Site Of Action Research Articles

Control of giant ragweed (Ambrosia trifida) in mesotrione-resistant soybean

Abstract Preemergence applications of mesotrione, an herbicide that inhibits 4-hydroxyphenolpyruvate dioxygenase (HPPD), have recently gained regulatory approval in soybean varieties with appropriate traits. Giant ragweed is an extremely competitive broadleaf weed, and biotypes resistant to acetolactate synthase inhibitors (ALS-R) can be particularly difficult to manage with soil-residual herbicides in soybean production. This study investigated control of giant ragweed from preemergence applications of cloransulam (32 g ai ha–1), metribuzin (315 g ai ha–1), and S-metolachlor (1,600 g ai ha–1) in a factorial design with and without mesotrione (177 g ai ha–1) at two different sites over 2 yr. Treatments with mesotrione were also compared with two commercial premix products: sulfentrazone (283 g ai ha–1) and cloransulam (37 g ai ha–1), and chlorimuron (19 g ai ha–1), flumioxazin (69 g ai ha–1), and pyroxasulfone (87 g ai ha–1). At 42 d after planting, control and biomass reduction of giant ragweed were greater in treatments with mesotrione than any treatment without mesotrione. Giant ragweed biomass was reduced by 84% in treatments with mesotrione, whereas treatments without mesotrione did not reduce biomass relative to the nontreated. Following these preemergence applications, sequential herbicide treatments utilizing postemergence applications of glufosinate (655 g ai ha–1) plus fomesafen (266 g ai ha–1) and S-metolachlor (1,217 g ai ha–1) resulted in at least 97% control of giant ragweed at 42 d after planting, which was greater than sequential applications of glufosinate alone in 3 of 4 site-years. Preemergence applications of mesotrione can be an impactful addition to soybean herbicide programs designed to manage giant ragweed, with the potential to improve weed control and delay the onset of herbicide resistance by providing an additional effective herbicide site of action.

Prodrugs as empowering tools in drug discovery and development: recent strategic applications of drug delivery solutions to mitigate challenges associated with lead compounds and drug candidates.

The delivery of a drug to a specific organ or tissue at an efficacious concentration is the pharmacokinetic (PK) hallmark of promoting effective pharmacological action at a target site with an acceptable safety profile. Sub-optimal pharmaceutical or ADME profiles of drug candidates, which can often be a function of inherently poor physicochemical properties, pose significant challenges to drug discovery and development teams and may contribute to high compound attrition rates. Medicinal chemists have exploited prodrugs as an informed strategy to productively enhance the profiles of new chemical entities by optimizing the physicochemical, biopharmaceutical, and pharmacokinetic properties as well as selectively delivering a molecule to the site of action as a means of addressing a range of limitations. While discovery scientists have traditionally employed prodrugs to improve solubility and membrane permeability, the growing sophistication of prodrug technologies has enabled a significant expansion of their scope and applications as an empowering tool to mitigate a broad range of drug delivery challenges. Prodrugs have emerged as successful solutions to resolve non-linear exposure, inadequate exposure to support toxicological studies, pH-dependent absorption, high pill burden, formulation challenges, lack of feasibility of developing solid and liquid dosage forms, first-pass metabolism, high dosing frequency translating to reduced patient compliance and poor site-specific drug delivery. During the period 2012-2022, the US Food and Drug Administration (FDA) approved 50 prodrugs, which amounts to 13% of approved small molecule drugs, reflecting both the importance and success of implementing prodrug approaches in the pursuit of developing safe and effective drugs to address unmet medical needs.

Nanotherapeutics for the delivery of antifungal drugs.

The treatment of fungal infections is challenging with high death rates reported among immunocompromised patients. The currently available antifungals suffer from poor bioavailability and solubility, pharmacokinetics, and drug resistance, with limited cellular uptake. The clinical pipeline of new antifungals is dry. The incorporation of antifungal drugs into polymer-based nanocarriers to form nanotherapeutics is a promising approach to enhance the therapeutic outcomes of the available antifungal drugs. This review summarizes different polymer-based nanotherapeutics strategies that have been explored for the delivery of antifungals, resulting in enhanced therapeutic outcomes, such as improved pharmacokinetics, targeted/sustained delivery, prolonged drug circulation, retention of the drugs at the localized site of action, and overcoming drug resistance when compared with the free antifungal drugs.

Review on novel targeted enzyme drug delivery systems: enzymosomes.

The goal of this review is to present enzymosomes as an innovative means for site-specific drug delivery. Enzymosomes make use of an enzyme's special characteristics, such as its capacity to accelerate the reaction rate and bind to a particular substrate at a regulated rate. Enzymosomes are created when an enzyme forms a covalent linkage with a liposome or lipid vesicle surface. To construct enzymosomes with specialized activities, enzymes are linked using acylation, direct conjugation, physical adsorption, and encapsulation techniques. By reducing the negative side effects of earlier treatment techniques and exhibiting efficient medication release, these cutting-edge drug delivery systems improve long-term sickness treatments. They could be a good substitute for antiplatelet medication, gout treatment, and other traditional medicines. Recently developed supramolecular vesicular delivery systems called enzymosomes have the potential to improve drug targeting, physicochemical characteristics, and ultimately bioavailability in the pharmaceutical industry. Enzymosomes have advantages over narrow-therapeutic index pharmaceuticals as focusing on their site of action enhances both their pharmacodynamic and pharmacokinetic profiles. Additionally, it reduces changes in normal enzymatic activity, which enhances the half-life of an enzyme and accomplishes enzyme activity on specific locations.

Advances in Gold Nanoparticles: Synthesis, Functionalization Strategies, and Theranostic Applications in Cancer.

Cancer is among the leading causes of mortality and morbidity in the world. Metallic nanoparticles, especially gold nanoparticles (AuNPs) have emerged to be attractive systems to circumvent the associated adverse effects. By the virtue of their unique properties of tunable size, shape, composition, optical properties, biocompatibility, minimal toxicity, multivalency, fluorescence-luminescence property and surface plasmon resonance; AuNPs have the potential to be used as drug delivery systems. It is vital to ensure that the drug reaches the target site of action for selective kill of cancer cells without harm to healthy cells. These AuNPs can be easily functionalized with a wide array of ligands like peptides, oligonucleotides, polymers, carbohydrates for active targeting to ensure site specific delivery and reduced systemic effects. AuNPs have been in-vestigated as carriers for gene delivery, drug delivery with or without photothermal therapy, in diagnosis based on radiation or spectroscopy. They have emerged as attractive theranostic approach in the overall management of cancer with superior benefit to risk features. In this review, we have discussed synthesis of different AuNPs (nanorods, spherical nanoparticles, and hollow AuNPs), their functionalization strategies and their applications in biomedical domain. Various research studies and clinical trials on application of AuNPs in diagnosis and therapeutics are highlighted.

Cholesterol modulation of interactions between psychostimulants and dopamine transporters.

The dopamine transporter (DAT) is a key site of action for cocaine and amphetamines. Dysfunctional DAT is associated with aberrant synaptic dopamine transmission and enhanced drug-seeking and taking behavior. Studies in cultured cells and ex vivo suggest that DAT function is sensitive to membrane cholesterol content. Although it is largely unknown whether psychostimulants alter cholesterol metabolism in the brain, emerging evidence indicates that peripheral cholesterol metabolism is altered in patients with psychostimulant use disorder and circulating cholesterol levels are associated with vulnerability to relapse. Cholesterol interacts with sphingolipids forming lipid raft microdomains on the membrane. These cholesterol-rich lipid raft microdomains serve to recruit and assemble other lipids and proteins to initiate signal transduction. There are two spatially and functionally distinct populations of the DAT segregated by cholesterol-rich lipid raft microdomains and cholesterol-scarce non-raft microdomains on the plasma membrane. These two DAT populations are differentially regulated by DAT blockers (e.g. cocaine), substrates (e.g. amphetamine), and protein kinase C providing distinct cholesterol-dependent modulation of dopamine uptake and efflux. In this chapter, we summarize the impact of depletion and addition of membrane cholesterol on DAT conformational changes between the outward-facing and the inward-facing states, lipid raft-associated DAT localization, basal and induced DAT internalization, and DAT function. In particular, we focus on how the interactions of the DAT with cocaine and amphetamine are influenced by membrane cholesterol. Lastly, we discuss the therapeutic potential of cholesterol-modifying drugs as a new avenue to normalize DAT function and dopamine transmission in patients with psychostimulant use disorder.

Nanotechnology for Novel Drug Delivery: A Systematic Review of Classification, Preparation, Characterization, and Applications of Nanoparticles in Drug Delivery

ABSTRACT: The goal of nanotechnology is to develop new nanoscale components by designing, fabricating, and using materials that are atomically, molecularly, and macromolecular organized. For several decades, there has been an abundance of scientific curiosity in the administration of medicines using particle delivery systems as carriers for small and big molecules. Particulate systems, such as nanoparticles, have been utilized as a physical method to modify and improve the pharmacokinetic and pharmacodynamics aspects of numerous pharmaceutical molecules. A typical nanoparticle is between 1 and 100 nm in size and has one or more dimensions. Nanoparticles are usually categorized as inorganic, organic, or carbon-based particles according to their superior characteristics in comparison to larger sizes of the corresponding materials. They have been utilized in vivo to protect the drug entity in the systemic circulation, limiting drug distribution to the targeted areas, and to transport the drug at a controlled and sustained rate to its site of action. The most innovative and promising medication delivery technique at the moment is nanoparticle technology. This methodical research examines the categorization, characteristics, techniques, characterizations, and applications of nanoparticles in the delivery of drug molecules.

Pulsatile Drug Delivery System: A Review

Abstract: The pulsatile drug delivery system has carried off a lot of importance in drug delivery technology in the last 30 years the aim of the present work was to formulate and evaluate an oral pulsatile drug delivery system to achieve time release of melonixcam, based on chronopharmaceutical approach for the treatment of anti-inflammatory agent. Thus drug can be delivered at righttime, in right amount and at right site of action by use of such approach. A pulse must be planned sothat a complete and rapid medication release is accomplished after the lag time. Holds good promises and provides benefit to the patients suffering from chronic problems like arthritis, asthma, hypertension etc.

STITCHING POLITICS AND IDENTITY ON TIKTOK

Though a relative newcomer among social media platforms, social video-sharing platform TikTok is one of the largest social media platforms in the world, boasting over one billion monthly active users, which it garnered in just five years (Dellatto, 2021). While much of the early attention to the platform focused on more frivolous elements, such as its dances and challenges, the political weight of TikTok has become ever clearer. In the 2020 US election, Donald Trump’s plan to fill the 19,000-seat BOK Center in Tulsa was stymied by young activists who reserved tickets with no intention of attending, organized largely on TikTok (Bandy & Diakopoulos, 2020). In the years since, political discourse on TikTok has continued to emerge from everyday users and political campaigns alike (see Newman, 2022), even as TikTok itself has become an object of political contention: calls for banning the app in the United States–citing security concerns influenced by xenophobia, given the app’s Chinese ownership–began in the Trump presidency (Allyn, 2020) and have recently culminated in state- and federal-level bans on the app for government-owned devices in the U.S. (Berman, 2023). While some studies have navigated limited data access and the platform’s relative infancy to offer an examination of political TikTok (see Literat & Kligler-Vilenchik, 2019; Medina Serrano et al., 2020; Vijay & Gekker, 2021; Guinaudeau et al., 2022), there remains a significant need for more analysis and theorization of how TikTok can become both a site for political discourse and a feature caught up within political mobilization. This panel seeks to bring together emerging work that deals with political participation on TikTok, in order to share current wisdom and forge future research directions. The presented works specifically focus on the relationship between political participation on TikTok and political identity for three primary reasons. First, as a video-based and thus embodied platform (Raun, 2012), creator identity is more prominent and easily perceptible in the visual and auditory elements of TikTok videos than in the primarily text-based posts on platforms like Twitter and Facebook. Second, TikTok relies more heavily on its recommendation algorithm for content distribution than its competitors traditionally have (Kaye et al., 2022; Cotter et al., 2022; Zeng & Kaye, 2022; Zhang & Liu, 2021), leading to the creation of “refracted publics” (Abidin, 2021) or Gemeinschaft-style communities (Kaye et al., 2022) around users’ common interests, which may include and/or be heavily informed by identity. Third, TikTok has long prioritized and found success with Generation Z and younger users more broadly (Zeng et al., 2021; Vogels et al., 2022; Stahl & Literat, 2022), which has made generational identity extremely salient on the app, while also implicating political identity, as young people tend to hold political beliefs more cognizant and accepting of diverse identities than older generations (Parker et al., 2019). The papers in this panel consider a wide range of identity characteristics of TikTok users and how these identities shape and are shaped by political discourse on TikTok. Paper 1 builds on TikTok’s targeting of Gen Z, considering the identities of age and generation through a content analysis of political remix on TikTok to uncover how younger users use TikTok for political activism as compared to their older counterparts, and finding evidence that TikTok is a powerful site of collective action. Also building from TikTok’s appeal to GenZ, Paper 2 presents a digital ethnographic analysis of the Trad-Wife phenomena on TikTok, offering that TikTok quietly (and thus insidiously) offers space for the cultivation of Christian Nationalist, ‘gentle fascisms’ within GenZ women, often without mention of ‘politics’ at all. Paper 3 offers a computational content analysis of political posts on TikTok with a focus on the interactions between identity and partisanship, and particularly the ways in which creators of marginalized identities on the right act as identity entrepreneurs, offering conservative critiques of their identity groups in ways which find popularity among conservative audiences of hegemonic identities. Finally, Paper 4 looks at differences in how TikTok users respond to male and female politicians’ TikTok videos using a combination of computational and qualitative methods, with exploratory analysis suggesting that male politicians receive more neutral and positive comments than female politicians. By focusing on identity and political discourse on TikTok, we recognize the wide range of political activity occurring on a platform often denigrated as frivolous, and foreground the importance of identity characteristics to the technological and social shaping of these dialogues.

#MassTestingNowPH tweets as acts of citizenship: The rhetorical functions of tweets in pandemic-stricken Philippines

Constrained physical mobility and oppositional action during the COVID-19 pandemic in the Philippines drove many Filipinos to turn to social media affordances, like Twitter’s hashtags, as sites of free speech, dissent, and collective action. One of which, #MassTestingNowPH, called for the implementation of mass testing for the vulnerable population and objected to Rodrigo Duterte’s militaristic pandemic response. This paper examined how #MassTestingNowPH tweets served as acts of citizenship and exerted their rhetorical functions in the digital space during this global medical crisis. Using rhetorical political analysis, this research found that #MassTestingNowPH tweets manifested acts of citizenship by asserting citizens’ rights and responsibilities, and exacting government’s accountability in newly-formed ad hoc publics. Users criticized the country’s COVID-19 response and the injustices of VIP testing for some of its officials. These criticisms enabled them to generate collective grievances for medical frontliners and the marginalized. With these sentiments, netizens called on their audiences to act on their judgment and assert their citizenship in online and offline platforms. These tweets, as acts of citizenship, performed three rhetorical functions: forensic, epideictic, and deliberative. This rhetorical process shaped Twitter’s hashtag as an ad hoc public and the meaning of citizenship in our highly-networked world.

Analogs of α-conotoxin PnIC selectively inhibit α7β2- over α7-only subtype nicotinic acetylcholine receptors via a novel allosteric mechanism.

This study was undertaken to identify and characterize the first ligands capable of selectively identifying nicotinic acetylcholine receptors containing α7 and β2 subunits (α7β2-nAChR subtype). Basal forebrain cholinergic neurons express α7β2-nAChR. Here, they appear to mediate neuronal dysfunction induced by the elevated levels of oligomeric amyloid-β associated with early Alzheimer's disease. Additional work indicates that α7β2-nAChR are expressed across several further critically important cholinergic and GABAergic neuronal circuits within the central nervous system. Further studies, however, are significantly hindered by the inability of currently available ligands to distinguish heteromeric α7β2-nAChR from the closely related and more widespread homomeric α7-only-nAChR subtype. Functional screening using two-electrode voltage-clamp electrophysiology identified a family of α7β2-nAChR-selective analogs of α-conotoxin PnIC (α-CtxPnIC). A combined electrophysiology, functional kinetics, site-directed mutagenesis, and molecular dynamics approach was used to further characterize the α7β2-nAChR selectivity and site of action of these α-CtxPnIC analogs. We determined that α7β2-nAChR selectivity of α-CtxPnIC analogs arises from interactions at a site distinct from the orthosteric agonist-binding site shared between α7β2- and α7-only-nAChR. As numerous previously identified α-Ctx ligands are competitive antagonists of orthosteric agonist-binding sites, this study profoundly expands the scope of use of α-Ctx ligands (which have already provided important nAChR research and translational breakthroughs). More immediately, analogs of α-CtxPnIC promise to enable, for the first time, both comprehensive mapping of the distribution of α7β2-nAChR and detailed investigations of their physiological roles.

Downregulation of ATF-4 Attenuates the Endoplasmic Reticulum Stress-Mediated Neuroinflammation and Cognitive Impairment in Experimentally Induced Alzheimer's Disease Model.

Protein aggregation is invariably associated with the inflammation as a factor in Alzheimer's disease (AD). We investigated the interaction between downstream factors of endoplasmic reticulum (ER) stress pathway and inflammation, with implications in cognitive impairment in AD. Amyloid-β(Aβ)(1-42) was administered by bilateral intracerebroventricular (icv) injection in the brain of adult male Wistar rats to experimentally develop AD. The cognitive impairment was assessed by measuring behavioral parameters such as Morris water maze and novel object recognition tests. Levels of pro-inflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α and anti-inflammatory cytokines IL-4 and IL-10 were measured by the enzyme-linked immunosorbent assay (ELISA) in different rat brain regions. Inflammatory marker proteins such as cyclo-oxygenase (COX)-2 and phosphorylation of nuclear factor kappa B(NF-КB) (p65) were measured by the western blotting. Gene expression of ER stress downstream factors such as ATF-4, CHOP, and GADD-34 was analyzed by qRT-PCR. Histological studies were performed to check Aβ accumulation and neuronal degeneration. Integrated stress response inhibitor (ISRIB) was used to confirm the specific role of ER stress-mediated inflammation in cognitive impairment. Administration of Aβ(1-42) resulted in alteration in levels of inflammatory cytokines, inflammatory proteins, and mRNA levels of ER stress downstream factors. ISRIB treatment resulted in attenuation of Aβ(1-42)-induced ER stress, inflammation, neurodegeneration, and cognitive impairment in rats. These results indicate that ER stress-mediated inflammation potentiates the cognitive impairment in AD. An understanding of cascade of events, interaction of ER stress which was a hallmark of the present investigation together with inflammation and modulation of downstream signalling factors could serve as potent biomarkers to study AD progression. Schematic representation of interaction between ER stress and inflammation. Administration of Aβ(1-42) resulted in ER stress which caused the activation of factors of PERK pathway, inflammation, neuronal degeneration, and cognitive impairment. ISRIB treatment caused downregulation of ATF-4 and attenuation of inflammation indicating a role of ER stress-mediated inflammation in the cognitive impairment in AD. The site of action of ISRIB is shown in blue color.

Review On Prodrug : An Advance Approach for The Drug Design to Enhance the Therapeutic Efficacy

Prodrugs are derivatives of drug molecules that are pharmacologically inactive but require either chemical or enzymatic transformation to release the active drug in vivo in order to exert a pharmacological effect. Prodrugs have better delivery properties that surpass the parent drug molecule. Prodrug concept is justified because it enables the active drug to overcome the barrier that would impede it from reaching the site of action to exert the required pharmacological activity. Some of the barriers that the prodrug approach helps to surmount are as follows, low bioavailability due to poor aqueous solubility (corticosteroids); poor permeability or absorption (ampicillin); high first pass metabolism (propranolol); metabolic instability leading to short half- life, (dopamine); poor site specificity (anticancer agents); incomplete absorption (epinephrine); unfavorable organoleptic properties (chloramphenicol); difficulties during formulation and adverse effects and toxicity. The prodrug approach is rapidly becoming a crucial part in the stratagem of delivery of drugs. The prodrug strategy implementation in the last 20 y has led to a steady advancement in the biopharmaceutical, physicochemical and/or pharmacokinetic attributes of the pharmacologically active compounds

In Rats, the Chemotherapeutic Drug Vincristine-Induced Neuropathic Nociception is Suppressed When Cannabinoid CB1 and CB2 Receptors are Activated

Rats were used to test the potential of cannabis to reduce mechanical hypersensitivity, or mechanical allodynia, which was brought on by vincristine chemotherapy. After that, action sites were located. Method of experimentation: After ten daily injections of vincristine, mechanical hypersensitivity developed in comparison to those that received saline at the same periods. The effects on chemotherapy-induced neuropathy were assessed for the CB1/CB2 receptor agonist WIN55, 212-2, the receptor-inactive enantiomer WIN55, 212-3, the CB2-selective agonist (R,S)-AM1241, the opiate agonist morphine, and vehicle. To determine the locations of action, WIN55, 212-2 was injected either locally in the hind paw or intrathecally (i.t.). By employing competitive antagonists for either CB1 (SR141716) or CB2 receptors (SR144528), pharmacological selectivity was demonstrated. Vincristine-evoked mechanical allodynia was decreased when WIN55, 212-2, but not WIN55, 212-3, were administered systemically. A change in the dose-response curve to the left was noticed after WIN55, 212-2 in comparison to morphine therapy. Antibodies of CB1 (SR141716) and CB2 (SR144528) inhibited WIN55, 212-2’s anti-allodynic actions. Via a CB2 mechanism, (R,S)-AM1241 reduced c-induced mechanical hypersensitivity. Without causing catalepsy, both cannabinoid agonists reduced the mechanical hypersensitivity brought on by vincristine. Cannabis-induced neuropathy may be modulated by cannabinoids at spinal sites of action. When delivered intraperitoneally, WIN55, 212-2 but not WIN55,212-3 inhibited vincristine-evoked mechanical hypersensitivity at dosages that were inert after local hindpaw injection. Spinal co-administration of CB1 and CB2 antagonists inhibited WIN55,212-2’s anti-allodynic effects.By activating CB1 and CB2 receptors, cannabinoids inhibit the maintenance of vincristine-induced mechanical allodynia. The spinal cord is involved in the mediation of these anti-allodynic actions, at least partially.

Localization of Sites of Osimertinib Action in Rat Intestine, Skin, and Lung by Immunohistochemistry.

Osimertinib is a third-generation, irreversible tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations and has shown efficacy in patients with non-small-cell lung cancer. In this study, we created osimertinib-specific antibodies and developed an immunohistochemistry (IHC) for locating the sites of osimertinib action. Moreover, we located osimertinib-protein conjugates in intestinal, dermal, and lung tissues of rats, thereby using our IHC to visualize the sites of the adverse effects of osimertinib, including diarrhea, skin disorder, and interstitial pneumonia. This report is the first to elucidate the localization of the sites of action of osimertinib in the rat intestine, skin, and lung and is expected to help clarify the mechanism of osimertinib-induced adverse effects.

Unleashing the Power of Proenzyme Delivery for Targeted Therapeutic Applications Using Biodegradable Lipid Nanoparticles.

Proenzymes, functioning as inactive precursor forms of enzymes, hold significant promise for regulating essential biological processes. Their inherent property of latency, remaining inert until they arrive at the intended site of action, positions them as particularly promising candidates for the development of targeted therapeutics. Despite this potential, the therapeutic potential of proenzymes is challenged by designing proenzymes with excellent selectivity for disease cells. This limitation is further exacerbated by the inability of proenzymes to spontaneously cross the cell membrane, a biological barrier that impedes the cellular internalization of exogenous macromolecules. Therefore, efficacious intracellular delivery is paramount to unlocking the full therapeutic potency of proenzymes.In this Account, we first elucidate our recent advancements made in designing biodegradable lipid nanoparticles (LNPs) for the cell-specific delivery of biomacromolecules, including proteins and nucleic acids. Using a strategy of parallel synthesis, we have constructed an extensive library of ionizable lipids, each integrated with different biodegradable moieties. This combinatorial approach has led to the identification of LNPs that are particularly efficacious for the delivery of biomacromolecules specifically to tumor cells. This innovation capitalizes on the unique intracellular environment of cancer cells to control the degradation of LNPs, thereby ensuring the targeted release of therapeutics within tumor cells. Additionally, we discuss the structure-activity relationship governing the delivery efficacy of these LNPs and their applicability in regulating tumor cell signaling, specifically through the delivery of bacterial effector proteins.In the second segment, we aim to provide an overview of our recent contributions to the field of proenzyme design, where we have chemically tailored proteins to render them responsive to the unique milieu of tumor cells. Specifically, we elaborate on the chemical principles employed to modify proteins and DNAzymes, thereby priming them for activation in the presence of NAD(P)H:quinone oxidoreductase 1 (NQO1), an enzyme that is prevalently upregulated within tumor cells. We summarize the methodologies for intracellular delivery of these proenzymes using biodegradable LNPs, both in vitro and in vivo. The concomitant intracellular delivery and activation of proenzymes are examined in the context of enhanced therapeutic outcomes and targeted CRISPR/Cas9 genome editing.In conclusion, we offer a perspective on the chemical principles that could be leveraged to optimize LNPs for tissue-specific delivery of proenzymes. We also explore chemical strategies for the irreversible modulation of proenzyme activity within living cells and in vivo. Through this discussion, we provide insights into potential avenues for overcoming existing limitations and enhancing the delivery of proenzymes using LNPs, particularly for developing tumor-targeted therapies and genome editing applications.

Effects of imidazolium ionic liquids on skin barrier lipids – Perspectives for drug delivery

Ionic liquids (ILs) have great potential to facilitate transdermal and topical drug delivery. Here, we investigated the mechanism of action of amphiphilic ILs 1-methyl-3-octylimidazolium bromide (C8MIM) and 3-dodecyl-1-methylimidazolium bromide (C12MIM) in skin barrier lipid models in comparison to their complex effects in human skin. C8MIM incorporated in a skin lipid model was a better permeation enhancer than C12MIM for water and model drugs, theophylline and diclofenac. Solid state 2H NMR and X-ray diffraction indicated that both ILs prefer the cholesterol-rich regions in skin lipids without significantly perturbing their lamellar arrangement and that C8MIM induces the formation of an isotropic lipid phase to a greater extent compared to C12MIM. C12MIM applied topically to the lipid model or human skin as a pretreatment was more potent than C8MIM. When co-applied with the drugs to human skin, aqueous C12MIM was more potent than C8MIM in enhancing theophylline permeation, but neither IL affected (even decreased) diclofenac permeation. Thus, the IL’s ability to permeabilize skin lipid barrier is strongly modulated by its ability to reach the site of action and its interactions with drug and solvent. Such an interplay is far from trivial and requires detailed investigation to realize the full potential of ILs.

Cuproptosis gene-related, neural network-based prognosis prediction and drug-target prediction for KIRC.

Kidney renal clear cell carcinoma (KIRC), as a common case in renal cell carcinoma (RCC), has the risk of postoperative recurrence, thus its prognosis is poor and its prognostic markers are usually based on imaging methods, which have the problem of low specificity. In addition, cuproptosis, as a novel mode of cell death, has been used as a biomarker to predict disease in many cancers in recent years, which also provides an important basis for prognostic prediction in KIRC. For postoperative patients with KIRC, an important means of preventing disease recurrence is pharmacological treatment, and thus matching the appropriate drug to the specific patient's target is also particularly important. With the development of neural networks, their predictive performance in the field of medical big data has surpassed that of traditional methods, and this also applies to the field of prognosis prediction and drug-target prediction. The purpose of this study is to screen for cuproptosis genes related to the prognosis of KIRC and to establish a deep neural network (DNN) model for patient risk prediction, while also developing a personalized nomogram model for predicting patient survival. In addition, sensitivity drugs for KIRC were screened, and a graph neural network (GNN) model was established to predict the targets of the drugs, in order to discover potential drug action sites and provide new treatment ideas for KIRC. We used the Cancer Genome Atlas (TCGA) database, International Cancer Genome Consortium (ICGC) database, and DrugBank database for our study. Differentially expressed genes (DEGs) were screened using TCGA data, and then a DNN-based risk prediction model was built and validated using ICGC data. Subsequently, the differences between high- and low-risk groups were analyzed and KIRC-sensitive drugs were screened, and finally a GNN model was trained using DrugBank data to predict the relevant targets of these drugs. A prognostic model was built by screening 10 significantly different cuproptosis-related genes, the model had an AUC of 0.739 on the training set (TCGA data) and an AUC of 0.707 on the validation set (ICGC data), which demonstrated a good predictive performance. Based on the prognostic model in this paper, patients were also classified into high- and low-risk groups, and functional analyses were performed. In addition, 251 drugs were screened for sensitivity, and four drugs were ultimately found to have high sensitivity, with 5-Fluorouracil having the best inhibitory effect, and subsequently their corresponding targets were also predicted by GraphSAGE, with the most prominent targets including Cytochrome P450 2D6, UDP-glucuronosyltransferase 1A, and Proto-oncogene tyrosine-protein kinase receptor Ret. Notably, the average accuracy of GraphSAGE was 0.817 ± 0.013, which was higher than that of GAT and GTN. Our KIRC risk prediction model, constructed using 10 cuproptosis-related genes, had good independent prognostic ability. In addition, we screened four highly sensitive drugs and predicted relevant targets for these four drugs that might treat KIRC. Finally, literature research revealed that four drug-target interactions have been demonstrated in previous studies and the remaining targets are potential sites of drug action for future research.

Very long chain fatty acid–inhibiting herbicides: Current uses, site of action, herbicide-resistant weeds, and future

Abstract The herbicides that inhibit very-long-chain fatty acid (VLCFA) elongases are primarily used for residual weed control in corn, barley, oat, sorghum, soybean, sugarcane, certain vegetable crops, and wheat production fields in the United States. They act primarily by inhibiting shoot development of susceptible species, preventing weed emergence and growth. The objectives of this review were to summarize 1) the chemical family of VLCFA-inhibiting herbicides and their use in the United States, 2) the VLCFA biosynthesis in plants and their site of action, 3) VLCFA-inhibitor resistant weeds and their mechanism of resistance, and 4) the future of VLCFA-inhibiting herbicides. After their reclassification as Group 15 herbicides to include shoot growth-inhibiting herbicides (Group 8), the VLCFA-inhibiting herbicides are currently represented by eight chemical families (benzofurans, thiocarbamates, α-chloroacetamides, α-oxyacetamides, azolyl-carboxamides, isoxazolines, α-thioacetamides, and oxiranes). On average, VLCFA-inhibiting herbicides are applied once a year to both corn and soybean crops in the United States with acetochlor and S-metolachlor being the most used VLCFA-inhibiting herbicides in corn and soybean production, respectively. The site of action of Group 15 herbicides results from inhibition of the VLCFA synthase, which is encoded by several fatty acid elongase (FAE1)-like genes in VLCFA elongase complex in an endoplasmic reticulum. The VLCFA synthase is a condensing enzyme, and relies on a conserved, reactive cysteinyl sulfur in its active site that performs a nucleophilic attack on either the natural substrate (fatty acyl-CoA) or the herbicide. As of August 2023, 13 weed species have been documented to be resistant to VLCFA inhibitors, including 11 monocot weeds and two dicot weeds (Palmer amaranth and waterhemp). The isoxazolines (pyroxasulfone and fenoxasulfone) are the most recently (2014) discovered VLCFA-inhibiting herbicides. Although the intensity of VLCFA-inhibitor-directed discovery efforts has decreased over the past decade, this biochemical pathway remains a viable mechanistic target for the discovery of herbicide premixes and a valuable component of them.

Dual stimuli-responsive delivery system for self-regulated colon-targeted delivery of poorly water-soluble drugs

Inflammatory bowel disease (IBD) are chronic inflammatory conditions which cause significant patient morbidity. Local drug delivery to the colon can improve treatment efficacy and reduce side effects associated with IBD treatment. Smart drug delivery systems are designed to regulate the release of therapeutic agents at the desired site of action. pH-responsive drug carriers have been previously utilised for improved oral drug delivery beyond stomach harsh conditions. Additionally, the colon possesses a diverse microbiome secreting bioactive molecules e.g., enzymes, that can be exploited for targeted drug delivery. We herein synthesised and characterised a 2-hydroxyethyl methacrylate and methacrylic acid copolymer, crosslinked with an azobenzyl crosslinker, that displayed pH- and enzyme-responsive properties. The swelling and drug release from hydrogel were analysed in pH 1.2, 6.5 and 7.4 buffers, and in the presence of rat caecal matter using metronidazole and mesalamine as model BCS Class I and IV drugs, respectively. Swelling studies displayed pH-responsive swelling behaviour, where swelling was maximum at pH 7.4 and minimum at pH 1.2 (69 % versus 32 %). Consequently, drug release was limited in gastric and small intestinal conditions but increased significantly when exposed to colonic conditions containing caecal matter. This system displays promising capacity for achieving colon-targeted drug delivery with enhanced dissolution of poorly water-soluble drugs for local treatment of IBD and other colon-targeted therapies.