Ingenane diterpenoids are a subgroup of Euphorbia diterpenes characterized by a tetracyclic 5/7/7/3 ring system. Their structural diversity primarily arises from variable acylation and hydroxylation at defined positions of the ingenane scaffold, particularly C-3, C-5, C-13, C-16, C-17, and C-20. This review aimed to provide an updated overview of ingenane diterpenoids published from January 2020 to November 2025, with a focus on their sources, structural features, biological properties, and structure-activity relationships. These compounds possess a wide range of biological properties, including cytotoxic, chemo-sensitizing, dermatological, keratinocyte-targeted, etc. These activities are mediated through multiple mechanisms, such as mitochondrial apoptosis, protein kinase C modulation, ROS-dependent autophagy, NF-κB/MAPK/Nrf2 and SRC/PI3K/Akt signaling, and regulation of lipid metabolism. Overall, the reported findings highlight that the structural diversity of the ingenane scaffolds has a central role in shaping their varied bioactivities through multi-target mechanisms. Although ingenane diterpenoids are known for their dermatological applications, accumulating evidence reveals their broader therapeutic potential in cancer therapy, immune-related conditions, metabolic regulation, and agrochemical uses. Nevertheless, further systematic studies focusing on pharmacokinetic, toxicological, and molecular target-validation, and long-term safety are required to support their progression toward preclinical and clinical applications.

Background and purpose: Rosanoid diterpenoids, including ent-rosane and rosane diterpenoids, are structurally unique and bioactive subclass diterpenes characterized by a tricyclic carbon skeleton. This work aims to provide a comprehensive review of the literature on these diterpenoids from 1975. to September 2025., including their occurrence, structural diversity, and biological activities. Approach: An extensive literature search was conducted through scientific databases (ScienceDirect, PubMed, Scopus, Web of Science, and Google Scholar) and publishers’ webpages (Elsevier, Wiley, ACS, RSC, Taylor & Francis, Springer, Bentham, Thieme, and MDPI), covering reports from 1975 to September 2025. Key Results: Rosanoid diterpenoids have been isolated from various natural sources, including fungi, liverworts, and higher plant families such as Euphorbiaceae, Lamiaceae, Alismataceae, Asteraceae, Velloziaceae, and Celastraceae. They are predominantly found in Euphorbia species, revealing their chemotaxonomic relevance to the Euphorbiaceae family. These compounds exhibit extensive structural diversity, encompassing a broad spectrum of biological activities, including anti-inflammatory, antimicrobial, antiviral, cytotoxic, enzyme-inhibitory, neuroactive, and anti-adipogenic effects. Conclusion: The reported findings highlight the chemical variability and pharmacological potential of rosanoid diterpenoids, making them promising building blocks for future drug discovery and natural product development. However, further studies are warranted to explore their pharmacokinetics, mechanisms of action, safety profiles, and biosynthetic pathways.

Celastrol (CELA) is a naturally occurring pentacyclic nortriterpenoid quinone found in Tripterygium wilfordii with diverse pharmacological activities. A major and constrictive adverse effect of cisplatin (CIS) is ovarian insufficiency, which affects both the reproductive and non-reproductive health. Current study investigated the ability of CELA to protect against CIS-induced ovarian toxicity in rats. Animals received CELA (0.5 and 1 mg/kg; orally) for 17 consecutive days and CIS (6.0 mg/kg; i.p.) on the 7th and 14th day of the study. CIS induced overt ovarian toxicity as indicated biochemically and histopathologically. CELA protected against CIS-induced reduction in the relative ovarian weight and serum levels of estradiol and anti-mullerian hormones. Co-treatment with CELA prevented the histopathological alterations in ovarian tissues and enhanced the fraction of healthy follicles. Further, it significantly ameliorated CIS-induced lipid peroxidation antioxidant enzyme exhaustion and inhibited the rise in the expression of the inflammatory markers; tumor necrosis factor-α, cyclooxygenase-2, inducible nitric oxide synthase, and nuclear factor kappa B. This was associated with modulation of Bax and Bcl-2 mRNA expression in favor of inhibition of apoptosis. Notably, co-treatment with CELA prevented CIS-induced reduction in both peroxisome proliferators–activated receptor-γ (PPAR-γ) and phospho-AMP-activated protein kinase (p-AMPK) content. In conclusion, CELA protects against CIS-induced ovarian toxicity in rats. This may be attributed, at least partly, to its antioxidant, anti-inflammatory, and anti-apoptotic activities in addition to enhancement of PPAR-γ and p-AMPK expression in ovarian tissues.

Irpex lacteus (Fr.) Fr. (white rot, milk-white toothed polypore) is a wood-decaying fungus belonging to Irpicaceae family. This fungus has been utilized as a folk remedy for hypertension, edema, and oliguria, and its polysaccharide fraction (Yishenkang) is clinically used to cure glomerulonephritis in China. Irpex lacteus biosynthesizes different classes of secondary metabolites, including sesquiterpenes, triterpenes, alkaloids, furan derivatives, azaphilones, and xanthones. Irpex lacteus has the potential to produce various enzymes with wide biotechnological relevance. The current review surveyed the reported metabolites from I. lacteus, including their structures and biological properties, as well as their biosynthetic pathways. Also, the biotechnological and industrial importance of I. lacteus has been discussed. In this work, 213 secondary metabolites were reported from this fungus from 1981 to June 2024. Meanwhile, these metabolites` bioactivities mainly involve antimicrobial, cytotoxic, anti-inflammatory, antioxidant, nematocidal, antifeedant, and anti-acetylcholinesterase. Interestingly, sesquiterpenoids constitute the main chemical compounds reported from I. lacteus, accounting for 46 percent (99 compounds). Irpex lacteus possesses marked potential applications in lignin degradation, bioremediation, bio-bleaching, ethanol production, and milk clotting.

Background: The colchicine-binding site on tubulin is of particular interest for new drug development due to its role in microtubule destabilization and potential to overcome resistance to other agents. Tiliroside, a naturally occurring flavonoid glycoside, has demonstrated anticancer potential in vitro, but its interaction with tubulin has not been previously elucidated. Objective: This study aimed to investigate the binding of tiliroside to the tubulin site of colchicine, in comparison with colchicine. Methods: Molecular docking and molecular dynamics (MD) simulations were employed. Induced-fit docking predicted tiliroside binding, and redocking of colchicine was used to validate the docking protocol. MD simulations (100 ns) were conducted for both tubulin–tiliroside and tubulin–colchicine complexes. Results: Induced-fit docking predicted that tiliroside binds strongly in the colchicine site, with more favorable scoring metrics than colchicine (Glide GScore –16.77 vs –10.25, and MMGBSA ΔGbind –50.46 vs –36.62 kcal/mol). Redocking of colchicine reproduced the binding pose (root-mean-square deviation (RMSD) ~0.6 Å). MD simulations further revealed that tiliroside forms a stable complex, remaining securely bound in the pocket. Tiliroside maintained multiple hydrogen bonds and hydrophobic contacts with tubulin, similar to or more persistent than those of colchicine. Conclusion: These results suggest that tiliroside can stably and snugly occupy the colchicine site of tubulin. In summary, our computational study provides structural and dynamic evidence that tiliroside is a high-affinity ligand for the colchicine site, supporting its potential as a lead compound for developing new tubulin-targeted anticancer agents.

The clinical use of 5-fluorouracil (5-FU) in cancer patients has been associated with nephrotoxicity, which is greatly curbing its therapeutic application. The pathogenesis of 5-FU-induced nephrotoxicity is complex; however, oxidative stress-mediated inflammation is considered a central pathogenic factor. Urolithin B (UB), a product of ellagitannins, has recently been assigned diverse pharmacological activities due to its potent antioxidant and anti-inflammatory properties. Therefore, the current study explored the potential renoprotective effect of UB on 5-FU-induced nephrotoxicity in mice and illuminated its potential mechanistic pathways. In this study, administration of UB (50 and 100 mg/kg) mitigated 5-FU-induced elevated levels of kidney injury indices, including renal somatic index, serum creatinine, blood urea nitrogen, and serum cystatin C, that were concurrent with histopathological improvement. UB maintained renal oxidant/antioxidant balance and enhanced the nuclear factor-erythroid-2-related factor-2 (Nrf2)/heme oxygenase 1 (HO-1) as well as the silent information regulator factor 2-related enzyme 1 (SIRT1)/forkhead box O 3 (FOXO3) antioxidant protective responses. On the other hand, 5-FU-driven activation of the NF-& kcy;B/TNF-alpha inflammatory signaling was opposed by UB administration. Conclusively, UB protected against 5-FU-induced nephrotoxicity through dose-dependent antioxidant and anti-inflammatory effects. These effects are mediated mainly through upregulating Nrf2/HO-1 and SIRT-1/ FOXO3 antioxidant responses with subsequent suppression of NF-kappa B inflammatory signaling.

BACE-1 is an encouraging target for the development of AD therapeutics. However, many BACE-1 inhibitors failed clinical trials due to their non-selectivity towards BACE-2 or adverse effects. Herein, a set of 96 benzothiazoles were designed based on the structural features of Atabecestat and Riluzole to find a promising selective BACE-1 inhibitor. Out of the 96 designed compounds, compound 72 showed comparable binding affinity with BACE-1 as compared to Atabecestat, and more selective towards BACE-1 as compared to BACE-2. The BACE-1 docking score of Atabecestat and compound 72 were found to be -7.76 and -7.49, respectively, while their corresponding MM-GBSA ΔGbind energy were -70.39 and -68.97 kcal/mol. In contrast, the BACE-2 docking score of Atabecestat and compound 72 were found to be -6.24 and -5.32, respectively, while their corresponding MM-GBSA ΔGbind energy were -56.02 and -43.46 kcal/mol. The strong binding affinity of compound 72 was further validated by 100 ns dynamics study. The physicochemical and pharmacokinetic (ADME) profile of compound 72 predicted it as an excellent orally bioavailable brain-penetrant molecule. To confirm these results, compound 72 was synthesized and spectrally characterized. The selectivity and inhibitory potential (IC50) of compound 72 was estimated by in vitro BACE-1 and BACE-2 FRET assay. Compound 72 was found to inhibit BACE-1 with IC50 121.65 nM, while it was found to be less potent on BACE-2 (IC50 480.92 nM), as compared to Atabecestat (BACE-1, IC50 13.25 nM and BACE-2, IC50 7.15 nM).

Background: Selective modulation of the serotonin 5-HT₂C receptor is a promising strategy for treating conditions, such as obesity and neuropsychiatric disorders. Aplysinopsins, a class of marine indole alkaloids, have emerged as potential 5-HT₂C-selective scaffolds. Objective: This work aims to assess the potential of aplysinopsin-based analogues as selective 5-HT₂C ligands. Methods: Here, we present conducted an in silico study of a library of aplysinopsin analogues and related indole alkaloids using induced-fit molecular docking, molecular dynamics (MD) simulations, and Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiling. Results: Dozens of analogues were docked into a serotonin receptor model, revealing sub-micromolar predicted binding affinities for several compounds. Top-ranked ligands, such as tubastrindole C, achieved docking scores around –12.7 kcal/mol and maintained stable binding poses in 100-ns MD simulations. Key ligand–receptor interactions included hydrogen bonding to the conserved Asp residue in the binding pocket and extensive π–π contacts with aromatic side chains. Notably, certain analogues with modest docking scores (e.g., N-propionyl-aplysinopsin) exhibited very favorable molecular mechanics generalized born surface area (MMGBSA) binding free energies, suggesting significant induced-fit effects upon binding. Predicted pharmacokinetic properties of the lead compounds were encouraging: all hits obeyed drug-likeness rules (0–1 Lipinski’s rule violations) and showed high oral absorption prospects. While polar analogues had limited blood–brain barrier permeability, several top candidates displayed moderate central nervous system (CNS) penetration scores. Conclusion: These results highlight aplysinopsin-based analogues as attractive selective 5-HT₂C ligand candidates and provide molecular insights to guide future optimization and experimental validation.

The hallmark of multiple sclerosis (MS) is neuronal demyelination. Glatiramer acetate (GA) injection is used in the management of MS. Nevertheless, it suffers unacceptable adverse reactions. Alternatively, nose-to-brain drug delivery escapes the blood–brain barrier. Diclofenac sodium (DCL), a non-steroidal anti-inflammatory drug, is used in MS pain management. The current study aimed to evaluate the neuroprotective effect of a nasally administrated glatiramer–diclofenac (GA-DCL) nanocomplex formula against cuprizone (CPZ)-induced demyelination in mice. By using Box–Behnken design, a GA-DCL optimized nanoconjugate was characterized and formulated in gellan gum in situ gel. DCL, GA, and the optimized GA-DCL formula were administrated intra-nasally, while cuprizone (CPZ) was given orally for six weeks. All mice were subjected to behavioral, histopathological, and biochemical investigations. The optimized GA-DCL nanocomplex prepared at a molar ratio of 1:1.4 was characterized with respect to particle size (198.21 ± 11.60 nm) and zeta potential (34.53 ± 2.13 mV). GA-DCL nanocomplex showed superior neuroprotective activities than either drug alone against CPZ toxicity. This was evidenced by inhibiting CPZ-induced body weight loss, motor impairment, oxidative stress, neuronal demyelination and inflammation. The optimized GA-DCL nasal formula exhibits higher neuroprotective activity than either drug alone in the CPZ mice model of MS. These findings warrant further experimental and clinical studies.

The journal retracts the article, “The Enhanced Cytotoxic and Pro-Apoptotic Effects of Optimized Simvastatin-Loaded Emulsomes on MCF-7 Breast Cancer Cells” [...]

Alzheimer's disease (AD) is one of the most pervasive and progressive neurodegenerative disorders. Recently, empagliflozin (EMPA) has been reported as a potent anti-inflammatory and antioxidant in neuroinflammatory disorders apart from antidiabetic activity. To use EMPA for neuroinflammation-associated AD, EMPA must first cross blood-brain barrier (BBB). Hence, an optimized EMPA-nanoemulsion (EMPA-NE) was formulated by applying Box-Behnken experimental design (BBD) approach. The focus of this investigation was to develop, optimize, and evaluate EMPA-NE for the management of neuroinflammation-associated AD. The experimental EMPA-NE had a particle size of 136.1 nm, 0.281 PDI, and zeta potential of -23.9 mV. The lower viscosity of optimized NE showed its usefulness for oral administration. The dispersibility and thermodynamic analysis showed NE stability under different environmental conditions. The release study demonstrated steady, regulated drug release after initial fast drug release from NE. In addition, a stability study of optimized EMPA-NE showed no notable changes in drug content, particle sizes, PDI, and zeta potential. Histopathological estimation showed cells with normal characteristics in EMPA-NE-treated group versus the EMPA-treated group. Antioxidant studies demonstrated a significant increment of SOD (p < 0.001), and CAT (p < 0.001) levels, and a reduction in MDA content (p < 0.001) and effective reversal of high AchE levels (p < 0.001) was also found in EMPA-NE-treated group as compared to LPS treated group. Treatment with EMPA-NE caused a marked reduction in Iba1 molecule and GFAP expression levels, thus demonstrating the anti-inflammatory and neuroprotective potency of EMPANE. Therefore, this study reveals promising antioxidant and anti-inflammatory properties of EMPA-NE, which could provide an effective approach to the management of neuroinflammation-associated AD.

The crop phosphorus (P) utilization efficiency of commercial fertilizers is only 10–15

The journal retracts the article "Chitosan-Based Microparticles Enhance Ellagic Acid's Colon Targeting and Proapoptotic Activity" [...].

Fulminant hepatic failure (FHF) is the terminal phase of acute liver injury, which is characterized by massive hepatocyte necrosis and rapid hepatic dysfunction in patients without preexisting liver disease. There are currently no therapeutic options for such a life-threatening hepatic failure except liver transplantation; therefore, the terminal phase of the underlying acute liver injury should be avoided. Tomatidine (TOM), asteroidal alkaloid, may have different biological activities, including antioxidant and anti-inflammatory effects. Herein, the lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced FHF mouse model was established to explore the protective potential of TOM and the underlying mechanisms of action. TOM pretreatment significantly inhibited hepatocyte necrosis and decreased serum aminotransferase activities in LPS/D-GalN-stimulated mice. TOM further increased the level of different antioxidant enzymes while reducing lipid peroxidation biomarkers in the liver. These beneficial effects of TOM were shown to be associated with targeting of NF-κB signaling pathways, where TOM repressed NF-κB activation and decreased LPS/D-GalN-induced TNF-α, IL-6, IL-1β, and iNOS production. Moreover, TOM prevented LPS/D-GalN-induced upregulation of Keap1 expression and downregulation of Nrf2 and HO-1 expression, leading to increased Nrf2-binding activity and HO-1 levels. Besides, TOM pretreatment repressed LPS/D-GalN-induced upregulation of proliferating cell nuclear antigen (PCNA) expression, which spared the hepatocytes from damage and subsequent repair following the LPS/D-GalN challenge. Collectively, our findings revealed that TOM has a protective effect on LPS/D-GalN-induced FHF in mice, showing powerful antioxidant and anti-inflammatory effects, primarily mediated via modulating Keap1/Nrf2/HO-1 and NF-κB/TNF-α/IL-6/IL-1β/iNOS signaling pathways.

Abstract Background α-Mangostin is a major xanthone in Garcinia mangostana L. (Clusiaceae) pericarps. It has promising anti-proliferative potential in different cancer cells; however, it has poor oral bioavailability. Phytosomes are used as a novel nano-based drug delivery system. The aim of this research was to enhance the anti-proliferative potency of α-mangostin by formulating it as α-mangostin-phytosome (α-M-PTMs) and assessing its impact on SKOV-3 ovarian cancer cells in comparison to pure α-mangostin. Results The size and entrapment efficiency of the proposed formulation were optimized using Box–Behnken statistics. The optimized formula was characterized using transmission electron microscope. The binding of α-mangostin to phospholipids was confirmed using Fourier-transform infrared (FTIR) spectroscopy. The optimized α-mangostin-phytosomes formula exhibited enhanced anti-proliferative activity with reference to raw α-mangostin. This was further substantiated by assessing the cell cycle phases that indicated an accumulation of SKOV-3 cells in the sub-G1 phase. Annexin-V staining revealed enhanced apoptotic activity in α-mangostin-phytosome-treated cells. This was associated with upregulation of CASP3 (Caspase-3), BAX (BCL2 Associated X, Apoptosis Regulator) and TP53 as well as down-regulation of BCL2 mRNA (B-Cell Leukemia/Lymphoma 2). Moreover, our data indicated enhanced ROS (Reactive oxygen species) production, cytochrome-C release, and disturbed MMP (mitochondrial membrane potential). Conclusion Encapsulation of α-mangostin in a phytosome nano-formula enhances its anti-proliferative effects in SKOV-3 cells via, at least in part, inducing mitochondrial apoptotic cell death.

Pulmonary fibrosis is a chronic and progressively deteriorating lung condition that can be replicated in laboratory animals by administering bleomycin, a chemotherapeutic antibiotic known for its lung fibrosis-inducing side effects. L-arginine, a semi-essential amino acid, is recognized for its diverse biological functions, including its potential to counteract fibrosis. This study aimed to evaluate the antifibrotic properties of L-arginine on bleomycin-induced pulmonary fibrosis in rats. The administration of a single intratracheal dose of bleomycin resulted in visible and microscopic damage to lung tissues, an uptick in oxidative stress markers, and an elevation in inflammatory, apoptotic, and fibrotic indicators. A seven-day treatment with L-arginine post-bleomycin exposure markedly improved the gross and histological architecture of the lungs, prevented the rise of malondialdehyde and carbonyl content, and enhanced total antioxidant capacity alongside the activities of antioxidant enzymes. Also, L-arginine attenuated the expression of the pro-fibrotic factors, transforming growth factor-beta and lactate dehydrogenase in bronchoalveolar lavage fluid. In the lung tissue, L-arginine reduced collagen deposition, hydroxyproline concentration, and mucus production, along with decreasing expression of alpha-smooth muscle actin, tumor necrosis factor-alpha, caspase-3, matrix metalloproteinase-9, and beta-catenin. Moreover, it boosted levels of nitric oxide and upregulated the expression of peroxisome proliferator-activated receptor-gamma (PPAR-gamma), heme oxygenase-1 (HO-1), and E-cadherin and downregulating the expression of beta-catenin. These findings suggest that L-arginine has preventive activities against bleomycin-induced pulmonary fibrosis. This effect can be attributed to the increased production of nitric oxide, which modulates the HO-1/PPAR-gamma/beta-catenin axis.