Search Results (130)

Background/Objectives: Insomnia is a prevalent clinical sleep disorder, with existing hypnotic therapies limited by safety concerns. There is an urgent clinical need for new safe, effective sleep-promoting candidates derived from natural products. Spinosin is one of the main active components of Semen Ziziphi Spinosae that exerts sedative and hypnotic effects. The adenosine receptor (AR) has been reported as a potential therapeutic target for insomnia; however, the hypnotic effect of spinosin through the A_2AR remains to be elucidated. Methods: In the study, the involvement of A_2ARs in spinosin’s hypnotic effect was investigated using caffeine and further elucidated in A_2AR-knockout (KO) mice. Diazepam was used as a positive control drug to validate the experimental model and evaluate the hypnotic effect of spinosin. Molecular docking and molecular dynamics (MDs) simulations were performed to validate the interaction of spinosin with the A_2AR. Results: The hypnotic effects of spinosin were effectively antagonized by caffeine. Compared with A_2AR-wild-type (WT) mice, spinosin-induced non-rapid eye movement (NREM) sleep and locomotor activity diminution were significantly reduced in A_2AR-KO mice. Spinosin significantly increased the activity of γ-aminobutyric acid (GABA)ergic medium spiny neurons (MSNs) in the nucleus accumbens (NAc) and significantly decreased the activity of orexin neurons in the lateral hypothalamus (LH), as revealed by c-Fos immunostaining. These effects were significantly reversed by caffeine pretreatment or in A_2AR-KO mice. Finally, the results of molecular docking showed that spinosin had a good binding potential with the A_2AR. MD simulations further demonstrated that spinosin had strong binding stability with the A_2AR. Conclusions: Our findings strongly suggest that spinosin exerts the hypnotic effects through the A_2AR, and thus may have therapeutic potential for insomnia. Our identification of spinosin’s direct molecular target supports its translational potential as a novel natural-origin candidate for clinical insomnia drug development. Full article

Background/Objectives: Metabolic dormancy in biofilms leads to reduced drug efficacy in these communities. Different pharmacokinetics and adverse side effects complicate the simultaneous delivery of multiple drugs at appropriate concentrations to the infection site. This study aimed to develop chitosan-coated mesoporous silica nanoparticles loaded with curcumin and amphotericin B (CS@MSNs-Cur-AmB) and to evaluate their antibiofilm activity combined with antimicrobial photodynamic therapy (PDT) against Streptococcus mutans and Candida albicans dual-species biofilms. Methods: CS@MSNs-Cur-AmB were developed. The structure and morphology of the nanoparticles were evaluated using Fourier transform-infrared spectroscopy (FTIR), zeta potential, field emission scanning electron microscopy (FESEM), and thermogravimetric analysis (TGA). Cytotoxicity toward human gingival fibroblasts was assessed. Colony-forming units per milliliter (CFU/mL) were determined. The metabolic activity of biofilm-forming cells was measured using the tetrazolium (MTT) assay. Results: Physicochemical analyses confirmed the synthesis of CS@MSNs-Cur-AmB, revealing a particle size of 228 nm and thermal stability up to 600 °C. Cytotoxicity assays showed that CS@MSNs-Cur-AmB exhibited good biocompatibility (>90%). CS@MSNs-Cur-AmB improved antimicrobial activity, which was further enhanced by blue light-emitting diode (LED) irradiation. CS@MSNs-Cur-AmB under LED irradiation showed the strongest effect, reducing metabolic activity to 27.74 ± 4.08% (1 W/cm², 1 min), p < 0.001). Conclusions: Formulating two drugs in nanocarrier systems may improve therapeutic efficacy by increasing local concentration and reducing systemic exposure. This offers an effective strategy for combating oral biofilms. Full article

Background: Quercetin (Q) can reduce cellular oxidative stress, though it is susceptible to degradation in physiological conditions. Through adsorption and protection of Q, mesoporous silica nanoparticles (MSNs) could enhance its bioactivity. This work aimed to determine the effect of Q loading in MSN and in its aminated (A-MSN), carboxylated (C-MSN) or thiolated (T-MSN) derivatives on its Caco-2-cytoprotective effect against H₂O₂-induced oxidative stress. Methods: The mesoporous silica materials were characterized (FT-IR, ζ-potential, TGA), and their cytotoxicity was assessed; then, they were loaded with Q and incubated with Caco-2 cells prior to oxidative stress induction, and the cytoprotective effect was evaluated through measurement of cell viability. Results: None of the nanoparticles showed toxicity to Caco-2 cells. A-MSN showed the highest Q loading capacity (5.26% ± 0.06%), due to hydrogen-bonding interactions. C-MSN clearly enhanced the Q cellular uptake compared to the other nanoparticles. Oxidative stress decreased Caco-2 cell viability, which was prevented by 100 µM free Q after 18 h incubation. In contrast, higher cell viability than in non-stressed cells was observed with the same Q concentration loaded across all nanoparticle types. Conclusions: Despite the high instability of free quercetin under cell culture conditions, it exerted a time-dependent cytoprotective effect against H₂O₂-induced oxidative stress that was enhanced upon loading into nanoparticles. Prior release of the Q molecule in the medium is ineffective, and the presence of the loaded material is required. Full article

Background/Objectives: Cisplatin (CDDP) is widely used in the treatment of non-small cell lung cancer (NSCLC); however, its clinical efficacy is limited by severe systemic toxicity. Hyaluronic acid (HA) modification enables the targeting of CD44-overexpressing cancer cells, enhances biocompatibility, provides controlled drug release, and prolongs systemic circulation. This study aimed to develop high-molecular-weight hyaluronic acid-modified, cisplatin-loaded mesoporous silica nanoparticles (HA-MSN-CDDP) to selectively target CD44-overexpressing lung adenocarcinoma cells. Methods: HA-MSN-CDDP nanoparticles were synthesized via the sol–gel method and characterized by FTIR, DLS, SEM, and TEM methods. Antitumor efficacy was evaluated using both in vitro and in vivo xenograft lung cancer models in mice. Results: HA modification enabled controlled and sustained release of cisplatin from the HA-MSN-CDDP drug delivery system. Through HA-mediated receptor-dependent endocytosis, the nanoparticles exhibited enhanced cellular uptake and selective cytotoxicity toward CD44-positive cells. HA-MSN-CDDP significantly reduced the cytotoxic, genotoxic, and oxidative stress effects of free cisplatin on healthy cells while markedly enhancing apoptosis in A549-Luc-C8 cells. The system showed excellent hemocompatibility, supporting its potential for intravenous use. In vivo, HA-MSN-CDDP effectively suppressed tumor growth, mitigated lipid peroxidation, and preserved antioxidant enzyme activities (SOD and CAT) in major organs. Histological analyses confirmed reduced cisplatin-induced nephrotoxicity. Conclusions: HA-MSN-CDDP demonstrates strong potential as a targeted chemotherapeutic platform for NSCLC, combining high antitumor efficacy with reduced systemic toxicity. Full article

Folate receptor alpha is expressed at low levels in normal tissues, but is elevated in aggressive breast cancer types and can be utilized for targeted nanoparticle delivery. Hence, we prepared a hybrid nanocarrier based on in-house synthesized mesoporous silica nanoparticles (MSNs) which were further lipid-coated and reinforced with folic acid (FA). Thorough physicochemical evaluation was performed including dynamic light scattering (DLS), powder x-ray diffraction (PXRD), thermogravimetric analysis (TGA), and nitrogen physisorption. In vitro dissolution of the model drug doxorubicin was carried out in release media with pH 7.4 and pH 5.5. The cytotoxic potential and cellular uptake were investigated in MCF-7 breast cancer cells via the MTT assay, doxorubicin fluorescence measurement, and microscopy. The potential amelioration of doxorubicin’s cardiotoxicity was evaluated in vitro on the H9c2 cell line. The results showed MSNs with significant pore volume (1.38 cm³/g) and relatively small sizes (98.05 ± 1.34 nm). The lipid coat and FA attachment improved the physicochemical stability and sustained release pattern over 24 h. MSNs were non-toxic, while when doxorubicin-loaded, they caused moderate cytotoxicity. The highest cytotoxic activity was observed with folate-functionalized, doxorubicin-loaded nanoparticles (NPs). Even though non-loaded folate-functionalized NPs exhibited significant cytotoxicity, their physical mixture with doxorubicin was inferior in MCF-7 cytotoxicity as opposed to the corresponding loaded nanocarrier. Fluorescence-based quantification showed a higher intracellular accumulation of doxorubicin when delivered via NPs. These results demonstrate the potential to use folate-functionalized NPs as carriers for doxorubicin delivery in breast cancer cells. Its cardiotoxicity was significantly reduced in the case of loading onto the folic acid-functionalized lipid-coated MSNs. All these findings provide a promising proof-of-concept, although further experimental validation, particularly regarding targeting selectivity and safety, is required. Full article

Background: Natural compounds, including ellagic acid (ELG), are promising anticancer agents with low adverse effects. In this paper, we test in vitro the effectiveness of mesoporous silica nanoparticles (MSN) as an ELG carrier against colon cancer. Methods: We produced MSNs functionalized with triptycene (TRP) and loaded with ELG, further called MSNTRPELG nanoformulation. The nanoformulation contained over 11 wt.% TRP and approximately 25 wt.% ELG in the mesoporous structure and on the surface of particles. It was assessed for anticancer effects against two colon cancer cells: HCT-116 and HT-29 for treatment with up to 200 µM. Results: Comparing to free ELG, we have shown a three times higher cancer inhibition. The lowest IC50 values were for HCT-116 (88.1 ± 0.1 µM) and HT-29 (77.6 ± 0.1 µM). When treated with free ELG, the values were 187.1 ± 0.1 µM and 300.0 ± 0.1 µM, respectively. MSNTRPELG enhanced apoptosis primarily by activating caspase-3, p53, and Bax while downregulating Bcl-2 in HCT-116 and HT-29 cells. It also inhibited receptor tyrosine kinases (HER2 and VEGFR2). Preliminary Western blot observations suggest suppression of B-RAF, C-RAF, and K-RAS oncogenes, with stronger inhibition by the nanoformulation than by free ELG. Conclusions: This work highlights the potential of MSNs to enhance the efficacy of natural prodrugs, particularly ELG, in cancer therapy. Full article

Functional foods like flax (Linum usitatissimum L.) are rich sources of specialized metabolites that contribute to their nutritional and health-promoting properties. Understanding the biosynthesis of these compounds is essential for improving their quality and potential applications. However, dissecting complex metabolic networks in plants remains challenging due to the dynamic nature and interconnectedness of biosynthetic pathways. In this study, we present a synergistic approach combining stable isotopic labeling (SIL), Candidate Substrate–Product Pair (CSPP) networks, and a time-course study with high temporal resolution to reveal the biosynthetic fluxes shaping phenylpropanoid metabolism in young flax seedlings. By feeding the seedlings with ¹³C₃-p-coumaric acid and isolating isotopically labeled metabolization products prior to the construction of CSPP networks, the biochemical validity of the connections in the network was supported by SIL, independent of spectral similarity or abundance correlation. This method, in combination with multistage mass spectrometry (MSⁿ), allowed confident structural proposals of lignans, neolignans, and hydroxycinnamic acid conjugates, including the presence of newly identified chicoric acid and related tartaric acid esters in flax. High-resolution time-course analyses revealed successive waves of metabolite formation, providing insights into distinct biosynthetic fluxes toward lignans and early lignification intermediates. No evidence was found here for the involvement of chlorogenic or caftaric acid intermediates in chicoric acid biosynthesis in flax, as has been described in other species. Instead, our findings suggest that in flax seedlings, chicoric acid is synthesized through successive hydroxylation steps of p-coumaroyl tartaric acid esters. This work demonstrates the power of combining SIL and CSPP strategies to uncover novel metabolic routes and highlights the nutritional potential of flax sprouts rich in chicoric acid. Full article

To address critical technical challenges in coalbed methane fracturing, including the uncontrollable release rate of conventional breaker agents and incomplete gel breaking, this study designs and fabricates an intelligent controlled-release breaker system based on paraffin-coated mesoporous silica nanoparticle carriers. Three types of mesoporous silica (MSN) carriers with distinct pore sizes are synthesized via the sol-gel method using CTAB, P123, and F127 as structure-directing agents, respectively. Following hydrophobic modification with octyltriethoxysilane, n-butanol breaker agents are loaded into the carriers, and a temperature-responsive controlled-release system is constructed via paraffin coating technology. The pore size distribution was analyzed by the BJH model, confirming that the average pore diameters of CTAB-MSNs, P123-MSNs, and F127-MSNs were 5.18 nm, 6.36 nm, and 6.40 nm, respectively. The BET specific surface areas were 686.08, 853.17, and 946.89 m²/g, exhibiting an increasing trend with the increase in pore size. Drug-loading performance studies reveal that at the optimal loading concentration of 30 mg/mL, the loading efficiencies of n-butanol on the three carriers reach 28.6%, 35.2%, and 38.9%, respectively. The release behavior study under simulated reservoir temperature conditions (85 °C) reveals that the paraffin-coated system exhibits a distinct three-stage release pattern: a lag phase (0–1 h) caused by paraffin encapsulation, a rapid release phase (1–8 h) induced by high-temperature concentration diffusion, and a sustained release phase (8–30 h) attributed to nano-mesoporous characteristics. This intelligent controlled-release breaker demonstrates excellent temporal compatibility with coalbed methane fracturing processes, providing a novel technical solution for the efficient and clean development of coalbed methane. Full article

The phytochemical investigation and evaluation of the antioxidant activity of the leaves, bark, and roots of Cochlospermum angolense Welw ex Oliv—a valued plant that is widely used in traditional Angolan medicine—hold significant importance. Compounds were extracted from the aforementioned plant using acetone and ethanol and identified by HPLC-ESI-MSn. Both extracts demonstrated notable abilities to scavenge 2,2-diphenyl-1-picrylhydrazyl, nitric oxide, and superoxide radicals, as well as to inhibit lipid peroxidation. A HPLC analysis revealed a diverse array of bioactive compounds, including flavonoids, phenols, alkaloids, quinones, and terpenes, which help neutralize free radicals and protect cells against oxidative stress, thereby contributing to the prevention of various diseases. Moreover, the acetone and ethanol extracts proved to be excellent sources of antioxidants. For the first time, the present study identified new compounds never reported in this species, such as (+)-abscisic acid, angustine B, pinobanksin, dihydrogenistein, (−)-8-prenylnaringenin, isoquercetin, samandarine, dihydromyricetin, and eupatoriocromene, in the leaves, bark, and roots, marking a significant advance in the chemical characterization of C. angolense. These findings enhance our understanding of the bioactive phytochemicals and antioxidant properties of C. angolense and open new avenues for future therapeutic and pharmacological research, further supporting its traditional use in Angolan medicine. Full article

Carpesium cernuum L., the most widespread representative of the genus Carpesium, has been traditionally used in some regions of Asia as a remedy for various ailments or as a vegetable. Although the plant is distributed in Europe, there is no data on its medicinal use in this part of the world. The chemical composition of European Carpesium cernuum L. has remained unknown until now, except for the compositions of essential oils distilled from the roots and aerial parts of the plant. Polyphenolic profiles of hydroalcoholic extracts from C. cernuum were studied using the HPLC-MSⁿ technique. The analysis revealed the presence of 24 hydroxycinnamates, which were dominated by caffeoylquinic and caffeoylhexaric acids. Moreover, fractionation of the chloroform extracts from the plant led to the isolation of three new compounds, 8α-angeloyloxy-4β-hydroxy-5β-(3-methylbutyryloxy)-9-oxo-germacran-6α,12-olide, 9β-angeloyloxy-4β,8α-dihydroxy-5β-(3-methylbutyryloxy)-3-oxo-germacran-6α,12-olide, and a dihydrobenzofuran derivative, together with twelve known compounds. 8-Hydroxy-9,10-diisobutyryloxythymol, a monoterpenoid thymol derivative from the roots of the plant, was evaluated for potential neuroprotective and cytotoxic activities using differentiated and undifferentiated SH-SY5Y neuroblastoma cells. At a concentration range of 1–10 μM, the compound provided partial (up to 50%) protection against H₂O₂-induced cell damage in the undifferentiated cells. At concentrations higher than 25 μM, the monoterpenoid significantly reduced the viability of the cells (IC₅₀: 65.7 μM for the undifferentiated cells and 40.9 μM for the differentiated cells). Full article

The incidence of fungal infections is significantly rising, posing a challenge due to the limited class of antifungal drugs. There is a necessity to combat emerging resistant fungal infections by developing novel antifungal agents. This study aimed to evaluate the antifungal effects of lawsone (LAW), a natural component extracted from herbal medicine, and LAW-loaded mesoporous silica nanoparticles (LAW-MSNs) on growth, biofilm formation, and expression of ALS1 and EPA1 genes contributing to cell adhesion of Candida spp. Twenty C. albicans and twenty C. glabrata isolates, including ten fluconazole-resistant and ten fluconazole-susceptible isolates, were examined. The findings of the study indicated that LAW and LAW-MSNs inhibited Candida isolates growth at MIC range of 0.31–>5 µg/mL and significantly reduced biofilm formation in C. albicans and C. glabrata. Moreover, both LAW and LAW-MSNs downregulated the expression of the adhesion genes ALS1 and EPA1 in C. albicans and C. glabrata. Based on the obtained findings, LAW emerged as a promising antifungal candidate. However, the nano-formulation (LAW-MSNs) improved its antifungal properties. Full article

Familial Alzheimer’s disease (FAD) is a complex multifactorial disorder clinically characterized by cognitive impairment and memory loss. Pathologically, FAD is characterized by intracellular accumulation of the protein fragment Aβ42 (iAβ), hyperphosphorylated microtubule-associated protein TAU (p-TAU), and extensive degeneration of basal forebrain cholinergic neurons of the nucleus basalis of Meynert (NbM) and the medial septal nucleus (MSN), mainly caused by mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1), and PSEN2 gene. Since the dopaminergic system may contribute to FAD symptoms, alterations in the nigro-hippocampal pathway may be associated with cognitive impairment in FAD. Interestingly, p-α-synuclein (p-α-Syn), Aβ, and p-TAU have been found to coexist in vulnerable regions of postmortem AD brains. However, the mechanism by which Aβ, p-TAU, and α-Syn coexist in DAergic neurons in AD brains has not been determined. We generated PSEN1 I416T dopaminergic-like neurons (DALNs) from I416T menstrual stromal cells (MenSCs) in NeuroForsk 2.0 medium for 7 days and then cultured them in minimal culture medium (MCm) for another 4 days. On day 11, DALNs were analyzed for molecular and pathological markers by flow cytometry and fluorescence microscopy. We found that mutant DALNs showed increased accumulation of iAβ as well as increased phosphorylation of TAU at S202/T205 compared to WT DALNs. Thus, mutant DALNs exhibited typical pathological hallmarks of Alzheimer’s disease. Furthermore, PSEN1 I416T DALNs showed concomitant signs of OS as evidenced by the appearance of oxidized sensor protein DJ-1 (i.e., DJ-1C106-SO₃) and apoptotic markers TP53, pS63-c-JUN, PUMA, and cleavage caspase 3 (CC3). Notably, these DALNs exhibited PD-associated proteins such as intracellular accumulation of α-Syn (detected as aggregates of pS129-α-Syn) and phosphorylation of LRRK2 kinase at residue S935. In addition, mutant DALNs showed a 17.16- and 6.17-fold decrease in DA-induced Ca²⁺ flux, compared to WT DALNs. These observations suggest that iAβ and p-TAU, together with p-α-Syn, and p-LRRK2 kinase, may damage DAergic neurons and thereby contribute to the exacerbation of neuropathologic processes in FAD. Remarkably, the LRRK2 inhibitor PF-06447475 (PF-475) significantly reversed PSEN1 I416T-induced neuropathological markers in DAergic neurons. PF-465 inhibitor reduced iAβ, oxDJ-1C106-SO₃, and p-TAU. In addition, this inhibitor reduced pS935-LRRK2, pS129-αSYN, pS63-c-JUN, and CC3. We conclude that the observed neuroprotective effects of PF-475 are due to direct inhibition of LRRK2 activity and that the LRRK2 protein is upstream of the molecular cascade of apoptosis and proteinopathy. Our results suggest that PF-475 is an effective neuroprotective agent against endogenous PSEN1 I416T-induced neurotoxicity in DALNs coexisting with Parkinson’s disease markers. Therefore, PF-475 may be of great therapeutic value in FAD. Full article

Cardiomyopathies, a cause of heart failure, are a predominant cause of death globally and may lead to discernible myocardial abnormalities. Several therapeutic agents were discovered, developed, investigated, and evaluated to save patients’ lives and improve their quality of life. The effective administration of drugs improves therapeutic outcomes while reducing side effects. Nanoparticles (NPs) have been utilised for the delivery of therapeutic agents and demonstrate promise in reducing myocardial ischaemia/reperfusion injury. However, significant limitations of NPs include non-specific targeting and immunogenicity. To improve cardiac targeting and biocompatibility, surface modifications using a cardiac cell membrane (cCM) coating on the surface of NPs have been hypothesised. Here, cCMs were isolated from the human ventricular cell line (AC16), and mesoporous silica nanoparticles (MSNs) were synthesised and then coated with cCMs. The cardiac cell membrane-coated mesoporous silica nanoparticles (cCMCMSNs) did not significantly alter the encapsulation efficiency or the release profile of the loaded drug (Rhodamine B) in comparison to MSN. Moreover, cCMCMSNs demonstrated a significantly enhanced distribution of RhB specifically to cardiac cells, compared to other cell types, without causing cytotoxicity. To evaluate immune escape, cCMCMSNs were exposed to activated macrophages, demonstrating that cCMCMSNs were phagocytosed to a lesser extent than MSN. This study demonstrated the synthesis of cardiac cell membranes coated on the surface of nanoparticles as nanomedicine technologies that enhance selective drug delivery to cardiac cells, potentially offering an alternate method for drug administration in cardiovascular diseases. Full article

Soil labile organic carbon (C) fractions play a key role in agricultural soil fertility. However, the effects of long-term organic substitution regimes on soil organic carbon (SOC), its labile fractions, stability, and vegetable yields as well as the relationships among these factors in the open-field are less well-studied. Hence, the objective of this study was to analyze the effects of long-term organic substitution regimes on SOC sequestration, labile C fractions [particulate organic C (POC), microbial biomass carbon (MBC), dissolved organic C (DOC), and readily oxidizable C (ROC)], SOC stability, the C pool management index (CMI), and vegetable yields in a long-term (13 years) open-field experiment. Five treatments were examined: 100% chemical nitrogen fertilizer (CN), substituting 25% of the chemical N with manure (MN) or straw (SN), and substituting 50% of the chemical N with manure (2MN) or manure plus straw (MSN). Compared to the CN, organic substitution treatments increased the average yields of vegetable, the SOC, the labile C fractions’ contents, and the C pool management index (CMI) to varying degrees, but only MSN reached significant levels for these factors. However, the MSN treatment had a significantly lower C stability index (SI) than the CN. ¹³C-NMR analyses also confirmed that organic substitution treatments increased the proportion of O-alkyl C and the OA/A, but reduced SOC stability. Pearson correlation analysis and the partial least squares path model indicated that labile C fractions were the mainly direct contributors to yield and SOC stability. Overall, substituting 50% of the chemical N with manure plus straw is a relatively ideal fertilization practice to improve vegetable yields and enhance C activity in an open field. Full article

The Cucurbita genus comprises various species that are globally consumed and that are commonly used for their nutritional value but also for medicinal applications. Within the Cucurbita genus can be found Cucurbita ficifolia Bouché, a species that is understudied regarding its potential value for the food industry, as a functional food, and for the pharmaceutical industry, as a source of nutraceuticals. Therefore, in this study we investigated the phytochemical composition and bioactivities of aqueous (AF) and methanolic (MF) fractions of C. ficifolia pulp and peel hydroethanolic (HE) extracts. HPLC-DAD-MSⁿ and HPAEC-PAD analyses of extracts’ fractions revealed a low content of polyphenols and a significant content of sugars. Through in vitro inhibition assays of the enzymes alpha-amylase, acetylcholinesterase (AChE), and elastase, all fractions showed, respectively, antidiabetic, neuroprotective, and anti-aging activities. The safety profile and anti-tumoral activities were evaluated in various cell models (Caco-2, HaCaT, HepG2, and RAW 264.7), and results showed that the fractions obtained from pulp extract induce no/low cytotoxicity, while the methanolic fraction of peel induced cytotoxicity in all cell lines. At non-cytotoxic concentrations, aqueous and methanolic fractions of both extracts significantly inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells, revealing anti-inflammatory activity. Flow cytometry analysis showed that both aqueous fractions increased basal levels of glutathione (GSH) in Caco-2 cells, while not inducing oxidative stress, revealing potential as antioxidant dietary agents. However, the MF of peel HE extract induced oxidative stress in Caco-2 cells, as it increased reactive oxygen species (ROS) and lipid peroxidation. AF fraction of peel extract induced cell cycle arrest in the G0/G1 phase, while the other fractions induced cell cycle arrest in the S phase. In conclusion, Cucurbita ficifolia fruit presents potential as a functional food but also as a potential source of nutraceuticals, and peel waste products can be valorized by pharmaceutical and cosmeceutical industries as sources of bioactive molecules. Full article