Piperine Research Articles

Fabrication of TPGS-Grafted Polyamidoamine Dendrimer for Enhanced Piperine Brain Delivery and Pharmacokinetics.

Piperine (PIP) is a neuroprotective phytomedicine that has profound acetylcholine esterase and reactive oxygen species inhibition effect in Alzheimer's disease (AD) model. However, the oral delivery of PIP is limited by poor aqueous solubility and low bioavailability in systemic circulation. To improve the PIP bioavailability, the polyamidoamine (PAMAM) G4 dendrimer is grafted with tocopheryl polyethylene glycol succinate-1000 (TPGS) through carbodiimide chemistry to form TPGS-PAMAM conjugate. The TPGS-PAMAM coupling was confirmed through proton NMR and FTIR techniques. PIP was encapsulated in the TPGS-PAMAM through solvent diffusion method to form PIP-TPGS-PAMAM. The particle size for PIP-TPGS-PAMAM found the less than 50nm, whereas entrapment efficiency found to 87 ± 3.5% and 10.6 ± 2.9% drug loading. The powder differential scanning calorimetry and powder X-ray diffraction characterization were employed to evaluate the amorphous encapsulation of the PIP in TPGS-PAMAM. The PIP-TPGS-PAMAM stability was studied in the gastric fluids which showed no drastic differencein particle size and encapsulation efficiency compared to PIP-PAMAM. The in vitro release analysis revealed 37 ± 4.1% PIP release from the PIP-TPGS-PAMAM matrix, and 71 ± 4.9% PIP release from the PIP-PAMAM dendrimer was observed in 48h. The single-dose oral gavage to Wistar rats of PIP-TPGS-PAMAM showed the AUC0-∞ 14.38µg/mL.h, Cmax 7.77 ± 1.65µg/mL, Tmax, 1.6 ± 0.18h, and half-life 3.47 ± 0.64h for PIP in systemic circulation. PIP-PAMAM and free PIP showed significantly poor AUC0-∞ compared to PIP-TPGS-PAMAM. The brain uptake studies revealed PIP-TPGS-PAMAM treated group showed 2.2 ± 0.37µg/g PIP content compared to free PIP administeredgroup which was 0.4 ± 0.10µg/g. Therefore, PIP-TPGS-PAMAM can offer excellent prospect for the delivery hydrophobic drugs to brain in AD.

In situ synthesis of piperine-loaded MIL-100 (Fe) in microwave for breast cancer treatment

Piperine (PIP) is a natural alkaloid that has strong activity against breast cancer. However, due to its low solubility and bioavailability, it is unfeasible for clinical applications. Herein, we proposed an in-situ method for PIP encapsulation into the Materials of the Institut Lavoisier (MIL-100 (Fe)) using microwaves technique for fabricating novel drug delivery nanocarriers. The PIP-loaded MIL-100 (Fe) (labeled PIP@MIL-100 (Fe)) exhibited a hydrodynamic diameter of 98 ± 27.83 nm, zeta potential of +7 ± 0.6 mV, and polydispersity index of 0.03 ± 0.006. Morphological analysis of the nanosystems revealed a rhombohedral shape and particle size up to 120 nm. PIP encapsulation efficiency (EE) was found to be 95 ± 3% and PIP loading capacity was 11.02% by weight (0.12 g g−1), according to high-performance liquid chromatography (HPLC) and thermogravimetric analysis (TGA) data, respectively. Cytotoxicity studies on breast cancer cell lines (MCF-7 and 4T1) displayed cytotoxicity (IC50) approximately three times higher than that of the free PIP within 48 h. The PIP@MIL-100(Fe) fabrication comprises a simple and cheap method for designing novel drug delivery nanosystems for further clinical assays and breast cancer treatment.

Piperine-loaded electrospun nanofibers, an implantable anticancer controlled delivery system for postsurgical breast cancer treatment

Tumorectomy followed by radiotherapy, hormone, and chemotherapy, are the current mainstays for breast cancer treatment. However, these strategies have systemic toxicities and limited treatment outcomes. Hence, there is a crucial need for a novel controlled release delivery system for implantation following tumor resection to effectively prevent recurrence. Here, we fabricated polycaprolactone (PCL)-based electrospun nanofibers containing piperine (PIP), known for chemopreventive and anticancer activities, and also evaluated the impact of collagen (Coll) incorporation into the matrices. In addition to physicochemical characterization such as morphology, hydrophilicity, drug content, release properties, and mechanical behaviors, fabricated nanofibers were investigated in terms of cytotoxicity and involved mechanisms in MCF-7 and 4T1 breast tumor cell lines. In vivo antitumor study was performed in 4T1 tumor-bearing mice. PIP-PCL75-Coll25 nanofiber was chosen as the optimum formulation due to sustained PIP release, good mechanical performance, and superior cytotoxicity. Demonstrating no organ toxicity, animal studies confirmed the superiority of locally administered PIP-PCL75-Coll25 nanofiber in terms of inhibition of growth tumor, induction of apoptosis, and reduction of cell proliferation compared to PIP suspension, blank nanofiber, and the control. Taken together, we concluded that PIP-loaded nanofibers can be introduced as a promising treatment for implantation upon breast tumorectomy.

Binding mechanism and antioxidant activity of piperine to hemoglobin

Piperine (PIP) is the most active main component in pepper. The interaction of small molecules with biomolecules leads to structural and functional changes. In this study, the binding mechanism and antioxidant activity of PIP with hemoglobin (Hb) are presented using spectroscopic and computational methods. Results showed that the redox activity of PIP on Hb showed concentration dependence. Fluorescence and isothermal titration calorimetric experiments showed that the Hb–PIP system had a static quenching mechanism at a single binding site. The addition of PIP caused a slight perturbation to the secondary structure of Hb by structural analysis. The structural stability of the Hb–PIP binding system was demonstrated by molecular dynamics simulations, and molecular docking and thermodynamic constants confirmed that the electrostatic interaction force was dominant in the energy contribution of the system. Research results are conducive to the potential use of PIP in related meat products.

Poly(butylene succinate) matrices obtained by thermally-induced phase separation: Pore shape and orientation affect drug release

Poly(butylene succinate) (PBS) scaffolds with 3D microporous interconnected architecture and crystallized PBS substructures have been prepared by thermally-induced phase separation (TIPS). Curcumin (CUR) and piperine (PIP) natural drugs were incorporated into the matrices during a one-step fabrication protocol. Alterations in TIPS parameters such as solvent system (1,4 dioxane (DXN) or THF) and cooling condition (intensity and direction of thermal gradient) affected the phase separation process and the scaffold properties. Controlling the crystallization of DXN in a uniaxial direction, resulted in the formation of microtubular scaffolds with oriented porosities. Well-developed PIP crystals and matrix-integrated CUR agglomerates were uniformly distributed throughout the scaffolds. The integration of CUR to the polymer matrix was confirmed by physicochemical evaluations, attributed to a possible interaction with PBS, resulting in a slower release than PIP. The scaffolds with uniaxially-oriented porosities displayed a greater sustained release (only 50–60% after 170 h) due to the restricted drug diffusion through their dense spherulitic pore walls. Due to such structure and smoother well-arranged surfaces, the oriented scaffolds also exhibited greater biocompatibility. Our results reveal the positive influence of TIPS-derived structural orientation on properties of PBS matrices for cell/drug delivery. • Controlling the porous architecture is crucial to designing cell/drug carriers. • Porosity orientation affects the final properties of the polymeric matrix. • Herein, porosity orientation has been controlled by adjusting TIPS thermal gradient. • Uniaxially-aligned pores had spherulitic and denser walls compared to random ones. • Such a structure could impede the drug diffusion, being achieved a sustained release.

Piperine Improves Lipid Dysregulation by Modulating Circadian Genes Bmal1 and Clock in HepG2 Cells.

Metabolic disorders are closely associated with the dysregulation of circadian rhythms. Many bioactive components with lipid metabolism-regulating effects have been reported to function through circadian clock-related mechanisms. As the main pungent principle of black pepper, piperine (PIP) has been demonstrated to possess anti-obesity bioactivity by affecting hepatic lipid metabolism-related factors. However, whether the circadian clock genes Bmal1 and Clock are involved in the protective effect of PIP against lipid metabolism disorders remains unknown. In this work, oleic acid (OA) induced lipid accumulation in HepG2 cells. The effect of PIP on redox status, mitochondrial functions, and circadian rhythms of core clock genes were evaluated. Results revealed that PIP alleviated circadian desynchrony, ROS overproduction, and mitochondrial dysfunction. A mechanism study showed that PIP could activate the SREBP-1c/PPARγ and AMPK/AKT-mTOR signaling pathways in a Bmal1/Clock-dependent manner in HepG2 cells. These results indicated that Bmal1 and Clock played important roles in the regulating effect of PIP on hepatic lipid homeostasis.

Evaluation of Piperine as Natural Coformer for Eutectics Preparation of Drugs Used in the Treatment of Cardiovascular Diseases.

Piperine (PIP) was evaluated as a natural coformer in the preparation of multicomponent organic materials for enhancing solubility and dissolution rate of the poorly water-soluble drugs: curcumin (CUR), lovastatin (LOV), and irbesartan (IBS). A screening based on liquid assisted grinding technique was performed using 1:1 drug-PIP molar ratio mixtures, followed by differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) analyses. Three eutectic mixtures (EMs) composed of CUR-PIP, LOV-PIP, and IBS-PIP were obtained. Therefore, binary phase and Tamman's diagrams were constructed for each system to obtain the exact eutectic composition, which was 0.41:0.59, 0.29:0.71, and 0.31:0.69 for CUR-PIP, LOV-PIP, and IBS-PIP, respectively. Further, bulk materials of each system were prepared to characterize them through DSC, PXRD fully, Fourier transform infrared spectroscopy (FT-IR), and solution-state nuclear magnetic resonance (NMR) spectroscopy. In addition, the contact angle, solubility, and dissolution rate of each system were evaluated. The preserved characteristic in the PXRD patterns and FT-IR spectra of the bulk material of each system confirmed the formation of EM mixture without molecular interaction in solid-state. The formation of EM resulted in improved aqueous solubility and dissolution rate associated with the increased wettability observed by the decrease in contact angle. In addition, solution NMR analyses of CUR-PIP, LOV-PIP, and IBS-PIP suggested no significant intermolecular interactions in solution between the components of the EM. Hence, this study concludes that PIP could be an effective coformer to improve the solubility and dissolution rate of CUR, LOV, and IBS.

Spray-Drying of Hydroxypropyl β-Cyclodextrin Microcapsules for Co-Encapsulation of Resveratrol and Piperine with Enhanced Solubility

The synergistic therapeutic benefits of resveratrol (RES) and piperine (PIP) have been proven for the treatment of various diseases. This study reports, for the first time, spray-drying of hydroxypropyl β-cyclodextrin (HP-β-CD) microcapsules for combined delivery of resveratrol and piperine. Phase solubility studies indicated that there was a strong interaction between the active ingredients and HP-β-CD, and both active ingredients can bind stably to HP-β-CD. The results of FTIR, XRD, and DSC demonstrated that RES-PIP/HP-β-CD inclusion complexes were successfully formed, with the RES and PIP encapsulated into the hollow spherical cavity of HP-β-CD. The results of SEM showed that the spray-dried microcapsules displayed a smooth surface and uniform particle size. Upon the formation of the spray-dried microcapsules, both RES and PIP presented significantly enhanced solubility. The results of DPPH and ABTS+ scavenging activity assays showed that the spray-drying process did not adversely influence the antioxidant activity of the bioactives, and the addition of PIP increased the antioxidation performance of RES.

Ionic liquid of ketoprofen-piperine modulates the pharmaceutical and therapeutic characters of ketoprofen

Efficiency of drug delivery is product of drug properties and formulation design. Modulating drug’s unfavorable properties such as poor solubility or permeation is the first step towards optimum delivery. By combining a drug with a selected bulky counter ion, it can be transformed into a low-melting point salt, i.e., an ionic liquid (IL), with favorable physicochemical properties. In this study, we prepared a novel IL of anti-inflammatory drug, ketoprofen (KP), to enable its transdermal administration. KP was paired with piperine (PI) forming equimolar KP-PI IL, via solvent evaporation. KP-PI IL showed extended stability. Thermal analysis and X-ray diffractometry proved that KP was transformed into a low-melting point amorphous form, while spectroscopic analysis and computational studies demonstrated that KP-PI interaction was mediated by hydrogen bonding. In the IL form, KP’s solubility increased due to IL formation by 71 to 83%, while 218% more KP was permeated through rat skin in the IL form, than in a KP/PI mixture. Importantly, upon transdermal administration to rats with induced paw edema; KP-PI IL resulted in a 68% less paw swelling than KP/PI mixture. These findings demonstrate the utility of IL as an economic, simple and efficient strategy for improving the therapeutic application of drugs/drug combinations.

Formulation development of tocopherol polyethylene glycol nanoengineered polyamidoamine dendrimer for neuroprotection and treatment of Alzheimer disease

Amyloid-beta (Aβ) aggregates deposition at extra neuronal sites induces neurotoxicity and major hallmarks of Alzheimer’s disease (AD). To reduce the Aβ fibril toxicity, multi-functional polyamidoamine (PAMAM) dendrimer was conjugated with tocopheryl polyethylene glycol succinate-1000 (TPGS) which acts as a carrier matrix for the delivery of neuroprotective molecule piperine (PIP). This PIP-TPGS-PAMAM dendrimer was fabricated to mitigate the Aβ1–42 fibril toxicity on SHSY5Y cells. TPGS-PAMAM was fabricated through carbodiimide coupling reaction, and PIP was encapsulated in dendrimer through solvent injection method to prepare PIP-TPGS-PAMAM. Antioxidant assay of PIP-TPGS-PAMAM showed 90.18% inhibition of 1, 1-diphenyl-2-picrylhydrazyl (DPPH) free radicals compared to free PIP, which was 28.27%. The SHSY5Y cells showed 37.25% for negative control group and 82.55% cell viability for PIP-TPGS-PAMAM treated group against Aβ1–42 toxicity. PIP-TPGS-PAMAM reduced the ROS activity to 15.21% and 48.5% for free PIP treated in cell group. Similarly, extent of Aβ1-42-induced apoptosis also reduced significantly from 38.2% to 12.36% in PIP-TPGS-PAMAM treated group. In addition, PIP-TPGS-PAMAM also disaggregated the Aβ1–42 fibril in SHSY5Y cells. Our findings suggested that PIP-TPGS-PAMAM showed mitigation of Aβ1-42-induced toxicity in neuronal cells, which can offer excellent prospect of neuroprotection and AD therapy.

Protective effect of coenzyme-10 and piperine against cyclophosphamide-induced cytotoxicity in human cancer HuH-7 cells

Cancer is one of the leading health problems worldwide with hepatic cancerbeing one of the most common cancers. To date, a number of anti-cancer agents have been employed for chemotherapeutic purposes one of which includes cyclophosphamide (CP). Because of the serious side effect of CP, this study aims to investigate the potential protective effect of coenzyme-10 (CoQ10) and piperine (PIP) against cytotoxicity induced by CP in HuH-7 cell line. Based on IC50, 10, 12, 10, and 12 µg/ml of CP, PIP, CoQ10, PIP + CoQ10 were selected for further investigations. MTT and NRU assays results showed the combinations of CP + PIP, CP + CoQ10, CP + PIP + CoQ10 demonstrated a potential cytotoxic effect on HuH-7 cells. Also, these drug combinations induced apoptosis and relative migration rate compared with CP as evaluated by TUNEL and wound healing assays respectively. Furthermore, mitochondrial membrane potential (MMP) indicated the three drug combinations improved the mitochondrial membrane permeability in HuH-7cells. Finally, upregulation of bcl-2, caspase-3 caspase-8, caspase-9 and p53 genes in HuH-7 cells were observed in the drug combination treatments compared to CP alone, confirming the positive effect of PIP and CoQ10 when combined with CP. In conclusion, current results showed that PIP and CoQ10 have anti-cancerous properties and may be a useful resource for effective remedies in the treatment of liver cancer.

Pectin coated nanostructured lipid carriers for targeted piperine delivery to hepatocellular carcinoma

Piperine (PIP) is a herbal drug with well-known anticancer activity against different types of cancer including hepatocellular carcinoma. However, low aqueous solubility and extensive first-pass metabolism limit its clinical use. In this study, positively charged PIP-loaded nanostructured lipid carriers (PIP-NLCs) were prepared via melt-emulsification and ultra-sonication method followed by pectin coating to get novel pectin-coated NLCs (PIP-P-NLCs) targeting hepatocellular carcinoma. Complete in vitro characterization was performed. In addition, cytotoxicity and cellular uptake of nanosystems in HepG2 cells were evaluated. Finally, in vivo anticancer activity was tested in the diethylnitrosamine-induced hepatocellular carcinoma mice model. Successful pectin coating was confirmed by an increased particle size of PIP-NLCs from 150.28 ± 2.51 nm to 205.24 ± 5.13 nm and revered Zeta potential from 33.34 ± 3.52 mV to −27.63 ± 2.05 mV. Nanosystems had high entrapment efficiency, good stability, spherical shape, and sustained drug release over 24 h. Targeted P-NLCs enhanced the cytotoxicity and cellular uptake compared to untargeted NLCs. Furthermore, PIP-P-NLCs improved in vivo anticancer effect of PIP as proved by histological examination of liver tissues, suppression of liver enzymes and oxidative stress environment in the liver, and alteration of cell cycle regulators. To conclude, PIP-P-NLCs can act as a promising approach for targeted delivery of PIP to hepatocellular carcinoma.

Inhibition of AdeB, AceI, and AmvA Efflux Pumps Restores Chlorhexidine and Benzalkonium Susceptibility in Acinetobacter baumannii ATCC 19606.

The management of infections caused by Acinetobacter baumannii is hindered by its intrinsic tolerance to a wide variety of biocides. The aim of the study was to analyze the role of different A. baumannii efflux pumps (EPs) in tolerance to chlorhexidine (CHX) and benzalkonium (BZK) and identify non-toxic compounds, which can restore susceptibility to CHX and BZK in A. baumannii. A. baumannii ATCC 19606 strain was tolerant to both CHX and BZK with MIC and MBC value of 32 mg/L. CHX subMIC concentrations increased the expression of adeB and adeJ (RND superfamily), aceI (PACE family) and amvA (MFS superfamily) EP genes. The values of CHX MIC and MBC decreased by eightfold in ΔadeB and twofold in ΔamvA or ΔaceI mutants, respectively, while not affected in ΔadeJ mutant; EPs double and triple deletion mutants showed an additive effect on CHX MIC. CHX susceptibility was restored in double and triple deletion mutants with inactivation of adeB gene. BZK MIC was decreased by fourfold in ΔadeB mutant, and twofold in ΔamvA and ΔaceI mutants, respectively; EPs double and triple deletion mutants showed an additive effect on BZK MIC. BZK susceptibility was recovered in ΔadeB ΔaceI ΔadeJ and ΔamvA ΔadeB ΔadeJ triple mutants. The structural comparison of AdeB and AdeJ protomers showed a more negatively charged entrance binding site and F-loop in AdeB, which may favor the transport of CHX. The carbonyl cyanide m-chlorophenylhydrazine protonophore (CCCP) EP inhibitor reduced dose-dependently CHX MIC in A. baumannii ATCC 19606 and in ΔadeJ, ΔaceI, or ΔamvA mutants, but not in ΔadeB mutant. Either piperine (PIP) or resveratrol (RV) at non-toxic concentrations inhibited CHX MIC in A. baumannii ATCC 19606 parental strain and EPs gene deletion mutants, and CHX-induced EP gene expression. Also, RV inhibited BZK MIC and EP genes expression in A. baumannii ATCC 19606 parental strain and EPs mutants. These results demonstrate that tolerance to CHX and BZK in A. baumannii is mediated by the activation of AdeB, AceI and AmvA EPs, AdeB playing a major role. Importantly, inhibition of EP genes expression by RV restores CHX and BZK susceptibility in A. baumannii.

Simultaneous Method Development and Validation of Anastrozole Along with Piperine: Degradation Studies and Degradants Characterization Using LC-QTOF-ESI-MS Along with In-silico ADMET Predictions.

Anastrozole (ATZ) is a selective non-steroidal inhibitor widely used for the treatment of breast cancer in post-menopausal women. ATZ exerts its biological activity by inhibiting the enzyme aromatase, which is responsible for converting androgens to estrogens. Piperine (PIP), a natural alkaloid and the main component of black pepper, is used as a bioenhancer and for combating a variety of health issues ranging from upset stomach to dental problems. ATZ has been reported to have poor water solubility and less bioavailability. The novel combination of ATZ and PIP was proposed to enhance the bioavailability of both the compounds. However, there are no reported studies on the simultaneous estimation of ATZ and PIP as well as stability studies to explore their potential interactions and degradation profiling. A simple, accurate, precise, robust, sensitive, reliable, and economic analytical method for the simultaneous estimation of ATZ and PIP was developed using acetonitrile and water (60:40) as the mobile phase. Forced degradation studies and characterization of degradants were performed, and degradants were identified for molecular weight using LC-QTOF-ESI-MS; the structures of degradants were confirmed with mass accuracy measurements. The mechanism of each degradant has also been described in more detail in the manuscript. A total of fourteen degradants were characterized and reported for their good human oral absorption. A precise, robust, accurate, cheap, and sensitive RP-HPLC-DAD simultaneous method for the estimation of ATZ and PIP has been developed. From the future point of view, there is huge scope to conduct pharmacological, pharmacodynamic, and drug-herb interaction studies based on this fruitful outcome. All the degradants may be screened against MDR-resistant breast cancer in the future to check their potential as a drug target.

Immunosuppression by piperine as a regulator of the NLRP3 inflammasome through MAPK/NF-κB in monosodium urate-induced rat gouty arthritis.

Background and Aim:Gouty arthritis is a metabolic disorder involving monosodium urate (MSU) crystal deposition as a key initiator of acute inflammation. Dysregulation of the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome is associated with the pathogenesis of gout through the maturation of interleukin-1β. Piperine (PIP) is a phytochemical with an anti-inflammatory activity that has the potential as an alternative treatment for gout. In this study, we examined the effect of PIP in immunosuppression of gout inflammation through the regulation of the NLRP3 inflammasome.Materials and Methods:An in silico study was done by pharmacodynamic modeling of PIP in suppressing MSU-induced inflammation through disruption of the NLRP3 inflammasome. In vivo tests, including inflammatory assessment, histopathology, cytology, estimation of lipid peroxidation index, and detection of systemic inflammatory reactants, were performed on two groups using preventive and curative protocols.Results:In silico studies of molecular docking demonstrated the activity of PIP as a competitive inhibitor of the mitogen-activated protein kinases/nuclear factor-kappa B axis, upstream of the NLRP3 inflammasome. Analysis of gout models with curative and preventive protocols revealed the immunosuppression activity of PIP by reducing inflammatory symptoms, inhibiting tophus formation resulting from NETosis, reducing cartilage erosion, inhibiting leukocyte exudation, suppressing lipid peroxidation index, and inhibiting the production of C-reactive protein.Conclusion:The results demonstrate the activity of PIP as an immunosuppressant in gout flare. These findings indicate the potential of PIP as a candidate for prophylactic and therapeutic agent for the treatment of gouty arthritis.

Mechanistic Basis for the Role of Phytochemicals in Inflammation-Associated Chronic Diseases.

Chronic inflammatory diseases occur in a large portion of the population and are associated with a poor diet. Key natural products found in fruits and vegetables may assist in lowering inflammation associated with chronic diseases such as obesity, diabetes, cardiovascular diseases, and cancer. This review seeks to examine the roles of several natural products, resveratrol (RES), quercetin (QUE), curcumin (CUR), piperine (PIP), epigallocatechin gallate (EGCG), and gingerol (GIN), in their ability to attenuate inflammatory markers in specific diseases states. Additionally, we will discuss findings in past and ongoing clinical trials, detail possible phytochemical–drug interactions, and provide a brief resource for researchers and healthcare professionals on natural product and supplement regulation as well as names of databases with information on efficacy, indications, and natural product–drug interactions. As diet and over-the-counter supplement use are modifiable factors and patients are interested in using complementary and alternative therapies, understanding the mechanisms by which natural products have demonstrated efficacy and the types of drugs they interact with and knowing where to find information on herbs and supplements is important for practicing healthcare providers and researchers interested in this field.

Piperine and Its Metabolite's Pharmacology in Neurodegenerative and Neurological Diseases.

Piperine (PIP) is an active alkaloid of black and long peppers. An increasing amount of evidence is suggesting that PIP and its metabolite’s could be a potential therapeutic to intervene different disease conditions including chronic inflammation, cardiac and hepatic diseases, neurodegenerative diseases, and cancer. In addition, the omnipresence of PIP in food and beverages made this compound an important investigational material. It has now become essential to understand PIP pharmacology and toxicology to determine its merits and demerits, especially its effect on the central nervous system (CNS). Although several earlier reports documented that PIP has poor pharmacokinetic properties, such as absorption, bioavailability, and blood–brain barrier permeability. However, its interaction with metabolic enzyme cytochrome P450 superfamily and competitive hydrophobic interaction at Monoamine oxide B (MAO-B) active site have made PIP both a xenobiotics bioenhancer and a potential MAO-B inhibitor. Moreover, recent advancements in pharmaceutical technology have overcome several of PIP’s limitations, including bioavailability and blood–brain barrier permeability, even at low doses. Contrarily, the structure activity relationship (SAR) study of PIP suggesting that its several metabolites are reactive and plausibly responsible for acute toxicity or have pharmacological potentiality. Considering the importance of PIP and its metabolites as an emerging drug target, this study aims to combine the current knowledge of PIP pharmacology and biochemistry with neurodegenerative and neurological disease therapy.

ESTUDO ONE-POT DA APLICAÇÃO DO CATALISADOR DE GRUBBS DE PRIMEIRA GERAÇÃO EM REAÇÕES DE METÁTESE DA PIPERINA E EUGENOL: A INFLUÊNCIA DA LIGAÇÃO DUPLA TERMINAL

ONE-POT STUDY OF THE APPLICATION OF CATALYST FIRST-GENERATION GRUBBS IN METATHESIS REACTIONS OF PIPERINE AND EUGENOL: THE INFLUENCE OF THE DOUBLE- BOND TERMINAL. In this paper, the piperine (PIP) and eugenol (EUG) organic compounds were used as substrates in olefin metathesis reactions catalyzed by first-generation Grubbs catalyst (G1) – [RuCl2(PCy3)2(=CHPh)], Cy is cyclohexyl and Ph is phenyl, in a one-pot system. The reactions occurred at 50 ºC, for 24, 48, or 96 h using the two substrates simultaneously in the ratio Ru:PIP:EUG of 1:1:1 and 1:10:10 mol. The results were evaluated by GC-MS, discussed in terms of the electronic and steric characteristics of the G1, and the structural proprieties of the substrates. In the Ru:PIP:EUG ratio of 1:1:1 mol, a dimeric species was observed for the olefin metathesis of EUG, in all time studied and in an additional experiment at 70 ºC for 48 h. When the Ru:PIP:EUG ratio was 1:10:10 mol, this dimer was not observed. Isomerization processes also were observed at all temperatures and catalyst:substrates ratio. The reaction yield increased with the raise of substrates amount. There was no cross-metathesis reaction. This fact was attributed to the chelating effect of the double coordination of the PIP to the catalyst.

Crystal Structure, Solubility, and Pharmacokinetic Study on a Hesperetin Cocrystal with Piperine as Coformer.

Hesperetin (HES) is a key biological active ingredient in citrus peels, and is one of the natural flavonoids that attract the attention of researchers due to its numerous therapeutic bioactivities that have been identified in vitro. As a bioenhancer, piperine (PIP) can effectively improve the absorption of insoluble drugs in vivo. In the present study, a cocrystal of HES and PIP was successfully obtained through solution crystallization. The single-crystal structure was illustrated and comprehensive characterization of the cocrystal was conducted. The cocrystal was formed by two drug molecules at a molar ratio of 1:1, which contained O–H–O hydrogen bonds between the carbonyl and ether oxygen of PIP and the phenolic hydroxyl group of HES. In addition, a solubility experiment was performed on powder cocrystal in simulated gastrointestinal fluid, and the result revealed that the cocrystal improves the dissolution behavior of HES compared with that of the pure substance. Furthermore, HES’s bioavailability in the cocrystal was six times higher than that of pristine drugs. These results may provide an efficient oral formulation for HES.

INTERACTION OF BIOACTIVE COMPOUNDS WITH CERAMIC MATERIALS – A REVIEW

This review examines the interaction between silymarin (SIL) and other plant-based bioactive compounds such as curcumin (CCM), piperine (PIP), resveratrol (RES), and icariin (ICA). Their combination revealed synergistic effects on colon (HCT116), breast (T47D) tumor cells, hepatocellular carcinoma, and periodontal disease. The review also addresses the interaction between these plant extracts with ceramic materials such as hydroxyapatite (HAP) and carotenoids with concrete examples of biomedical applications. Silymarin’s interaction with chemotherapeutic drugs (doxorubicin-DOX, paclitaxel-PCT and 5-Fluorouracil-5-FLU) and gold nanoparticles-GNPs and silver nanoparticles-SNPs is also debated. All these combinations can form composites of major importance in the biomedical field and to contribute significantly to orthopedic surgery where materials are needed for implants that face severe infections. This short review highlights the variety of multifunctional nanoparticles that open new opportunities in cancer treatment and the need to use the Langmuir Blodgett Technique that mimics the biological membrane and provides rich medical information.