Search Results (5,053)

During production, storage, and administration, drug products (and their intermediates) are in contact with many different types of materials, which include manufacturing components, container closure systems, and administration materials; therefore, there is a potential for their interactions and the introduction of leachables. The presence of leachables may impact key quality attributes of drug products in many ways. These include potential alterations in drug product stability, resulting in a reduced shelf-life, compromised drug product efficacy due to degradation or inactivation of active pharmaceutical ingredients, and impaired drug product physical acceptability due to precipitation, discolouration and/or change in odour or flavour. Moreover, some leachables may be inherently toxic (mutagenic, carcinogenic, immunogenic, etc.) posing direct risks to patient safety. Comprehensive toxicological evaluation of extractables and leachables is therefore essential. Documented cases demonstrate that presence of leachables can lead to serious and clinically significant adverse effects, underscoring the importance of their identification, quantification, and toxicological assessment during pharmaceutical development. This paper provides an overview of the toxicological limits used in the analyses of extractables and leachables and illustrates how they are translated into analytical limits. It also outlines the workflow for toxicological risk assessment of extractables and/or leachables, including evaluations of mutagenicity and other relevant toxicological endpoints. Special attention is given to the interpretation of the draft ICH Q3E guideline, which represents a pivotal development in harmonizing global expectations for extractables and leachables safety assessments. Understanding and correctly applying ICH Q3E is crucial, as it will shape regulatory strategies, analytical approaches, and risk management practices across the pharmaceutical industry. The paper concludes by highlighting emerging challenges that demand sustained advancements in both scientific methodologies and regulatory frameworks. Full article

Mangosteen (Garcinia mangostana L.) has long been used in traditional Southeast Asian medicine to treat inflammatory-related conditions. In this study, three new compounds, including garcimangone A (1), garcimangone B (2), and the S-form of garcimangone C (3), and 18 known compounds were isolated and investigated for their anti-inflammatory properties and effects on M1- and M2-associated markers. Among the isolated components, γ-mangostin (5), garcinone D (6), morusignin J (15), and fuscaxanthone C (16) showed the most potent NO-inhibitory effects in LPS-stimulated RAW264.7 cells. SAR study revealed that chromeno moiety at C-3,4, oxygen substituents at C-1,3,6,7, and isoprenyl groups at C-2,8 are key structural features that promoted anti-inflammatory activity. Cytokine analysis results indicated that morusignin J (15) and fuscaxanthone C (16) could modulate the production of pro-inflammatory cytokines, such as TNF-α and IL-6, while modulating the anti-inflammatory cytokine IL-10. Western blot results demonstrated that morusignin J (15) modulated the inflammatory response through NF-κB and MAPK signaling and increased the expression of M2-associated markers KLF4 and arginase-1 in LPS-induced RAW264.7 macrophages. Further molecular docking analysis confirmed the high binding affinity of morusignin J (15) with key iNOS residues, such as Gln257, Pro344, Glu371, and Hem901, and the in silico prediction supported its potent oral bioavailability and drug-likeness. These in vitro and in silico findings highlight that pericarps of G. mangostana possess potential as promising natural sources for functional extracts and bioactive constituents for the development of antioxidative and anti-inflammatory candidates, and warrant further in vivo investigation in the future. Full article

The threats leading to the extinction of humanity accelerate the evolution and development of materials that are capable of providing conditions for preserving health and, implicitly, life. In our work, we developed drug delivery systems based on mesoporous silica which can deliver an antibiotic, bacitracin, in a more controlled manner. The synthesis of the FDU-12 was performed through a sol–gel method and alternatively functionalized with -NH₂ groups or with poly(N-acryloylmorpholine) chains. The loading of bacitracin was performed using the vacuum-assisted method we successfully used to load these mesoporous materials preferentially within the pores as proved by the TGA-DSC results. The release was performed in two types of simulated body fluid (SBF) and this process was evaluated with chromatographic method using UV detection. The obtained data were fitted in three mathematical models of kinetic drug release (Weibull model, Korsmeyer–Peppas model, and nonlinear regression). The antimicrobial evaluation demonstrated that bacitracin-loaded FDU-12 formulations exhibited strong activity against both reference and clinical Staphylococcus strains. At sub-inhibitory concentrations, all formulations significantly reduced microbial adherence and biofilm formation, although certain strain-dependent stimulatory effects were observed. Furthermore, exposure to sub-MIC levels modulated the production of soluble virulence factors (hemolysins, lipase, and amylase), in a formulation- and strain-dependent manner, underscoring the ability of surface-functionalized FDU-12 carriers to influence bacterial pathogenicity while enhancing antimicrobial efficacy. Full article

There are a vast number of monoclonal antibodies (MAbs) against biological components; however, the number for natural products is less than 50. MAbs against ginsenosides, i.e., dammarane triterpene glycosides contained in ginseng, were prepared to develop an Eastern blotting method that can estimate the number of bound sugars and pharmacological activity. Meanwhile, as a method for producing ginsenoside Rg3, which is used as an anti-cancer drug, an affinity column for ginsenoside Rb1 was prepared to isolate the raw material ginsenoside Rb1 in a single step, and a method for obtaining ginsenoside Rg3 through fermentation was proposed. A unique MAb capable of detecting all solasodine glycosides contained in Solanum plants was created to prepare an affinity column capable of isolating solasodine glycosides from S. khasianum fruit in a single step. The single-chain variable fragment gene was induced from the MAb against solasodine glycoside and introduced into the hairy root system of S. khasianum, thereby increasing the solasodine glycoside content more than twofold. As a result, we recognized that this method can be used to breed plants with higher concentrations of plant secondary metabolites like solasodine glycosides. The above results collectively demonstrate that solasodine glycoside can be isolated from S. khasianum in high yields and that this compound enables the production of steroids in high yields through a one-step chemical reaction. Full article

Gastrointestinal nematode (GIN) infections are the most prevalent parasitic diseases in grazing sheep worldwide, causing significant productivity losses, high mortality and, as a result, economic losses and emerging animal welfare concerns. Conventional control strategies, primarily relying on anthelmintic treatments, face limitations due to rising drug resistance and environmental concerns, underscoring the need for sustainable alternatives. Selective breeding for host genetic resistance has emerged as a promising strategy, while recent advances in transcriptomics and integrative omics research are providing deeper insights into the immune pathways and molecular and genetic mechanisms that underpin host–parasite interactions. This review summarizes current evidence on transcriptomic signatures associated with resistance and susceptibility to H. contortus and T. circumcincta GIN infections, highlighting candidate genes, functional genetic markers, key immune pathways, and regulatory networks. Furthermore, we discuss how other omics approaches, including genomics, proteomics, metabolomics, microbiome, and multi-omics integrations, provide perspectives that enhance the understanding of the complexity of the GIN resistance trait. Transcriptomic studies, particularly using RNA-Sequencing technology, have revealed differential gene expression, functional genetic variants, such as SNPs and INDELs, in expressed regions and splice junctions, and regulatory long non-coding RNAs that distinguish resistance from susceptible sheep, highlighting pathways related to Th2 immunity, antigen presentation, tissue repair, and stress signaling. Genomic analyses have identified SNPs, QTL, and candidate genes linked to immune regulation and parasite resistance. Proteomic and metabolomic profiling further elucidates breed- and tissue-specific alterations in protein abundance and metabolic pathways, while microbiome studies demonstrate distinct microbial signatures in resistant sheep, suggesting a role in modulating host immunity. In conclusion, emerging multi-omics approaches and their integration strategies provide a comprehensive framework for understanding the complex host–parasite interactions that govern GIN resistance, offering potential candidate biomarkers for genomic selection and breeding programs aimed at developing sustainable, parasite-resistant sheep populations. Full article

Systemic lupus erythematosus (SLE) is an autoimmune disease with multiple and heterogeneous clinical manifestations (e.g., skin lesions, kidney damage, neuropsychiatric dysfunction), that primarily affects women and whose etiology remains unclear. Various therapies that regulate and reduce the immune system activity are in use or are being developed; however, many of them have serious side effects. Therefore, new approaches are needed to maximize remission periods and reduce associated side effects. In this review, we summarize the currently recommended therapeutic strategies. Furthermore, we hypothesize that the combined use of drugs targeting various dysregulated cellular processes in SLE (i.e., cytokine production, neutrophil extracellular traps (NETs), phagocytosis) might have therapeutic potential, at least in some disease phenotypes. Preliminary data show that Toll-like receptors 7/8 (TLR 7/8) inhibition (e.g., Enpatoran) may reduce interferon-α (IFN-α) production by monocytes and NET formation by neutrophils. Our hypothesis is that future therapies combining compounds that modulate the three cellular processes might result in a better disease management as current therapies. Full article

The continuous emergence of SARS-CoV-2 variants, especially the Omicron strain with its heightened transmissibility, has posed ongoing challenges to the efficacy of existing vaccine and drug regimens. This situation highlights the pressing demand for antiviral drugs employing novel mechanisms of action. Pentacyclic triterpenoids (PTs), a structurally varied group of compounds derived from plants, exhibit both antiviral and anti-inflammatory activities, making them attractive candidates for further therapeutic development. These natural products, along with their saponin derivatives, show broad-spectrum inhibitory effects against multiple SARS-CoV-2 variants (from Alpha to Omicron) via interactions with multiple targets, such as the spike protein, main protease (Mpro), RNA-dependent RNA polymerase (RdRp), and inflammatory signaling pathways. This review consolidates recent findings on PTs and their saponins, emphasizing their influence on the key structural features required for inhibiting viral attachment, membrane fusion, reverse transcription, and protease function. We systematically summarized the structure–activity relationships and their antiviral results of PTs based on different target proteins in existing studies. Furthermore, this work points toward new strategies for designing multi-target PT-based inhibitors with improved efficacy against Omicron and future variants. Full article

Since their discovery in the 1960s, liposomes have become a versatile platform for drug delivery in cancer research, capable of carrying both hydrophilic and hydrophobic drugs. Throughout the past decades, liposomes have evolved to improve stability, blood circulation time, and targeting ability, overcoming many disadvantages of early formulations. Lipid–polymer hybrid liposomes (LPHLs), a third-generation nanoparticle model, are vesicles where polymers are incorporated in or around the lipid bilayer to increase their stability, to control drug release, and to provide multifunctional capabilities. More recently, cell membrane-coated (CMC) liposomes, which consist of “core” liposomes (preformed liposomes) cloaked in natural cell membranes, have emerged as an even more innovative approach, offering superior immune evasion and highly selective targeting, which are both particularly promising for cancer therapy. Preclinical studies in cancer models demonstrate that these advanced liposomal systems improve pharmacokinetics and therapeutic outcomes. They hold significant potential for developing next-generation, personalized nanomedicines for cancer and other complex diseases. However, challenges related to large-scale production, long-term stability, and safety evaluation remain. Full article

Activation of JAK/STAT and MAPK/ERK1,2 signalling pathways has been shown to increase the production of reactive oxygen species (ROS) in multiple cell types involved in cardiovascular diseases (CVDs), including vascular smooth muscle cells (VSMCs). However, these have not yet been studied in human saphenous vein SMCs (HSVSMCs) responsible for the maladaptive remodelling leading to saphenous vein graft failure (VGF), to which patients with type 2 diabetes mellitus (T2DM) are more susceptible. Therefore, this study aimed to evaluate the contributions of the JAK/STAT and MAPK/ERK1,2 pathways towards production of mitochondrial ROS (mROS) in HSVSMCs from T2DM patients versus non-diabetic controls. HSVSMCs explanted from surplus HSV tissues from consenting patients undergoing coronary artery bypass graft surgery were stimulated in vitro with mitogenic stimuli known to be involved in neointimal hyperplasia (NIH) and VGF, which are known activators of the JAK/STAT and the MAPK/ERK1,2 signalling pathways. Flow cytometry was then used to analyse the production of mROS (superoxide) in MitoSOX-stained HSVSMCs. Additionally, we examined the effect of ruxolitinib and trametinib, selective inhibitors of JAK1/2 and MEK1/2 signalling pathways, respectively, on mROS levels in these cells. From our findings, mROS production was significantly higher in HSVSMCs from T2DM patients versus non-diabetic controls. Activation of either the JAK/STAT or MAPK/ERK1,2 signalling pathways did not significantly alter the production of mROS in HSVSMCs from both T2DM and non-diabetic patients. However, inhibition of JAK/STAT and MAPK/ERK1,2 signalling pathways with ruxolitinib and trametinib, respectively, resulted in a significant reduction in mROS in HSVSMCs from both T2DM and non-diabetic patients. Our findings demonstrate a JAK/STAT- and MAPK/ERK1,2-mediated production of mROS in HSVSMCs. Hence, they are potential targets for drug development to limit ROS production in ROS-driven proliferation and migration of HSVSMCs responsible for VGF. Full article

Alzheimer’s disease (AD) remains an unmet medical challenge, as there are no effective therapies that alter the disease’s progression. While approaches have targeted molecules like acetylcholine (ACh) and glutamate, these strategies have provided only limited benefits and do not address the complex molecular mechanisms underlying AD development. This review suggests that β-alanine (3-aminopropanoic acid) is an underexplored neurotransmitter that could serve as a potential AD drug target. Existing evidence indicates that β-alanine modulates GABAergic and glutamatergic neurotransmission, thereby affecting neuronal hyperexcitability. Additionally, studies suggest that β-alanine has antioxidant effects, reducing oxidative stress caused by reactive oxygen species (ROS). We propose that β-alanine might bind to Aβ/tau proteins, possibly targeting the six-amino acid sequences EVHHQK/DDKKAK, which are involved in protein aggregation. β-Alanine may also influence the release of pro-inflammatory cytokines from microglia, potentially reducing neuroinflammation. We also hypothesize that β-alanine may help regulate metal dyshomeostasis, which leads to ROS production. Taurine, structurally like β-alanine, appears to influence comparable mechanisms. Although structural similarity doesn’t ensure therapeutic effectiveness, this evidence supports considering β-alanine as a treatment for AD. Furthermore, β-alanine and its analogues face challenges, including crossing the blood–brain barrier (BBB) and optimizing structure–activity relationships (SAR). This review includes articles through September 2025, sourced from four databases. Full article

Cell-based potency assays (CBPAs) are required for the potency testing and commercial release of botulinum neurotoxin (BoNT)-based drug products. These CBPAs must account for the toxin’s biological activities while meeting regulatory guidelines for precision and accuracy. Here, studies describe the characterization and qualification of the BoSapient CBPA and demonstrate that it is fit for use as a relative potency assay for BoNT/A-containing samples. The CBPA is operated in a 96-well plate format and relies upon the fluorescence emissions of a reporter that directly responds to BoNT/A activity. The BoSapient cell line expresses the BoNT/A-receptors SV2 and complex gangliosides, is responsive only to intact BoNT/A, and can robustly detect picomolar and sub-picomolar BoNT/A quantities, making the CBPA appropriate for quantifying BoNT/A-based drug products. The cell line was passaged 30 times without significant loss of reporter expression or BoNT/A sensitivity. Manual and semi-automated CBPA methods were developed and qualified according to regulatory guidelines and shown to have low bias (<4% from expected) and high precision (standard deviation < 8) across all test concentrations. Furthermore, the semi-automated method using the CBPA is demonstrated to improve intermediate precision by 39% compared to the manual method, while reducing operator dependency during method execution. Full article

Currently, the increased incidence of invasive fungal infections globally is posing a significant challenge to public health. Due to drug resistance issues, the clinical efficacy of existing antifungal drugs is seriously insufficient, while new drug development progresses slowly. Consequently, there is an urgent need to discover and develop novel antifungal therapeutics. Natural products have the characteristics of wide sources and few adverse reactions and are one of the sources for developing antifungal drugs. Numerous studies have shown that many compounds isolated from plants and traditional Chinese medicine have antifungal activity and diverse antifungal mechanisms. Thymol, a monoterpene phenol compound from thyme (Lamiaceae), has multiple biological functions such as antibacterial, antioxidant, and anti-inflammatory. Recent research has found that thymol has strong antifungal activity, and its molecular mechanisms involve cell membrane rupture, interference with cell wall synthesis, disruption of mitochondrial function and energy metabolism, inhibition of biofilm, inhibition of virulence factor expression, inhibition of key enzymes, and induction of cell apoptosis. This review aimed to summarize the antifungal activity of thymol and the underlying molecular mechanisms, safety, and potential clinical applications. Emerging technologies in thymol delivery systems and future research directions are also discussed. The comprehensive analysis aims to provide a detailed understanding of fungal infections and the role of thymol in antifungal treatment, offering insights for further research and clinical practice. Full article

Antimicrobials are common drugs used to treat and prevent infectious diseases in plants, animals, and humans. Since their discovery in the mid-20th century, their use has dramatically increased for the benefit of humanity, and also for animal care. However, antimicrobial resistance soon appeared, which, according to the WHO, will limit or impede their use at the horizon of 2050. Indeed, antimicrobial resistance (AMR), which is a natural phenomenon in bacteria increased dramatically over the last 3 decades mainly due to the overuse and misuse of antibiotics in humans, animals, and plants. Apart from affecting human health, drug-resistant diseases also adversely affect plant and animal health, reduce agricultural productivity, and threaten food security. AMR affects all countries, regardless of economic status, and imposes high costs on health systems and national economies. Therefore, antimicrobial resistance should be studied and analyzed under the One Health paradigm. In mind of the One Health paradigm, to reduce and overcome AMR, we must take at least 3 complementary and integrated actions: (i) monitoring the resistome; (ii) developing protective strategies against antibiotic resistance; (iii) taking curative actions by designing new and original treatments. Moreover, the three actions must be conducted simultaneously due to the continuous adaptation of bacteria. Full article

Selective inhibition of CYP17A1 17,20-lyase is critical for treating hyperandrogenic disorders without the cortisol-depleting side effects of non-selective drugs like abiraterone. We evaluated tanshinones from Salvia miltiorrhiza as potential selective inhibitors using biochemical assays and computational modeling. Dihydrotanshinone (DT) emerged as the superior candidate; at 10 µM, it inhibited 17,20-lyase activity by 56.6% while preserving >93% of 17α-hydroxylase activity. This yields a selectivity index of 8.67, drastically outperforming abiraterone (0.73). Furthermore, DT displayed minimal off-target inhibition of CYP21A2 (14.9%) compared to abiraterone (29.8%). Molecular modeling suggests DT’s efficacy arises from a unique, functionally disruptive binding pose rather than superior thermodynamic affinity. Consequently, DT is validated as a potent natural product lead. Its dual selectivity over 17α-hydroxylase and CYP21A2 establishes the tanshinone scaffold as a promising candidate for developing safer therapies that suppress androgens while sparing cortisol biosynthesis. Full article

In this work, sodium alginate/chitosan (SA/CS) blend films were prepared by thermo-compression for the first time. Glycerol and lactic acid were used as de-structuring agents for SA and CS, respectively. The chemical structures, thermal stability, phase morphology, mechanical properties, water resistance, film opacity, film color, and soil burial test of thermo-compressed SA/CS films were investigated. The results indicate that intermolecular interactions in polyelectrolyte complexes in SA/CS blends were detected. Blending with CS improved the thermal stability of SA-based films. The SA/CS films showed excellent phase compatibility between SA and CS. The addition of CS improved the tensile properties of the SA-based films. The incorporation of CS in SA films resulted in enhanced water resistance and opacity and a decrease in biodegradability under soil burial. Thermo-compressed SA/CS films show promise for development and increased production capacity. These films can be tailored by varying the SA/CS ratios to display different properties. This versatility makes them suitable for a range of sustainable and diverse applications, including wound dressing, drug delivery, biosorbents, and packaging. Full article