Conventional paclitaxel (PTX) chemotherapy for hepatocellular carcinoma (HCC) is severely restricted by insufficient tumor-targeting specificity, unsatisfactory therapeutic efficacy, and marked systemic toxicity. To address these drawbacks, a redox-responsive and liver-targeted nanoplatform was designed for efficient PTX delivery in HCC therapy. Herein, we synthesized a disulfide-bridged amphiphilic glycyrrhetinic acid-indomethacin prodrug conjugate (GA-ss-IND), which could spontaneously self-assemble into uniform nanomicelles driven by hydrophobic interaction and van der Waals forces, as verified by molecular dynamics simulations. After PTX encapsulation, the fabricated PTX@GA-ss-IND nanomicelles (NMs) displayed regular spherical morphology and favorable colloidal stability. In vitro drug release experiments showed that the nanomicelles displayed prominent redox-responsive release behavior, achieving rapid and on-demand PTX release in high-glutathione intracellular tumor microenvironments. Benefiting from the glycyrrhetinic acid-mediated receptor targeting, cellular uptake assays and ex vivo organ imaging results demonstrated the prominent liver-targeting accumulation of PTX@GA-ss-IND NMs. In vitro cytotoxicity evaluation revealed that the fabricated nanosystem exhibited better antiproliferative activity against HepG2 cells compared with free PTX. Moreover, this nanoplatform effectively improved the in vivo bioavailability of PTX and reduced systemic adverse effecs. In conclusion, the constructed redox-responsive and liver-targeted nanodelivery system presents a feasible and promising strategy for precise and safe chemotherapy toward hepatocellular carcinoma.

Nonsteroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, frequently cause gastric injury, often characterized by ulceration. This study investigated the comparative gastroprotective effects of white quinoa and tri-color quinoa (a combination of red, black, and white varieties) in mitigating indomethacin-induced gastric damage in male rats. Thirty-six male rats were divided into dietary groups and administered quinoa-supplemented diets for 21 days before gastric injury was induced using indomethacin. Biochemical markers, including TNF-α and IL-6, were assessed, and molecular docking was employed to examine the interactions of quinoa-derived compounds, such as procyanidin B2 and cinchonain IB, with target proteins Atp4a, COX-2, and NF-κB. Tri-color quinoa demonstrated greater efficacy than white quinoa, reducing mucosal necrosis by 83%, attenuating oxidative stress, and significantly enhancing anti-inflammatory markers (p < 0.05). Furthermore, bioactive compounds showed strong binding affinities (-7.1 to -8.9 kcal/mol) to target proteins through hydrogen and hydrophobic interactions. Histological examination confirmed superior protection for the tri-color group, displaying near-normal mucosa (lesion score 0.4 vs. 2.4) and minimal submucosal edema. In conclusion, tri-color quinoa provides more effective protection against NSAID-induced gastric injury than white quinoa, likely due to its enhanced phytochemical profile and broader range of plant-derived compounds that collectively reduce inflammation and preserve gastric mucosal integrity.

Drug-induced hyperglycemia is an important metabolic complication that may arise when medications disrupt insulin secretion, insulin sensitivity, or glucose homeostasis. In obstetric practice, several commonly used drugs, including glucocorticoids, progesterone, antihypertensive agents, tocolytic drugs, and immunosuppressants, may impair glycemic control to varying degrees, and prolonged exposure may even lead to drug-induced diabetes mellitus. These effects are particularly important in pregnant women with pregestational diabetes, gestational diabetes, obesity, or other risk factors for dysglycemia.

Xanthostemon chrysanthus (F.Muell.) Benth. is a species from the Myrtaceae family with limited phytochemical and pharmacological studies. In this study, ten compounds (1-10) were isolated and purified from X. chrysanthus, among which compound 2, identified as des-O-methyllasiodiplodin (DML), exhibited the most potent anti-inflammatory activity. This is the first report of DML being isolated from this species. DML significantly inhibited lipopolysaccharide (LPS)-induced inflammation in RAW264.7 macrophages by reducing the expression of TNF-α, IL-1β, and IL-6, as well as nitric oxide (NO) and reactive oxygen species (ROS) production. Moreover, DML promoted autophagy by increasing LC3 II/LC3 I conversion and decreasing p62 expression, accompanied by suppression of the PI3K/AKT/mTOR signaling pathway. The autophagy inhibitor chloroquine (CQ) reversed these effects, confirming that DML exerts its anti-inflammatory action through autophagy activation. In a mouse ear edema model, DML effectively reduced inflammation, showing even greater efficacy than indomethacin. Collectively, this study provides the first evidence that DML isolated from X. chrysanthus exerts strong anti-inflammatory effects by promoting autophagy and modulation of the PI3K/AKT/mTOR pathway. These findings enrich the chemical and pharmacological understanding of X. chrysanthus and highlight DML as a promising natural candidate for the development of novel anti-inflammatory therapeutics.

Hemicrania continua-trigeminal neuralgia is a rare, but severe pain syndrome treated with a combination of indomethacin and carbamazepine. Combination therapy is often associated with high pill burden, which reduces patient compliance and compromises therapeutic outcomes. Fixed-dose combinations, which combine multiple drugs into a single formulation, address the issue of high pill burden by reducing the number of pills patients need to take, thereby improving patient compliance. However, both drugs exhibit poor aqueous solubility, which limits their oral bioavailability. To overcome this limitation, various formulation strategies have been developed, including amorphous solid dispersions (ASDs). This study aimed to address both challenges by developing multi-composed ASDs (MC-ASDs) containing indomethacin and carbamazepine dispersed within a single polymer matrix (PVPVA, PVP, or HPMC).The MC-ASDs as well as the corresponding binary ASDs were prepared by spray drying and characterized using modulated differential scanning calorimetry, X-ray powder diffraction and Fourier transform infrared spectroscopy. In vitro dissolution behaviour was evaluated using a USP II apparatus with a pH-shift method simulating gastrointestinal conditions, while physical stability was assessed for one month under stress conditions. MC-ASDs containing PVPVA and HPMC outperformed the crystalline counterparts and, for carbamazepine, even the binary ASDs. Furthermore, the MC-ASDs exhibited good physical stability. Overall, multi-composed ASDs represent a promising approach for the development of fixed-dose combinations of poorly water-soluble drugs.

Advanced wound dressings should actively promote tissue repair while preventing microbial infection and excessive inflammation. In this study, multifunctional electrospun nanofibers composed of poly(vinyl alcohol)/chitosan/gelatin were developed by incorporating green-synthesized mesoporous silica nanoparticles (MSNs), Acacia gum, and Hypericum perforatum extract (HPE). Biological activity and safety were evaluated using disk-diffusion antimicrobial testing, MTT cell viability assays, nitric oxide measurement in LPS-stimulated RAW 264.7 macrophages, an L929 fibroblast scratch assay, and Ames and comet assays. The optimized nanofibers exhibited a uniform morphology with an average fiber diameter of approximately 400 nm and high encapsulation efficiencies (86-96%). MSN incorporation significantly prolonged hypericin release, producing a biphasic release profile with approximately 1.4-fold slower release than nanofibers without MSNs, while increasing Young's modulus from 2.1 to 2.5 MPa. The hybrid nanofibers demonstrated broad-spectrum antimicrobial activity against Gram-positive bacteria, Gram-negative bacteria, and Candida albicans, achieving approximately 70% of the efficacy of standard antimicrobial agents. In lipopolysaccharide-stimulated RAW 264.7 macrophages, the optimized formulation reduced nitric oxide production by approximately 51%, comparable to indomethacin and L-NAME. Although fibroblast migration was not significantly enhanced, the nanofibers exhibited acceptable cytocompatibility and showed no mutagenic or genotoxic effects in Ames and comet assays. These findings demonstrate that green-synthesized MSN-enhanced herbal nanofibers represent a safe and promising platform for sustained drug delivery and advanced wound-healing applications.

Ziziphus lotus (L.) Lam (wild jujube) leaves are traditionally used in Moroccan medicine to treat hypertension. The present study evaluated the aqueous extract of Z. lotus leaves (ZLAqExt) for its vasorelaxant effects, mechanisms of action, acute toxicity, antioxidant potential, and phytochemical profile. In phenylephrine-precontracted rat aortic rings, the ZLAqExt induced concentration-dependent relaxation (Emax = 79.25 ± 2.77% at 10[-1] mg/mL). The mechanism of action was investigated using specific antagonists and blockers. Complete inhibition by endothelium denudation, and preincubation with L-NAME, hydroxocobalamin, ODQ, and thapsigargin confirmed endothelium-dependent nitric oxide (NO)/cyclic GMP (cGMP)/sarco/endoplasmic reticulum Ca[2+]-ATPase (SERCA) pathway involvement. A partial inhibition by BaCl2, indomethacin, calmidazolium, and KCl indicated cyclooxygenase (COX), endothelium-derived hyperpolarizing factor (EDHF), and inward-rectifier potassium (Kir) channel contributions. Acute oral toxicity did not show any mortality at 2 g/kg BW in mice. The extract displayed potent antioxidant activity (DPPH IC50: 18.12 ± 1.49 µg/mL; β-carotene bleaching IC50: 8.3 ± 0.014 µg/mL). UHPLC-ESI-MS identified rutin as the major compound, followed by 3',5'-di-C-β-glucopyranosyl phloretin with high docking affinity for guanylate cyclase and SERCA pump. The presence of flavonoids in the ZLAqExt might have mediated its vasorelaxant effects, supporting its traditional use as an antihypertensive. Our results highlight that Z. lotus is a potential natural therapeutic agent against vascular dysfunction-related cardiovascular disorders.

Salvia elegans Vahl. is used to treat inflammatory conditions; however, its direct anti-inflammatory activity has been scarcely investigated. This study evaluated the ethyl acetate extract (SeAcOEt) in vivo and in vitro, using the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse ear edema model, and the effects of selected isolated metabolites on inflammatory signaling by measuring NF-κB/AP-1-dependent SEAP reporter activity in LPS-stimulated RAW-Blue™ macrophages. Phytochemical characterization was performed using thin-layer chromatography, column chromatography, high-performance liquid chromatography (HPLC), mass spectrometry, and nuclear magnetic resonance (NMR). SeAcOEt yielded the following three fractions: SeFA, containing the terpene mixture rosifoliol (1)/agarospirol (2); SeFB, ursolic acid (3) and 7α-hydroxysandaracopimaric acid (4); and SeFC, jaceosidin (5) and isosakuranetin-5-O-rutinoside (6). SeAcOEt inhibited TPA-induced ear edema by 87.3%, whereas SeFB showed the highest activity (97.4%), comparable to indomethacin. The terpene mixture and 7α-hydroxysandaracopimaric acid reduced NF-κB/AP-1-dependent SEAP reporter activity in LPS-stimulated RAW-Blue™ macrophages. The anti-inflammatory activity of S. elegans could be associated with the combined contribution of phytochemicals enriched in the bioactive fraction SeFB rather than with a single active constituent. This study expands the phytochemical knowledge of S. elegans by reporting 7α-hydroxysandaracopimaric acid and provides pharmacological evidence supporting the traditional use of this species for inflammatory conditions.

Dietary strategies and plant-based fermented foods have attracted increasing interest for supporting gastrointestinal health, particularly under conditions of drug-induced mucosal stress. Soybean fermentation broth (SFB), a fermented soybean-derived product, may possess enhanced nutritional and functional properties through fermentation-associated generation of bioactive peptides and antioxidant metabolites. This study evaluated the gastroprotective effects of SFB in an indomethacin-induced gastric injury model in rats and investigated the underlying mechanisms. Indomethacin markedly induced gastric ulcer formation (16.61 ± 1.38 mm[2]), whereas SFB pretreatment significantly attenuated ulcer development in a dose-dependent manner, reducing ulcer area to 6.66 ± 0.98, 3.89 ± 0.63, and 1.46 ± 0.32 mm[2] in low-, medium-, and high-dose groups, respectively (p < 0.05 vs. Vehicle). Histopathological examination revealed that SFB preserved epithelial integrity and reduced submucosal edema. SFB pretreatment significantly decreased lipid peroxidation, restored gastric glutathione content, and enhanced antioxidant enzyme activities, including glutathione peroxidase (GPx), glutathione reductase (GRd), superoxide dismutase (SOD), and catalase (CAT). Furthermore, SFB suppressed pro-inflammatory mediator expression and favorably modulated cyclooxygenase-1 (COX-1) and COX-2 expression, accompanied by restoration of prostaglandin E2 (PGE2) production. These findings indicate that SFB protects gastric mucosa against indomethacin-induced injury through coordinated regulation of oxidative stress, inflammatory signaling, and prostaglandin-mediated mucosal defense, supporting its potential as a functional fermented soybean product.

Hemicrania continua is a primary headache disorder characterized by strictly unilateral pain, cranial autonomic features, and absolute responsiveness to indomethacin. Presentation as an acute stroke mimic with transient focal neurologic deficits is rare. We report a 40-year-old woman with a 4-year history of strictly right-sided headaches who presented with acute right-sided sensory marching and motor weakness, accompanied by ipsilateral facial flushing, sweating, and miosis. Emergent multimodal neuroimaging was negative; intravenous tenecteplase was administered for suspected ischemic stroke. Subsequent brain magnetic resonance imaging revealed no acute infarction. After the postthrombolysis safety window, an oral indomethacin trial led to complete headache resolution and rapid clearing of deficits. This case illustrates that hemicrania continua can manifest with hemiplegic features due to overlapping cortical spreading depression biology and highlights the diagnostic utility of an inpatient indomethacin trial.

At present, there are no US Food and Drug Administration (FDA)-approved tocolytics for the management of preterm labor. To identify drugs for repurposing as tocolytics, a phenotypic high-throughput screen against a library of 1191 FDA-approved drugs was performed for inhibitors of in vitro uterine myometrial contractions. A total of 51 drugs inhibited calcium (Ca[2+]) mobilization in primary human myometrial cells. To minimize potential off-target effects, hit drugs were counterscreened against primary human aortic vascular smooth muscle cells, identifying 10 uterine-selective drugs. Of these, two drugs, the antiemetic fosaprepitant dimeglumine and the glucocorticoid ciclesonide, displayed favorable in vitro therapeutic indices (TIs > 5), inhibited contractions in human myometrial tissue ex vivo, and did not alter tone in the fetal murine ductus arteriosus ex vivo. Next, the potential synergy among hit drugs and clinically used tocolytics was evaluated using a high-throughput combination screen based on Ca[2+] mobilization in primary human myometrial cells. Four synergistic drug combinations incorporating ciclesonide, indomethacin, ivermectin, atosiban, or nelfinavir mesylate displayed favorable TIs of >5 and improved ex vivo tocolytic potency, efficacy, or both. Last, aprepitant, ciclesonide, and four synergistic drug combinations delayed delivery until term and improved neonatal viability and skin and lung maturation in a mouse model of induced preterm labor, with several combinations outperforming their component drugs. This approach established a systematic strategy for identifying uterus-selective tocolytics, and these findings support further preclinical development of repurposed drugs and drug combinations for the treatment of preterm labor to improve pregnancy and neonatal outcomes.