Celastrol, acknowledged as a prominent exemplar of the potential for transforming traditional medicinal compounds into contemporary pharmaceuticals, has garnered considerable attention owing to its extensive pharmacological activities. The increasing volume of publications concerning celastrol highlights its importance in current scientific inquiry. Despite the growing interest in this compound, a bibliometric analysis focused on this subject remains to be undertaken.

Our study explored a bibliometric approach to identify and characterize global research trends and frontiers related to celastrol, including mapping research outputs, influential contributors, and thematic areas, as well as highlighting gaps and opportunities for future investigations.

In this study, we utilized the Web of Science Core Collection (WoSCC) to source and review articles related to celastrol published from 1997 to 2023. The bibliometric analysis was conducted using the R package 'Bibliometrix,' supplemented by visualization tools including CiteSpace, VOSviewer, and GraphPad Prism 10.

Celastrol related research papers have exhibited an upward trend annually and can be categorized into three distinct phases, each highlighting different areas of focus. China, the United States, and South Korea rank as the top three nations for publication volume, with varied research interests across these countries. Several prolific research teams have emerged, each with distinct areas of interest. Examining the primary research domains of celastrol (anti-inflammatory, anticancer, and toxicity) reveals a notable intersection between the first two domains.

The scope and depth of celastrol research have been steadily expanding, with regional and team-specific variations. Key research areas include anti-inflammatory, anticancer, and toxicity studies. Future research is expected to focus on enhancing the effectiveness and reducing the toxicity of celastrol. Meanwhile, given the multi-target characteristics of celastrol's effects, integrating methods such as network biology and molecular simulation will provide a novel perspective for celastrol research.

Andrographolide, a labdane diterpenoid isolated from Andrographis paniculata, putatively functions through covalent inhibition of NF-κB, a transcription factor that modulates tumor survival and metastasis. Previous studies have found that functionalization of the C-19 hydroxyl alters the primary mode of action from inhibition of NF-κB to the modulation of the Wnt1/β-catenin signaling pathway. Here, we synthesized a series of twelve C-19 trityl and silyl ether analogs, including three novel substituted trityl analogs and four novel substituted silyl analogs of andrographolide. MTT assays revealed cell line selectivity between colorectal and breast cancer cells, which is consistent with known mechanisms of β-catenin-driven cell proliferation in colorectal cancer cell lines. Most compounds exhibited cell line specific antiproliferative activity in HCT-116 and HT-29 colorectal cancer cell lines. Specifically, within 24 h, C-19 analogs of andrographolide exhibit far more limited antiproliferative activity in MCF-7 breast cancer cells compared to HCT-116, HT-29, and MDA-MB-231 cells. Through in vitro TNF-α-dependent NF-κB reporter and Wnt1-dependent luciferase reporter assays, we observed that several analogs generally exhibit greater inhibitory activity compared to andrographolide. Fluorescence imaging demonstrated that cells treated with andrographolide and its C-19 analogs retained similar distributions of active β-catenin, but notable differences in antiproliferative potency upon co-delivery with GSK-3β inhibitor CHIR99021 indicate that several lead compounds exhibit attenuated biological activity selectively in HT-29 cells. Collectively, this work indicates that modest structural modifications at C-19 of andrographolide can have profound implications for its biological activity in mechanisms connected to its anticancer activity.

Plants and microorganisms are at the forefront of natural exploitable bioresources for the discovery of novel bioactive compounds (BACs) to provide solutions to food and agricultural challenges. The present study aimed to produce a novel biotechnologically-relevant BAC from a mangrove sediment bacterium under optimized bioprocess medium conditions. The BAC-producing bacteria were isolated via the crowded plate technique, and medium optimization was performed via sequential statistics of response surface methodology (RSM). The RSM model predictions were optimized, validated, and scaled up in a 5-L bioreactor via submerged batch fermentation. The BAC was extracted with ethyl acetate, purified via silica gel column chromatography, and identified via semipreparative high-performance liquid chromatography using bioactive standards with known retention times. The biocontrol, antioxidant and biopreservation potential of the BAC were evaluated via standard methods.

The results revealed that strain GKRMS-A9 produced the largest inhibition zone diameter (ZND) of 17 mm against the susceptible mould. The bacterium and its susceptible mould were identified as Lysinibacillus macroides and Aspergillus austroafricanus strains, respectively. Bioprocess medium optimization produced 9.6 g L- 1 of the BAC with a ZND of 47.1 mm using 44.84% [v v- 1] rice processing effluent, 8.58 gL- 1 casamino acid, 1.39 g L- 1 MgSO4.7H2O, 2.78 g L- 1 CaCl2.2H2O, 16.94% [v v- 1] inoculum volume, and 10.45 g L- 1 Na2HPO4/NaH2PO4. The BAC concentration increased 48.7-fold in response to biological induction with susceptible mould. Silica gel chromatography revealed 9 bioactive fractions in the ethyl acetate extract, with fraction C (retention time of 9.02 min) eliciting the largest mean ZND of 38.1 ± 1.7 mm against Aspergillus austroafricanus. Fraction C was identified as a heterocycloanthracin-like class II bacteriocin with a molecular weight of 10.5 kDa.

The bacteriocin 'macroidin' is stable over a wide range of pH values and temperatures and has significant antimicrobial activity against Gram-positive food-borne and phytopathogenic strains of bacteria and moulds. Its antioxidant activities against DPPH and ABTS*+ radicals are comparable to those of ascorbic acid, making this biomolecule a promising agent for biopreservation and phytopathogen control applications in the food and agricultural sectors.

Mass spectrometry (MS)-based metabolomics has emerged as a transformative tool to unraveling components and their mechanisms in traditional Chinese medicine (TCM). The integration of advanced analytical platforms, such as LC-MS and GC-MS, coupled with metabolomics, has propelled the qualitative and quantitative characterization of TCM's complex components. This review comprehensively examines the applications of MS-based metabolomics in elucidating TCM efficacy, spanning chemical composition analysis, molecular target identification, mechanism-of-action studies, and syndrome differentiation. Recent innovations in functional metabolomics, spatial metabolomics, single-cell metabolomics, and metabolic flux analysis have further expanded TCM research horizons. Artificial intelligence (AI) and bioinformatics integration offer promising avenues for overcoming analytical bottlenecks, enhancing database standardization, and driving interdisciplinary breakthroughs. However, challenges remain, including the need for improved data processing standardization, database expansion, and understanding of metabolite-gene-protein interactions. By addressing these gaps, metabolomics can bridge traditional practices and modern biomedical research, fostering global acceptance of TCM. This review highlights the synergy of advanced MS techniques, computational tools, and TCM's holistic philosophy, presenting a forward-looking perspective on its clinical translation and internationalization.

Researchers have uncovered hundreds of thousands of natural products, many of which contribute to medicine, materials, and agriculture. However, missing knowledge about the biosynthetic pathways of these products hinders their expanded use. Nucleotide sequencing is key to pathway elucidation efforts, and analyses of the molecular structures of natural products, although seldom discussed explicitly, also play an important role by suggesting hypothetical pathways for testing. Structural analyses are also important in drug discovery, for which many molecular representation systems-methods of representing molecular structures in a computer-friendly format-have been developed. Unfortunately, pathway elucidation investigations seldom use these representation systems. This gap likely occurs because those systems are primarily built to document molecular connectivity and topology rather than the absolute positions of bonds and atoms in a common reference frame, which would enable chemical structures to be connected with potential underlying biosynthetic steps. Here, we expand on recently developed skeleton-based molecular representation systems by implementing a common-reference-frame-oriented system. We tested this system using triterpenoid structures as a case study and explored its applications in biosynthesis and structural diversity tasks. The common-reference-frame system can identify structural regions of high or low variability on the scale of atoms and bonds and enable hierarchical clustering that is closely connected to underlying biosynthesis. Combined with information on phylogenetic distribution, the system illuminates distinct sources of structural variability, such as different enzyme families operating in the same pathway. These characteristics outline the potential of common-reference-frame molecular representation systems to support large-scale pathway elucidation efforts.

The carnivorous plant Sarracenia purpurea has been traditionally used in various ethnobotanical applications, including treatments for type 2 diabetes and tuberculosis-like symptoms. This study investigates the cytotoxic effects of S. purpurea root extract (Sp-R) on human non-small-cell lung cancer (NSCLC) cell lines, including H1975, H838, and A549, focusing on its impact on cell survival, apoptosis, proliferation, and migration. Additionally, its ability to inhibit the single-stranded DNA-binding activity of human RPA32 (huRPA32), a key protein in DNA replication, was evaluated. Extracts from different plant parts (leaf, stem, and root) were prepared using various solvents (water, methanol, ethanol, and acetone) and screened for apoptosis-inducing potential using the chromatin condensation assay. Among these, the acetone-extracted root fraction (Sp-R-A) exhibited the most potent pro-apoptotic effects. The MTT assay demonstrated a dose-dependent cytotoxic effect on NSCLC cells, with IC50 values of 33.74 μg/mL for H1975, 60.79 μg/mL for H838, and 66.52 μg/mL for A549. Migration and clonogenic assays further revealed that Sp-R-A significantly inhibited cancer cell migration and colony formation in a dose-dependent manner. Moreover, Sp-R-A enhanced apoptosis when combined with the EGFR inhibitor afatinib, suggesting a potential synergistic effect. The electrophoretic mobility shift assay confirmed that Sp-R-A significantly inhibited the DNA-binding activity of huRPA32, with an IC50 of 13.6 μg/mL. AlphaFold structural prediction and molecular docking studies indicated that major bioactive compounds in S. purpurea, including α-amyrin, ursolic acid, and betulinaldehyde, strongly interact with the DNA-binding domain of huRPA32, potentially contributing to its inhibitory effect. Overall, these findings suggest that huRPA32 is a potential molecular target of Sp-R-A and the anticancer potential of S. purpurea root extract against NSCLC is highlighted, supporting further investigation into its therapeutic applications.

Natural products have applications as biopharmaceuticals, agrochemicals, and other high-value chemicals. However, there are challenges in isolating natural products from their native producers (e.g. bacteria, fungi, plants). In many cases, synthetic chemistry or heterologous expression must be used to access these important molecules. The biosynthetic machinery to generate these compounds is found within biosynthetic gene clusters, primarily consisting of the enzymes that biosynthesise a range of natural product classes (including, but not limited to ribosomal and nonribosomal peptides, polyketides, and terpenoids). Cell-free synthetic biology has emerged in recent years as a bottom-up technology applied towards both prototyping pathways and producing molecules. Recently, it has been applied to natural products, both to characterise biosynthetic pathways and produce new metabolites. This review discusses the core biochemistry of cell-free synthetic biology applied to metabolite production and critiques its advantages and disadvantages compared to whole cell and/or chemical production routes. Specifically, we review the advances in cell-free biosynthesis of ribosomal peptides, analyse the rapid prototyping of natural product biosynthetic enzymes and pathways, highlight advances in novel antimicrobial discovery, and discuss the rising use of cell-free technologies in industrial biotechnology and synthetic biology.

Chemotherapy for patients with pancreatic cancer typically has a poor prognosis. Immunotherapy is currently a hot therapeutical approach to treat tumors. Various studies have shown that natural products have numerous activities, especially in the anti-tumor field. The triterpenoid class compound Obacunone has been shown to have various bioactivities, including anti-cancer properties. In this study, combining Obacunone with anti-PD-1 to treat pancreatic cancer in mice enhanced the anti-cancer activity of anti-PD-1 and suppressed tumor growth significantly. Proteomic analysis, immunofluorescence, Western blot, and flow cytometry revealed that this combination of compounds modulated the CD36-mediated PPAR signaling pathway to improve the infiltration and number of immune-associated CD4+ and CD8+ T cells in tumors. This report provides a new strategy for discovering immunotherapy for pancreatic cancer.

MS/MS-based molecular networking is an effective strategy to rapidly dereplicate known compounds and to guide the discovery process for new and novel natural products. In the present study, the chemical diversity of indole diterpenoids from the marine-derived fungus Penicillium sp. N4-3 was investigated using molecular networking techniques. Guided by this information, targeted isolation resulted in two new indole diterpenoids shearinines R and S (1, 2) and an oxidative artifact shearinine T (3), together with the verification of two known analogs (4, 5). Furthermore, five indole diterpenoids (6-10), including three putatively new ones, shearinines U-W (6, 9, 10), were predicted from the molecular ion cluster by the combination of GNPS molecular networking and manual analysis of MS/MS fragmentation clusters. Shearinines T (3) and W (10) are characterized by an oxidative cleavage of the C-2-C-18 double bond. Feature fragment ions of these shearinines revealed two type of dominant ions related to the indole moiety and the breaking of C-9 side chain or Ring I. Compound 1 showed antibacterial activities against a panel of pathogenic bacteria with IC50 values ranging from 6.34 to 47.96 μg/mL and inhibited the growth of the human hepatic (HepG2) and gastric (SGC-7901) cancer cells lines with IC50 values of 6.27 and 19.16 μg/mL, respectively.

The online version contains supplementary material available at 10.1007/s42995-024-00274-6.

Natural products have been pivotal in drug discovery, offering a wealth of bioactive compounds that significantly contribute to therapeutic developments. Despite the rise of synthetic chemistry, natural products continue to play a crucial role due to their unique chemical structures and diverse biological activities. This study reviews and evaluates the potential of natural products in drug discovery and development, emphasizing the integration of traditional knowledge with modern drug discovery methodologies and addressing the associated challenges. A comprehensive literature search was conducted across PubMed/MedLine, Scopus, Web of Science, Google Scholar, and Cochrane Library, covering publications from 2000 to 2023. Inclusion criteria focused on studies related to natural products, bioactive compounds, medicinal plants, phytochemistry, and AI applications in drug discovery. Data were categorized into source, extraction methods, bioactivity assays, and technological advances. The current review underscores the historical and ongoing importance of natural products in drug discovery. Technological advancements in chromatographic and spectroscopic techniques have improved the isolation and structural elucidation of bioactive compounds. AI and machine learning have streamlined the identification and optimization of natural product leads. Challenges such as biodiversity sustainability and development complexities are discussed, alongside innovative approaches like biosynthetic engineering and metagenomics. Natural products remain a vital source of novel therapeutic agents, providing unique chemical diversity and specific biological activities. Integrating traditional knowledge with modern scientific methods is essential for maximizing the potential of natural products in drug discovery. Despite existing challenges, ongoing research and technological advancements are expected to enhance the efficiency and success of natural product-based drug development.

Fluorine has become an essential element in the development of modern pharmaceuticals, due to its unique chemical properties that can significantly enhance the biological activity, metabolic stability, and lipophilicity of drug molecules. This review explores recent advancements in the synthesis and application of fluorine-containing drugs approved by the US Food and Drug Administration (FDA) in 2024. These novel drugs demonstrate improved efficacy and safety profiles, addressing a range of therapeutic areas including oncology, infectious diseases, metabolic disorders and genetic disorders that affect the adrenal glands. The incorporation of fluorine atoms into drug candidates has facilitated the development of molecules with optimized pharmacokinetic and pharmacodynamic properties, leading to better patient outcomes. The review further discusses the synthetic methodologies employed, the structural characteristics of these drugs, and their clinical implications, providing insights into the ongoing innovation within the pharmaceutical industry driven by fluorine chemistry.

Cancer remains one of the most pressing challenges to global healthcare, exerting a significant impact on patient life expectancy. Cancer metastasis is a critical determinant of the lethality and treatment resistance of cancer. The urokinase-type plasminogen activator receptor (uPAR) shows great potential as a target for anticancer and antimetastatic therapies. In this work, we aimed to identify potential uPAR inhibitors by structural dynamics-based virtual screenings against a natural product library on four representative apo-uPAR structural models recently derived from long-timescale molecular dynamics (MD) simulations. Fifteen potential inhibitors (NP1-NP15) were initially identified through molecular docking, consensus scoring, and visual inspection. Subsequently, we employed MD-based molecular mechanics-generalized Born surface area (MM-GBSA) calculations to evaluate their binding affinities to uPAR. Structural dynamics analyses further indicated that all of the top 6 compounds exhibited stable binding to uPAR and interacted with the critical residues in the binding interface between uPAR and its endogenous ligand uPA, suggesting their potential as uPAR inhibitors by interrupting the uPAR-uPA interaction. We finally predicted the ADMET properties of these compounds. The natural products NP5, NP12, and NP14 with better binding affinities to uPAR than the uPAR inhibitors previously discovered by us were proven to be potentially orally active in humans. This work offers potential uPAR inhibitors that may contribute to the development of novel effective anticancer and antimetastatic therapeutics.

Chemotherapy was one of indispensable methods for treating cancer, and the development of novel antitumor drugs was necessary due to the emergent drug resistance and undesirable side effects. In the current study, we successfully constructed a novel library of isatin-phenol hybrids by chemical coupling of isatin (1) with a series of active phenols including honokiol (2), magnolol (3), bis(4-hydroxy-3-methylphenyl) sulfide (4), bisphenol A (5), carvacrol (6), and hydroxyqunioline (7) respectively. The target molecules were screened for anticancer activity, and we further investigate the anti-cancer mechanism of the most potent compound IPH10 in vitro and in vivo. Animal experiments demonstrated that IPH10 possessed strong anti-tumor effects in vivo without hepatic and renal toxicity. Moreover, the effects of IPH10 on mitochondrial membrane potential (JC-1) and reactive oxygen species (ROS) in tumor cells were investigated, and the results showed that IPH10 could significantly increase the content of ROS and dramatically decrease the mitochondrial membrane potential in tumor cells. Furthermore, the effect of IPH10 on apoptotic proteins in tumor cells was also explored by Western blotting analysis, which revealed that IPH10 could significantly increase the protein content of cleaved caspase-9/cleaved caspase-3/cleaved caspase-7/cleaved PARP. Taken together, the current study reported a promising novel chemotherapeutic drug candidate IPH10 that could inhibit the growth and induce the apoptosis of tumor cells.

Diabetes mellitus has emerged as a global public health crisis, with Type 2 diabetes (T2D) constituting over 90% of cases. Current treatments are palliative, primarily focusing on blood glucose modulation. This review systematically evaluates 181 bioactive compounds isolated from 66 marine fungal strains for their inhibitory activities against key diabetes-related enzymes, including α-glucosidase, protein tyrosine phosphatase 1B (PTP1B), dipeptidyl peptidase-4 (DPP-4), glycogen synthase kinase-3β (GSK-3β), and fatty acid-binding protein 4 (FABP4). These compounds, categorized into polyketides, alkaloids, terpenoids, and lignans, exhibit multitarget engagement and nanomolar-to-micromolar potency. The review highlights the potential of marine fungal metabolites as novel antidiabetic agents, emphasizing their structural novelty and diverse mechanisms of action. Future research should focus on overcoming challenges related to yield and extraction, leveraging advanced technologies such as genetic engineering and synthetic biology to enhance drug development.

4(3H)-quinazolinone is a functional scaffold that exists widely both in natural products and synthetic organic compounds. Its drug-like derivatives have been extensively synthesized with interesting biological features including anticancer, anti-inflammatory, antiviral, antimalarial, antibacterial, antifungal, and herbicidal, etc. In this review, we highlight the medicinal and agrochemical versatility of the 4(3H)-quinazolinone scaffold according to the studies published in the past six years (2019-2024), and comprehensively give a summary of the target recognition, structure-activity relationship, and mechanism of its analogs. The present review is expected to provide valuable guidance for discovering novel lead compounds containing 4(3H)-quinazolinone moiety in both drug and agrochemical research.

The incidence of anxiety and depression disorders is increasing worldwide. There is an increasing incidence of hard-to-treat depression with various aspects of origin. Almost 80% of people prefer to use natural remedies and supplements as their primary healthcare solution. Not surprisingly, around one-third of drugs were inspired by nature. Over the past three decades, the use of such remedies has increased significantly. Synthetic antidepressants may cause various negative side effects, whereas herbal medicines are favored because of their ability to relieve symptoms with minimal to no side effects and lower financial burden. This review provides an overview of herbs and biologically active compounds used to treat depression.

The enzyme dipeptidyl peptidase 4 (DPP4) is a potential therapeutic target for type 2 diabetes (T2DM). Many synthetic anti-DPP4 medications are available to treat T2DM. The need for secure and efficient medicines has been unmet due to the adverse side effects of existing DPP4 medications. The present study implemented a combined approach to machine learning and structure-based virtual screening to identify DPP4 inhibitors. Two ML models were trained based on DPP4 IC50 datasets. The ML models random forest (RF) and multilayer perceptron (MLP) neural network showed good accuracy, with the area under the curve being 0.93 and 0.91, respectively. The natural compound library was screened through ML models, and 1% (217) of compounds were selected for further screening. Structure-based virtual screening was performed along with positive control sitagliptin to obtain more specific and selective leads for DPP4. Based on binding affinity, drug-likeness properties, and interaction with DPP4, Z-614 and Z-997 compounds showed high binding affinity and specificity in the catalytic pocket of DPP4. Finally, the stability conformation of the DPP4 enzyme complex was checked by a molecular dynamics (MD) simulation. The MD simulation showed that both compounds bind better in the catalytic pocket, but the Z-614 compound altered the DPP4 native conformation. Therefore, Z-614 showed a high deviation in the backbone. This combined approach (ML and structure-based) study reported that Z-997 binds most stably to DPP4 in their catalytic pocket with a binding free energy of -70.3 kJ/mol, suggesting its therapeutic potential as a treatment option for T2DM disease.Communicated by Ramaswamy H. Sarma.

Betulinic acid (BA) is a kind of naturally occurring lupane pentacyclic triterpenoid, possessing various biological activities including antiviral, anti-inflammatory and antitumor activity. Covalent inhibitors, characterized by electrophilic warheads that form covalent bonds with specific amino acid residues of target proteins, have garnered enormous attention in anticancer agent discovery over the past decade owing to their exceptional selectivity and efficacy. In this study, BA was structurally modified with electrophilic groups, and 23 derivatives of BA were synthesized. Most of these BA derivatives exhibited improved antiproliferative activity against MCF-7, HeLa, MDA-MB-231 cells in MTT assay, especially the compound 15b (IC50 = 1.09 μM against MCF-7 cells). Further study demonstrated that 15b inhibited the migration and clone formation of MCF-7 cells, induced the apoptosis, autophagy and cycle arrest at G2/M phase in MCF-7 cells, and promoted the production of intracellular reactive oxygen species (ROS). Western blot analysis showed that 15b inhibited AKT/mTOR signaling pathway in MCF-7 cells. In addition, 15b reversed the resistance of JIMT-1 cells to trastuzumab, which might be related to the inhibition of AKT/mTOR pathway. Finally, 15b significantly inhibited the growth of tumor in the breast cancer xenograft mouse model with 36 % inhibition rate of tumor growth and without significant reduction of mouse body weight.

The phytochemistry study of Aconitum bulbilliferum Hand.-Mazz. is firstly reported. Two C20-diterpenoid alkaloids, named bulbilliferines A and B (1 and 2), three C19-diterpenoid alkaloids, bulbillifedines A-C (3-5), and twenty known compounds (6-25) were isolated from the roots of A. bulbilliferum. The structures of these compounds were determined by the comprehensive spectroscopic analyses (HRESIMS, IR, 1D and 2D NMR). Among them, bulbilliferine A (1) is a denudatine-type diterpenoid alkaloid bearing a 16, 17-epoxy group. At a nontoxic dose of 10 mg/kg, 14-O-anisoylchasmanine (14) hydrochloride and austroconitine B (17) hydrochloride respectively exhibited the excellent analgesic effects with 83.6 % and 83.1 % inhibitions against acetic acid-induced writhing of mice.

Cdc2-like kinase 4 (Clk4), a key member of the CMGC kinase family, plays a crucial role in alternative splicing, which profoundly influences various physiological processes, including cellular signaling, proliferation, and survival. Its involvement in these vital functions has positioned Clk4 as an important target for therapeutic intervention in a range of diseases, such as neurodegenerative disorders, viral and parasitic infections, and cancer. This review highlights recent advancements in Clk4 inhibitors, covering both natural, and synthetic compounds. It further examines the core scaffolds and essential functional groups of Clk4 small-molecule inhibitors, emphasizing the most promising chemical structures. Additionally, the review explores the structure-activity relationships (SARs) and molecular binding modes of existing Clk4 inhibitors, offering insights and strategies for the development of novel Clk4-targeted drugs. This review highlights recent advancements in small molecule inhibitors targeting Clk4, emphasizing their potential in treating cancers and neurodegenerative diseases. It explores SARs, binding modes, and challenges in developing selective Clk4 inhibitors, offering insights for future therapeutic strategies.

Naturally occurring compounds have widely been applied to treat diverse pharmacological effects, including asthma, allergic diseases, antioxidants, inflammation, antibiotics, and cancer. Recent research has revealed the essential role of the thymic stromal lymphopoietin (TSLP) in regulating inflammatory responses at mucosal barriers and maintaining immune homeostasis. Asthma, inflammation, and chronic obstructive pulmonary disease are allergic disorders in which TSLP plays a significant role. Although TSLP's role in type 2 immune responses has undergone comprehensive investigation, its involvement in inflammatory diseases and cancer has also been found to be expanding. However, investigating how to block the TSLP pathway using natural products has been limited. This paper summarizes the roles of various medicinal plants and their chemical components that effectively inhibit the TSLP pathway. In addition, we also highlight the contributions of several plant-derived compounds to treat allergic diseases via targeting TSLP. This review intends to offer innovative concepts to scientists investigating the use of naturally produced compounds and extracts for the treatment of allergic illnesses.

Drug discovery, a multifaceted process from compound identification to regulatory approval, historically plagued by inefficiencies and time lags due to limited data utilization, now faces urgent demands for accelerated lead compound identification. Innovations in biological data and computational chemistry have spurred a shift from trial-and-error methods to holistic approaches to medicinal chemistry. Computational techniques, particularly artificial intelligence (AI), notably machine learning (ML) and deep learning (DL), have revolutionized drug development, enhancing data analysis and predictive modeling. Natural products (NPs) have long served as rich sources of biologically active compounds, with many successful drugs originating from them. Advances in information science expanded NP-related databases, enabling deeper exploration with AI. Integrating AI into NP drug discovery promises accelerated discoveries, leveraging AI's analytical prowess, including generative AI for data synthesis. This perspective illuminates AI's current landscape in NP drug discovery, addressing strengths, limitations, and future trajectories to advance this vital research domain.

Protein tyrosine phosphatase 1B (PTP1B) is an attractive target for the treatment of metabolic diseases such as type 2 diabetes and obesity. In this study, a novel fluorescent probe with aggregation-induced emission (AIE) characteristics was designed and synthesized. Within the fluorescent probe, a tetraphenylethene core is connected to a peptide sequence that can be specifically recognized and hydrolysed by PTP1B. Due to the dephosphorylation of PTP1B, the fluorescent probe exhibited AIE in a turn-on manner, indicating PTP1B activity. This probe was successfully used to detect PTP1B activity in HepG2 cell lysates. Then, a probe-based method was applied to screen for potential PTP1B inhibitors from a natural product library, and three novel PTP1B inhibitors were discovered. These findings indicated that the proposed approach offered a new avenue for discovering potential PTP1B inhibitors.

Peripheral modification is often the main approach to optimize natural products for improved biological activity or desired physicochemical properties. This procedure inevitably increases molecular weight, often accompanied by undesired increased lipophilicity. Removing structural elements from natural products is not always tolerated. This is also the case for the antibiotic fidaxomicin (Fdx), where every structural component has been shown to be crucial for antibiotic activity. In this work, we demonstrate how the residue switching approach can maintain biological activity of Fdx derivatives by replacing the rhamnoside-dichlorohomoorsellinate moiety of Fdx with smaller, more polar building blocks. We used palladium-catalysed allylic substitution to selectively install N-nucleophiles on the core of Fdx. The new derivatives were designed to mimic the binding of Fdx to the bacterial RNA polymerase. Evaluation against Mycobacterium tuberculosis, Clostridioides difficile, and the Gram-negative model organism Caulobacter crescentus demonstrated that the newly introduced residues can restore antibiotic activity, which was further supported by on-target RNA polymerase assays. We combined the allylic substitution with an organocatalysed novioside acylation protocol to enable the functionalisation of two vectors on Fdx in one pot. This platform greatly expands the accessible chemical space for Fdx derivatives and enables the future development of systemic Fdx antibiotics.

Despite being discovered nearly a century ago, the Diels-Alder (DA) reaction remains a crucial tool in the total synthesis of natural products. It accommodates a broad range of building blocks with varying complexity and levels of derivatization, allowing the formation of six-membered rings with precise stereochemistry. This, in turn, simplifies the synthesis of core structures found in many natural products. In recent years, modifications to the traditional Diels-Alder reaction have expanded its scope. These modifications include the inverse electron demand Diels-Alder reaction, dehydro Diels-Alder reaction, hetero-Diels-Alder reaction, photoenolization Diels-Alder reaction, asymmetric Diels-Alder reaction, and domino Diels-Alder reaction have been employed to extend the scope of this process in the synthesis of natural products. This review discusses the application of the Diels-Alder reaction in the total synthesis of natural products from 2020 to 2023, along with select methodologies that are inspired by or can be used to synthesize natural products.

RF-amide peptide receptors including the neuropeptide FF receptor 1 (NPFFR1) are G protein-coupled receptors (GPCRs) that modulate diverse physiological functions. High conservation of endogenous ligands and receptors makes the identification of selective ligands challenging. Previously identified antagonists mimic the C-terminus of peptide ligands and lack selectivity towards the closely related neuropeptide FF receptor 2 (NPFFR2) or the neuropeptide Y1 receptor (Y1R). In a high-throughput screening, we identified the pentacyclic triterpenoid hederagenin (1) as a novel selective antagonist for the NPFFR1. Hederagenin (1) is a natural product isolated from Hedera helix (ivy). We characterized its mode of activity using in vitro and in silico methods, revealing an overlapping binding site of the small molecule with the orthosteric peptide agonists. Despite the high similarity of the orthosteric binding pockets of NPFFR1 and NPFFR2, hederagenin (1) shows strong subtype selectivity, particularly caused by slight differences in the shape of the binding pockets and the rigidity of the small molecule. Several residues inhibiting the activity of hederagenin (1) at the NPFFR2 were identified. As NPFFR1 antagonists are discussed as potential candidates for the treatment of chronic pain, these insights into the structural determinants governing subtype specificity will facilitate the development of next-generation analgesics with improved safety and efficacy.

In this paper, the pH-sensitive targeting functional material NGR-poly(2-ethyl-2-oxazoline)-cholesteryl methyl carbonate (NGR-PEtOz-CHMC, NPC) modified quercetin (QUE) liposomes (NPC-QUE-L) was constructed. The structure of NPC was confirmed by infrared spectroscopy (IR) and nuclear magnetic resonance hydrogen spectrum (1H-NMR). Pharmacokinetic results showed that the accumulation of QUE in plasma of the NPC-QUE-L group was 1.28 times and 2.43 times that of the QUE Solution and QUE-L groups, respectively. The release amount of NPC-QUE-L in an acidic environment was significantly higher than in physiological pH value. The order of the tumor cell inhibition rate in different pH environments was NPC-QUE-L > PC-QUE-L > QUE-L. In addition, the cellular uptake of NPC-modified liposomes was higher than that of PC-modified and unmodified liposomes, indicating that NPC had good pH-sensitivity and targeting. In the triple-negative breast cancer (TNBC) model, the relative tumor proliferation rate of NPC-QUE-L is about 73%, which is better than that of the QUE solution group. Western blot results show that NPC-QUE-L can effectively reduce the expression of α-smooth actin and transforming growth factor-β1 in tumor tissues, and improve the degree of tumor fibrosis. In this study, NPC could endow QUE liposomes with good stability, pH-sensitivity, and targeting, which provides a reference for improving the solubility and targeting of poorly soluble natural drug components.

The purpose of this review is to better characterize the contribution and properties of FDA-approved drugs that can be found unmodified in nature. Defined inclusion criteria were applied to drugs identified in previous studies and in annual FDA approval reports to compile a comprehensive list of approved drugs found in nature. Databases and scientific literature were searched to identify chemical and drug properties of these entities, including chemical classes, approval years, drug indications, and approved delivery methods. A random sample of FDA-approved drugs not found in nature was also created for comparison. Drugs from nature are estimated to represent 5 % of FDA approved drugs. The most common classes of natural product drugs are alkaloids, oligopeptides, polyphenols, and polyketides. Approvals of unmodified drugs from nature have declined at a rate of about two per decade since the mid-1900s. Compared to non-natural drugs, drugs from nature are more likely to be used as antibacterials and for dermatological conditions. Natural drugs are also less likely to be delivered orally and more likely to have narrow therapeutic indexes. Given the limitations of unmodified natural products as drugs, the pharmaceutical sciences will likely continue to play an important role in improving the drug-likeness of natural scaffolds.

Mosquitoes are considered one of the most lethal creatures on the planet and are responsible for millions of fatalities annually through the transmission of several diseases to humans. Green trash is commonly employed in agricultural fertilizer manufacturing and microbial bioprocesses for energy production. However, there is limited information available on the conversion of green waste into biocides. This study investigates the viability of utilizing green waste as a new biopesticide against Culex pipiens mosquito larvae. The current study found that plant extracts from Punica granatum (98.4 % mortality), Citrus sinensis (92 % mortality), Brassica oleracea (88 % mortality), Oryza sativa (81.6 % mortality), and Colocasia esculenta (53.6 % mortality) were very good at killing Cx. pipiens larvae 24 h post-treatment. The LC50 values were 314.43, 370.72, 465.59, 666.67, and 1798.03 ppm for P. granatum, C. sinensis, B. oleracea, O. sativa, and C. esculenta, respectively. All plant extracts, particularly P. granatum extract (14.93 and 41.87 U/g), showed a significant reduction in acid and alkaline phosphate activity. Additionally, pomegranate extract showed a significant decrease (90 %) in field larval density, with a stability of up to five days post-treatment. GC-MS results showed more chemical classes, such as terpenes, esters, fatty acids, alkanes, and phenolic compounds. HPLC analysis revealed that the analyzed extracts had a high concentration of phenolic and flavonoid components. Moreover, there are many variations among these plants in the amount of each compound. The docking interaction showed a simulation of the atomic-level interaction between a protein and a small molecule through the binding site of target proteins, explaining the most critical elements influencing the enzyme's activity or inhibitions. The study's findings showed that the various phytochemicals found in agro-waste plants had high larvicidal activity and provide a safe and efficient substitute to conventional pesticides for pest management, as well as a potential future in biotechnology.

Cimicifuga heracleifolia Kom. (C. heracleifolia) has demonstrated efficacy in treating gastrointestinal disorders, including splenasthenic diarrhea. Ulcerative colitis (UC), a chronic inflammatory bowel disease, shares similarities with splenasthenic diarrhea. However, the pharmacological effects of C. heracleifolia on UC and the underlying mechanisms remain unexplored.

The present study investigates the therapeutic potential and mechanisms of C. heracleifolia in UC.

Initially, network pharmacology analysis, encompassing ingredient screening, target prediction, protein-protein interaction (PPI) network analysis, and enrichment analysis, was employed to predict the mechanisms of C. heracleifolia. The findings were further validated using transcriptomics and functional assays in a dextran sulfate sodium (DSS)-induced UC model. Additionally, bioactive compounds were identified through surface plasmon resonance (SPR) analysis, molecular docking, and cell-based assays.

A total of 52 ingredients of C. heracleifolia were screened, and 32 key targets were identified within a PPI network comprising 285 potential therapeutic targets. Enrichment analysis indicated that the anti-UC effects of C. heracleifolia are mediated through immune response modulation and the inhibition of inflammatory signaling pathways. In vivo experiments showed that C. heracleifolia mitigated histological damage in the colon, reduced the expression of phosphorylated Akt1, nuclear factor-kappa B (NF-κB) p65, and inhibitor of Kappa B kinase α/β (IKKα/β), suppressed the content of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), and enhanced the expression of tight junction proteins. Moreover, cimigenoside, caffeic acid, and methyl caffeate were identified as the bioactive constituents responsible for the UC treatment effects of C. heracleifolia.

In summary, this study is the first to demonstrate that C. heracleifolia exerts therapeutic effects on UC by enhancing the intestinal mucosal barrier and inhibiting the phosphatidylinositol 3-kinase (PI3K)/AKT/NF-κB signaling pathway. These findings offer valuable insights into the clinical application of C. heracleifolia for UC management.

Cancer ranks among the top causes of illness and death globally. Nanotechnology holds considerable promise for enhancing the effectiveness of therapeutic and diagnostic approaches in cancer treatment. Our study presents a promising strategy for applying thiocompound nanomedicine in cancer therapy. Our first study aimed to investigate the biological properties of a new compound thiodiosgenin (TDG)-a new derivative of diosgenin-a natural compound with known antioxidant and anticancer properties. Our current second study aimed to compare the therapeutic efficacy of a new diosgenin-functionalized gold nanoparticles-with its precursor on prostate cancer (DU-145) cell lines. Moreover, the safety of the new thio-derivative and new conjugates was tested against the human epithelial line PNT-2. New advanced analytical techniques were developed for the characterization of nanomaterials using methods such as SP-ICP-MS, UV-Vis, TEM, NMR, FT-IR ELS, and TGA. Our synthetic approach was based, on the one hand, on the ligand exchange of citrates to thiodiosgenin (TDG) on gold nanoparticles, and on the other hand, on the attachment of DG through an ester bond to the linker, which was 3-mercaptopropionic acid (MPA) on gold nanoparticles. Initial in vitro studies indicate that TDG shows greater cytotoxic effects on cancer cells but poses risks to normal prostate epithelial cells (PNT-2). It was demonstrated that all the conjugates produced exhibited significant cytotoxic effects against cancer cells while being less harmful to normal prostate epithelial cells (PNT-2) compared to TDG itself. All the obtained conjugates showed antitumor properties; however, for targeted transport, the system referred to as AuNPs-MPAm1-DG is promising, due to the size of the nanoparticles of 53 nm, zeta potential of -30 mV, and loading content of 27.6%. New methods for synthesizing conjugates with diosgenin were developed and optimized for medical applications. Advanced new analytical methodologies were developed to characterize new conjugates, particularly the use of SP-ICP-MS, to solve existing differences in the shape and morphology of the surface of new conjugates.

Covering: 2016 to 2024Natural products, particularly cyclic peptides, are a promising source of bioactive compounds. Nonribosomal peptide synthetases (NRPSs) play a key role in biosynthesizing these compounds, which include antibiotic and anticancer agents, immunosuppressants, and others. Traditional methods of discovering natural products have limitations including cryptic biosynthetic gene clusters (BGCs), low titers, and currently unculturable organisms. This has prompted the exploration of alternative approaches. Synthetic-bioinformatic natural products (syn-BNPs) are one such alternative that utilizes bioinformatics techniques to predict nonribosomal peptides (NRPs) followed by chemical synthesis of the predicted peptides. This approach has shown promise, resulting in the discovery of a variety of bioactive compounds including peptides with antibacterial, antifungal, anticancer, and proteasome-stimulating activities. Despite the success of this approach, challenges remain especially in the accurate prediction of fatty acid incorporation, tailoring enzyme modifications, and peptide release mechanisms. Further work in these areas will enable the discovery of many bioactive peptides that are currently inaccessible.

The convergence of marine sciences and medical studies has the potential for substantial advances in healthcare. This study uses bibliometric and topic modeling studies to map the progression of research themes from 2000 to 2023, with an emphasis on the interdisciplinary subject of marine and medical sciences. Building on the global publication output at the interface between marine and medical sciences and using the Hierarchical Dirichlet Process, we discovered dominating research topics during three periods, emphasizing shifts in research focus and development trends. Our data show a significant rise in publication output, indicating a growing interest in using marine bioresources for medical applications. The paper identifies two main areas of active research, "natural product biochemistry" and "trace substance and genetics", both with great therapeutic potential. We used social network analysis to map the collaborative networks and identify the prominent scholars and institutions driving this research and development progress. Our study indicates important paths for research policy and R&D management operating at the crossroads of healthcare innovation and marine sciences. It also underscores the significance of quantitative foresight methods and interdisciplinary teams in identifying and interpreting future scientific convergences and breakthroughs.

Gut dysbiosis, chronic diseases, and microbial recurrent infections concerns have driven the researchers to explore phytochemicals from medicinal and food homologous plants to modulate gut microbiota, mitigate diseases, and inhibit pathogens. Gingerols have attracted attention as therapeutic agents due to their diverse biological activities like gut microbiome regulation, gastro-protective, anti-inflammatory, anti-microbial, and anti-oxidative effects.

This review aimed to summarize the gingerols health-promoting potential, specifically focusing on the regulation of gut microbiome, attenuation of disease symptoms, mechanisms of action, and signaling pathways involved.

Research findings from experimental and clinical studies have been summarized regarding gingerols effects on the modulation of gut microbiome and its metabolites, and attenuation of disease symptoms.

Gingerols are phenolic compounds characterized by a common 3-methoxy-4-hydroxyphenyl moiety in their chemical structures, and further divided into different gingerol types, including gingerols (major), shogaols, paradols, gingerdiols, gingerdiones, and zingerones (minor). Advanced extraction techniques (e.g., ionic liquid-based-, enzyme-assisted-, microwave-assisted-, pressurized liquid-, ultrasound-assisted-, and supercritical fluid extractions) were reported as optimal alternatives to conventional methods for gingerols extraction. Research studies reported that gingerols positively modulated the composition of gut microbiome that helped to combat disease symptoms (e.g., obesity by decreasing weight gain- (Lactobacillus reuteri and Lachnospiraceae) and increasing weight loss associated-bacteria (Akkermansia, Muribaculaceae, and Alloprevotella). Gingerols intervention also ameliorated ulcerative colitis by increasing relative abundance of the beneficial bacteria (Akkermansia, Lachnospiraceae NK4A136, and Muribaculaceae_norank), and decreasing pathogenic microorganisms (Bacteroides, Parabacteroides, and Desulfovibrio). Emerging delivery systems (e.g., microcapsules, nanoparticles, nanostructured lipid carriers, nanoemulsions, and nanoliposomes) can enhance the bioavailability and therapeutic efficacy of gingerols by preserving their inherent properties and addressing challenges of stability, solubility, and absorption.

Gingerols are promising therapeutic agents to modulate gut microbiome (increase beneficial bacteria and inhibit pathogenic microbes), and attenuate chronic disease symptoms such as diabetes, colitis, obesity, oxidative stress, and cancer. Despite significant progress, challenges persist in transforming research findings into industrial applications, such as stability and solubility during processing and low bioavailability in the distal gut to impart desirable health benefits.

Natural products are invaluable resources in drug discovery due to their substantial structural diversity. However, predicting their interactions with druggable protein targets remains a challenge, primarily due to the limited availability of bioactivity data. This study introduces CTAPred (Compound-Target Activity Prediction), an open-source command-line tool designed to predict potential protein targets for natural products. CTAPred employs a two-stage approach, combining fingerprinting and similarity-based search techniques to identify likely drug targets for these bioactive compounds. Despite its simplicity, the tool's performance is comparable to that of more complex methods, demonstrating proficiency in target retrieval for natural product compounds. Furthermore, this study explores the optimal number of reference compounds most similar to the query compound, aiming to refine target prediction accuracy. The findings demonstrated the superior performance of considering only the most similar reference compounds for target prediction. CTAPred is freely available at https://github.com/Alhasbary/CTAPred, offering a valuable resource for deciphering natural product-target associations and advancing drug discovery.

Citrus peel essential oils (CPEOs) have demonstrated substantial medicinal potential for glioblastoma treatment because of their extensive antitumor effects, low potential for drug resistance, and ability to cross the human blood-brain barrier. In this study, the chemical compositions of five CPEOs were analyzed via gas chromatography-mass spectrometry (GC-MS). CCK8 assays were used to evaluate the ability of five CPEOs to inhibit U251 human glioblastoma cells, and XLB and RA were selected for further investigation. Through wound healing assays and cell cycle and apoptosis analyses via flow cytometry, it was revealed that these CPEOs inhibited cell migration, arrested the cell cycle at G1/G0, and induced apoptosis with similar levels of inhibition. After CPEOs treatment, the intracellular Ca2+ content and reactive oxygen species levels in U251 cells increased significantly, whereas the mitochondrial membrane potential decreased. Additionally, the antioxidant enzyme system (SOD, POD, CAT, and GR) and the nonenzymatic defense system (GSH) were inhibited, leading to an increase in lipid peroxidation. qRT-PCR indicated the significant upregulation of intracellular calcium ion signaling pathways and the upregulation of mitochondrial apoptosis-related genes. Additionally, the activation of calcicoptosis-related indicators induced by the CPEOs could be reversed by inhibitor treatment, confirming that both of the selected CPEOs inhibit tumors by activating calcicoptosis-related pathways. These findings highlight the immense potential of CPEOs in healthcare and pharmaceutical applications by not only providing a scientific basis for the potential application of CPEOs in the treatment of glioblastoma but also offering new insights for the development of novel antitumor drugs.

Marine fungal natural products (MFNPs) are a vital source of pharmaceuticals, primarily synthesized by relevant biosynthetic gene clusters (BGCs). However, many of these BGCs remain silent under standard laboratory culture conditions, delaying the development of novel drugs from MFNPs to some extent. This review highlights recent efforts in genome mining and biosynthetic pathways of bioactive natural products from marine fungi, focusing on methods such as bioinformatics analysis, gene knockout, and heterologous expression to identify relevant BGCs and elucidate the biosynthetic pathways and enzyme functions of MFNPs. The research efforts presented in this review provide essential insights for future gene-guided mining and biosynthetic pathway analysis in MFNPs.

Target-based strategy is a prevalent means of drug research and development (R&D), since targets provide effector molecules of drug action and offer the foundation of pharmacological investigation. Recently, the artificial intelligence (AI) technology has been utilized in various stages of drug R&D, where AI-assisted experimental methods show higher efficiency than sole experimental ones. It is a critical need to give a comprehensive review of AI applications in drug R &D for biopharmaceutical field.

Relevant literatures about AI-assisted drug R&D were collected from the public databases (Including Google Scholar, Web of Science, PubMed, IEEE Xplore Digital Library, Springer, and ScienceDirect) through a keyword searching strategy with the following terms [("Artificial Intelligence" OR "Knowledge Graph" OR "Machine Learning") AND ("Drug Target Identification" OR "New Drug Development")].

In this review, we first introduced common strategies and novel trends of drug R&D, followed by characteristic description of AI algorithms widely used in drug R&D. Subsequently, we depicted detailed applications of AI algorithms in target identification, lead compound identification and optimization, drug repurposing, and drug analytical platform construction. Finally, we discussed the challenges and prospects of AI-assisted methods for drug discovery.

Collectively, this review provides comprehensive overview of AI applications in drug R&D and presents future perspectives for biopharmaceutical field, which may promote the development of drug industry.