting in substrate-dependent resistance or susceptibility. Here, we performed a broad screen to identify potential substrates of three other SMRs: PAsmr from Pseudomonas aeruginosa; FTsmr from Francisella tularensis; and SAsmr from Staphylococcus aureus. This screen tested metabolic differences in E.coli expressing each transporter versus an inactive mutant, for a clean comparison of sequence and substrate-specific differences in transporter function, and identified many substrates for each transporter. In general, resistance compounds were charged, and susceptibility substrates were uncharged, but hydrophobicity was not correlated with phenotype. Two resistance hits and two susceptibility hits were validated via growth assays and IC50 calculations. Susceptibility is proposed to occur via substrate-gated proton leak, and the addition of bicarbonate antagonizes the susceptibility phenotype, consistent with this hypothesis.

Unravelling competitive adsorption phenomena in the aqueous phase reforming of carboxylic acids on Pt catalysts: An experimental and theoretical study

Biorefinery-derived wastewater is considered a valuable source of energy and chemicals thanks to its organic loading. However, it is constituted by different compounds which influence the performance of a catalytic valorization process. In this work, we investigated the treatment of a synthetic hydrothermal liquefaction-derived wastewater (HTL-WW) via aqueous phase reforming (APR) to obtain hydrogen. As a case study, we examined the underlying driving forces for performance differences in the APR of mono- and bi-component solutions of carboxylic acids as a model corn stover HTL-WW over Pt catalysts via a combined experimental and theoretical approach. In mono-component solutions, the conversion ranked as glycolic acid > propionic acid ≈ acetic acid, and the same was found for the hydrogen production tendency. Binary solutions of glycolic and acetic acid, with different concentration among the constituents, showed a strong inhibition of the acetic acid reactivity due to the prevalent adsorption of glycolic acid on Pt surface. The results from the APR of acetic and propionic acid solutions were less affected by such phenomena. DFT results showed that there are strong, attractive lateral interactions between carboxylic acids due to intermolecular hydrogen bonding that cause all carboxylic acids to preferentially adsorb in dimer structures. The lateral interaction strength was determined for both pure and binary mixtures of carboxylic acid dimers, with results showing that pure mixtures of carboxylic acids have stronger attractions and that glycolic acid dimers see the strongest attractions due to the added terminal hydroxyl functional group. The findings presented herein offer significant insights into the utilization of APR for industrial-like multi-component solutions, as well as for any catalytic process involving small organic compounds in an aqueous phase.

Mangiferin alleviates diabetic pulmonary fibrosis in mice via inhibiting endothelial-mesenchymal transition through AMPK/FoxO3/SIRT3 axis.

Diabetes mellitus results in numerous complications. Diabetic pulmonary fibrosis (DPF), a late pulmonary complication of diabetes, has not attracted as much attention as diabetic nephropathy and cardiomyopathy. Mangiferin (MF) is a natural small molecular compound that exhibits a variety of pharmacological effects including anti-inflammatory, anti-cancer, anti-diabetes, and anti-fibrosis effects. In this study, we investigated whether long-term diabetes shock induces DPF, and explored whether MF had a protective effect against DPF. We first examined the lung tissues and sections of 20 diabetic patients obtained from discarded lung surgical resection specimens and found that pulmonary fibrosis mainly accumulated around the pulmonary vessels, accompanied by significantly enhanced endothelial-mesenchymal transition (EndMT). We established a mouse model of DPF by STZ injections. Ten days after the final STZ injection, the mice were administered MF (20, 60 mg/kg, i.g.) every 3 days for 4 weeks, and kept feeding until 16 weeks and euthanized. We showed that pulmonary fibrotic lesions were developed in the diabetic mice, which began around the pulmonary vessels, while MF administration did not affect long-term blood glucose levels, but dose-dependently alleviated diabetes-induced pulmonary fibrosis. In human umbilical vein endothelial cells (HUVECs), exposure to high glucose (33.3 mM) induced EndMT, which was dose-dependently inhibited by treatment with MF (10, 50 μM). Furthermore, MF treatment promoted SIRT3 expression in high glucose-exposed HUVECs by directly binding to AMPK to enhance the activity of FoxO3, which finally reversed diabetes-induced EndMT. We conclude that MF attenuates DPF by inhibiting EndMT through the AMPK/FoxO3/SIRT3 axis. MF could be a potential candidate for the early prevention and treatment of DPF.

Ligand-Based Design of Novel Quinoline Derivatives as Potential Anticancer Agents: An In-Silico Virtual Screening Approach.

In this study, using the Comparative Molecular Field Analysis (CoMFA) approach, the structure-activity relationship of 33 small quinoline-based compounds with biological anti-gastric cancer activity in vitro was analyzed in 3D space. Once the 3D geometric and energy structure of the target chemical library has been optimized and their steric and electrostatic molecular field descriptions computed, the ideal 3D-QSAR model is generated and matched using the Partial Least Squares regression (PLS) algorithm. The accuracy, statistical precision, and predictive power of the developed 3D-QSAR model were confirmed by a range of internal and external validations, which were interpreted by robust correlation coefficients (RTrain2=0.931; Qcv2=0.625; RTest2=0.875). After carefully analyzing the contour maps produced by the trained 3D-QSAR model, it was discovered that certain structural characteristics are beneficial for enhancing the anti-gastric cancer properties of Quinoline derivatives. Based on this information, a total of five new quinoline compounds were developed, with their biological activity improved and their drug-like bioavailability measured using POM calculations. To further explore the potential of these compounds, molecular docking and molecular dynamics simulations were performed in an aqueous environment for 100 nanoseconds, specifically targeting serine/threonine protein kinase. Overall, the new findings of this study can serve as a starting point for further experiments with a view to the identification and design of a potential next-generation drug for target therapy against cancer.

Regulation of polysaccharide in Wu‐tou decoction on intestinal microflora and pharmacokinetics of small molecular compounds in AIA rats

Wu-tou decoction (WTD), a traditional Chinese medicine prescription, is used to treat rheumatoid arthritis (RA). It works by controlling intestinal flora and its metabolites, which in turn modulates the inflammatory response and intestinal barrier function. Small molecular compounds (SM) and polysaccharides (PS) were the primary constituents of WTD extract. In this work, a model of adjuvant-induced arthritis (AIA) in rats was established and treated with WTD, SM, and PS, respectively. 16S rRNA gene sequencing was used to examine the regulatory impact of the various groups on the disturbance of the gut flora induced by RA. Further, since PS cannot be absorbed into the blood, the influence of PS on the absorption and metabolism of SM was studied by examining their pharmacokinetic (PK) parameters of 23 active components in SM by UPLC-MS/MS. WTD was found to be more effective than PS and SM in alleviating arthritis in AIA rats, which may be related to changes in gut flora. The PK properties of 13 active compounds were altered after PS intervene. Based on the findings, PS may be able to manage the disruption of intestinal microbiota, enhance the intestinal environment of model animals, and hence influence SM absorption and metabolism.

Pharmacophore-based computational study on inhibitor of TMPRSS6 as hepcidin modulator in an iron overload of beta-thalassaemia

ABSTRACT TMPRSS6 (transmembrane protease, serine 6) plays an important role in the cleavage of hemojuvelin (HJV), a key protein involved in the regulation of hepcidin metabolism. TMPRSS6 cleaves HJV at specific sites, leading to the activation of the bone morphogenetic protein (BMP6-SMAD) pathway. This pathway further leads to the production of hepcidin (a liver peptide enzyme), which promotes iron absorption and removal from the bloodstream. In-silico pharmacophore analysis is used in this study to identify potential small therapeutic compounds that inhibit TMPRSS6 activity. Pharmacophore investigations of known inhibitors (peptidomimetic benzothiazole) were carried out to identify the molecules’ important properties for interacting with the target. The pharmacophore model of the TMPRSS6 (PDB ID: 6N4T) inhibitor (KD7) pharmacophore features were used to screen the small molecules library that binds to the target and modulates its activity. The docking parameters of the top 5 hit molecules had lower binding energy in comparative analysis to reference molecule. The best-fit pharmacophore feature ligands were docked at the binding site of the target protein. This study demonstrates that knocking out the enzyme reduces the effects of iron overload in conditions like hemochromatosis and beta-thalassemia. In-silico investigation discovered significant evidence of catalytic activity.

Wetlands harbor lactic acid-driven chain elongators.

Wetlands are globally significant carbon cycling hotspots that both sequester large amounts of CO2 as soil carbon as well as emit a third of all CH4 globally. Their outsized role in the global carbon cycle makes it critical to understand microbial processes contributing to carbon breakdown and storage in these ecosystems. Here, we confirm the presence of chain-elongating organisms in freshwater wetland soils. These organisms take small carbon compounds formed during the breakdown of biomass and turn them into larger compounds (six to eight carbon organic acids) that may potentially contribute to the formation of soil organic matter and long-term carbon storage. Moreover, we find that these chain-elongating organisms may be widely distributed in wetlands globally. Future work should identify these organisms' contribution to carbon cycling in wetlands and the potential role of the products they form in carbon sequestration in wetlands.

Current status of PSMA-targeted imaging and therapy.

Currently, the incidence of prostate cancer is increasing, and it has become a great threat to men's health. The detection, staging, and follow-up of prostate cancer patients are inseparable from morphology or magnetic resonance imaging (MRI). However, these do not fully meet the needs of diagnosis and patient management. In particular, owing to the late diagnosis, metastatic castration-resistant prostate cancer (mCRPC) patients usually have poor survival and few options for further effective treatment. Prostate-specific membrane antigen (PSMA), because of its overexpression on prostate cancer cells, has gained interest due to its application in the imaging and theranostics field. Several PSMA radioligands have been developed for imaging and treating prostate cancer. Many clinical trials have assessed the efficacy and safety profiles of these radionuclide agents and show promise in patients who have exhausted other standard treatment options. To date, several small compounds for targeting PSMA have been developed, and 68Ga-PSMA-11 and 18F-DCFPyL have been approved by the United States (US) Food and Drug Administration (FDA) for imaging of prostate cancer. 111In- or 99mTc-labeled PSMA-ligand can guide surgeons searching for radioactive metastatic lymph nodes, and 177Lu- or 225Ac-labeled PSMA-ligand can be used for internal radiotherapy. Moreover, some molecules for therapeutic application are undergoing different stages of clinical trials. In this review, we present current perspectives on the use of PSMA-targeted imaging and theranostics in prostate cancer. As PSMA-targeted imaging and therapeutics are becoming the standard of care for prostate cancer patients, we emphasize the importance of integrating nuclear medicine physicians into multidisciplinary oncology teams.

Active substances of myxobacteria against plant diseases and their action mechanisms.

Myxobacteria have a complex life cycle and unique social behavior, and obtain nutrients by preying on bacteria and fungi in soil. Chitinase, β-1,3 glucanase and β-1,6 glucanase produced by myxobacteria can degrade the glycosidic bond of cell wall of some plant pathogenic fungi, resulting in a perforated structure in the cell wall. In addition, isooctanol produced by myxobacteria can lead to the accumulation of intracellular reactive oxygen species in some pathogenic fungi and induce cell apoptosis. Myxobacteria can also perforate the cell wall of some plant pathogenic oomycetes by β-1,3 glucanase, reduce the content of intracellular soluble protein and protective enzyme activity, affect the permeability of oomycete cell membrane, and aggravate the oxidative damage of pathogen cells. Small molecule compounds such as diisobutyl phthalate and myxovirescin produced by myxobacteria can inhibit the formation of biofilm and lipoprotein of bacteria, and cystobactamids can inhibit the activity of DNA gyrase, thus changing the permeability of bacterial cell membrane. Myxobacteria, as a new natural compound resource bank, can control plant pathogenic fungi, oomycetes and bacteria by producing carbohydrate active enzymes and small molecular compounds, so it has great potential in plant disease control.