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There is still a need for new antiepileptic drugs (AEDs) as the clinical efficacy, tolerability, toxicity or pharmacokinetic properties of existing AEDs may not be satisfactory. One new AED has recently been approved (rufinamide in 2007) and six others are in late-stage development (phase III and onwards) [brivaracetam, carisbamate, eslicarbazepine, lacosamide, retigabine and stiripentol]. The purpose of this review is to provide updated data on proposed mechanisms of action, efficacy and tolerability on these new AEDs, and to discuss the rationale for their development and possible advantages compared with existing treatment, based on recent publications and MEDLINE searches. Rufinamide, brivaracetam and stiripentol have been given the status of orphan drugs. Rufinamide was approved in Europe in 2007 for the use in Lennox-Gastaut syndrome. Brivaracetam has gained orphan status for development in progressive and symptomatic myoclonic seizures in Europe and the US, respectively. Stiripentol has gained orphan status in children with Dravet’s syndrome and pharmaco-resistant epilepsy. All of these drugs demonstrate efficacy as adjunctive therapy in partial seizures. Three of the drugs are derivatives of existing AEDs: brivaracetam is a derivative of levetiracetam with improved affinity for the target molecule; carisbamate is a derivative of felbamate with improved tolerability; and eslicarbazepine is a derivative of carbamazepine with less interaction potential and no auto-induction. Lacosamide, retigabine, rufinamide and stiripentol are new compounds, unrelated to other AEDs. Further investigation and development of new broad-spectrum drugs is important for improved treatment of patients with epilepsy and other neurological and psychiatric disorders.

Food-derived bioactive peptides are reported as beneficial and safe for human health. Glycomacropeptide (GMP) is a milk-protein-derived peptide that, in addition to its nutritional value, retains many biological properties and has therapeutic effects in several inflammatory disorders. GMP was shown under in vitro and in vivo conditions to exert a number of activities that regulate the physiology of important body systems, namely the gastrointestinal, endocrine, and immune systems. This review represents a comprehensive compilation summarizing the current knowledge and updated information on the major biological properties associated with GMP. GMP bioactivity is addressed with special attention on mechanisms of action, signaling pathways involved, and structural characteristics implicated. In addition, the results of various studies dealing with the effects of GMP on models of inflammatory diseases are reviewed and discussed.

Low success rates during drug development are due, in part, to the difficulty of defining drug mechanism‐of‐action and molecular markers of therapeutic activity. Here, we integrated 199,219 drug sensitivity measurements for 397 unique anti‐cancer drugs with genome‐wide CRISPR loss‐of‐function screens in 484 cell lines to systematically investigate cellular drug mechanism‐of‐action. We observed an enrichment for positive associations between the profile of drug sensitivity and knockout of a drug's nominal target, and by leveraging protein–protein networks, we identified pathways underpinning drug sensitivity. This revealed an unappreciated positive association between mitochondrial E3 ubiquitin–protein ligase MARCH5 dependency and sensitivity to MCL1 inhibitors in breast cancer cell lines. We also estimated drug on‐target and off‐target activity, informing on specificity, potency and toxicity. Linking drug and gene dependency together with genomic data sets uncovered contexts in which molecular networks when perturbed mediate cancer cell loss‐of‐fitness and thereby provide independent and orthogonal evidence of biomarkers for drug development. This study illustrates how integrating cell line drug sensitivity with CRISPR loss‐of‐function screens can elucidate mechanism‐of‐action to advance drug development. Synopsis This study integrates pharmacological and CRISPR screens in 484 cancer cell lines to systematically investigate anticancer drug mechanism of action, yielding insights into the genetic contexts and cellular networks underpinning drug response. CRISPR screens reveal important aspects of drug mechanism‐of‐action, specifically in the context of cellular activity, isoform specificity, off‐target and polypharmacological effects. By leveraging protein interaction networks that underlie drug‐responses, novel drug‐target interactions involving anti‐apoptotic MCL1 inhibitors are identified. Improved pharmacogenomic biomarker discovery using two independent and orthogonal cell viability screens. Graphical Abstract This study integrates pharmacological and CRISPR screens in 484 cancer cell lines to systematically investigate anticancer drug mechanism of action, yielding insights into the genetic contexts and cellular networks underpinning drug response.

The rapid dissemination of antibiotic resistance accelerates the desire for new antibacterial agents. Here, a class of antimicrobial peptides (AMPs) is designed by modifying the structural parameters of a natural chickpea‐derived AMP–Leg2, termed “functionalized chickpea‐derived Leg2 antimicrobial peptides” (FCLAPs). Among the FCLAPs, KTA and KTR show superior antibacterial efficacy against the foodborne pathogen Escherichia coli (E. coli) O157:H7 (with MICs in the range of 2.5–4.7 µmol L−1) and demonstrate satisfactory feasibility in alleviating E. coli O157:H7‐induced intestinal infection. Additionally, the low cytotoxicity along with insusceptibility to antimicrobial resistance increases the potential of FCLAPs as appealing antimicrobials. Combining the multi‐omics profiling andpeptide‐membrane interaction assays, a unique dual‐targeting mode of action is characterized. To specify the antibacterial mechanism, microscopical observations, membrane‐related physicochemical properties studies, and mass spectrometry assays are further performed. Data indicate that KTA and KTR induce membrane damage by initially targeting the lipopolysaccharide (LPS), thus promoting the peptides to traverse the outer membrane. Subsequently, the peptides intercalate into the peptidoglycan (PGN) layer, blocking its synthesis, and causing a collapse of membrane structure. These findings altogether imply the great potential of KTA and KTR as promising antibacterial candidates in combating the growing threat of E. coli O157:H7. Functionalized chickpea‐derived Leg2 antimicrobial peptides (FCLAPs) show superior antibacterial activity, and they combat Escherichia coli O157:H7 through a dual‐targeting mechanism. First, FCLAPs induce membrane damage by initially targeting the lipopolysaccharide, thus promoting the peptides to traverse the outer membrane. Subsequently, the peptides intercalate into the peptidoglycan layer, blocking its synthesis, and causing a collapse of membrane structure.

Diabetic wound healing remains a significant clinical challenge, characterized by persistent hyperglycemia, chronic inflammation, impaired angiogenesis, and recurrent infections. Traditional wound dressings often fail to address the complex pathological microenvironment of diabetic wounds. Nanohydrogels, particularly nanohybrid systems such as polyhedral oligomeric silsesquioxane (POSS)-based hydrogels, metal-organic framework (MOF) nanozyme hydrogels, and zinc-based polyoxometalate (Zn-POM) hydrogels, have emerged as advanced multifunctional platforms for diabetic wound repair. This review systematically summarizes the pathological mechanisms underlying diabetic wound chronicity and the material properties of nanohydrogels that enable targeted therapeutic interventions. We focus on the unique advantages of nanohybrid systems, including their high water retention, tunable mechanical properties, stimuli-responsiveness, and biocompatibility. Furthermore, we provide a detailed analysis of representative nanohybrid hydrogel applications, highlighting their antibacterial, anti-inflammatory, pro-angiogenic, and cell-promoting functions. Despite promising preclinical outcomes, challenges remain in large-scale production, mechanistic understanding, and clinical translation. Future directions include the development of intelligent, personalized nanohybrid systems and the integration of multi-omics approaches to elucidate their in vivo mechanisms. This review aims to provide a comprehensive and critical overview of nanohybrid hydrogels for diabetic wound healing, offering insights for researchers and clinicians in the field.

Colorectal cancer is one of the most common and most diagnosed cancers in the world. There are many predisposing factors, for example, genetic predisposition, smoking, or a diet rich in red, processed meat and poor in vegetables and fruits. Probiotics may be helpful in the prevention of cancer and may provide support during treatment. The main aim of this study is to characterize the potential mechanisms of action of probiotics, in particular the prevention and treatment of colorectal cancer. Probiotics’ potential mechanisms of action are, for example, modification of intestinal microbiota, improvement of colonic physicochemical conditions, production of anticancerogenic and antioxidant metabolites against carcinogenesis, a decrease in intestinal inflammation, and the production of harmful enzymes. The prevention of colorectal cancer is associated with favorable quantitative and qualitative changes in the intestinal microbiota, as well as changes in metabolic activity and in the physicochemical conditions of the intestine. In addition, it is worth noting that the effect depends on the bacterial strain, as well as on the dose administered.

Viral infections have always been the main global health challenge, as several potentially lethal viruses, including the hepatitis virus, herpes virus, and influenza virus, have affected human health for decades. Unfortunately, most licensed antiviral drugs are characterized by many adverse reactions and, in the long-term therapy, also develop viral resistance; for these reasons, researchers have focused their attention on investigating potential antiviral molecules from plants. Natural resources indeed offer a variety of specialized therapeutic metabolites that have been demonstrated to inhibit viral entry into the host cells and replication through the regulation of viral absorption, cell receptor binding, and competition for the activation of intracellular signaling pathways. Many active phytochemicals, including flavonoids, lignans, terpenoids, coumarins, saponins, alkaloids, etc., have been identified as potential candidates for preventing and treating viral infections. Using a systematic approach, this review summarises the knowledge obtained to date on the in vivo antiviral activity of specialized metabolites extracted from plant matrices by focusing on their mechanism of action.

The low rate of discovery and rapid spread of resistant pathogens have made antibiotic discovery a worldwide priority. In cell-based screening, the mechanism of action (MOA) is identified after antimicrobial activity. This increases rediscovery, impairs low potency candidate detection, and does not guide lead optimization. In this study, high-throughput Fourier-transform infrared (FTIR) spectroscopy was used to discriminate the MOA of 14 antibiotics at pathway, class, and individual antibiotic level. For that, the optimal combinations and parametrizations of spectral preprocessing were selected with cross-validated partial least squares discriminant analysis, to which various machine learning algorithms were applied. This coherently resulted in very good accuracies, independently of the algorithms, and at all levels of MOA. Particularly, an ensemble of subspace discriminants predicted the known pathway (98.6%), antibiotic classes (100%), and individual antibiotics (97.8%) with exceptional accuracy, and similar results were obtained for simulated novel MOA. Even at very low concentrations (1 μg/mL) and growth inhibition (15%), over 70% pathway and class accuracy was achieved, suggesting FTIR spectroscopy can probe the grey chemical matter. Prediction of inhibitory effect was also examined, for which a squared exponential Gaussian process regression yielded a root mean square error of 0.33 and a R2 of 0.92, indicating that metabolic alterations leading to growth inhibition are intrinsically reflected on FTIR spectra beyond cell density.Key points• Antibiotic MOA and potency estimated with high-throughput FTIR spectroscopy• Sub-inhibitory MOA identification suggests ability to explore grey chemical matter• Data analysis optimization improved MOA identification at antibiotic level by 38%

Artemisinin is an endoperoxide sesquiterpene lactone isolated from Artemisia annua and is often used to treat malaria. Artemisinin's peroxide bridge is the key structure behind its antimalarial action. Scientists have created dihydroartemisinin, artemether, artesunate, and other derivatives preserving artemisinin's peroxide bridge to increase its clinical utility value. Artemisinin compounds exhibit excellent efficacy, quick action, and minimal toxicity in malaria treatment and have greatly contributed to malaria control. With the wide and unreasonable application of artemisinin-based medicines, malaria parasites have developed artemisinin resistance, making malaria prevention and control increasingly challenging. Artemisinin-resistant Plasmodium strains have been found in many countries and regions. The mechanisms of antimalarials and artemisinin resistance are not well understood, making malaria prevention and control a serious challenge. Understanding the antimalarial and resistance mechanisms of artemisinin drugs helps develop novel antimalarials and guides the rational application of antimalarials to avoid the spread of resistance, which is conducive to malaria control and elimination efforts. This review will discuss the antimalarial mechanisms and resistance status of artemisinin and its derivatives, which will provide a reference for avoiding drug resistance and the research and development of new antimalarial drugs.

As human life expectancy increases, the incidence of neurodegenerative diseases in older adults has increased in parallel. Walnuts contain bioactive peptides with demonstrated neuroprotective effects, making them a valuable addition to the diet. We here present a comprehensive review of the various methods used to prepare, isolate, purify, and identify the neuroprotective peptides found in walnuts. We further summarise the different approaches currently used to evaluate the activity of these peptides in experimental settings, highlighting their potential to reduce oxidative stress, neuroinflammation, and promote autophagy, as well as to regulate the gut microflora and balance the cholinergic system. Finally, we offer suggestions for future research concerning bioavailability and improving or masking the bitter taste and sensory properties of final products containing the identified walnut neuroprotective peptides to ensure successful adoption of these peptides as functional food ingredients for neurohealth promotion.