Search Results (313)

High-mobility group box 1 (HMGB1) is a nuclear protein that can interact with a transmembrane cell surface receptor for advanced glycation end products (RAGEs) and mediates the inflammatory pathways that lead to various pathological conditions like cancer, diabetes, cardiovascular diseases, and neurodegenerative disorders. Blocking the HMGB1/RAGE axis using various small synthetic or natural molecules has been proven to be an effective therapeutic approach to treating these inflammatory conditions. However, the low water solubility of these pharmacoactive molecules limits their clinical use. Pharmaceutically active molecules with low solubility and bioavailability in vivo convey a higher risk of failure for drug development and drug innovation. The pharmacokinetic and pharmacodynamics parameters of these compounds are majorly affected by their solubility. Enhancement of the bioavailability and solubility of drugs is a significant challenge in the area of pharmaceutical formulations. This review mainly describes various technologies utilized to improve the bioavailability of synthetic or natural molecules which have been particularly used in various inflammatory conditions acting specifically through the HMGB1/RAGE pathway. Full article

Recent studies have increasingly focused on molecular interactions between small molecules and proteins, especially binding mechanisms and thermodynamics, using multispectroscopic and molecular dynamics approaches. This study elucidated the molecular interaction mechanism between bovine serum albumin (BSA) and trans-resveratrol (Res) through an integrated approach combining multispectroscopic analyses and molecular dynamics simulations. The fluorescence quenching study revealed a static quenching mechanism between BSA and Res, which was further confirmed via ultraviolet–visible (UV-Vis) absorption spectroscopy. In particular, K_SV decreased from 5.01 × 10⁴ M⁻¹ at 298 K to 3.99 × 10⁴ M⁻¹ at 318 K. Furthermore, the calculated K_q values significantly exceeded 1 × 10¹² M⁻¹ s⁻¹. With increasing Res concentration, the peak fluorescence intensities of Tyr and Trp residues both exhibited a blue shift. The α-helix content of the BSA–Res complex was 59.8%, slightly lower than that of BSA (61.3%). Res was found to bind to site I in subdomain IIA of BSA. The molecular dynamics simulation also identified the specific binding of Res to site I of BSA, while thermodynamic studies revealed that the binding process occurs spontaneously and is primarily mediated by hydrogen bonding interactions. These findings not only enrich the theoretical framework of small-molecule–protein interactions but also provide a crucial scientific foundation for the development and utilization of natural products. Full article

Cisplatin (Cis) is a commonly used chemotherapeutic agent for the clinical management of malignant tumors, but its toxic side effects could cause hearing loss, and there is an urgent need to find drugs that ameliorate Cis ototoxicity. Previous studies have found that ferulic acid (FA), a phenolic compound derived from natural plants, exerts antioxidant and anti-inflammatory effects by scavenging free radicals, preventing lipid peroxidation and cell death. Combination therapy, the use of multiple drugs to improve clinical outcomes, has multiple advantages compared to monotherapy. Another small-molecule ascorbic acid (AA) shows robust antioxidant function. However, the optimal route of administration, dosage, concentration, and effective time must be determined. More importantly, whether the combination of FA and AA can improve Cis ototoxicity and reduce the risk of large doses of AA is unclear. This study aims to evaluate the therapeutic potential of FA combined with AA in Cis-induced hearing impairment. In vitro and in vivo experiments were performed to observe the effects of FA, AA, and FA+AA on Cis-induced apoptosis. Compared with the Cis-only group, FA combined with AA ameliorated the Cis-induced decrease in cell viability, production of reactive oxygen species (ROS), and apoptosis of cells to varying degrees, respectively, and the improvement in cell viability, ROS, and apoptosis was even more pronounced with the combination of the two treatments. Network pharmacology combined with transcriptomics and molecular docking results showed that FA and AA could inhibit the Cis-induced apoptosis of cochlear hair cells through Matrix Metalloproteinase 9(MMP9)via the p38 Mitogen-Activated Protein Kinase (p38 MAPK) signaling pathway. In this study, we discovered that FA+AA reduced Cis ototoxicity by suppressing MMP9 in the MAPK signaling pathway. Full article

Uridine diphosphate glycosyltransferase (UGT) is a core protein for glycosylation of plant natural products and other small molecules. Although many studies on functional identification of UGTs are now available, analysis of UGTs in Platycodon grandiflorus is still relatively scarce. We identified 107 PgUGTs genome-wide from P. grandiflorus and investigated their phylogenetic relationships, chromosomal localisation, collinearity, cis-regulatory elements, motifs, domains, and gene structures. PgUGT29 and PgUGT72 were two putative glycosyltransferases for platycodins biosynthesis in P. grandiflorus according to our previous study and bioinfornatical analyses. In vitro enzyme activity showed that PgUGT29 can catalyse the glycosylation of the C3 position of Platycodin D (PD) to generate Platycodin D3 (PD3), while candidate enzyme PgUGT72 does not function as a glycosyltransferase. Molecular docking indicated that T145, D392, Q393, and N396 may be the crucial residues for PgUGT29 to catalyse the generation of PD3 from UDP-Glc and PD. In this study, we identified and cloned PgUGT29, elucidated its catalytic function in converting PD to PD3, and predicted key residues critical for its enzymatic activity. These findings provide a theoretical foundation and technical framework for future targeted metabolic engineering and directional regulation of medicinal components in Platycodon grandiflorus. Full article

Chronic inflammatory diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), atherosclerosis, and inflammatory bowel disease (IBD), pose major global health concerns. These disorders are marked by persistent inflammation, immune system dysfunction, tissue injury, and fibrosis, ultimately leading to severe organ dysfunction and diminished quality of life. Osteopontin (OPN), a multifunctional extracellular matrix protein, plays a crucial role in immune regulation, inflammation, and tissue remodeling. It promotes immune cell recruitment, stimulates pro-inflammatory cytokine production, and contributes to fibrosis through interactions with integrins and CD44 receptors. Additionally, OPN activates key inflammatory pathways, including NF-κB, MAPK, and PI3K/Akt, further aggravating tissue damage in chronic inflammatory conditions. Our review highlights the role of OPN in chronic inflammation, its potential as a biomarker, and its therapeutic implications. We explore promising preclinical approaches, such as monoclonal antibodies, small molecule inhibitors, and natural compounds like curcumin, which have demonstrated potential in mitigating OPN-driven inflammation. However, challenges persist in selectively targeting OPN while maintaining its essential physiological roles, including bone remodeling and wound healing. Our review offers insights into therapeutic strategies and future research directions. Full article

Chinese herbal medicines have played a significant role in the development of new and effective drugs, but how to identify the active ingredients from complex extracts of traditional Chinese herbal medicines was a research difficulty. In recent years, few studies have focused on high-efficiency identification of small-molecule inhibitors of Programmed Death Ligand 1 with lower antigenicity and flexible structure tunability. In order to identify small molecule inhibitors of PD-L1 from complex Chinese herbal extracts, this study established a protein–ligand trapping system based on high-performance liquid chromatography coupled with a photo-diode array detector, ion trap/quadrupole time-of-flight tandem mass spectrometry, and a Programmed Death Ligand 1 affinity chromatography unit (ACPD-L1-HPLC-PDA-IT-TOF (Q-TOF)-MS) to rapidly screen and identify small-molecule inhibitors of Programmed Death Ligand 1 from Toddalia asiatica (L.) Lam. Fourteen components were then identified as PD-L1 binders, and surface plasmon resonance (SPR) validation results showed that six of them—magnoflorine (6), nitidine (22), chelerythrine (24), jatrorrhizine (13), toddaculin (68), and toddanol (45)—displayed PD-L1 binding activity. Laser scanning confocal microscopy results demonstrated that these compounds effectively inhibited the binding of PD-1 to PD-L1 in a dose-dependent manner. Additionally, flow cytometry analysis indicated they could promote human lung cancer cell line (A549) apoptosis when co-cultured with Peripheral Blood Mononuclear Cells (PBMCs). The system’s innovation lies in its first integration of dynamic protein–ligand trapping with multi-dimensional validation, coupled with high-throughput screening capacity for structurally diverse natural products. This workflow overcomes traditional phytochemical screening bottlenecks by preserving native protein conformations during affinity capture while maintaining chromatographic resolution, offering a transformative template for accelerating natural product-derived immunotherapeutics through the PD-1/PD-L1 pathway. Full article

This perspective sets out to raise awareness about the chemical and photophysical properties of indigo, a highly distinguished colorant with an extraordinary history. Indigo, like many other dyes, was first extracted from plants at an inordinately low yield and at great ecological expense. Such was its popularity that indigo was among the first natural colorants to be synthesized in a laboratory before refinement and cost reduction resulted in its economical industrial-scale production. The color of indigo is highly characteristic but difficult to describe, since it falls at the blue/violet interface. It is a small, planar molecule with an exceptionally high degree of π-electron conjugation that pushes the absorption maximum to above 600 nm. Its structure helps explain the high level of photostability enjoyed by indigo, while recent spectroscopic studies have added to our understanding of the longevity of this emblematic colorant. The reversible formation of leuco-indigo increases the ways in which indigo can be used to add color to objects while helping to circumvent the effects of attack by free radicals. It is stressed that the journal Colorants would welcome submissions that describe the chemistry and/or spectroscopy of other representative colorants. Full article

Interest in pulmonary/nasal routes for local delivery has significantly increased over the last decade owing to challenges faced in the delivery of molecules with poor solubility, systemic side effects, or new modalities such as biologics. This increasing interest has attracted new stakeholders to the field who have yet to explore inhaled drug product development. Contract development and manufacturing organizations (CDMOs) play a key role in supporting the development of drug products for inhalation, from early feasibility to post marketing. However, a critical gap exists for these newcomers: a clear, integrated, and a CDMO-centric roadmap for navigating the complexities of pulmonary/nasal drug product development. The purpose of this publication is to highlight the key aspects considered in the product development of inhaled dry powder products from a CDMO perspective, providing a novel and stepwise development strategy. A roadmap for the development of inhalable drug products is proposed with authors’ recommendations to facilitate the decision-making process, starting from the definition of the desired target product profile followed by dose selection in preclinical studies. The importance of understanding the nature of the API, whether a small molecule or a biologic, will be highlighted. Additionally, technical guidance on the choice of formulation (dry powder/liquid) will be provided with special focus on dry powders. Selection criteria for the particle engineering technology, mainly jet milling and spray drying, will also be discussed, including the advantages and limitations of such technologies, based on the authors’ industry expertise. Lastly, the paper will highlight the challenges and considerations for encapsulating both spray dried and jet milled powders. Unlike existing literature, this paper offers a unified framework that bridges preclinical, formulation, manufacturing, and encapsulation considerations, providing a practical tool for newcomers. Full article

Natural matrices have historically been a cornerstone in drug discovery, offering a rich source of structurally diverse and biologically active compounds. However, research on natural products often faces significant challenges due to the complexity of natural matrices, such as urine, and the limitations of bioactivity assessment assays. To ensure reliable insights, it is crucial to optimize experimental conditions to reveal the bioactive potential of samples, thereby improving the validity of statistical analyses. Approaches in metabolomics further strengthen this process by identifying and focusing on the most promising compounds within natural matrices, enhancing the precision of bioactive metabolite prioritization. In this study, we assessed the bioactivity of 17 dromedary urine samples on human renal cells under serum-reduced conditions (1%FBS) in order to minimize possible FBS-derived interfering factors. Using viability assays and Annexin V/PI staining, we found that the tumor renal cell lines Caki-1 and RCC-Shaw were more sensitive to the cytotoxic effects of the small molecules present in dromedary urine compared to non-tumor HK-2 cells. Employing NMR metabolomics analysis combined with detected in vitro activity, our statistical model highlights the presence of bioactive compounds in dromedary urine, such as azelaic acid and phenylacetyl glycine, underscoring its potential as a sustainable source of bioactive molecules within the framework of green chemistry and circular economy initiatives. Full article

Cannabinoid molecules are the family of molecules that bind to the cannabinoid receptors (CB1 and CB2) of the human body and cause changes in numerous biological functions including motor coordination, emotion, and pain reception. Cannabinoids occur either naturally in the Cannabis Sativa plant or can be produced synthetically in the laboratory. The need for accurate analytical methods for analyzing cannabinoid molecules is of considerable current importance due to demands for detecting illegal cannabinoids and for monitoring the manufacture of popular, non-illegal cannabinoid products. Mass spectrometry has been shown to be an optimum technique for identifying cannabinoids. In this work, we perform Higher Collisional Dissociation (HCD) mass spectrometric measurements on an Orbitrap Fusion Tribrid Mass Spectrometer to measure the collision-energy-dependent molecular fragmentation pathways of a group of key cannabinoids and their metabolites (cannabidiol, Δ9-Tetrahydrocannabinol, 11-Hydroxy-Δ9-tetrahydrocannabinol, 11-nor-9-Carboxy-Δ9-tetrahydrocannabinol, cannabidiolic acid, tetrahydrocannabinolic acid), along with two synthetic cannabinoids (JWH-018 and MDMB-FUBINACA). This is the first time that cannabinoid molecules have been studied using energy-resolved HCD methods. We identified a number of common, primary fragmentation pathways, including loss of water, loss of other small neutral molecule units (e.g., butene), and rupture of the central C-C bond that links the aromatic and alkyl ring groups. Quantum chemical calculations are presented to provide insights into preferred protonation sites and to characterize isomerization of protonated open-ring cannabinoids (e.g., [CBDA + H]⁺) into closed-ring analogues (e.g., [THCA + H]⁺). A key result to emerge from our study is that energy-resolved HCD measurements are particularly valuable in identifying isomerization, since the isobaric pairs of molecular ions studied here (e.g., [CBDA + H]⁺ and [THCA + H]⁺) are associated with identical HCD profiles indicating that isomerization of one structure into the other has occurred during the electrospray–mass spectrometry process. This is an important result as it will have general applicability to other tautomeric ions and thus demonstrates the application of energy-resolved HCD as a tool for identifying tautomerization proclivity. Full article

The genus Ruspolia refers to a small group of plants in the Acanthaceae family, with two dominant species R. decurrens and R. hypocrateriformis essentially distributed in tropical parts of Africa. Decoctions from these plants are used in folk medicine for the treatment of a few human pathologies but the active ingredients at the origin of the bioactivities have been little studied. Here, we give an insight into the main phytochemicals of the Ruspolia species published in the literature so far and their pharmacological properties. The flavone glycosides justicialosides A-B likely serve as antioxidant agents and free radical scavengers. Several pyrrolidine alkaloids have been isolated from these Ruspolia species, notably (nor)ruspolinone and a few related products. These molecules have attracted the interest of medicinal chemists, with different synthetic routes leading to ruspolinone and analogues. There are versatile operating procedures to synthesize (nor)ruspolinone isomers. Despite these chemical efforts, the pharmacology of ruspolinone remains largely unknown. A few other Ruspolia alkaloids have been isolated, notably the rare bispyrrolidine benzodioxin alkaloid hypercratine, possibly acting as a ligand of β2-adrenergic receptors. A phytochemical survey of the Ruspolia species sheds light on the diversity of products in this family to promote further investigations into the mechanism of action of ruspolinone and related natural products. Full article

The U.S. Food and Drug Administration (FDA) has authorized 50 new drugs in 2024, which matches the average figure for recent years (2018–2023). The approval of 13 monoclonal antibodies (mAbs) sets a new record, with these molecules accounting for more than 25% of all drugs authorized this year. Three proteins have been added to the list of biologics, and with the inclusion of four TIDES (two oligonucleotides and two peptides), only one in three approved drugs this year is a small molecule. As of 2023, no antibody-drug conjugates (ADCs) have reached the market this year. Two deuterated drugs have been approved, bringing the total approvals for this class of compounds to four. This year saw the authorization of two more PEGylated drugs—both peptides—highlighting a renewed interest in this strategy for extending drug half-life, despite the setback caused by the withdrawal of peginesatide from the market in 2014 due to adverse side effects. N-aromatic heterocycles and fluorine atoms are present in two-thirds of all the small molecules approved this year. Herein, the 50 new drugs authorized by the FDA in 2024 are analyzed exclusively on the basis of their chemical structure. They are classified as the following: biologics (antibodies, proteins), TIDES (oligonucleotides and peptides), combined drugs, natural products, F-containing molecules, nitrogen aromatic heterocycles, aromatic compounds, and other small molecules. Full article

One of the methods for obtaining zinc oxide nanoparticles (ZnO NPs) is electrochemical synthesis. In this study, the anodic dissolution process of metallic zinc in alcohol solutions of LiCl was used to synthesize ZnO NPs. The products were obtained as colloidal suspensions in an electrolyte solution. Due to the small size and ionic nature of the zinc oxide molecule, colloidal nanoparticles tend to cluster into larger groupings, so the size of nanoparticles in solutions will differ from the size of nanoparticles observed in ZnO powders after solvent evaporation. The main goal of this research is to investigate the influence of the temperature of synthesis and the kind of alcohol on the size of ZnO NP micelles. Nanocrystals of zinc oxide were obtained in all tested alcohols: methanol, ethanol, and 1-propanol. The particle size was determined using the Dynamic Light Scattering (DLS) method. It was observed that the particles synthesized in methanol were the largest, followed by smaller particles in ethanol, while the smallest particles were obtained in 1-propanol. Additionally, the particles obtained in ethanol were the most uniform in size, showing the highest level of size homogeneity. Full article

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease and is closely associated with metabolic diseases such as obesity, type 2 diabetes mellitus (T2DM), and metabolic syndrome. However, effective treatment strategies for NAFLD are still lacking. In recent years, progress has been made in understanding the pathogenesis of NAFLD, identifying multiple therapeutic targets and providing new directions for drug development. This review summarizes the recent advances in the treatment of NAFLD, focusing on the mechanisms of action of natural products, small-synthetic-molecule drugs, and combination therapy strategies. This review aims to provide new insights and strategies in treating NAFLD. Full article

miRNAs are small non-coding RNA molecules that play critical roles in the regulation of gene expression and have been closely associated with various diseases, including cancer. These molecules significantly influence the cell cycle of tumor cells and control programmed cell death (apoptosis). Currently, research on miRNAs has become a major focus in developing cancer therapies. Osteosarcoma, a malignant neoplasm predominantly occurring during adolescence and later in life, is characterized by a high propensity for metastasis. This review explores the role of miRNAs in the initiation and progression of cancer, highlighting their potential as predictive biomarkers for disease. It discusses the mechanisms by which natural products modulate miRNA activity to influence apoptosis, ferroptosis, and autophagy in osteosarcoma cells, aiming to identify new strategies for osteosarcoma treatment. Recent studies on how natural products regulate miRNAs to reduce tumor cell resistance to chemotherapy are also reviewed. Furthermore, the review elaborates on how natural products regulate m6A modifications to influence miRNA expression, thereby exerting antitumor effects. In this process, interactions between m6A modifications and miRNAs have been identified, with both jointly influencing tumorigenesis and cancer progression, offering a new perspective in osteosarcoma treatment. These approaches could help uncover novel regulatory mechanisms in osteosarcoma pathways and provide a theoretical foundation for developing new drugs and identifying novel therapeutic targets. Full article