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.

Investigation of the effects of curcumin and piperine on cyclophosphamide-induced brain injury in rats.

Cyclophosphamide (CP) is an antineoplastic drug widely used in chemotherapy. Curcumin (CUR) and piperine (PP) show a protective effect on neurodegenerative and neurological diseases. This research was designed to measure several biochemical parameters in the brain tissue of CP-applied rats to investigate the impact of combined CUR-PP administration. The study evaluated six groups of eight rats: Group 1 was the control; Groups 2 and 3 were administered 200 or 300 mg/kg CUR-PP via oral gavage; Group 4 received only 200 mg/kg CP on day 1; Groups 5 and 6 received CP + CUR-PP for 7 days. Data from all parameters indicated that CP caused brain damage. Phosphorylated TAU (pTAU), amyloid-beta peptide 1-42 (Aß1-42), glutamate (GLU), and gamma amino butyric acid (GABA) parameters were the same in Groups 4, 5, and 6. On the other hand, 8-hydroxy-2-deoxyguanosine (8-OHdG), nitric oxide (NO), interleukin-6 (IL-6), nuclear factor kappa beta (NF-kß), malondialdehyde (MDA), and tumor necrosis factor-alpha (TNF-α) levels in the CP + CUR-PP groups were lower than those in the CP group (p < 0.05). However, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and reduced glutathione (GSH) parameters were higher in the CP + CUR-PP groups compared to the CP group (p < 0.05). It is thought that the similarity of Groups 5 and 6 with Group 4 in Aß1-42, pTAU, GLU, and GABA parameters hinder the determination of treatment protection however, they might have a therapeutic effect if the applied dose or study duration were changed. This study attempted to evaluate the effects of a CUR-PP combination on CP-induced brain damage in rats by measuring biochemical parameters and performing histopathological examinations. Based on the findings, this CUR-PP combination could be considered an alternative medicine option in cases with conditions similar to those evaluated in this study.

Design, synthesis and biological evaluation of piperine derivatives as potent antitumor agents.

A series of piperine derivatives were designed and successfully synthesized. The antitumor activities of these compounds against 293 T human normal cells, as well as MDA-MB-231 (breast) and Hela (cervical) cancer cell lines, were assessed through the MTT assay. Notably, compound H7 exhibited moderate activity, displaying reduced toxicity towards non-tumor 293 T cells while potently enhancing the antiproliferative effects in Hela and MDA-MB-231 cells. The IC50 values were determined to be 147.45 ±â€¯6.05 µM, 11.86 ±â€¯0.32 µM, and 10.50 ±â€¯3.74 µM for the respective cell lines. In subsequent mechanistic investigations, compound H7 demonstrated a dose-dependent inhibition of clone formation, migration, and adhesion in Hela cells. At a concentration of 15 µM, its inhibitory effect on Hela cell function surpassed that of both piperine and 5-Fu. Furthermore, compound H7 exhibited promising antitumor activity in vivo, as evidenced by significant inhibition of tumor angiogenesis and reduction in tumor weight in a chicken embryo model. These findings provide a valuable scientific foundation for the development of novel and efficacious antitumor agents, particularly highlighting the potential of compound H7 as a therapeutic candidate for cervical cancer and breast cancer.

Does curcumin improve liver enzymes levels in nonalcoholic fatty liver disease? A systematic review, meta-analysis, and meta-regression.

The aim of this meta-analysis is to investigate the sources of heterogeneity in randomized clinical trials examining the effects of curcumin supplementation on liver aminotransferases in subjects with nonalcoholic fatty liver disease (NAFLD). We conducted a systematic search of the PubMed, SCOPUS, and Web of Science databases for randomized clinical trials and identified 15 studies (n = 835 subjects). We used random-effects models with DerSimonian-Laird methods to analyze the serum levels of alanine aminotransferase and aspartate aminotransferase enzymes. Our results indicate that curcumin did not affect serum alanine aminotransferase, but it did reduce aspartate aminotransferase levels. Notably, both outcomes showed high heterogeneity (p < 0.01). Subgroup analysis revealed that adding piperine to curcumin did not benefit aminotransferase levels in NAFLD patients. Additionally, we found a negative correlation between the duration of the intervention and the relative (mg/kg/day) curcumin dose with the reduction in liver aminotransferases. In summary, the sources of heterogeneity identified in our study are likely attributed to the duration of the intervention and the relative dose of curcumin. Consequently, longer trials utilizing high doses of curcumin could diminish the positive impact of curcumin in reducing serum levels of aminotransferases in patients with NAFLD.

Piperine induces autophagy of colon cancer cells: Dual modulation of AKT/mTOR signaling pathway and ROS production.

BACKGROUND: Colorectal cancer (CRC) is a prevalent malignancy and poses a significant clinical challenge. Piperine, an alkaloid molecule extracted from Piper nigrum and Piper longum, has emerged as a promising anticancer agent. However, the molecular mechanisms of piperine' antitumor effects in CRC need to be further elucidated. METHODS: Human colorectal cancer cells were treated with piperine in vitro. CCK-8 and clone formation assays were adopted to detect cell viability. The accumulation of autophagosomes was assessed by Western blotting and immunofluorescence. Apoptosis and reactive oxygen species (ROS) levels were analyzed by flow. In vivo, a xenograft tumor mouse model was constructed using CT26 cells. RESULTS: Piperine inhibited CRC cell viability and suppressed tumor weight and volume in a mouse model. Additionally, piperine treatment induced the accumulation of autophagosomes in CRC cells. This effect was attributed to the inhibition of the AKT/mTOR pathway and the accumulation of ROS. activation of AKT or clearance of ROS attenuated piperine-mediated tumor suppression. CONCLUSION: This study shows that piperine induces autophagy-dependent cell death in CRC cells by increasing ROS production and inhibiting Akt/mTOR signaling.

Evaluation of the effectiveness of curcumin and piperine co-supplementation on inflammatory factors, cardiac biomarkers, atrial fibrillation, and clinical outcomes after coronary artery bypass graft surgery.

BACKGROUND: Coronary artery bypass graft (CABG) is one of the preferred treatments for patients with heart problems, especially in individuals with other comorbidities and when multiple arteries are narrowed. This study aimed to assess the effects of administrating curcumin-piperine on patients who underwent CABG surgery. METHODS: This was a randomized, double-blind, placebo-controlled clinical trial, in which 80 eligible adults who underwent CABG surgery, were randomized into 4 groups. Patients received 3 tablets daily for 5 days after the surgery, which contained curcumin-piperine (each tablet contained 500 mg curcumin +5 mg piperine) or a placebo (each tablet contained 505 mg maltodextrin). Group A received 3 placebo tablets, group B received 2 placebos and one curcumin-piperine tablet, group C received 1 placebo and 2 curcumin-piperine tablets, and group D received 3 curcumin-piperine tablets. Before and after the intervention, C-reactive protein (CRP), total antioxidant capacity (TAC), cardiometabolic factors, clinical outcomes, and 28-day mortality were evaluated. RESULTS: Between-group analysis showed that CRP significantly decreased (P = 0.028), and TAC significantly increased (P = 0.033) after the intervention (Post hoc analysis showed that for CRP, the difference was between group B and D, and for TAC was between group C and D). Between-group analysis also showed that creatine kinase mono-phosphate (CK-MB) marginally reduced (P = 0.077); however, changes for troponin I (P = 0.692), lactate dehydrogenase (LDH) (P = 0.668), ejection fraction (P = 0.340), and arterial fibrillation (P = 0.99) were not significant. Blood urea nitrogen (P = 0.820) and serum creatinine (P = 0.244) did not show notable changes between groups. CONCLUSION: Supplementation with curcumin-piperine had a promising effect on serum CRP and TAC. It also had a favorable impact on CK-MB among patients who underwent CABG surgery. TRIAL REGISTRATION: IRCT20201129049534N4, available on https://en.irct.ir/trial/56930.

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.

The Potential Radioprotective Effect of Piperine against Radiation-Induced Lung Injury in Mice: Histopathological and Biochemical Evaluations.

INTRODUCTION: It has been hypothesized that piperine, the main alkaloid component of black pepper, possesses a unique radioprotective effect. This study aimed to investigate the protective effect of piperine against Radiation-Induced Lung Injury (RILI) in mice. METHOD: Firstly, eighty male mice were divided into eight groups; the control group did not receive any dosage of piperine and radiation (6 Gy), and the other groups received piperine alone at doses 10, 25, and 50 mg/kg, radiation, and radiation-piperine combination (6 Gy + 10, 25, and 50 mg/kg). Animals received piperine by gavage for 7 consecutive days. To investigate the effect of piperine pretreatment in mice that were exposed to radiation, histopathological and biochemical evaluations (markers of oxidative stress) were performed. Irradiation led to an increase in oxidative stress (increase in MDA and PC). Pretreatment of piperine in all three doses in irradiated mice was able to reduce oxidative stress compared to mice that were only exposed to radiation. RESULTS: Piperine at a dose of 25 mg/kg exhibited the highest protective effect as compared to other doses. Also, in the histopathological examination, it was seen that pretreatment with piperine was able to improve the infiltration of inflammatory cells and reduce the thickness of the alveolar septum and air sac damage. CONCLUSION: The outcomes completely proved significant lung protection by piperine in mice through reducing oxidative stress. This natural compound could be considered a protective agent against lung injury induced by ionizing radiation.

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.

Mechanism of 5-fluorouracil induced resistance and role of piperine and curcumin as chemo-sensitizers in colon cancer.

Among cancer-related deaths worldwide, colorectal cancer ranks second, accounting for 1.2% of deaths in those under 50 years and 0.6% of deaths in those between 50 and 54 years. The anticancer drug 5-fluorouracil is widely used to treat colorectal cancer. Due to a better understanding of the drug's mechanism of action, its anticancer activity has been increased through a variety of therapeutic alternatives. Clinical use of 5-FU has been severely restricted due to drug resistance. The chemoresistance mechanism of 5-FU is challenging to overcome because of the existence of several drug efflux transporters, DNA repair enzymes, signaling cascades, classical cellular processes, cancer stem cells, metastasis, and angiogenesis. Curcumin, a potent phytocompound derived from Curcuma longa, functions as a nuclear factor (NF)-κB inhibitor and sensitizer to numerous chemotherapeutic drugs. Piperine, an alkaloid found in Piper longum, inhibits cancer cell growth, causing cell cycle arrest and apoptosis. This review explores the mechanism of 5-FU-induced chemoresistance in colon cancer cells and the role of curcumin and piperine in enhancing the sensitivity of 5-FU-based chemotherapy. CLINICAL TRIAL REGISTRATION: Not applicable.

Effects of Combination of Curcumin and Piperine Supplementation on Glycemic Profile in Patients with Prediabetes and Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis.

Objective: This study aimed to evaluate the effects of the combination of curcumin and piperine supplementation on Fasting Plasma Glucose (FPG), Homeostatic Model of Insulin Resistance (HOMA-IR), and Body Mass Index (BMI) in patients with prediabetes and type 2 Diabetes Mellitus (T2DM). This review was done to identify potential herbal remedies that may help improve glycemic parameters, leading to better health outcomes in combination with current antidiabetic treatment. Methodology: This systematic review was based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). It was conducted in 2023 with sources and databases from MEDLINE, EBSCO-Host, ScienceDirect and ProQuest. This paper included randomized-controlled trials exploring the effects of the combination of curcumin and piperine on patients with prediabetes and T2DM. Systematic reviews, observational studies, case reports, case series, conference abstracts, book sections, commentaries/editorials, non-human studies and articles with unavailable full-text and written in non-English language, were excluded. The key terms for the literature search were "curcumin," "piperine," "prediabetes" and "Type 2 Diabetes Mellitus." We use Cochrane Risk of Bias (RoB) 2 for quality assessment of the included studies and Review Manager (RevMan) 5.4 to do the meta-analysis. Results: A total of three studies were included in this systematic review. Two studies from Neta et al., and Cicero et al., showed no significant difference in HOMA-IR, BMI and FPG levels between the curcumin, piperine and placebo groups. One study from Panahi et al. demonstrated a significant difference in BMI levels between the curcumin and piperine and placebo groups (p <0.01). The meta-analysis showed that FPG levels, HOMA-IR and BMI improved among patients with diabetes given in curcumin and piperine with reported mean differences (MD) of = -7.61, 95% CI [-15.26, 0.03], p = 0.05, MD = -0.36, 95% CI [-0.77 to 0.05], p = 0.09, and MD = -0.41, 95% CI [-0.85 to 0.03], p = 0.07, respectively). Conclusions: The supplementation of curcumin and piperine showed a numerical reduction in FPG, HOMA-IR and BMI, but were not statistically significant. Further research is needed as there is a paucity of studies included in the review.

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.

Piperine-hydroxybenzoate as phytochemistry antiosteoarthritis combination: Structural, solubility, and in vivo antiinflammatory study.

This study discusses the composition and structure determination of a new multicomponent system from antiinflammatory natural ingredients, consisting of piperine (Pip) and 4-hydroxybenzoic acid (HBA), named Pip-HBA. In addition, this research studied its solubility and anti-inflammatory activity. After screening the stoichiometric proportions, this multicomponent system formation reaction was carried out using the solvent-dropped grinding and evaporation methods. Characterizations using solid analysis including differential scanning calorimetry (DSC), powder X-ray diffractometry (PXRD), and Fourier transform infrared spectroscopy (FTIR), confirmed the formation of Pip-HBA. These multicomponent systems showed different thermograms and diffractograms. Furthermore, the FTIR spectrum of Pip-HBA multicomponent system differs from the physical mixture and its constituent components. Single crystal diffractometry (SCXRD) determined Pip-HBA to be a new multicomponent system structure in three dimensions. Pip-HBA showed increased solubility and anti-inflammatory activity compared to single piperine. Therefore, Pip-HBA multicomponent system has quite potential for further preparation 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.

Pharmacokinetic Drug Interactions of Piperine: A Review of Pre-clinical and Clinical Studies.

Piperine (amide alkaloid) derived from pepper is globally utilized in diverse conventional and traditional systems of medicine. The co-administration of piperine has been observed to induce subtle modifications in the absorption, membrane transport, and drug metabolism of several high-efficacy medicines. The occurrence of medication interactions might have a notable impact on the pharmacokinetic parameters, resulting in either a favorable or unfavorable pharmacological effect. This comprehensive pharmacokinetic drug interaction evaluation of piperine encompasses a total of 34 scholarly articles (specific for pharmacokinetic interactions), consisting of 62 studies (56 preclinical studies and 6 clinical investigations). In this study, we propose that piperine has the ability to increase the bioavailability and bioactive molecules of a natural origin of a variety of medications, making it an effective bioenhancer. By enhancing bioavailability, piperine can reduce the required dosage, lower drug costs, minimize the occurrence of drug resistance, and mitigate dose-dependent side effects associated with various medications such as ciprofloxacin, ampicillin, metronidazole carbamazepine, curcumin, and oxytetracycline. However, a limited number of published studies have indicated a reduction in bioavailability following oral administration of isoniazid, puerarin, diltiazem, desacetyldiltiazem, and magnolol in combination with piperine or pepper/Trikatu (containing piperine majorly). Several other critical studies have demonstrated that there is no significant variation in pharmacokinetic characteristics along with piperine. The medications containing piperine have led to significant modifications in their pharmacokinetic properties, finally yielding advantageous outcomes for drugs with low bioavailability. Additionally, these alterations have resulted in reduced side effects and extended half-life (T1/2) for specific drugs.

Piperine-coated zinc oxide nanoparticles target biofilms and induce oral cancer apoptosis via BCl-2/BAX/P53 pathway.

BACKGROUND: Dental pathogens play a crucial role in oral health issues, including tooth decay, gum disease, and oral infections, and recent research suggests a link between these pathogens and oral cancer initiation and progression. Innovative therapeutic approaches are needed due to antibiotic resistance concerns and treatment limitations. METHODS: We synthesized and analyzed piperine-coated zinc oxide nanoparticles (ZnO-PIP NPs) using UV spectroscopy, SEM, XRD, FTIR, and EDAX. Antioxidant and antimicrobial effectiveness were evaluated through DPPH, ABTS, and MIC assays, while the anticancer properties were assessed on KB oral squamous carcinoma cells. RESULTS: ZnO-PIP NPs exhibited significant antioxidant activity and a MIC of 50 µg/mL against dental pathogens, indicating strong antimicrobial properties. Interaction analysis revealed high binding affinity with dental pathogens. ZnO-PIP NPs showed dose-dependent anticancer activity on KB cells, upregulating apoptotic genes BCL2, BAX, and P53. CONCLUSIONS: This approach offers a multifaceted solution to combatting both oral infections and cancer, showcasing their potential for significant advancement in oral healthcare. It is essential to acknowledge potential limitations and challenges associated with the use of ZnO NPs in clinical applications. These may include concerns regarding nanoparticle toxicity, biocompatibility, and long-term safety. Further research and rigorous testing are warranted to address these issues and ensure the safe and effective translation of ZnO-PIP NPs into clinical practice.

Piperine Enhances Antimalarial Activity of Methyl Gallate and Palmatine Combination.

PURPOSE: Artemisinin combination therapies, the first-line antimalarials in Nigeria, have reportedly suffered multiple failures in malaria treatment, hence the search for novel combination of other compounds. Methyl gallate and palmatine have been reported to exhibit antiplasmodial activities but the antimalarial activity of their combination has not been evaluated. Therefore, the evaluation of the combination of methyl gallate and palmatine for antimalarial activity in vitro and in vivo in the presence of piperine was carried out. MATERIALS AND METHODS: The inhibitory potential of methyl gallate and palmatine combination on ß-hematin (hemozoin) formation was studied in vitro. Also, the antimalarial activity of methyl gallate and palmatine combination with/without a bioenhancer (piperine) was evaluated in Plasmodium berghei NK65-infected mice. RESULTS: Methyl gallate and palmatine in the ratio 3:2 acted synergistically in vitro and had the highest inhibitory effect (IC50 = 0.73 µg/mL) on ß-hematin (hemozoin) formation. The 3:2 combination of methyl gallate and palmatine exhibited no antimalarial activity in vivo in the absence of piperine but caused reduction in parasitemia that exceeded 40% in the presence of piperine at the dose of 25 mg/kg body weight on days 6 and 8 post-inoculation in mice. CONCLUSION: The 3:2 combination of methyl gallate and palmatine in the presence of piperine exhibited antimalarial activity in vivo, possibly by synergistic inhibition of hemozoin formation which may cause accumulation of haem within the food vacuole of Plasmodium spp. and its death.

Development of a rapid HPLC-fluorescence method for monitoring warfarin metabolites formation: In vitro studies for evaluating the effect of piperine on warfarin metabolism and plasma coagulation.

Warfarin, a widely prescribed anticoagulant, is highly effective for various coagulation disorders. However, its efficacy is limited by a narrow therapeutic index and frequent drug interactions, especially those involving metabolism by Cytochrome P450 (CYP450) enzymes. Piperine, found in black and long pepper, possesses blood-thinning properties and has been observed to inhibit CYP3A and CYP2C enzymes linked to warfarin metabolism. This study investigated the effect of piperine on warfarin metabolism in liver microsomes using a rapid and sensitive HPLC-Fluorescence method. The use of PFP (pentafluorophenyl) column with core shell particles provided the selectivity and resolution to resolve warfarin and its 4-, 6-, 7-, and 10-hydroxy metabolites in addition to the internal standard naproxen in less than 3 min. This is the fastest analytical assay for warfarin and its major metabolites reported to date, making it ideal for metabolic studies. The applicability of the method was demonstrated by monitoring the metabolism of S-warfarin in human and rat liver microsomes, and evaluating the inhibitory effect of piperine on metabolite formation. The results showed that piperine inhibited the formation of the major metabolite, 7-hydroxywarfarin, with half-maximal inhibitory concentration (IC50) 14.2 µM and 3.2 µM in human and rat liver microsomes, respectively. Furthermore, coagulation studies in vitro using rat plasma showed that piperine does not affect prothrombin time (PT) and activated partial thromboplastin time (aPTT). This study suggested that piperine may present a potential drug interaction with warfarin at the metabolism level, but has no direct effect on the activation of the extrinsic or intrinsic coagulation cascades. Further clinical investigation is therefore required, as piperine may increase the bioavailability of warfarin, thus increasing risk of serious adverse events in patients.

Curcumin, Piperine and Taurine Combination Enhances the Efficacy of Transarterial Chemoembolization Therapy in patients with Intermediate Stage Hepatocellular Carcinoma: A Pilot Study.

INTRODUCTION: Diagnosis of the majority of hepatocellular carcinoma (HCC) patients occurs at intermediate to advanced stages, with a few curative therapeutic options being available. It is therefore strongly urgent to discover additional adjuvant therapy for this lethal malignancy. This study aimed to assess the effectiveness of curcumin (C), piperine (P) and taurine (T) combination as adjuvant agents on serum levels of IFN-γ, immunophenotypic and molecular characterization of mononuclear leukocytes (MNLs) in HCC patients treated with Transarterial chemoembolization (TACE). PATIENTS AND METHODS: Serum and MNLs were collected from 20 TACE-treated HCC patients before (baseline-control samples) and after treatment with 5 g curcumin capsules , 10 mg piperine and 0.5 mg taurine taken daily for three consecutive months. Immunophenotypic and molecular characterization of MNLs were determined by flow cytometry and quantitative real time PCR, respectively. In addition, serum IFN-γ level was quantified by ELISA. RESULTS: After receiving treatment with CPT combination, there was a highly significant increase in IFN- γ levels in the sera of patients when compared to basal line control samples. Additionally, the group receiving combined therapy demonstrated a downregulation in the expression levels of PD-1, in MNLs as compared to controls. MNLs' immunophenotyping revealed a significant decline in CD4+CD25+cells (regulatory T lymphocytes). Furthermore, clinicopathological characteristics revealed a highly significant impact of CPT combination on aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and alpha feto protein (AFP) levels. CONCLUSION: This study introduces a promising adjuvant CPT combined treatment as natural agents to enhance the management of HCC patients who are candidates to TACE treatment.

Analgesic Potential Comparison Between Piperine-Combined Curcumin Patch and Non-Piperine Curcumin Patch: A Pragmatic Trial on Post-Cleft Lip/Palate Surgery Pediatric Patients.

Purpose: Despite its well-acknowledged analgesic potential, curcumin's low bioavailability has been recognized. Piperine, a substance naturally contained in pepper, has been known for its effect on increasing curcumin bioavailability. To investigate the analgesic potential of curcumin and piperine addition to curcumin patch used as adjuvant therapy in the management of acute postoperative orofacial pain. Patients and Methods: This pragmatic trial recruited 75 patients that underwent oromaxillofacial surgery at Unpad Dental Hospital, Bandung, Indonesia. Research participants were randomly assigned to three different groups: the first group that did not receive any intervention other than the post-operative standard treatment (POST), the second group that received POST and non-piperine curcumin patch, and the third group that received POST and piperine-combined curcumin patch. Participants' pain intensity was evaluated by using the face, leg, activity, cry, and consolability (FLACC) pain scale and salivary prostaglandin-E2 (PGE2) level for two-time points, which were eight hours apart. All data were gathered and analyzed to compare the within and between-group differences. Results: Within groups comparison of the FLACC scores for two evaluation points showed significant differences for all groups (p < 0.01). For salivary PGE2 analysis, a comparison of the non-piperine group to the piperine group also showed significant results. Yet, when all three groups were compared, regardless of the differences, the results were not statistically significant. Conclusion: Despite of the proven efficacy of curcumin patch, the addition of piperine to the curcumin patch in the current study did not provide any significant effects. Further investigation is of importance.