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Protein homeostasis is a tightly conserved process that is regulated through the ubiquitin proteasome system (UPS) in a ubiquitin-independent or ubiquitin-dependent manner. Over the past two decades, the proteasome has become an excellent therapeutic target through inhibition of the catalytic core particle, inhibition of subunits responsible for recognizing and binding ubiquitinated proteins, and more recently, through targeted protein degradation using proteolysis targeting chimeras (PROTACs). The majority of the developed inhibitors of the proteasome's core particle rely on gaining selectivity through binding interactions within the unprimed substrate channel. Although this has allowed for selective inhibitors and chemical probes to be generated for the different proteasome isoforms, much remains unknown about the interactions that could be harnessed within the primed substrate channel to increase potency or selectivity. Herein, we discuss small molecules that interact with the primed substrate pocket and how their differences may give rise to altered activity. Taking advantage of additional interactions with the primed substrate pocket of the proteasome could allow for the generation of improved chemical tools for perturbing or monitoring proteasome activity.

Naturally occurring gas hydrates are established as an abundant reserve of natural gas. Production initiatives raised challenges such as low production rate, freezing problems, water, and sand production along with geomechanical concerns. Recent studies suggest that fracturing the sediment can significantly improve the conductivity and productivity of such reserves. This study is an initiative to verify the suitability of conventionally used polymer (guar) for fracturing at extremely low temperatures along with the integration of widely available gas hydrate inhibitors for efficient stimulation. Established inhibitors such as NaCl, CaCl 2 and KCl were introduced to linear and crosslinked gels to study their compatibility with the reference guar-based gels. The inhibitor integrated linear gel samples demonstrated similar performance trends to that of the reference gel establishing their compatibility with the polymer, whereas the inhibitor integrated crosslinked samples displayed deswelling nature. The low concentration inhibitor integrated linear gel samples performed superior to the reference gel whereas the high concentration sample inhibited the swelling performance of the polymer. Both the reference and inhibitor integrated linear gel samples gradually disintegrated after 48 h leaving behind soft cloudy residue, whereas the inhibitor integrated crosslinked samples rapidly released water and contracted into a solid residue which can cause serious flow related disruptions during operations and apparently damage the conductivity of the sediment for long term. This study delivers crucial understanding on how various salts interact with guar polymers at low temperatures and whether their presence can be a boon or bane during the design of a fracturing fluid. • Low temperature fracturing of hydrate-bearing sediments for improved gas recovery. • Integration of hydrate inhibitors with conventional gelling polymer used in hydraulic fracturing. • Inhibitor integrated linear gel samples demonstrated good integrity during tests. • Inhibitor integrated low concentration samples performed superiorly. • Inhibitor integrated crosslinked gels prone to deswelling and residue formation. [ABSTRACT FROM AUTHOR]

The protein tyrosine phosphatase 1B (PTP1B) is a critical therapeutic target for type 2 diabetes mellitus (T2DM). Many PTP1B inhibitors have been reported, however, most of them lack high specificity and have adverse effects. Designing effective PTP1B inhibitors requires understanding the molecular mechanism of action between inhibitors and PTP1B. To this end, molecular dynamics (MD) simulations and molecular mechanics Poisson Boltzmann Surface Area (MM-PB/ SA) methods were used to observe the binding patterns of compounds with similar pentacyclic triterpene parent ring structures but different inhibition abilities. Through structure and energy analysis, we found that the positions of cavities and substituents significantly affect combining capacity. Besides, we constructed a series of potential inhibitor molecules using LUDI and rational drug design methods. The ADMET module of Discovery Studio 2020 was used to predict the properties of these inhibitor molecules. Lastly, we obtained compounds with low toxicity and significant inhibitory activity. The study will contribute to the treatment of T2DM. [ABSTRACT FROM AUTHOR]

This article, published in Frontiers in Pharmacology, explores the design of novel inhibitors for ischemia/reperfusion injury targeting ferroptosis. Ischemic cardiovascular disease, a leading cause of death worldwide, is caused by reduced blood flow to the heart. The article emphasizes the importance of understanding the mechanisms of cardiovascular disease progression and the role of ferroptosis in ischemic cardiovascular disease. It presents research on the use of novel inhibitors, such as pyrroloquinoline quinone (PQQ) and activating transcription factor 3 (ATF3), in protecting the heart from ischemia/reperfusion injury by inhibiting ferroptosis. The article discusses the potential therapeutic use of ferroptosis inhibitors for various cardiovascular diseases and highlights three specific studies that investigate the role of different compounds in inhibiting ferroptosis and improving cardiac health. These studies focus on Resveratrol, Allicin, and ATF3 expression inhibition as potential treatments for myocardial infarction and atherosclerosis. The article concludes that these studies provide valuable insights into the mechanisms of ferroptosis and offer new possibilities for clinical treatment. [Extracted from the article]

Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic pathogen accountable for severe illness and mortality among immunocompromised individuals due to its extraordinary resistance to antibiotics. The regulation of pathogenic traits in P. aeruginosa is governed by a quorum sensing (QS) signaling molecule named acyl homoserine lactone (AHL). The present study investigated the inhibitory effects of the compound, Artocarpus heterophyllus Lam (A. heterophyllus), on the number of AHL-dependent components produced by P. aeruginosa (PAO1). A. heterophyllus is considered as a beneficial natural compound with notable inhibitory effects on several pathogens. The present study investigated the antimicrobial and antibiofilm activities of A. heterophyllus against PAO1 through in vitro experiments, including minimum inhibitory concentration tests, biofilm inhibition assays and growth curve analysis. The results demonstrated that the methanolic extract of A. heterophyllus at a concentration of 10 mg/ml effectively inhibited PAO1. Additionally, the extract exhibited a 55.12% biofilm inhibitory effect at the lowest sub-inhibitory concentration of 2.5 mg/ml, without affecting planktonic cell growth. On the whole, the findings of the present study indicate the prospective signifi- cance of A. heterophyllus as an anti-pathogenic agent, which is effective in reducing QS-dependent infection in PAO1. [ABSTRACT FROM AUTHOR]

Insulin‐regulated aminopeptidase (IRAP) is an enzyme with important biological functions and the target of drug‐discovery efforts. We combined in silico screening with a medicinal chemistry optimization campaign to discover a nanomolar inhibitor of IRAP based on a pyrazolylpyrimidine scaffold. This compound displays an excellent selectivity profile versus homologous aminopeptidases, and kinetic analysis suggests it utilizes an uncompetitive mechanism of action when inhibiting the cleavage of a typical dipeptidic substrate. Surprisingly, the compound is a poor inhibitor of the processing of the physiological cyclic peptide substrate oxytocin and a 10mer antigenic epitope precursor but displays a biphasic inhibition profile for the trimming of a 9mer antigenic peptide. While the compound reduces IRAP‐dependent cross‐presentation of an 8mer epitope in a cellular assay, it fails to block in vitro trimming of select epitope precursors. To gain insight into the mechanism and basis of this unusual selectivity for this inhibitor, we solved the crystal structure of its complex with IRAP. The structure indicated direct zinc(II) engagement by the pyrazolylpyrimidine scaffold and revealed that the compound binds to an open conformation of the enzyme in a pose that should block the conformational transition to the enzymatically active closed conformation previously observed for other low‐molecular‐weight inhibitors. This compound constitutes the first IRAP inhibitor targeting the active site that utilizes a conformation‐specific mechanism of action, provides insight into the intricacies of the IRAP catalytic cycle, and highlights a novel approach to regulating IRAP activity by blocking its conformational rearrangements. [ABSTRACT FROM AUTHOR]

To solve the downhole problems correlated with clay hydration swelling and dispersion under high‐temperature conditions, a 1‐aminoethyl‐3‐vinylimidazolium bromide ([NVim]Br) and a [NVim]Br/acrylamide copolymer (poly([NVim]Br‐co‐AM)) are synthesized and used as inhibitors. The molecular structures of [NVim]Br and poly([NVim]Br‐co‐AM) are characterized by FT‐IR and 1H‐NMR. The inhibition properties of [NVim]Br and poly([NVim]Br‐co‐AM) are evaluated by free swelling and dispersion tests, linear swelling, hot roll recovery experiments and thermogravimetric analyses.The inhibition mechanisms were revealed by X‐ray diffraction, zeta potential, wettability analysis and ESEM observation. The results showed that both [NVim]Br and poly([NVim]Br‐co‐AM) has significantly superior inhibition performance compared with the common inhibitors KCl, polyether amine D230 and polyquaternium‐7. Both [NVim]Br and poly([NVim]Br‐co‐AM) can resist 250 °C. [NVim]Br performed excellently in inihibiting both crystalline and osmotic swelling, which depended on the strong electrostatic adsorption and hydrogen bonds of imidazole cations and primary amine in [NVim]+. Poly([NVim]Br‐co‐AM) exerted excellent inhibition by minimizing osmotic swelling, reducing hydrophilicity and increasing clay bonding. The results are important for understanding the rational design of novel efficient inhibitors for drilling high‐temperature shale formation. [ABSTRACT FROM AUTHOR]

Ferroptosis is a form of regulated cell death that can be modulated by small molecules and has the potential for the development of therapeutics for oncology. Although excessive lipid peroxidation is the defining hallmark of ferroptosis, DNA damage may also play a significant role. In this study, a potential mechanistic role for MIF in homologous recombination (HR) DNA repair is identified. The inhibition or genetic depletion of MIF or other HR proteins, such as breast cancer type 1 susceptibility protein (BRCA1), is demonstrated to significantly enhance the sensitivity of cells to ferroptosis. The interference with HR results in the translocation of the tumor suppressor protein p53 to the mitochondria, which in turn stimulates the production of reactive oxygen species. Taken together, the findings demonstrate that MIF‐directed small molecules enhance ferroptosis via a putative MIF‐BRCA1‐RAD51 axis in HR, which causes resistance to ferroptosis. This suggests a potential novel druggable route to enhance ferroptosis by targeted anticancer therapeutics in the future. [ABSTRACT FROM AUTHOR]

SUMMARY Structural prediction by artificial intelligence can be powerful new instruments to discover novel protein–protein interactions, but the community still grapples with the implementation, opportunities and limitations. Here, we discuss and re‐analyse our in silico screen for novel pathogen‐secreted inhibitors of immune hydrolases to illustrate the power and limitations of structural predictions. We discuss strategies of curating sequences, including controls, and reusing sequence alignments and highlight important limitations caused by different platforms, sequence depth and computing times. We hope these experiences will support similar interactomic screens by the research community. [ABSTRACT FROM AUTHOR]

Mitochondrial NADH–ubiquinone oxidoreductase (complex I) couples electron transfer from NADH to ubiquinone with proton translocation in its membrane part. Structural studies have identified a long (~ 30 Å), narrow, tunnel‐like cavity within the enzyme, through which ubiquinone may access a deep reaction site. Although various inhibitors are considered to block the ubiquinone reduction by occupying the tunnel's interior, this view is still debatable. We synthesized a phosphatidylcholine‐quinazoline hybrid compound (PC‐Qz1), in which a quinazoline‐type toxophore was attached to the sn‐2 acyl chain to prevent it from entering the tunnel. However, PC‐Qz1 inhibited complex I and suppressed photoaffinity labeling by another quinazoline derivative, [125I]AzQ. This study provides further experimental evidence that is difficult to reconcile with the canonical ubiquinone‐accessing tunnel model. [ABSTRACT FROM AUTHOR]

Inhibition of soluble epoxide hydrolase (sEH) is a promising therapeutic strategy for treating neuropathic pain. These inhibitors effectively reduce diabetic neuropathic pain and inflammation induced by Freund's adjuvant which makes them a suitable alternative to traditional opioids. This study showcased the notable analgesic effects of compound AMHDU (1,1′-(hexane-1,6-diyl)bis(3-((adamantan-1-yl)methyl)urea)) in both inflammatory and diabetic neuropathy models. While lacking anti-inflammatory properties in a paw edema model, AMHDU is comparable to celecoxib as an analgesic in 30 mg/kg dose administrated by intraperitoneal injection. In a diabetic tactile allodynia model, AMHDU showed a prominent analgesic activity in 10 mg/kg intraperitoneal dose (p < 0.05). The effect is comparable to that of gabapentin, but without the risk of dependence due to a different mechanism of action. Low acute oral toxicity (>2000 mg/kg) and a high therapeutic index makes AMHDU a promising candidate for further structure optimization and preclinical evaluation. [ABSTRACT FROM AUTHOR]

Prevention of hydrate plugs during oil and natural gas transportation in the pipeline network is challenging and may require significant operating expenditure. Synthetic inhibitors are deployed in large volumes to inhibit hydrate formation, and these inhibitors are highly expensive and toxic to the environment. Consequently, this study investigates the effectiveness of cassava (Manihot esculenta) leaf extract as an environmentally friendly, biodegradable, and cost-efficient novel green inhibitor of gas hydrate. Cassava is a tropical plant cultivated majorly in Nigeria, and its leaf is, in almost all cases, discarded as waste. In this study, an extract is made from cassava leaf and used in varying weight percentages as hydrate inhibitors using a locally fabricated mini flow. Results show cassava leaf extract (CLE) performed significantly better than conventional inhibitor methanol (MeOH) at a higher weight percentage. The presented results show that at varying weights of 0.02 wt%, 0.04 wt%, and 0.06 wt% of the CLE, the final pressures were found to be the pressures were found to be 29 psi, 27 psi, and 24 psi, respectively. These pressures indicates that more gas was converted to hydrate with the lower pressure value in the system. These results were compared with 2 wt%, 4 wt%, and 6 wt% of MeOH, with a differential pressure of 28 psi, 46 psi, and 50 psi, respectively. CLE's gas hydrate inhibition capacity was found at pressure conditions of 51.7 psi, 55 psi, and 60 psi for 0.02 wt%, 0.04 wt%, and 0.06 wt%, respectively. These results demonstrate that CLE performed significantly better than methanol as a gas hydrate inhibitor, despite being used in a much lower dosage than methanol, which had inhibition pressures conditions of 53.3 psi, 23.3 psi, and 16.7 psi for 2 wt%, 4 wt%, and 6 wt%, respectively. [ABSTRACT FROM AUTHOR]

The acid pollution produced from coal gangue piles is a global environmental problem. Terminal technologies, such as neutralization, precipitation, adsorption, ion exchange, membrane technology, biological treatment, and electrochemistry, have been developed for acid mine drainage (AMD) treatment. These technologies for treating pollutants with low concentrations over a long period of time in coal gangue piles appear to be costly and unsustainable. Conversely, in situ remediation appears to be more cost-effective and material-efficient, but it is a challenge that coal producing countries need to solve urgently. The primary prerequisite for preventing acidic pollutants is to clarify the oxidation mechanisms of coal gangue, which can be summarized as four aspects: pyrite oxidation, microbial action, low-temperature oxidation of coal, and free radical action. The two key factors of oxidation are pyrite and coal, and the four necessary conditions are water, oxygen, microorganisms, and free radicals. The current in situ remediation technologies mainly focus on one or more of the four necessary conditions, forming mixed co-disposal, coverage barriers, passivation coatings, bactericides, coal oxidation inhibitors, microorganisms, plants, and so on. It is necessary to scientifically and systematically carry out in situ remediation coupled with various technologies based on oxidation mechanisms when carrying out large-scale restoration and treatment of acidic coal gangue piles. [ABSTRACT FROM AUTHOR]

The orf virus (ORFV) poses a serious threat to the health of domestic small ruminants (i.e., sheep and goats) and humans on a global scale, causing around $150 million in annual losses to livestock industry. However, the host factors involved in ORFV infection and replication are still elusive. In this study, we compared the RNA-seq profiles of ORFV-infected or non-infected sheep testicular interstitial cells (STICs) and identified a novel host gene, potassium voltage-gated channel subfamily E member 4 (KCNE4), as a key host factor involved in the ORFV infection. Both RNA-seq data and RT-qPCR assay revealed a significant increase in the expression of KCNE4 in the infected STICs from 9 to 48 h post infection (hpi). On the other hand, the RT-qPCR assay detected a decrease in ORFV copy number in both the STICs transfected by KCNE4 siRNA and the KCNE4 knockout (KO) HeLa cells after the ORFV infection, together with a reduced fluorescence ratio of ORFV-GFP in the KO HeLa cells at 24 hpi, indicating KCNE4 to be critical for the ORFV infection. Furthermore, the attachment and internalization assays showed decreased ORFV attachment, internalization, replication, and release by the KO HeLa cells, demonstrating a potential inhibition of ORFV entry into the cells by KCNE4. Pretreatment with the KCNE4 inhibitors such as quinidine and fluoxetine significantly repressed the ORFV infection. All our findings reveal KCNE4 as a novel host regulator of the ORFV entry and replication, shedding new insight into the interactive mechanism of ORFV infection. The study also highlights the K+ channels as possible druggable targets to impede viral infection and disease. [ABSTRACT FROM AUTHOR]

Abstract\nHIGHLIGHTSA new Schiff base inhibitor known as “N, N’ carbonyl- Bis (para-hydroxy benzaldehyde imine)” has been synthesized and characterized by FTIR, NMR, and UV-Visible spectroscopy, the molecule was then assessed for its ability to prevent copper from corroding in a solution of 0.5 M H2SO4 using potentiodynamic polarization, electrochemical impedance spectroscopy, scanning electron microscopy SEM combined with energy dispersion spectroscopy EDX, and atomic force microscopy AFM. The tested inhibitor exhibits good copper corrosion inhibition performance in a 0.5 M H2SO4 solution. As inhibitor concentration rises, inhibition performance also rises, reaching a maximum inhibitory efficacy of around 84.76 ± 0.69% at 5.10−4 M. The inhibitor was adsorbable to the metal surface and followed the Langmuir isotherm. It has been done such that the addition of KI increased the inhibitory effectiveness, the mixed additives worked together. There is good agreement between the conclusions drawn from theoretical calculations using DFT and MD simulation and actual observations.A new Schiff base inhibitor has been synthesized.The inhibitory efficiency increase with increasing inhibitor concentration.The investigated molecule adsorbs on the copper surface through active centers like N and O.The synthesized molecule has good inhibitory effectiveness with respect to copper corrosion in an acidic medium.A new Schiff base inhibitor has been synthesized.The inhibitory efficiency increase with increasing inhibitor concentration.The investigated molecule adsorbs on the copper surface through active centers like N and O.The synthesized molecule has good inhibitory effectiveness with respect to copper corrosion in an acidic medium. [ABSTRACT FROM AUTHOR]

• Janus kinase 1 (JAK1) is highly expressed in colorectal cancer (CRC). • Several natural compounds possess significant anticancer properties. • Methyl betulate, EGCG & Eriocalyxin B were found as potential JAK1 inhibitors. • Compounds are also cytotoxic and have the potential to induce apoptosis in CRC. Colorectal cancer (CRC) has become a global threat worldwide with constantly increasing incidence and mortality rates every year, especially in the US and China. Janus kinase (JAK) is an intracellular non-receptor tyrosine that mediates the signal transducer and activator of transcription (STAT) which orchestrates cytokine signalling, oncogene expression, and modulation of transcription factors. Targeting JAK holds promise as a therapeutic strategy for CRC. This present study focused on natural products, due to their renowned for their diverse pharmacological properties including anticancer, antimicrobial, anti-proliferative, and antioxidant effects. Employing a range of bioinformatics analyses such as molecular docking, drug-likeness evaluation, ADME profiling, toxicity assessment, in silico cytotoxicity prediction, and molecular target identification, and in vitro assays such as cytotoxicity assay & ROS induction assay were performed to investigate the potency of the natural compounds. Among the screened compounds, Methyl betulate (L1), Epigallocatechin-3-gallate (EGCG) (L2), and Eriocalyxin B (L3) exhibited stronger binding affinities than the standard Golidocitinib (AZD4205). These compounds not only met Lipinski's criteria for drug-likeness and displayed favourable ADME properties but also demonstrated reduced toxicity profiles and exhibited promising activity against various kinases. Furthermore, molecular dynamics simulations revealed the stability of these compounds with JAK1. Notably, they also exhibited potent cytotoxicity and induced apoptosis in SW480 and HT29 colon adenocarcinoma cells. Consequently, the findings suggest that these three compounds hold potential as potent JAK1 inhibitors, warranting further investigation in future in vivo studies. [Display omitted] [ABSTRACT FROM AUTHOR]

Simple Summary: Aquaporins (AQPs) have emerged as potential predictors of response to cancer therapy and as targets for increasing sensitivity to treatment. However, systemic therapeutic inhibition using pan-AQP or AQP-specific inhibitors has not been characterized for efficacy in treating breast cancer or as a component of combination treatment. We evaluated AQP inhibition using established AQP inhibitors in cytotoxicity and pharmacologic assays. This study identified AQPs as a targetable vulnerability in breast cancer. AQP inhibitors can increase therapeutic efficacy, both as single agents and in a combination therapy strategy, in treating breast cancer progression and metastasis. These results provide significant insights that support the future development of improved AQP inhibitors. AQPs contribute to breast cancer progression and metastasis. We previously found that genetic inhibition of Aqp7 reduces primary tumor burden and metastasis in breast cancer. In this study, we utilized two AQP inhibitors, Auphen and Z433927330, to evaluate the efficacy of therapeutic inhibition of AQPs in breast cancer treatment. The inhibitors were evaluated in breast cancer for both cytotoxicity and metabolic stability assays across both murine and human breast cancer cell lines. Both AQP inhibitors also affected the expression of other AQP transcripts and proteins, which demonstrates compensatory regulation between AQP family members. As a single agent, Auphen treatment in vivo extended overall survival but did not impact primary or metastatic tumor burden. However, Auphen treatment made cells more responsive to chemotherapy (doxorubicin) or endocrine treatment (tamoxifen, fulvestrant). In fact, treatment with Tamoxifen reduced overall AQP7 protein expression. RNA-seq of breast cancer cells treated with Auphen identified mitochondrial metabolism genes as impacted by Auphen and may contribute to reducing mammary tumor progression, lung metastasis, and increased therapeutic efficacy of endocrine therapy in breast cancer. Interestingly, we found that Auphen and tamoxifen cooperate to reduce breast cancer cell viability, which suggests that Auphen treatment makes the cells more susceptible to Tamoxifen. Together, this study highlights AQPs as therapeutic vulnerabilities of breast cancer metastasis that are promising and should be exploited. However, the pharmacologic results suggest additional chemical refinements and optimization of AQP inhibition are needed to make these AQP inhibitors appropriate to use for therapeutic benefit in overcoming endocrine therapy resistance. [ABSTRACT FROM AUTHOR]

Simple Summary: Individualized medicine means understanding how each tumor is different from normal cells and how each tumor is different from other tumors, including profiling mutations, non-mutational epigenetic changes, and differences in gene expression. This allows the discovery of key processes each tumor absolutely depends on for survival and growth, which are intrinsic weaknesses. This profiling means selecting treatments to specifically target each tumor's survival-dependent pathways, killing them. Tip60 is a master controller of processes that maintain genome stability and signaling regulating gene expression. While disrupted in many cancers, Tip60 is essential for cell survival, and inhibiting Tip60 kills tumors. While we understand some key aspects of the molecular roles Tip60 plays, much more remains to be discovered. A more complete understanding of the diverse roles and functions of Tip60 in cancer, and how targeting Tip60 kills cancer cells, will lead to better treatments for patients and increased survival. Precision (individualized) medicine relies on the molecular profiling of tumors' dysregulated characteristics (genomic, epigenetic, transcriptomic) to identify the reliance on key pathways (including genome stability and epigenetic gene regulation) for viability or growth, and then utilises targeted therapeutics to disrupt these survival-dependent pathways. Non-mutational epigenetic changes alter cells' transcriptional profile and are a key feature found in many tumors. In contrast to genetic mutations, epigenetic changes are reversable, and restoring a normal epigenetic profile can inhibit tumor growth and progression. Lysine acetyltransferases (KATs or HATs) protect genome stability and integrity, and Tip60 is an essential acetyltransferase due to its roles as an epigenetic and transcriptional regulator, and as master regulator of the DNA double-strand break response. Tip60 is commonly downregulated and mislocalized in many cancers, and the roles that mislocalized Tip60 plays in cancer are not well understood. Here we categorize and discuss Tip60-regulated genes, evaluate Tip60-interacting proteins based on cellular localization, and explore the therapeutic potential of Tip60-targeting compounds as epigenetic inhibitors. Understanding the multiple roles Tip60 plays in tumorigenesis will improve our understanding of tumor progression and will inform therapeutic options, including informing potential combinatorial regimes with current chemotherapeutics, leading to improvements in patient outcomes. [ABSTRACT FROM AUTHOR]

Inhibition of SIRT3 exhibited potency in triggering leukemic cell differentiation. In discovery of potent SIRT3 inhibitors for cancer differentiation therapy, structural modification was performed on the previously developed lead compound P6. A total of 33 compounds were designed and synthesized. In the enzyme inhibitory assay, several molecules S18, S26, S27 and T5 showed potent SIRT3 inhibitory activity with IC50 value of 0.53, 1.86, 5.06, and 2.88 μM, respectively. Moreover, the tested compounds exhibited SIRT3 inhibitory selectivity over SIRT1 and SIRT2. Compounds S27 and T5 were potent in inhibition the growth of MM1.S and RPMI‐8226 cells in the in vitro antiproliferative test. Significantly, representative compounds, especially S27 and T5, promoted differentiation of tested MM cells in the cellular morphological evaluation, accompanied by increasing the expression of differentiation antigen CD49e and human immunoglobulin light chain lambda and kappa. Additionally, molecule S18 without antiproliferative potency itself, showed significant inhibitory activity against growth factor IL‐6 induced RPMI‐8226 cell proliferation. Collectively, potent SIRT3 selective inhibitors with MM cell differentiation potency were developed for further discovery of anticancer drugs. [ABSTRACT FROM AUTHOR]

Selenoprotein glutathione peroxidase 4 (GPX4) serves as a crucial suppressor of oxidative stress-induced ferroptosis, making it an attractive target for disease therapy. Here, we discuss recent strategies and challenges associated with targeting GPX4 through covalent inhibitors, proteolysis targeting chimera (PROTAC) degraders, and cell-type-specific degraders in the context of cancer. [ABSTRACT FROM AUTHOR]

Intensively grazed dairy systems use high inputs of fertiliser nitrogen (N), and often supplementary irrigation, to ensure adequate pasture production to support milk output and meet the growing food demand. However, the efficiency of N use in these systems can be low and potential environmental impacts high. This study aimed to test the hypothesis that (1) use of two inhibitors, the urease inhibitor N-(n-butyl) thiophosphorictriamide (NBTPT) and the nitrification inhibitor 3,4-Dimethylpyrazole phosphate (DMPP) reduced N loss and improved pasture production compared to conventional N fertiliser (urea) in irrigated temperate perennial ryegrass (Lolium perenne L.) dairy pasture, and (2) their efficiency was affected by soil and environmental parameters. The effect of repeated applications of urea, at different rates, and the inhibitors were studied on pasture production and agronomic apparent fertiliser N use efficiency (NUE) over 2.5 years. The fate of a single application of N was determined through recovery of 15N-labeled fertiliser applied at 20 and 40 kg N ha−1 was studied in the field for one year. The highest yield and NUE occurred in spring–summer (from August to February) reflecting optimal growing conditions. The highest NUE occurred at low rates of urea application (20 and 40 kg N ha−1). Mineralisation played a key role in supplying N to pasture with 64–82% of total plant N derived from soil organic matter (SOM). Less than 50% of the applied N was recovered in the pasture (37–43%) with a large component retained in the soil (26–43% after one year, 0–40 cm), and slowly released in small amounts (< 2%) to the pasture over time, highlighting the abundant capacity of the native soil N pool to supply pasture N. Loss of N fertiliser (14–31%) was attributed to primarily ammonia (NH3) volatilisation and nitrate (NO3−) leaching. Use of the inhibitors NBTPT and DMPP did not significantly affect pasture yield or NUE, most likely because fertiliser N saved with the inhibitors only played a minor role in plant nutrition with the majority of the plant nutrition provided by the soil organic matter pool. [ABSTRACT FROM AUTHOR]

The increasing need for new treatments for obesity and diabetes has led to the development of new drugs and food supplements that could reduce carbohydrate absorption. Many starch blockers, based on common bean proteinaceous inhibitors against α-amylase (α-AI), are already present on the market. The extraction and purification of α-amylase inhibitor from a promising common bean cultivar from Sardinia (Nieddone) is described, highlighting the unique value of the Nieddone cultivar, particularly for its inhibitory activity on digestive enzymes and its complete lack of a hemagglutination effect on human red blood cells. The purification of α-AI involved two chromatographic steps (IEC and SEC) and was essential for revealing certain properties of the inhibitor. The purified inhibitor has a tetrameric structure (α2β2) and a molecular weight of approximately 42 kDa, as determined by SEC and SDS-PAGE, confirming it as a lectin-like inhibitor. The identification of the α-AI sequence was obtained by bottom-up high-resolution mass spectrometry, which allowed us to identify a unique peptide from the α chain and six unique peptides from the β chains. α-AI exhibited an optimum temperature of around 40 °C and two pH optima at 5 and 6.5, respectively. Its remarkable stability at high temperatures was measured (approximately 25% of activity retained even after 5 h at 100 °C), whereas the raw extract lost its activity entirely after just 10 min at 90 °C. Thus, the purification process significantly enhances the thermal stability of α-AI. The demonstrated effectiveness of the purified α-AI against the α-amylase enzyme in pigs, humans and insects underscores the protein's potential for treating obesity and diabetes, as well as for managing insect pests. [ABSTRACT FROM AUTHOR]

Inhibition of the proteolytic processing of hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP) is an attractive approach for the drug discovery of novel anticancer therapeutics which prevent tumor progression and metastasis. Here, we utilized an improved and expanded version of positional scanning of substrate combinatorial libraries (PS‐SCL) technique called HyCoSuL to optimize peptidomimetic inhibitors of the HGF/MSP activating serine proteases, HGFA, matriptase, and hepsin. These inhibitors have an electrophilic ketone serine trapping warhead and thus form a reversible covalent bond to the protease. We demonstrate that by varying the P2, P3, and P4 positions of the inhibitor with unnatural amino acids based on the protease substrate preferences learned from HyCoSuL, we can predictably modify the potency and selectivity of the inhibitor. We identified the tetrapeptide JH‐1144 (8) as a single digit nM inhibitor of HGFA, matriptase and hepsin with excellent selectivity over Factor Xa and thrombin. These unnatural peptides have increased metabolic stability relative to natural peptides of similar structure. The tripeptide inhibitor PK‐1‐89 (2) has excellent pharmacokinetics in mice with good compound exposure out to 24 h. In addition, we obtained an X‐ray structure of the inhibitor MM1132 (15) bound to matriptase revealing an interesting binding conformation useful for future inhibitor design. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease is a prevalent chronic metabolic condition, for which no approved medications are available. As a condiment and traditional Chinese medicine, ginger can be useful in reducing the symptoms of non-alcoholic fatty liver disease. Although its active ingredients and mechanisms of action are unknown, there is a lack of research on them. The purpose of this study is to prepare magnetite (Fe3O4)@Stearoyl-CoA desaturase 1 (SCD1) materials and analyze them using ultra-high performance liquid-chromatography-mass spectrometry (UPLC-MS) for rapid screening of potential inhibitors of SCD1 in ginger. Based on this analysis, it has been shown that the primary components in ginger that bind SCD1 directly are gingerols, with 10-gingerol having a greater affinity for binding to SCD1 than 8-gingerol and 6-gingerol. Moreover, further studies indicated that free fatty acids (FFA)-induced lipid accumulation is improved by this class of compounds in normal human hepatocytes (THLE-3), with 10-gingerol being the most effective compound. This study provides a new insight into the mechanism, by which ginger contributes to the improvement of non-alcoholic fatty liver disease (NAFLD) and provide support for the effective use of 10-gingerol for the treatment of NAFLD. [ABSTRACT FROM AUTHOR]

Zika Virus (ZIKV) is a positive-strand RNA virus that can lead to Guillain-Barré syndrome or encephalitis in some individuals and hence presents a serious public health risk. Since the first outbreak of ZIKV in Brazil in 2015, no effective clinical inhibitors have been developed, making the development of effective ZIKV drugs an urgent issue that needs to be addressed. ZIKV belongs to the Flaviviridae family, and its structure includes three structural proteins, namely, capsular (C), premembrane (prM), and envelope (E) proteins, as well as seven nonstructural proteins, namely, NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. To provide a reference for the development of future ZIKV drugs, this paper reviews the structure of the ZIKV based on recent literature reports, analyzes the potential therapeutic targets of various proteins, and proposes feasible drug design strategies. Additionally, this paper reviews and classifies the latest research progress on several protease inhibitors, such as E protein inhibitors, NS2BNS3 inhibitors, and NS5 inhibitors, so that researchers can quickly understand the current status of development and the interconnections among these inhibitors. [ABSTRACT FROM AUTHOR]

Lymphoma positions as the fifth most common cancer, in the world, reporting remarkable deaths every year. Several promising strategies to counter this disease recently include utilizing small molecules that specifically target the lymphoma cellular proteins to overwhelm its progression. FGFBP1 is a soluble intracellular protein that progresses cancer cell proliferation and is upregulated in several cancers. Therefore, inhibiting FGFBP1 could significantly slow down lymphoma progression through triggering apoptosis. Thus, in this study, a flavonoid B4, isolated from Cajanus cajan, has been investigated for its effects of B4 on lymphoma, specifically as an FGFBP1 inhibitor. B4 could selectively hinder the growth of lymphoma cells by inducing caspase-dependent intrinsic apoptosis through G1/S transition phase cell cycle arrest. RNA sequencing analysis revealed that B4 regulates the genes involved in B-cell proliferation and DNA replication by inhibiting FGFBP1 in vitro. B4 increases the survival rate of lymphoma mice. B4 also represses the growth of patient-derived primary lymphoma cells through FGFBP1 inhibition. Drug affinity responsive target stability experimentations authorize that B4 powerfully binds to FGFBP1. The overexpression of FGFBP1 raises the pharmacological sensitivity of B4, supplementing its specific action on lymphoma cells. This study pioneers the estimation of B4 as a possible anticancer agent for lymphoma treatment. These outcomes highlight its selective inhibitory effects on lymphoma cell growth by downregulating FGFBP1 expression through intrinsic apoptosis, causing mitochondrial and DNA damage, ultimately leading to the inhibition of lymphoma progression. These suggest B4 may be a novel FGFBP1 inhibitor for the lymphoma treatment. [ABSTRACT FROM AUTHOR]

The development of cancer therapeutics is often hindered by the fact that specific oncogenes cannot be directly pharmaceutically addressed. Targeting deubiquitylases that stabilize these oncogenes provides a promising alternative. USP28 and USP25 have been identified as such target deubiquitylases, and several small-molecule inhibitors indiscriminately inhibiting both enzymes have been developed. To obtain insights into their mode of inhibition, we structurally and functionally characterized USP28 in the presence of the three different inhibitors AZ1, Vismodegib and FT206. The compounds bind into a common pocket acting as a molecular sink. Our analysis provides an explanation why the two enzymes are inhibited with similar potency while other deubiquitylases are not affected. Furthermore, a key glutamate residue at position 366/373 in USP28/USP25 plays a central structural role for pocket stability and thereby for inhibition and activity. Obstructing the inhibitor-binding pocket by mutation of this glutamate may provide a tool to accelerate future drug development efforts for selective inhibitors of either USP28 or USP25 targeting distinct binding pockets. Synopsis: The inhibitors AZ1, VSM and FT206 bind USP28 and USP25 in the same conserved cleft which explains their bi-specificity. A glutamate only found in both homologs, plays a central role for inhibition through multiple mechanisms. AZ1, VSM and FT206 bind in an extended cleft between the thumb and palm subdomains. Inhibition is achieved by a common allosteric mechanism. The poorly conserved USP28 E366 and USP25 E373 residues impair catalytic activity and promote inhibitor binding. The inhibitors AZ1, VSM and FT206 bind USP28 and USP25 in the same conserved cleft which explains their bi-specificity. A glutamate only found in both homologs, plays a central role for inhibition through multiple mechanisms. [ABSTRACT FROM AUTHOR]

Erythrina sp. contains alkaloids and flavonoids, which are the primary bioactive compounds found in these species. These organisms are a rich source of secondary metabolites. Two known pterocapans in this study, eryvarin D (1) and eryvarin E (2), were successfully isolated from the root bark extract of Erythrina variegata. The isolated compounds were elucidated using 1D- and 2D-NMR spectroscopy. Among the two compounds, only compound 2 was evaluated for its inhibitory activity against eight receptor tyrosine kinases (EGFR, HER2, HER4, IGFR, InsR, KDR, PDGFRα, and PDGFRβ). Compound 2 exhibited weak insulin receptor inhibitory activity. Thus, compound 2 could be a lead compound as an anticancer drug targeting insulin receptors for future development. [ABSTRACT FROM AUTHOR]

The ribonuclease H (RNase H) active site of HIV-1 reverse transcriptase (RT) is the only viral enzyme not targeted by approved antiretroviral drugs. Using a fluorescence-based in vitro assay, we screened 65,239 compounds at a final concentration of 10 µM to identify inhibitors of RT RNase H activity. We identified 41 compounds that exhibited 50% inhibitory concentration (i.e., IC50) values < 1.0 µM. Two of these compounds, 2-(4-methyl-3-(piperidin-1-ylsulfonyl)phenyl)benzo[d]isothiazol-3(2H)-one (1) and ethyl 2-(2-(3-oxobenzo[d]isothiazol-2(3H)-yl)thiazol-4-yl)acetate (2), which both share the same benzisothiazolone pharmacophore, demonstrate robust antiviral activity (50% effective concentrations of 1.68 ± 0.94 µM and 2.68 ± 0.54, respectively) in the absence of cellular toxicity. A limited structure–activity relationship analysis identified two additional benzisothiazolone analogs, 2-methylbenzo[d]isothiazol-3(2H)-one (3) and N,N-diethyl-3-(3-oxobenzo[d]isothiazol-2(3H)-yl)benzenesulfonamide (4), which also resulted in the inhibition of RT RNase H activity and virus replication. Compounds 1, 2 and 4, but not 3, inhibited the DNA polymerase activity of RT (IC50 values~1 to 6 µM). In conclusion, benzisothiazolone derivatives represent a new class of multifunctional RT inhibitors that warrants further assessment for the treatment of HIV-1 infection. [ABSTRACT FROM AUTHOR]

Eukaryotic elongation factor 2 kinase (eEF2K) is a Ca2+/CAM-dependent protein kinase, which inhibits the activity of substrate eEF2 by phosphorylating eEF2 to prevent protein synthesis, promote tumor cell proliferation, invasion, metastasis and to regulate tumor microenvironment. The eFF2K is "α-kinase" member of the atypical protein kinase family and has little sequence homology with typical protein kinases. Targeting eEF2K can avoid the toxic side effects caused by most kinases, so it is considered as a potential molecular target for tumor targeted therapy. [ABSTRACT FROM AUTHOR]

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is pivotal in immunotherapy. Several agonists and inhibitors of the cGAS-STING pathway have been developed and evaluated for the treatment of various diseases. The agonists aim to activate STING, with cyclic dinucleotides (CDNs) being the most common, while the inhibitors aim to block the enzymatic activity or DNA binding ability of cGAS. Meanwhile, non-CDN compounds and cGAS agonists are also gaining attention. The omnipresence of the cGAS-STING pathway in vivo indicates that its overactivation could lead to undesired inflammatory responses and autoimmune diseases, which underscores the necessity of developing both agonists and inhibitors of the cGAS-STING pathway. This review describes the molecular traits and roles of the cGAS-STING pathway and summarizes the development of cGAS-STING agonists and inhibitors. The information is supposed to be conducive to the design of novel drugs for targeting the cGAS-STING pathway [ABSTRACT FROM AUTHOR]

Tuberculosis is a serious public health problem worldwide. The search for new antibiotics has become a priority, especially with the emergence of resistant strains. A new family of imidazoquinoline derivatives, structurally analogous to triazolophthalazines, which had previously shown good antituberculosis activity, were designed to inhibit InhA, an essential enzyme for Mycobacterium tuberculosis survival. Over twenty molecules were synthesized and the results showed modest inhibitory efficacy against the protein. Docking experiments were carried out to show how these molecules could interact with the protein’s substrate binding site. Disappointingly, unlike triazolophthlazines, these imidazoquinoline derivatives showed an absence of inhibition on mycobacterial growth. [ABSTRACT FROM AUTHOR]

A small library of 79 substituted phenylsulfonamidoalkyl sulfamates, 1b–79b, was synthesized starting from arylsulfonyl chlorides and amino alcohols with different numbers of methylene groups between the hydroxyl and amino moieties yielding intermediates 1a–79a, followed by the reaction of the latter with sulfamoyl chloride. All compounds were screened for their inhibitory activity on bovine carbonic anhydrase II. Compounds 1a–79a showed no inhibition of the enzyme, in contrast to sulfamates 1b–79b. Thus, the inhibitory potential of compounds 1b–79b towards this enzyme depends on the substituent and the substitution pattern of the phenyl group as well as the length of the spacer. Bulkier substituents in the para position proved to be better for inhibiting CAII than compounds with the same substituent in the meta or ortho position. For many substitution patterns, compounds with shorter spacer lengths were superior to those with long chain spacers. Compounds with shorter spacer lengths performed better than those with longer chain spacers for a variety of substitution patterns. The most active compound held inhibition constant as low as Ki= 0.67 µM (for 49b) and a tert-butyl substituent in para position and acted as a competitive inhibitor of the enzyme. [ABSTRACT FROM AUTHOR]

Pterygium is a frequent eye surface condition that is characterized by a high rate of proliferation, fibrovascular development, cellular migration, corneal infiltration, and angiogenesis. We investigated that ex vivo primary pterygium and conjunctival cell cultures were generated to analyze the effect of trehalose on cellular proliferation. After trehalose treatment, we performed microarray analysis to evaluate changes in the mRNA profile. We analyzed gene ontology (GO) and KEGG pathways to identify hub genes that changed expression levels after treatment and were associated with pterygium development. We selected three genes to verify their expression levels using qRT–PCR. The study also evaluated the impact of trehalose treatment on cell migration through a wound‐healing assay. Our results suggested that pterygium cell proliferation was inhibited in a dose‐dependent manner by trehalose. 2354 DEG were identified in pterygium and conjunctiva cells treated with trehalose compared to untreated groups. Functional enrichment analysis showed that differentially expressed mRNAs are involved in proliferation, vasculature development, and cell migration. We identified ten hub genes including upregulated (RANBP3L, SLC5A3, RERG, ANKRD1, DHCR7, RAB27B, GPRC5B, MSMO1, ASPN, DRAM1) and downregulated (TNC, PTGS2, GREM2, NPTX1, NR4A1, HMOX1, CXCL12, IL6, MYH2, TXNIP). Microarray analysis and functional investigations suggest that trehalose affects the pathogenesis of pterygium by modifying the expression of genes involved in crucial pathways related to cell function. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to investigate the corrosion behavior of cold-rolled Fe35Ni20Cr12Mn(28-x)Alx high-entropy alloys (HEAs) using the potentiodynamic polarization technique in 1 M H2SO4 acid. Additionally, the influence of molybdenum (Mo) additions as inhibitors and the effect of variations in cold rolling reduction ratios and Al content on corrosion behavior are examined. Design/methodology/approach: Two cold rolling reduction ratios, namely, 50% (R50) and 90% (R90), were examined for the cold-rolled Fe35Ni20Cr12Mn28Al5 (Al5) and Fe35Ni20Cr12Mn23Al10 (Al10) HEAs. Mo inhibitor additions were introduced at varying concentrations of 0.3, 0.6 and 0.9 Wt.%. The potentiodynamic polarization technique was used to evaluate the corrosion rates (CRs) under different experimental conditions. Findings: The results indicate that the addition of 0.3 Wt.% Mo in 1 M H2SO4 yielded the lowest CR for both R50 and R90, irrespective of the Al content in the HEAs. However, the highest CR was observed at 0.6 Wt.% Mo addition. Furthermore, increasing the concentration of Al resulted in a corresponding rise in the CR. Comparatively, the CR decreased significantly when the cold rolling reduction ratio increased from R50 to R90. Originality/value: This research provides valuable insights into the intricate relationship between Mo inhibitors, cold rolling reduction ratio, Al content and the resulting corrosion behavior of Fe35Ni20Cr12Mn(28-x)Alx HEAs. The comprehensive analysis of corroded HEAs, including surface morphology, compositions and elemental distribution mapping, contributes to the understanding of the corrosion mechanisms and offers potential strategies for enhancing the corrosion behavior of HEAs. [ABSTRACT FROM AUTHOR]

Ductile iron (DI) samples were immersed in near-neutral, alkaline sodium hydroxide (NaOH), and sodium chloride (NaCl) environments for 180 days. The influence of microstructure on the corrosion resistance of three DI specimens was investigated. Microstructures, electrochemical measurements, and the characterization of the corroded surfaces were analyzed. The experimental results from this study were used to validate a model generated from hybrid adaptive neuro-fuzzy inferences system-particle swarm optimization (ANFIS-PSO) algorithms. The hybrid ANFIS-PSO modelling technique was improvised for a detailed evaluation of corrosion rate of ductile cast iron materials in different environments. The integrated hybrid ANFIS-PSO model revealed a sharp rise in localized corrosion caused by chloride-induced structural deterioration at the nanoscale for some of the grains. The performance results revealed that the fuzzy c-mean (FCM) clustering outperformed other clustering approach in the neuro-fuzzy model. Accuracy values of 92.9% and 93.7% were recorded for the training phase of ANFIS-FCM and ANFIS-PSO-FCM respectively for corrosion rates. The percentage error of the ANFIS-PSO predictions is significantly lower than the ANFIS-standalone prediction. This shows that the ANFIS-PSO with FCM approach is a better model for predicting corrosion rates. This will contribute to the body of knowledge for ductile iron, corrosion, and corrosion modelling using machine learning. [ABSTRACT FROM AUTHOR]

Context: Breast cancer stem cells (BCSCs) are a small subset of cells within breast tumors with characteristics similar to normal stem cells. Despite advancements in chemotherapy and targeted therapy for breast cancer, the prognosis for breast cancer patients has remained poor due to drug resistance, reoccurrence, and metastasis. Growing evidence suggests that deregulation of the self-renewal pathways, like the Wnt signaling pathway mediated by β-catenin, plays a crucial role in the survival of breast cancer stem cells. Targeting the Wnt signaling pathway in breast cancer stem cells offers a promising avenue for developing effective therapeutic strategies targeting these cells, potentially leading to improved patient outcomes and reduced tumor recurrence. Methods: For this purpose, we have screened a 1615 FDA-approved drug library against our target protein, β-catenin, which is involved in the Wnt signaling pathway using molecular docking analysis, molecular dynamics (MD) simulations, and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations. Results: Molecular docking studies showed that the Lumacaftor- β-catenin complex had the lowest docking score of − 8.7 kcal/mol towards β-catenin protein than the reference inhibitor. Molecular dynamic simulations and MM/PBSA calculations were also performed for the Lumacaftor-β-catenin complex to establish the stability of the interactions involved. Considering its promising attributes and encouraging results, Lumacaftor holds significant potential as a novel therapeutic option to target BCSCs. This study opens avenues for further investigation and may pave the way for developing therapeutic potential in breast cancer treatment. Further confirmation is warranted through in vitro and clinical studies to validate the findings of this study. [ABSTRACT FROM AUTHOR]

A novel series of imidazole appended quinoline derivatives (6a–j) have been synthesized using the one-pot three-component reaction that occurred between the starting materials of substituted 2-phenoxyquinolin-3-carbaldehydes (3a-j), benzil (4), and ammonium acetate (5) by taking equimolar ratio. The newly synthesized imidazole-appended quinolines were subjected to probable inhibition against the anti-diabetic drug target maltase enzyme. The efficacy was tested using in-silico molecular docking analysis and molecular dynamics simulation. The studies revealed that the test 6f ligand (3-(4,5-diphenyl-1H-imidazol-2-yl)-2-phenoxy quinoline) is a strong inhibitor of the target protein maltase when compared with the known inhibitor acarbose and sheds new light on the medicinal chemistry research for the application of the synthesized 6f ligand in the pharmaceutical industry. [ABSTRACT FROM AUTHOR]

Inhibition of Angiotensin-converting enzyme I (ACE I) is a modern therapeutic approach to treatment of hypertension. In recent years, research into natural ACE peptide inhibitors without side effects has become important. The aim of this study is to isolate and characterize novel bioactive peptides from skim and/or whole cow's milk fermented with selected lactobacillus strains. Several homo/heterofermentative strains of the Lactobacillus species of dairy origin have been pre-selected and different milk fermented samples have been studied. A protocol for analyses was designed and the milk proteins were separated by centrifugation at 4°C at 10000 × g, with molecular mass cut off (MWCO) membranes of 3 and 10 kDa. The samples with molecular mass below 3 kDa were further separated by ultrafiltration by dialysis cell (cut off membrane 1 kDa) by continuous stirring at room temperature. The milk fractions under 1 kDa molecular mass were characterized by UPLC-MS. The ACE-inhibitory activity was determined using the FAPGG (N-[3-(2-Furyl) acryloyl]-L-phenylalanyl-glycyl-glycine) degradation method. All tested samples (1 kDa) exhibit ACE I inhibitory activity with IC50 in a range of 6 - 37 mg mL-1. In silico logP prediction of selected peptides was used to assess whether lipophilicity of the compounds falls within the so-called "therapeutically relevant pharmacokinetic space". [ABSTRACT FROM AUTHOR]

COVID-19 can cause neurological symptoms such as fever, dizziness, and nausea. However, such neurological symptoms of SARS-CoV-2 infection have been hardly assessed in mouse models. In this study, we infected two commonly used wild-type mouse lines (C57BL/6J and 129/SvEv) and a 129S calcitonin gene-related peptide (αCGRP) null-line with mouse-adapted SARS-CoV-2 and demonstrated neurological signs including fever, dizziness, and nausea. We then evaluated whether a CGRP receptor antagonist, olcegepant, a “gepant” antagonist used in migraine treatment, could mitigate acute neuroinflammatory and neurological signs of SARS-COV-2 infection. First, we determined whether CGRP receptor antagonism provided protection from permanent weight loss in older (>18 m) C57BL/6J and 129/SvEv mice. We also observed acute fever, dizziness, and nausea in all older mice, regardless of treatment. In both wild-type mouse lines, CGRP antagonism reduced acute interleukin 6 (IL-6) levels with virtually no IL-6 release in mice lacking αCGRP. These findings suggest that migraine inhibitors such as those blocking CGRP receptor signaling protect against acute IL-6 release and subsequent inflammatory events after SARS-CoV-2 infection, which may have repercussions for related pandemic or endemic coronavirus outbreaks. IMPORTANCE Coronavirus disease (COVID-19) can cause neurological symptoms such as fever, headache, dizziness, and nausea. However, such neurological symptoms of severe acute respiratory syndrome CoV-2 (SARS-CoV-2) infection have been hardly assessed in mouse models. In this study, we first infected two commonly used wild-type mouse lines (C57BL/6J and 129S) with mouse-adapted SARS-CoV-2 and demonstrated neurological symptoms including fever and nausea. Furthermore, we showed that the migraine treatment drug olcegepant could reduce long-term weight loss and IL-6 release associated with SARS-CoV-2 infection. These findings suggest that a migraine blocker can be protective for at least some acute SARS-CoV-2 infection signs and raise the possibility that it may also impact long-term outcomes. [ABSTRACT FROM AUTHOR]

In this paper, the inhibition effects of Ar/He/N2 on the H2-O2 system near the extended second explosion limit were investigated by ReaxFF simulations. It was found that all three inert gases can inhibit the reactions, delaying the initiation reaction, and prolonging ignition delay since the generation and consumption of free radicals such as HO2 and OH were suppressed. Further, the inhibitory effect has the correlation of Ar > He > N2. The inhibitory effect of Ar is more pronounced compared to He due to the bigger effective radius and physical mass. Moreover, the addition of N2 introduced extra initiation reaction (H2 + N2 → NNH + H) and generated additional intermediate products such as NNH and N2OH, which result in the weakest inhibitory effect. Compared to diatomic inhibitors (e.g., N2), the monatomic inhibitors such as Ar and He exhibit stronger inhibitory effects on the hydroxide reaction under high pressure. [ABSTRACT FROM AUTHOR]

The Gag‐Pol polyprotein in human immunodeficiency virus type I (HIV‐1) encodes enzymes that are essential for virus replication: protease (PR), reverse transcriptase (RT), and integrase (IN). The mature forms of PR, RT and IN are homodimer, heterodimer and tetramer, respectively. The precise mechanism underlying the formation of dimer or tetramer is not yet understood. Here, to gain insight into the dimerization of PR and RT in the precursor, we prepared a model precursor, PR‐RT, incorporating an inactivating mutation at the PR active site, D25A, and including two residues in the p6* region, fused to a SUMO‐tag, at the N‐terminus of the PR region. We also prepared two mutants of PR‐RT containing a dimer dissociation mutation either in the PR region, PR(T26A)‐RT, or in the RT region, PR‐RT(W401A). Size exclusion chromatography showed both monomer and dimer fractions in PR‐RT and PR(T26A)‐RT, but only monomer in PR‐RT(W401A). SEC experiments of PR‐RT in the presence of protease inhibitor, darunavir, significantly enhanced the dimerization. Additionally, SEC results suggest an estimated PR‐RT dimer dissociation constant that is higher than that of the mature RT heterodimer, p66/p51, but slightly lower than the premature RT homodimer, p66/p66. Reverse transcriptase assays and RT maturation assays were performed as tools to assess the effects of the PR dimer‐interface on these functions. Our results consistently indicate that the RT dimer‐interface plays a crucial role in the dimerization in PR‐RT, whereas the PR dimer‐interface has a lesser role. [ABSTRACT FROM AUTHOR]

In order to solve the enzymatic browning phenomenon in the pulping unit of Lonicera caerulea fruits and improve its utilization value. The main phenolic substrates involved in the enzymatic browning reaction in the pulping process of Lonicera caerulea fruits and the inhibition ability were investigated, and the interactions between phenolic substrates and epicatechin on the reaction of polyphenol oxidase (PPO) were analyzed and its mechanism of enzymatic browning was also determined. The three most effective inhibitors were further selected by comparing the effects of ascorbic acid, L-cysteine, calcium chloride, EDTA-2Na, and citric acid additions on the browning inhibition rate. The results showed that epicatechin was the primary influencing factor involved in enzymatic browning in the pulping process of Lonicera caerulea fruits, and the quenching mechanism of epicatechin on PPO was static quenching. The response surface optimization test determined the optimal combination of composite inhibitors as 0.11% ascorbic acid, 0.11% L-cysteine, and 0.08% EDTA-2Na, and the browning inhibition rate of Lonicera caerulea fruits juice under this condition was 93.17%. It indicates that the above composite inhibitors can inhibit the enzymatic browning in the pulping process of Lonicera caerulea fruits. [ABSTRACT FROM AUTHOR]

Honokiol, a naturally occurring compound from Magnolia obovata Thunb., has many biological activities, but its anti-a-glucosidase activity is still unclear. Therefore, we determined its inhibitory effects against a-glucosidase. Activity assays showed that honokiol was a reversible mixed-type inhibitor of α-glucosidase, and its IC50 value was 317.11 ± 12.86 µM. Fluorescence results indicated that the binding of honokiol to α-glucosidase caused a reduction in α-glucosidase activity. 3D fluorescence and CD spectra results indicated that the binding of honokiol to α-glucosidase caused conformational change in α-glucosidase. Docking simulated the detailed interactions between honokiol and α-glucosidase, including hydrogen and hydrophobic bonds. All findings showed that honokiol could be used as a natural inhibitor to develop α-glucosidase agents. [ABSTRACT FROM AUTHOR]

Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment of B‐cell malignancies. They target BTK, a key effector in the B‐cell receptor (BCR) signaling pathway, crucial for B‐cell survival and proliferation. The first‐in‐class irreversible BTK inhibitor, ibrutinib, was approved for various B‐cell malignancies but has limitations due to off‐target effects. Second‐generation inhibitors, such as acalabrutinib and zanubrutinib, offer improved selectivity and reduced side effects. However, resistance to BTK inhibitors, driven by BTK mutations, remains a challenge. Combinatorial therapies with PI3K inhibitors, immune checkpoint inhibitors, BH3 mimetics, and anti‐CD20 antibodies show promise in overcoming resistance. Noncovalent BTK inhibitors and proteolysis‐targeting chimeras (PROTACs) are emerging strategies with potential to combat resistance. Overall, advancements in BTK‐targeted therapies provide hope for improved outcomes in patients with B‐cell malignancies and a promising avenue to address drug resistance. Further research is needed to optimize combination therapies and identify optimal treatment regimens. [ABSTRACT FROM AUTHOR]

Simple Summary: Mycotoxins pose a serious threat to human and animal health by causing acute poisoning and chronic effects. However, the toxicological mechanism of mycotoxins is complicated and unclear. Recent reports have revealed that activation of the nucleotide-binding, oligomerization domain (NOD)-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is linked with the tissue damage and inflammation induced by mycotoxin exposure. Through a comprehensive literature review, this study illuminates the dysregulated expression of NLRP3 inflammasome responses to mycotoxin exposure. This study not only advances our knowledge of the role of the NLRP3 inflammasome in mycotoxin exposure but also offers valuable insights for future studies of novel anti-inflammatory agents used in cases of mycotoxin exposure. Mycotoxins are secondary metabolites produced by several fungi and moulds that exert toxicological effects on animals including immunotoxicity, genotoxicity, hepatotoxicity, teratogenicity, and neurotoxicity. However, the toxicological mechanisms of mycotoxins are complex and unclear. The nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasome is a multimeric cytosolic protein complex composed of the NLRP3 sensor, ASC adapter protein, and caspase-1 effector. Activation of the NLRP3 inflammasome plays a crucial role in innate immune defence and homeostatic maintenance. Recent studies have revealed that NLRP3 inflammasome activation is linked to tissue damage and inflammation induced by mycotoxin exposure. Thus, this review summarises the latest advancements in research on the roles of NLRP3 inflammasome activation in the pathogenesis of mycotoxin exposure. The effects of exposure to multiple mycotoxins, including deoxynivalenol, aflatoxin B1, zearalenone, T-2 toxin, ochratoxin A, and fumonisim B1, on pyroptosis-related factors and inflammation-related factors in vitro and in vivo and the pharmacological inhibition of specific and nonspecific NLRP3 inhibitors are summarized and examined. This comprehensive review contributes to a better understanding of the role of the NLRP3 inflammasome in toxicity induced by mycotoxin exposure and provides novel insights for pharmacologically targeting NLRP3 as a novel anti-inflammatory agent against mycotoxin exposure. [ABSTRACT FROM AUTHOR]

Acetylcholinesterase (AChE) is indispensable for neurotransmission, while glutathione S-transferase (GST) plays a crucial role in cellular detoxification and protection. These enzymes are pivotal subjects in scientific investigations aimed at understanding neurological functions and maintaining cellular equilibrium. In pursuit of this objective, a set of disulfide–triazine hybrids (1, 2, and 3a–h) was effectively synthesized and methodically examined for their capacity to inhibit both AChE and GST (the Ki values for AChE range from 0.893 ± 0.117 μM to 7.961 ± 0.421 μM, while the IC50 values fall within the range of 1.919–6.243 μM. For GST, the Ki values span from 2.093 ± 0.276 μM to 8.840 ± 1.934 μM, with IC50 values ranging from 2.152 to 4.747 μM). After synthesizing the compounds and studying their biological effects, molecular docking analyses were conducted to understand how these compounds interact with target enzymes. This helped identify how the compounds bind and which amino acid residues are crucial for inhibition. The positive results highlight the potential of disulfide–triazine hybrids as strong inhibitors of AChE and GST, suggesting they could be further developed and optimized as therapeutic agents. [ABSTRACT FROM AUTHOR]

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The introduction of new regulations needs to develop eco-friendly systems to prevent corrosion. In this work, a natural corrosion inhibitor caffeine (CAF) was encapsulated in polysaccharide-based nanoparticles, capable of the responsive release of CAF during corrosion. The nanoparticles were prepared using electrostatic complexation between two natural polysaccharides which are oppositely charged—chitosan (CHI) and sodium alginate (ALG), crosslinked by tripolyphosphate (TPP). The particle size distribution and zeta potential were evaluated using dynamic light scattering and laser Doppler velocimetry. The encapsulation efficiency and release of CAF from nanocontainers was evaluated with UV-spectroscopy. The nanoparticles were incorporated via electrodeposition into the zinc coating on low-carbon steel to ensure self-healing. Cyclic voltammetry demonstrated the cathodic and anodic processes in the starting electrolytes. Surface hydrophobicity was investigated by water contact angle (WCA). The corrosion resistance of the coatings was estimated with polarization resistance (Rp) measurements and potentiodynamic polarization (PDP) curves. The study of the chemical composition of the coatings was carried out with X-ray photoelectron spectroscopy. The data obtained confirm the indisputable influence of the nanoparticles/nanocontainers on the protective feature of the hybrids—the latter have about twice-higher Rp values compared to the ordinary zinc. [ABSTRACT FROM AUTHOR]

Multifunctional anti-corrosive coatings are a key focus in the development of modern coatings. In this study, the corrosion inhibitor benzotriazole (BTA) was loaded onto fumed silica (SiP) through physical adsorption, and then the surface of SiP was modified with octadecyl trimethylsilane (OTMS) to create a modified fumed silica supported by BTA (BTA-SiP@OTMS). The resulting sample was blended with epoxy resin to create a composite coating with both anti-corrosive and hydrophobic properties. The OTMS modification effectively covers the surface of the fumed silica, transforming the composite coating from hydrophilic to hydrophobic. This hydrophobicity prevents the penetration of corrosive mediums. The addition of BTA-SiP@OTMS significantly increases the impedance value of the composite coating, indicating improved corrosion resistance. Due to its hydrophobic and anti-corrosion properties, the composite coating shows promising potential in weather-resistant coatings. [ABSTRACT FROM AUTHOR]