Characterization and Dissolution Mechanism of Low-Molecular-Weight Organic Acids or Inorganic Mesoporous Particle-Based Piperine Amorphous Solid Dispersions.

The objective of the current study is to prepare amorphous solid dispersions (ASDs) containing piperine (PIP) by utilizing organic acid glycyrrhizic acid (GA) and inorganic disordered mesoporous silica 244FP (MSN/244FP) as carriers and to investigate their dissolution mechanism. The physicochemical properties of ASDs were characterized with scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC). Fourier transform infrared spectroscopy (FTIR) and one-dimensional proton nuclear magnetic resonance (1H NMR) studies collectively proved that strong hydrogen-bonding interactions formed between PIP and the carriers in ASDs. Additionally, molecular dynamic (MD) simulation was conducted to simulate and predict the physical stability and dissolution mechanisms of the ASDs. Interestingly, it revealed a significant increase in the dissolution of amorphous PIP in ASDs in in vitro dissolution studies. Rapid dissolution of GA in pH 6.8 medium resulted in the immediate release of PIP drugs into a supersaturated state, acting as a dissolution-control mechanism. This exhibited a high degree of fitting with the pseudo-second-order dynamic model, with an R2 value of 0.9996. Conversely, the silanol groups on the outer surface of the MSN and its porous nanostructures enabled PIP to display a unique two-step drug release curve, indicating a diffusion-controlled mechanism. This curve conformed to the Ritger-Peppas model, with an R2 > 0.9. The results obtained provide a clear evidence of the proposed transition of dissolution mechanism within the same ASD system, induced by changes in the properties of carriers in a solution medium of varying pH levels.

Design, synthesis, and evaluation of benzodioxolane compounds for antitumor activity.

This study reports the design, synthesis, and comprehensive biological evaluation of 13 benzodioxolane derivatives, derived from the core structure of piperine, a natural product with established antitumor properties. Piperine, primarily found in black pepper, has been noted for its diverse pharmacological activities, including anti-inflammatory, antioxidant, and anticancer effects. Leveraging piperine's antitumor potential, we aimed to enhance its efficacy through structural modifications. Among the synthesized compounds, HJ1 emerged as the most potent, exhibiting a 4-fold and 10-fold increase in inhibitory effects on HeLa and MDA-MB-231 cell lines, respectively, compared to piperine. Furthermore, HJ1 demonstrated a favorable safety profile, characterized by significantly lower cytotoxicity towards the human normal cell line 293T. Mechanistic investigations revealed that HJ1 markedly inhibited clonogenicity, migration, and adhesion of HeLa cells. In vivo studies utilizing the chick embryo chorioallantoic membrane (CAM) model substantiated the robust antitumor activity of HJ1, evidenced by its ability to suppress tumor angiogenesis and reduce tumor weight. These results suggest that HJ1 holds significant promise as a lead compound for the development of novel antitumor therapies.

The synthetic cathinones MDPHP and MDPV: Comparison of the acute effects in mice, in silico ADMET profiles and clinical reports.

The 3,4-methylenedioxy-alpha-pyrrolidinohexanophenone (MDPHP) is a synthetic cathinone closely related to 3,4-methylenedioxypyrovalerone (MDPV), one of the most common synthetic cathinones present in the "bath salts". MDPHP has recently gained attention due to increasing seizures and involvement in human intoxications which occurred in Europe and Italy in the last years, but currently there is a lack of information about its pharmaco-toxicological effects. With the aim at filling this gap, the present study is endeavoured to (i) evaluate the effects of acute administration of MDPHP (0.01-20 mg/kg; i.p.) on behaviour, cardiorespiratory and cardiovascular parameters in CD-1 male mice, comparing them to those observed after administration of MDPV; (ii) predict the ADMET profile of the two analogues using the Plus ADMET Predictor®; (iii) present clinical data related to MDPHP and MDPV-induced intoxications recorded between 2011 and 2023 by the Pavia Poison Control Centre (PCC) - National Toxicology Information Centre (Istituti Clinici Scientifici Maugeri, IRCCS Pavia, Italy). Our results substantiated that MDPHP and MDPV similarly affect sensorimotor and behavioural responses in mice, importantly increased locomotion and induced aggressive behaviour, and, at higher dosage, increased heart rate and blood pressure. These findings are in line with those observed in humans, revealing severe toxidromes typically characterized by Central Nervous System (CNS) alterations (behavioural/neuropsychiatric symptoms), including psychomotor agitation and aggressiveness, cardiovascular and respiratory disorders (e.g. tachycardia, hypertension, dyspnoea), and other peripheral symptoms (e.g. hyperthermia, acidosis, rhabdomyolysis).

Driving forces and large scale affinity calculations for piperine/γ-cyclodxetrin complexes: Mechanistic insights from umbrella sampling simulation and DFT calculations.

Piperine (PiP), a bioactive molecule, exhibits numerous health benefits and is frequently employed as a co-delivery agent with various phytomedicines (e.g., curcumin) to enhance their bioavailability. This is attributed to PiP's inhibitory activity against drug-metabolizing proteins, notably CYP3A4. Nevertheless, PiP encounters solubility challenges addressed in this study using cyclodextrins (CDs). Specifically, γ-CD and its derivatives, Hydroxypropyl-γ-CD (HP-γ-CD), and Octakis (6-O-sulfo)-γ-CD (Octakis-S-γ-CD), were employed to form supramolecular complexes with PiP. The conformational space of the complexes was assessed through 1 µs molecular dynamics simulations and umbrella sampling. Additionally, quantum mechanical calculations using wB97X-D dispersion-corrected DFT functional and 6-311 + G(d,p) basis set were conducted on the complexes to examine the thermodynamics and kinetic stability. Results indicated that Octakis-S-γ-CD exhibits superior host capabilities for PiP, with the most favorable complexation energy (-457.05 kJ/mol), followed by HP-γ-CD (-249.16 kJ/mol). Furthermore, two conformations of the Octakis-S-γ-CD/PiP complex were explored to elucidate the optimal binding orientation of PiP within the binding pocket of Octakis-S-γ-CD. Supramolecular chemistry relies significantly on non-covalent interactions. Therefore, our investigation extensively explores the critical atoms involved in these interactions, elucidating the influence of substituted groups on the stability of inclusion complexes. This comprehensive analysis contributes to emphasizing the γ-CD derivatives with improved host capacity.

In vitro modulation the Notch pathway by piperine: A therapeutic strategy for docetaxel-resistant and non-resistant prostate cancer.

Docetaxel (DTX) resistance poses a significant challenge in the treatment of prostate cancer (PCa), often leading to chemotherapy failure. This study investigates the ability of piperine, a compound derived from black pepper, to enhance the sensitivity of PCa cells to DTX and elucidates its underlying mechanism. We established a DTX-resistant PCa cell line, DU145/DTX, to conduct our experiments. Through a series of assays, including MTT for cell viability, flow cytometry for apoptosis, Transwell for cell migration and invasion, and western blot for protein expression analysis, we assessed the effects of piperine on these cellular functions and on the Notch signaling pathway components. Our results demonstrated that we successfully established the DTX-resistant PCa cell line DU145/DTX. Piperine effectively decreased the viability of both DU145 and its DTX-resistant counterpart, DU145/DTX, in a concentration and time-dependent manner when used alone and in combination with DTX. Notably, piperine also induced apoptosis and reduced the migration and invasion capabilities of these cells. At the molecular level, piperine down-regulated the Notch pathway by inhibiting Notch1 and Jagged1 signaling, as well as reducing the expression of downstream effectors Hey1 and hes family bHLH transcription factor 1. The study concludes that piperine's ability to modulate the Notch signaling pathway and induce apoptosis highlights its potential as a complementary treatment for DTX-resistant PCa, paving the way for the use of traditional Chinese medicinal compounds in modern oncology treatment strategies.

Lumacaftor as a potential repurposed drug in targeting breast cancer stem cells: insights from in silico study.

CONTEXT: Breast cancer stem cells (BCSCs) are a small subset of cells within breast tumors with characteristics similar to normal stem cells. Despite advancements in chemotherapy and targeted therapy for breast cancer, the prognosis for breast cancer patients has remained poor due to drug resistance, reoccurrence, and metastasis. Growing evidence suggests that deregulation of the self-renewal pathways, like the Wnt signaling pathway mediated by ß-catenin, plays a crucial role in the survival of breast cancer stem cells. Targeting the Wnt signaling pathway in breast cancer stem cells offers a promising avenue for developing effective therapeutic strategies targeting these cells, potentially leading to improved patient outcomes and reduced tumor recurrence. METHODS: For this purpose, we have screened a 1615 FDA-approved drug library against our target protein, ß-catenin, which is involved in the Wnt signaling pathway using molecular docking analysis, molecular dynamics (MD) simulations, and molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) calculations. RESULTS: Molecular docking studies showed that the Lumacaftor- ß-catenin complex had the lowest docking score of - 8.7 kcal/mol towards ß-catenin protein than the reference inhibitor. Molecular dynamic simulations and MM/PBSA calculations were also performed for the Lumacaftor-ß-catenin complex to establish the stability of the interactions involved. Considering its promising attributes and encouraging results, Lumacaftor holds significant potential as a novel therapeutic option to target BCSCs. This study opens avenues for further investigation and may pave the way for developing therapeutic potential in breast cancer treatment. Further confirmation is warranted through in vitro and clinical studies to validate the findings of this study.

Discovery of piperine derivatives as inhibitors of human dihydroorotate dehydrogenase to induce ferroptosis in cancer cells.

Inhibition of human dihydroorotate dehydrogenase (hDHODH) represents a promising strategy for suppressing the proliferation of cancer cells. To identify novel and potent hDHODH inhibitors, a total of 28 piperine derivatives were designed and synthesized. Their cytotoxicities against three human cancer cell lines (NCI-H226, HCT-116, and MDA-MB-231) and hDHODH inhibitory activities were also evaluated. Among them, compound H19, exhibited the strongest inhibitory activities (NCI-H226 IC50 = 0.95 µM, hDHODH IC50 = 0.21 µM). Further pharmacological investigations revealed that H19 exerted anticancer effects by inducing ferroptosis in NCI-H226 cells, with its cytotoxicity being reversed by ferroptosis inhibitors. This was supported by the intracellular growth or decline of ferroptosis markers, including lipid peroxidation, Fe2+, GSH, and 4-HNE. Overall, H19 emerges as a promising hDHODH inhibitor with potential anticancer properties warranting development.

Preparation, pungency and bioactivity transduction of piperine from black pepper (Piper nigrum L.): A comprehensive review.

Piperine, derived from black pepper (Piper nigrum L.), is responsible for the pungent sensation. The diverse bioactivities of piperine underscores its promising potential as a functional food ingredient. This review presents a comprehensive overview of the research progress in extraction, synthesis, pungency transduction mechanism and bioactivities of piperine. Piperine can be extracted through various methods, such as traditional, modern, and innovative extraction techniques. Its synthesis mainly included both chemical and biosynthetic approaches. It exhibits a diverse range of bioactivities, including anticancer, anticonvulsant, antidepressant, anti-inflammatory, antioxidant, immunomodulatory, anti-obesity, neuroprotective, antidiabetic, hepatoprotective, and cardiovascular protective activities. Piperine can bind to TRPV1 receptor to elicit pungent sensation. Overall, the present review can provide a theoretical reference for advancing the potential application of piperine in the field of food science.

Sesame lignans modulate aroma formation in sesame oil through the Maillard reaction and lipid oxidation in model systems.

The unknown effect of sesame lignans on aroma formation in sesame oil via the Maillard reaction (MR) and lipid oxidation was investigated. Sesamin, sesamolin, or sesamol was added to 3 models: lysine+glucose (MR), cold-pressed sesame oil (SO), and MR + SO, and were heated at 120 °C for 60 min. All three lignans suppressed SO oxidation while increasing DPPH scavenging ability (p < 0.05). Lignans increased depletions of lysine and glucose and MR browning (p < 0.05). Lignans reduced most aroma-active pyrazines, aldehydes, ketones, alcohols, and esters (p < 0.05). Sesamol and sesamolin increased perceptions of the preferable aromas of nutty, roasted sesame, and popcorn while reducing the undesirable green and rancid aromas (p < 0.05). Sesamol demonstrated a stronger effect on lipid oxidation, MR browning, aroma formation, and sensory perception than sesamin and sesamolin. This study suggests that sesame lignans can modulate aroma formation and sensory perception of sesame oil by interacting with the MR and lipid oxidation pathways.

Development of piperine nanoparticles stabilized by OSA modified starch through wet-media milling technique with enhanced anti-adipogenic effect in 3T3-L1 adipocytes.

Piperine (PIP) has been known for its pharmacological activities with low water solubility and poor dissolution, which limits its nutritional application. The purpose of this research was to enhance PIP stability, dispersibility and biological activity by preparing PIP nanoparticles using the wet-media milling approach combined with nanosuspension solidification methods of spray/freeze drying. Octenyl succinic anhydride (OSA)-modified waxy maize starch was applied as the stabilizer to suppress aggregation of PIP nanoparticles. The particle size, redispersibility, storage stability and in vitro release behavior of PIP nanoparticles were measured. The regulating effect on adipocyte differentiation was evaluated using 3T3-L1 cell model. Results showed that PIP nanoparticles had a reduced particle size of 60 ± 1 nm, increased release rate in the simulated gastric (SGF) and intestinal fluids (SIF) and enhanced inhibition effect on adipogenesis in 3T3-L1 cells compared with free PIP, indicating that PIP-loaded nanoparticles with improved stability and anti-adipogenic property were developed successfully by combining wet-media milling and drying methods.

Computational Predictive and Electrochemical Detection of Metabolites (CP-EDM) of Piperine.

In this article, we introduce a proof-of-concept strategy, Computational Predictive and Electrochemical Detection of Metabolites (CP-EDM), to expedite the discovery of drug metabolites. The use of a bioactive natural product, piperine, that has a well-curated metabolite profile but an unpredictable computational metabolism (Biotransformer v3.0) was selected. We developed an electrochemical reaction to oxidize piperine into a range of metabolites, which were detected by LC-MS. A series of chemically plausible metabolites were predicted based on ion fragmentation patterns. These metabolites were docked into the active site of CYP3A4 using Autodock4.2. From the clustered low-energy profile of piperine in the active site, it can be inferred that the most likely metabolic position of piperine (based on intermolecular distances to the Fe-oxo active site) is the benzo[d][1,3]dioxole motif. The metabolic profile was confirmed by comparison with the literature, and the electrochemical reaction delivered plausible metabolites, vide infra, thus, demonstrating the power of the hyphenated technique of tandem electrochemical detection and computational evaluation of binding poses. Taken together, we outline a novel approach where diverse data sources are combined to predict and confirm a metabolic outcome for a bioactive structure.

Dual Drug Repurposing: The Example of Saracatinib.

Saracatinib (AZD0530) is a dual Src/Abl inhibitor initially developed by AstraZeneca for cancer treatment; however, data from 2006 to 2024 reveal that this drug has been tested not only for cancer treatment, but also for the treatment of other diseases. Despite the promising pre-clinical results and the tolerability shown in phase I trials, where a maximum tolerated dose of 175 mg was defined, phase II clinical data demonstrated a low therapeutic action against several cancers and an elevated rate of adverse effects. Recently, pre-clinical research aimed at reducing the toxic effects and enhancing the therapeutic performance of saracatinib using nanoparticles and different pharmacological combinations has shown promising results. Concomitantly, saracatinib was repurposed to treat Alzheimer's disease, targeting Fyn. It showed great clinical results and required a lower daily dose than that defined for cancer treatment, 125 mg and 175 mg, respectively. In addition to Alzheimer's disease, this Src inhibitor has also been studied in relation to other health conditions such as pulmonary and liver fibrosis and even for analgesic and anti-allergic functions. Although saracatinib is still not approved by the Food and Drug Administration (FDA), the large number of alternative uses for saracatinib and the elevated number of pre-clinical and clinical trials performed suggest the huge potential of this drug for the treatment of different kinds of diseases.

Investigation of the formation mechanism of the pepper starch-piperine complex.

In this study, a new carrier for loading piperine was prepared using pepper starch, and its interaction mechanism was investigated. The porous pepper starch-piperine complex (PPS-PIP) showed higher loading efficiency (76.15 %) compared to the porous corn starch-piperine complex (PCS-PIP (52.34 %)). This may be ascribed to the hemispherical shell structure of porous pepper starch (PPS) compared to the porous structure of porous corn starch (PCS) based on the SEM result. PPS-PIP had smaller particle size (10.53 µm), higher relative crystallinity (38.95 %), and better thermal stability (87.45 °C) than PCS-PIP (17.37 µm, 32.17 %, 74.35 °C). Fourier transform infrared spectroscopy (FTIR) results implied that piperine not only forms a complex with amylose but may also be physically present in porous starch. This was demonstrated by the short-range order and X-ray type. Molecular dynamics simulations confirmed that hydrogen bonding is the primary interaction between amylose and piperine. Besides the formation of the amylose-piperine complex, some of the piperine is also present in physical form.

Formulation and evaluation of dissolving microneedle for transdermal delivery of piperine: the effect of polymers concentration.

This research aims to develop the formulation of Dissolving Microneedle Piperine (DMNs PIP) and evaluate the effect of polymer concentration on characterisation and permeation testing results in ex vivo. DMNs PIP were prepared from varying concentrations of piperine (PIP) (10, 15, and 20% w/w) and polymers of polyvinyl alcohol (PVA): Polyvinyl pyrrolidone (30:60 and 60:25), respectively. Then the morphological evaluation of the formula was carried out, followed by mechanical strength testing. Furthermore, the density, LOD, and weight percentage of piperine in the dried microneedle were calculated and the determination of volume, needle weight and piperine weight and analysed. Ex vivo testing, X-Ray Diffraction, FTIR and hemolysis tests were carried out. PIP with PVA and PVP (F1) polymers produced DMN with mechanical strength (8.35 ± 0.11%) and good penetration ability. In vitro tests showed that the F1 polymer mixture gave good penetration (95.02 ± 1.42 µg/cm2), significantly higher than the F2, F3, F4, and F5 polymer mixtures. The DMNs PIP characterisation results through XRD analysis showed a distinctive peak in the 20-30 region, indicating the presence of crystals. The FTIR study showed that the characteristics of piperine found in DMNs PIP indicated that piperine did not undergo interactions with polymers. The results of the ex vivo study through DMNs PIP hemolytic testing showed no hemolysis occurred, with the hemolysis index below the 5% threshold reported in the literature. These findings indicate that DMNs PIP is non-toxic and safe to use as alternative for treating inflammation.

Insight into Formation, Synchronized Release and Stability of Co-Amorphous Curcumin-Piperine by Integrating Experimental-Modeling Techniques.

Intermolecular interactions between drug and co-former are crucial in the formation, release and physical stability of co-amorphous system. However, the interactions remain difficult to investigate with only experimental tools. In this study, intermolecular interactions of co-amorphous curcumin-piperine (i.e., CUR-PIP CM) during formation, dissolution and storage were explored by integrating experimental and modeling techniques. The formed CUR-PIP CM exhibited the strong hydrogen bond interaction between the phenolic OH group of CUR and the CO group of PIP as confirmed by FTIR, ss 13C NMR and molecular dynamics (MD) simulation. In comparison to crystalline CUR, crystalline PIP and their physical mixture, CUR-PIP CM performed significantly increased dissolution accompanied by the synchronized release of CUR and PIP, which arose from the greater interaction energy of H2O-CUR molecules and H2O-PIP molecules than CUR-PIP molecules, breaking the hydrogen bond between CUR and PIP molecules, and then causing a pair-wise solvation of CUR-PIP CM at the molecular level. Furthermore, the stronger intermolecular interaction between CUR and PIP was revealed by higher binding energy of CUR-PIP molecules, which contributed to the excellent physical stability of CUR-PIP CM over amorphous CUR or PIP. The study provides a unique insight into the formation, release and stability of co-amorphous system from MD perspective. Meanwhile, this integrated technique can be used as a practical methodology for the future design of co-amorphous formulations.

Sesamol: A Phenolic Compound of Health Benefits and Therapeutic Promise in Neurodegenerative Diseases.

Sesamol, one of the key bioactive ingredients of sesame seeds (Sesamum indicum L.), is responsible for many of its possible nutritional benefits. Both the Chinese and Indian medical systems have recognized the therapeutic potential of sesame seeds. It has been shown to have significant therapeutic potential against oxidative stress, inflammatory diseases, metabolic syndrome, neurodegeneration, and mental disorders. Sesamol is a benign molecule that inhibits the expression of inflammatory indicators like numerous enzymes responsible for inducing inflammation, protein kinases, cytokines, and redox status. This review summarises the potential beneficial effects of sesamol against neurological diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Recently, sesamol has been shown to reduce amyloid peptide accumulation and attenuate cognitive deficits in AD models. Sesamol has also been demonstrated to reduce the severity of PD and HD in animal models by decreasing oxidative stress and inflammatory pathways. The mechanism of sesamol's pharmacological activities against neurodegenerative diseases will also be discussed in this review.

Long-term bonding efficacy of adhesives containing benzodioxioles as alternative co-initiators

Abstract This study evaluated the three-year lifespan of the bond to dentin of experimental self-etch adhesives containing benzodioxole derivatives - 1,3-benzodioxole (BDO) and piperonyl alcohol (PA) - as co-initiator alternative to amines. Adhesive resins were formulated using Bis-GMA, TEGDMA, HEMA, camphorquinone and different co-initiators: BDO, PA or ethyl 4-dimethylamino benzoate (EDAB - amine). An experimental self-etch primer was used to complete the two-step, self-etch adhesive system. Clearfil SE Bond (CSE) was used as commercial reference. Bond strength to human dentin was assessed by microtensile bond strength (µTBS) test, and failure mode was classified. Morphology of the dentin bonding interface was assessed via scanning electron microscopy (SEM). Irrespective of the dental adhesives evaluated, µTBS was higher after 24 hours compared with that after 1.5 and 3 years (p ≤ 0.001). However, adhesives with BDO and PA as co-initiators showed significantly higher bond strength than the bonding resin with EDAB (p ≤ 0.002), independent of the time evaluated. The commercial adhesive CSE showed similar bond strength compared with the other groups (p ≥ 0.05). Mixed failures were mainly observed after 24 hours, while adhesive failures were more frequently observed after 1.5 and 3 years. No notable differences in homogeneity and continuity along the bonded interfaces were detected among the materials in the SEM analysis. In conclusion, benzodioxole derivatives are feasible alternative co-initiators to tertiary amine in camphorquinone-based self-etching dental adhesive formulations.