Piperine Research Articles

Comparing the Effect of Piperine and Ilepcimide on the Pharmacokinetics of Curcumin in SD Rats.

The poor bioavailability and rapid metabolism of curcumin (CUR) restrict its clinical application. Piperine (PIP), which was extracted from natural compounds, can increase the plasma concentration of curcumin in humanidad. As an artificial synthetic piperine analog, silepcimide (ILE) has significant advantages because of the low price and simple synthesis process. In this study, a simple and rapid HPLC-UV method was developed for determination of the plasma concentration of CUR, PIP,ILE and dihydrocurcumin (DHC, a metabolite of CUR) simultaneously. Meanwhile, the effects of PIP and ILE on the plasma concentration and pharmacokinetics of DHC in SD rats was studied to explore whether ILE could serve as a CUR bioavailability enhancer. The metabolic pathway of CUR was studied by comparing the differences of CUR plasma concentration between intravenous injection and oral administration over the same time period, and reacting with small intestine homogenate without microbes of SD rats. The results of drug-time curve showed that combined administration of ILE and CUR had significant effect on plasma concentrations of DHC. Repeated administration of PIP or ILE could significantly increase the plasma concentration of DHC. Plasma CUR could be detected in the samples of from intravenous injection of CUR rats, whereas, it couldn’t be detected in the plasma sample form oral administration rats. CUR incubated with intestinal homogenate without intestinal bacteria could not be transformed into DHC. In conclusion, our results show that ILE can improve the bioavailability of CUR. Additionally, it was inferred that most of the CUR was reduced to DHC by NADPH when it was absorbed from gastrointestinal tract, and our results demonstrated that this pathway might be mediated by gastrointestinal microorganisms.

Curcumin-Induced Membrane Property Changes in DMPC Multilamellar Vesicles and the Effects of Membrane-Destabilizing Molecules on Curcumin-Loaded Multilamellar Vesicles.

Curcumin (CUR) is the major bioactive component of turmeric (Curcuma longa), commonly used as a spice and traditional medicine in India. CUR possesses a wide range of pharmacological benefits, including antioxidant, anticarcinogenic, antimutagenic, anti-inflammatory, anti-Alzheimer, and anti-Parkinson effects. The CUR-membrane interaction is believed to be the reason for such biological activity of CUR. Several research groups have modeled the interaction of CUR with artificial model lipid membranes using various techniques such as nuclear magnetic resonance (NMR), small-angle X-ray scattering (SAXS), and differential scanning calorimetry (DSC). However, the mechanism of its action is still unclear. A fluorescent-probe-based technique could be advantageous to study the CUR-lipid membrane interaction due to its sensitivity toward the local environment and its multiparametric nature. In this work, we have used the intrinsic fluorescence properties of CUR to investigate CUR-induced physical property changes in 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) multilamellar vesicles (MLVs) at various CUR concentrations. By rationalizing the results of steady-state fluorescence intensity, fluorescence anisotropy, temperature-dependent fluorescence intensity, temperature-dependent fluorescence anisotropy, and quenching experiments, we have proposed a model showing concentration-dependent effects of CUR on the DMPC bilayer membrane. We suggest that at low concentrations (≤1 mol %), CUR is homogeneously distributed in the DMPC bilayer membrane in both the solid gel (SG) and liquid crystalline (LC) phases. At high concentrations (>1 mol %), CUR molecules form segregated domains that fluidize both membrane phases. However, the CUR-induced fluidization is less pronounced in the LC phase as some CUR molecules from the domain partition into the bilayer core. Further, the effects of membrane-destabilizing molecules such as bile salts, capsaicin (CAP), and piperine (PIP) on CUR-loaded DMPC multilamellar vesicles were studied. Our work also shows that CUR has a stabilizing effect on the DMPC membrane at high concentrations.

Piperine for treating breast cancer: A review of molecular mechanisms, combination with anticancer drugs, and nanosystems.

Piperine (PIP) is an alkaloid found primarily in Piper longum, and this natural compound has been shown to exert effects on proliferation and survival against various types of cancer. In particular, PIP has potent inhibitory effects on breast cancer (BC), the most prevalent type of cancer in women worldwide. PIP targets numerous signaling pathways associated with the therapy of BC cells through the following mechanisms: (a) induction of arrest of the cell cycle and apoptosis; (b) alteration of the signaling protein expression; (c) reduction in transcription factors; and (d) inhibition of tumor growth. BC cells have the ability to resist conventional drugs, so one of the strategies is the combination of PIP with other phytochemicals such as paclitaxel, thymoquinone, hesperidin, bee venom, tamoxifen, mitoxantrone, piperlongumin, and curcumin. Nanotechnology-based drug encapsulation systems are currently used to enhance the release of PIP. This includes polymer nanoparticles, carbon nanotubes, and liposomes. In the present review, the chemistry and bioavailability of PIP, its molecular targets in BC, and nanotechnological strategies are discussed. Future research directions are also discussed to further understand this promising natural product.

Antioxidant effects of piperine on steroid-induced hepatotoxicity.

Glucocorticoids (GCs) are steroids that play an essential role in physiological processes and are valuable therapeutic agents against various diseases. The aim of our study was to evaluate the antioxidant effects of piperine (PIP) on steroid-induced oxidative stress in liver tissue. We used 36 fertilized specific-pathogen-free (SPF) chicken eggs that were divided into the following 6 groups: group 1 (n=6), phosphate buffered saline (PBS) (pH 7.4 saline solution [0.9%] isotonic); group 2 (n=6), 0.50 µmol hydrocortisone succinate sodium (HC); group 3 (n=6), 0.50 µmol HC and 100 mg/kg piperine (PIP); group 4 (n=6), 0.50 µmol HC and 50 mg/kg PIP; group 5 (n=6), 0.50 µmol HC and 25 mg/kg PIP; and group 6 (n=6), 0.50 µmol HC and 10 mg/kg PIP. Chick embryos were removed from the eggs and the livers dissected from the embryos. The total antioxidant status (TAS), total oxidant status (TOS), reduced glutathione (GSH), and lipid peroxidation (malondialdehyde [MDA]) levels were measured. The highest levels of GSH and TAS in the liver tissues were observed in group 3, with a significant difference from those in group 2 (p <0.001 and p =0.006, respectively). The lowest levels of MDA and TOS in the liver tissues were observed in group 3, with a significant difference from those in group 2 (p <0.001 and p =0.021, respectively). The antioxidant and hepatoprotective properties of PIP were observed only at high doses.

Mechanism of piperine in affecting apoptosis and proliferation of gastric cancer cells via ROS-mitochondria-associated signalling pathway.

Piperine (PIP), the main active ingredient in pepper, belongs to the cinnamamide alkaloid. PIP has been found to have functions, including anti‐oxidation, immune regulation, anti‐tumour and promotion of drug metabolism. The present study was mainly designed to reveal the anti‐tumour effect of PIP against gastric cancer and the relevant mechanism. In brief, the undifferentiated human gastric cancer cell HGC‐27 was used, which was treated with different concentrations of PIP. As a result, PIP could inhibit proliferation and induce apoptosis of HGC‐27 cells in a dose‐dependent manner. The mechanism of PIP was associated with ROS increase and mitochondrial damage, simultaneously, the expression of key proteins of apoptosis was affected, including Bcl‐2, Bax, Cyt‐c, Caspase‐9 and Caspase‐3. Pre‐treatment of ROS scavenger NAC HGC‐27 cells could significantly reduce PIP‐induced apoptosis and inhibit the activation of apoptotic signals. Consistently, PIP could induce ROS to increase and activate apoptotic signals in the animal model. Therefore, the present study showed that PIP can induce the generation of ROS, thereby promoting the activation of mitochondrial apoptotic pathway and exerting anti‐tumour effects.

Formulation of Chitosan-Coated Piperine NLCs: Optimization, In Vitro Characterization, and In Vivo Preclinical Assessment

In the present research work, surface-modified nanostructured lipid carriers (NLCs) with chitosan (CH) were prepared to improve the therapeutic efficacy of piperine (PP). NLCs were developed and optimized (CH-PP-NLCs-opt) by design expert software and the selected NLCs surface was coated with chitosan (0.2% w/v). CH-PP-NLCs-opt have shown a particle size of 149.34 ± 4.54 nm and entrapment efficiency of 80.65 ± 1.23%. The results of the solid-state characterization study exhibited that PP enclosed in lipids and present amorphous form. It might be due to the nanoparticle size of NLCs. The drug release study revealed PP-NLCs-opt and CH-PP-NLCs-opt exhibited significant (P < 0.05) difference in PP release (88.87 ± 5.23% and 76.34 ± 4.54%) as compared to pure PP (19.02 ± 2.87%). CH-PP-NLCs-opt exhibited strong bioadhesion than PP-NLCs-opt which has a positive influence the drug permeation and absorption. CH-PP-NLCs-opt showed higher permeation (1083.34 ± 34.15 μg/ cm2) than pure PP (106.65 ± 15.44 μg/cm2) and PP-NLCs-opt (732.45 ± 28.56 μg/ cm2). The significantly enhanced bioavailability of PP was observed from CH-PP-NLCs-opt (3.76- and 1.21-fold) than PP-dispersion and PP-NLCs-opt. The diabetes was induced in rats by a single intraperitoneal administration of streptozotocin (STZ, 40 mg/kg, citrate buffer pH 4.5), and results revealed that PP-NLCs-opt and CH-PP-NLCs-opt reduce the blood glucose level (28.26% and 36.52% respectively) as compared to PP-dispersion (10.87%). It also helps to maintain the altered biochemical parameters. In conclusion, CH-PP-NLC can be a novel oral nanocarrier for the management of diabetes.

Harnessing the mitochondrial integrity for neuroprotection: Therapeutic role of piperine against experimental ischemic stroke

Ischemic stroke (IS) is a rapidly increasing global burden and is associated with severe neurological decline and mortality. There is urgent requirement of the efforts, aimed to identify therapeutic strategies that are effective in clinic to promote significant recovery from IS. Studies have shown that mitochondria mediated neuroprotection can be a competent target against ischemic damage. Therefore, we examined whether mitochondrial impairment is regulated by Piperine (PIP), an alkaloid of Piper Longum, which has neuroprotective activity against ischemic brain injury. In this study, transient middle cerebral artery occlusion (tMCAO) surgery was performed on male Wistar rats for 90 min followed by 22.5 h of reperfusion for mimicking the IS condition. This study consisted of three groups: sham, tMCAO and tMCAO + PIP (10 mg/kg b.wt., p.o/day for 15 days), and studied for behavioral tests, infarct volume, brain pathological changes, mitochondrial dysfunction, inflammation alongwith cell survival status. PIP pre-treatment showed reduction in neurological alterations and infarct volume. In addition, PIP pre-treatment suppressed the mitochondrial dysfunction and might have anti-apoptotic potential by preventing Cytochrome c (Cyt c) release from mitochondria to cytoplasm and caspase 3 activation. It also regulates pro-apoptotic, Bax and anti-apoptotic, Bcl-2 proteins accompanied by glial fibrillary acidic protein (GFAP) positive cells in cortex region. Quantitative Reverse transcription-polymerase chain reaction (qRT-PCR) results also showed that PIP reduced the expression of pro-inflammatory protein, interleukin-1 β (IL-1β) and enhanced cell survival by restoring the activity of brain derived neurotrophic factor (BDNF) and its transcription protein, cAMP response element binding protein (CREB). Taken together, PIP reduced the mitochondrial dysfunction, neurological impairment, and enhanced neuronal survival. In conclusion, our findings reinforce PIP as an effective neuroprotective agent and provide important evidence about its role as a potential target to serve as a promising therapy for treatment of IS.

Piperine promotes autophagy flux by P2RX4 activation in SNCA/α-synuclein-induced Parkinson disease model

ABSTRACT Olfactory dysfunction, one of the earliest non-motor symptoms of Parkinson disease (PD), is accompanied by abnormal deposition of SNCA/α-synuclein in the olfactory bulb (OB). The macroautophagy/autophagy-lysosome pathway (ALP) plays an important role in degrading pathological SNCA and modulating this pathway may be a promising treatment strategy. P2RX4 (purinergic receptor P2X, ligand-gated ion channel 4), a member of the purinergic receptor X family, is a key molecule regulating ALP. Piperine (PIP) is a Chinese medicine with anti-inflammatory and anti-oxidant effects. The present study investigated the neuroprotective effects of PIP on SNCA overexpression-induced PD cell and mouse models. We found that PIP oral administration (25, 50 and 100 mg/kg) for 6 weeks attenuated olfactory deficits and delayed motor deficits in Thy 1-SNCA transgenic mice overexpressing human SNCA. This was accompanied by a degradation of pathological SNCA in OB. In addition, PIP improved cell viability and promoted degradation of human SNCA in SK-N-SH cells. These protective effects were exerted via autophagy flux promotion by enhancing autophagosome-lysosome membrane fusion. Furthermore, tandem mass tag proteomics analyses showed that P2RX4 plays an important role in PIP treatment-induced activation of autophagy flux. These findings demonstrate that PIP exerts neuroprotective effects in PD models via promotion of autophagy flux and may be an effective agent for PD treatment. Abbreviations: 6-OHDA, 6-hydroxydopamine; ALP, autophagy-lysosome pathway; BafA1, bafilomycin A1; CoQ10, coenzyme Q10; DMSO: dimethyl sulfoxide; HPLC, high-performance liquid chromatography; IVE, ivermectin; LDH, lactate dehydrogenase; MAP1LC3/LC3-II, lipid-conjugated microtubule-associated protein 1 light chain 3; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; mRFP-GFP, tandem monomeric red fluorescent protein-green fluorescent protein; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; OB, olfactory bulb; P2RX4, purinergic receptor P2X, ligand-gated ion channel 4; PD, Parkinson disease; PBS: phosphate-buffered saline; PI: propidium iodide; PIP, piperine; PLG, piperlongumine; p-SNCA, SNCA phosphorylated at Ser129; Rap, rapamycin; RT-PCR: quantitative real-time PCR; SNARE, soluble N-ethylmaleimide-sensitive factor-attachment protein receptor; SNCA/α-synuclein, synuclein, alpha; STX17, syntaxin17; TG, transgenic; TH, tyrosine hydroxylase; UPS, ubiquitin-proteasome system; WT, wild-type

Rescue of streptomycin activity by piperine in Mycobacterium tuberculosis.

Aim: To evaluate the modulatory effect of piperine (PIP) on streptomycin (SM) activity in Mycobacterium tuberculosis (Mtb). Materials & methods: SM and PIP minimum inhibitory concentration (MIC) and combinatory activity were determined in Mtb H37Rv and in susceptible and resistant clinical isolates. Ethidium bromide accumulation assay and relative quantification of efflux pumps genes (rv1258c, rv1218c and rv2942), after SM and SM+PIP combination exposure, were also performed. Results: PIP concentration of 25μg/ml (1/4×MIC) was able to inhibit efflux pumps activity, to modulate SM activity in Mtb, and conducted changes in the relative quantification of efflux pumps genes. Conclusion: SM+PIP combination was able to rescue the SM-susceptible MIC values in SM-resistant Mtb.

Anti-adipogenic and lipid-lowering activity of piperine and epigallocatechin gallate in 3T3-L1 adipocytes

The present study was aimed to evaluate the anti-adipogenic activity of piperine (PIP) and epigallocatechin gallate (EGCG) in 3T3-L1 cells. In cytotoxicity studies, PIP and EGCG showed IC50 values of 260 and 218 µM respectively and in combination (20 µM each) did not show cytotoxicity. Treatment with PIP and EGCG (20 µM each) significantly (p<.01) inhibited cell differentiation, lipid droplets deposition and enhanced glycerol release in 3T3-L1 cells. The secreted level of leptin was decreased but adiponectin level was increased in treated 3T3-L1 cells than untreated cells. In molecular expression studies, key adipogenic genes PPAR-γ, SREBP-1c, FAS, Fab-4, C/EBP-α and HMG-CoA reductase were markedly down-regulated but UCP-1 was up-regulated in treated 3T3-L1 cells and the same trend was observed in expression levels of selected proteins. In conclusion, our results demonstrated a combination of PIP and EGCG exhibited strong anti-adipogenic and lipid lowering effect than individual treatments due to synergism.

Solubility of Piperine and Its Inclusion Complexes in Biorelevant Media and Their Effect on Attenuating Mouse Ileum Contractions.

This study evaluated the solubility of piperine (PP) in biorelevant media and the effect of its ground mixtures (GMs) and coprecipitates (CPs) on intestinal contractions when presented in inclusion complexes with α-, β-, and γ-cyclodextrins (CDs). In the powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC) measurements, CP (PP/αCD) and CP (PP/γCD) suggest the formation of inclusion complexes. The 1H-nuclear magnetic resonance (NMR) analysis showed the integrated intensity ratios of CP (PP/αCD) and CP (PP/γCD) protons to be 1/2 and 1/1, the same as the respective molar ratios in the respective GM inclusion complexes. The intestinal contraction test confirmed that the intestinal contraction rate of carbachol (CCh) in the presence of 2.0 × 10–5 M PP was comparable to that in the absence of PP. On the other hand, CP (PP/αCD), GM (PP/αCD = 1/2), and GM (PP/βCD = 1/1) formed inclusion complexes that significantly suppressed the intestinal contractility at PP 1.0 × 10–8 M. No significant differences were observed between CP and GM. The solubility of the PP/αCD inclusion complex was 6–7 times higher than that of PP in the fasted-state-simulated intestinal fluid (FaSSIF, pH 6.5). PP functioned to suppress intestinal contraction by forming an inclusion complex. Based on this result, PP/αCD might be expected to be effective as an antidiarrheal.

Piperine protects against myocardial ischemia/reperfusion injury by activating the PI3K/AKT signaling pathway.

Piperine (PIP) exerts numerous pharmacological effects and its involvement in endoplasmic reticulum (ER) stress (ERS)-led apoptosis has garnered attention. The present study focused on whether PIP played protective effects on hypoxia/reoxygenation (H/R)-induced cardiomyocytes by repressing ERS-led apoptosis. The potential molecular mechanisms in association with the PI3K/AKT signaling pathway were investigated. Primary neonatal rat cardiomyocytes (NRCMs) were isolated and randomized into four groups: Control + vehicle group, control + PIP group, H/R + vehicle group and H/R + PIP group. The H/R injury model was constructed by 4 h of hypoxia induction followed by 6 h of reoxygenation. A total of 10 µM PI3K/AKT inhibitor LY294002 was supplemented to the cells during the experiments. Cell viability and myocardial enzymes were detected to evaluate myocardial damage. A flow cytometry assay was performed to assess apoptotic response. Western blot analysis was performed to detect the expression of related proteins including PI3K, AKT, CHOP, GRP78 and cleaved caspase-12. The results showed that H/R markedly promoted myocardial damage as shown by the increased release of lactate dehydrogenase and creatine kinase levels, but a reduction in cell viability. In addition, ERS-induced apoptosis was markedly promoted by H/R in NRCMs, as shown by the increased apoptotic rates and expression of C/EBP-homologous protein, endoplasmic reticulum chaperone BiP and caspase-12. PIP administration reversed cell injury and ERS-induced apoptosis in H/R. Mechanistic studies concluded that the apoptosis-inhibitory contributions and cardio-favorable effects of PIP were caused partly by the activation of the PI3K/AKT signaling pathway, which was verified by LY294002 administration. To conclude, PIP can reduce ERS-induced apoptosis by activating the PI3K/AKT signaling pathway during the process of H/R injury, which could be a potential therapeutic target for the treatment of myocardial ischemia/reperfusion injury.

Functionalization of Gold Nanostars with Cationic β-Cyclodextrin-Based Polymer for Drug Co-Loading and SERS Monitoring

Gold nanostars (AuNSs) exhibit modulated plasmon resonance and have a high SERS enhancement factor. However, their low colloidal stability limits their biomedical application as a nanomaterial. Cationic β-cyclodextrin-based polymer (CCD/P) has low cytotoxicity, can load and transport drugs more efficiently than the corresponding monomeric form, and has an appropriate cationic group to stabilize gold nanoparticles. In this work, we functionalized AuNSs with CCD/P to load phenylethylamine (PhEA) and piperine (PIP) and evaluated SERS-based applications of the products. PhEA and PIP were included in the polymer and used to functionalize AuNSs, forming a new AuNS-CCD/P-PhEA-PIP nanosystem. The system was characterized by UV–VIS, IR, and NMR spectroscopy, TGA, SPR, DLS, zeta potential analysis, FE-SEM, and TEM. Additionally, Raman optical activity, SERS analysis and complementary theoretical studies were used for characterization. Minor adjustments increased the colloidal stability of AuNSs. The loading capacity of the CCD/P with PhEA-PIP was 95 ± 7%. The physicochemical parameters of the AuNS-CCD/P-PhEA-PIP system, such as size and Z potential, are suitable for potential biomedical applications Raman and SERS studies were used to monitor PhEA and PIP loading and their preferential orientation upon interaction with the surface of AuNSs. This unique nanomaterial could be used for simultaneous drug loading and SERS-based detection.

Piperine and Celecoxib synergistically inhibit colon cancer cell proliferation via modulating Wnt/β-catenin signaling pathway

BackgroundCelecoxib (CXB), a selective COX-2 inhibitor NSAID, has exhibited prominent anti-proliferative potential against numerous cancers. However, its low bioavailability and long term exposure related cardiovascular side effects, limit its clinical application. In order to overcome these limitations, natural bioactive compounds with lower toxicity profile are used in combination with therapeutic drugs. Therfore, in this study Piperine (PIP), a natural chemo-preventive agent possessing drug bioavailability enhancing properties, was considered to be used in combination with low doses of CXB. PurposeWe hypothesized that the combination of PIP with CXB will have a synergistic anti-proliferative effect on colon cancer cells. Study designThe potency of PIP and CXB alone and in combination was evaluated in HT-29 human colon adenocarcinoma cells and mechanism of growth inhibition was investigated by analyzing the players in apoptotic and Wnt/β-catenin signaling pathways. MethodsThe effect of PIP on the oral bioavailability of CXB in mice was investigated using HPLC analysis. The study investigated the synergistic anti-proliferative effect of CXB and PIP on HT-29 cells and IEC-6 non-tumorigenic rat intestinal epithelial cells by SRB cell viability assay. Further, the cellular and molecular mechanism(s) involved in the anti-proliferative combinatorial effect was extensively explored in HT-29 cells by flow cytometry and western blotting. The in vivo efficacy of this combination was studied in CT26.WT tumor syngeneic Balb/c mice model. ResultsPIP as a bioenhancer increased the oral bioavailability of CXB (129%). The IC50 of CXB and PIP were evaluated to select doses for combination treatment of HT-29 cells. The drug combinations having combination index (CI) less than 1 were screened using CompuSyn software. These combinations were significantly cytotoxic to HT-29 cells but IEC-6 were least effected. Further, the mechanism behind CXB and PIP mediated cell death was explored. The co-treatment led to reactive oxygen species generation, mitochondrial dysfunction, caspase activation and enhanced apoptosis in HT-29 cells. Additionally, the combination treatment synergistically modulated Wnt/β-catenin pathway, downregulated the stemness markers and boosted therapeutic response in CT26 syngeneic Balb/c mice. ConclusionThe outcomes of the study suggests that combining CXB and PIP offers a novel approach for the treatment of colon cancer.

Co-Amorphous Formulations of Furosemide with Arginine and P-Glycoprotein Inhibitor Drugs.

In this study, the amino acid arginine (ARG) and P-glycoprotein (P-gp) inhibitors verapamil hydrochloride (VER), piperine (PIP) and quercetin (QRT) were used as co-formers for co-amorphous mixtures of a Biopharmaceutics classification system (BCS) class IV drug, furosemide (FUR). FUR mixtures with VER, PIP and QRT were prepared by solvent evaporation, and mixtures with ARG were prepared by spray drying in 1:1 and 1:2 molar ratios. The solid-state properties of the mixtures were characterized with X-ray powder diffraction (XRPD), Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC) in stability studies under different storage conditions. Simultaneous dissolution/permeation studies were conducted in side-by-side diffusion cells with a PAMPA (parallel artificial membrane permeability assay) membrane as a permeation barrier. It was observed with XRPD that ARG, VER and PIP formed co-amorphous mixtures with FUR at both molar ratios. DSC and FTIR revealed single glass transition values for the mixtures (except for FUR:VER 1:2), with the formation of intermolecular interactions between the components, especially salt formation between FUR and ARG. The co-amorphous mixtures were found to be stable for at least two months under an elevated temperature/humidity, except FUR:ARG 1:2, which was sensitive to humidity. The dissolution/permeation studies showed that only the co-amorphous FUR:ARG mixtures were able to enhance both the dissolution and permeation of FUR. Thus, it is concluded that formulating co-amorphous salts with ARG may be a promising option for poorly soluble/permeable FUR.

Effect of the curcumin and piperine co-administration on the blood lipid levels and the cardiovascular risk: a systematic review

Some plant species show medicinal potential in atherosclerosis and other coronary diseases. Curcumin (CUR) is a yellow-colored phenolic compound from rhizomes of Curcuma longa L. that is mainly used as anti-inflammatory, antioxidant, and anticancer. Piperine (PIP) is an alkaloid from the fruits and the seeds of Piper nigrum L. and Piper longum L. It has several pharmacological activities, including the antioxidant and the immunomodulatory properties. PIP also increases the nutrients absorption. This review aims at investigating the effect of the CUR and PIP co-administration on the lipid profile and the cardiovascular events based on animal and human studies. This study was performed in the main scientific search bases. Among the 4,992 references found, 2,004 papers were initially chosen for the partial reading and 15 of them filled all the selection criteria for the entire reading. The CUR and PIP co-administration generally demonstrated positive effects on lipid profile in animals and humans by reducing total cholesterol, triglycerides, and LP(a) and by increasing HDL-c. In spite of no long-term clinical trial was carried out for investigating the effect of CUR and PIP co-administration on cardiovascular events, the reduction of glucose, AST, and ALP, and the increase of CAT and SOD were recorded as secondary serum markers to avoid the cardiovascular risk. Therefore, the studies usually report that co-administration of CUR and PIP shows efficacy for reducing serum lipids. The effect on preventing cardiovascular events by reducing the cardiovascular risk is lacking of direct evidence.

Synergistic effect of ursolic acid and piperine in CCl4 induced hepatotoxicity

Background Ursolic acid (UA) is a potent plant-based hepatoprotective agent having poor bioavailability, which hampers its therapeutic efficacy. The present study tries to overcome this limitation by combining it with piperine (PIP), a proven bioenhancer and hepatoprotective agent. Methods The type of interaction (synergism, addition, or antagonism) resulting between UA and PIP was analyzed and quantified by isobologram and combination index analysis. The hepatoprotective activity of UA and PIP was evaluated by measuring the level of hepatic marker enzymes. Pharmacokinetic analysis was carried out to ascertain the improvement of bioavailability. Results The combinations significantly decrease the enzyme levels, which indicate better hepatoprotective activity compared to single drugs. The relative oral bioavailability of UA was increased about tenfold (from AUC0– t =12.78 ± 2.59 µg/h/ml to 125.15 ± 1.84 µg/h/ml) along with the improvement of plasma concentration and elimination half-life. Conclusions The findings indicated that the combination of PIP and UA is an effective strategy in enhancing the bioavailability and hepatoprotective potential of UA. KEY MESSAGES Ursolic acid in a combination with piperine provides a synergistic hepatoprotective effect in carbon tetrachloride induced liver damage in rats. Piperine improves the pharmacokinetic properties of ursolic acid when given in combination. Piperine improves the relative oral bioavailability of ursolic acid by tenfold when combined together.

Exploring protein stabilized multiple emulsion with permeation enhancer for oral delivery of insulin

In present study, we have developed W/O/W microemulsion (ME) containing piperine (PiP) as a permeation enhancer and albumin (Alb) serving as a stabilizer for oral delivery of insulin (INS). The resultant formulation, ME(INS)-PiP-Alb exhibited droplet size of 3.35 ± 0.25 μm along with polydispersity index (PDI) of 0.30 ± 0.10. The formulation process employed for developing ME(INS)-PiP-Alb showed no effect on INS's chemical and conformational stability. Further, ME(INS)-PiP-Alb was able to maintain desired attributes (size & PDI) along with INS stability in simulated gastrointestinal fluids. Also, ME(INS)-PiP-Alb rendered higher protection to INS in presence of pepsin and trypsin than ME(INS)-PiP. In qualitative Caco-2 cell uptake, INS loaded ME's showed higher uptake in comparison to free INS. Whereas, in permeability studies ME(INS)-PiP-Alb showed ~4 and ~1.5-fold enhanced permeation than free INS and ME(INS) without PiP groups respectively. Also, in ex vivo intestinal permeation studies similar fold increment in permeation were observed. Interestingly, the pharmacodynamic studies revealed ~3.2-fold higher hypoglycemic effect in animals treated with ME(INS)-PiP-Alb in comparison to ME(INS)-PiP. Similarly, the pharmacokinetic studies also revealed ~1.6 fold higher AUC for ME(INS)-PiP-Alb than ME(INS)-PiP. Thus, in vivo results suggested that Alb as a stabilizer can assist in improving the hypoglycemic effect of the developed ME with PiP. Hence, this strategy can also be extrapolated for delivering other bio-macromolecules orally.

Piperine protects against pyroptosis in myocardial ischaemia/reperfusion injury by regulating the miR-383/RP105/AKT signalling pathway.

miRNA‐mediated pyroptosis play crucial effects in the development of myocardial ischaemia/reperfusion (I/R) injury (MIRI). Piperine (PIP) possesses multiple pharmacological effects especially in I/R condition. This study focuses on whether PIP protects MIRI from pyroptosis via miR‐383‐dependent pathway. Rat MIRI model was established by 30 minutes of LAD ligation and 4 hours of reperfusion. Myocardial enzymes, histomorphology, structure and function were detected to evaluate MIRI. Recombinant adenoviral vectors for miR‐383 overexpression or miR‐383 silencing or RP105 knockdown were constructed, respectively. Luciferase reporter analysis was used to confirm RP105 as a target of miR‐383. Pyroptosis‐related markers were measured by Western blotting assay. The results showed that I/R provoked myocardial injury, as shown by the increases of LDH/CK releases, infarcted areas and apoptosis as well as worsened function and structure. Pyroptosis‐related mediators including NLRP3, cleaved caspase‐1, cleaved IL‐1β and IL‐18 were also reinforced after MIRI. However, PIP treatment greatly ameliorated MIRI in parallel with pyroptotic repression. In mechanistic studies, MIRI‐caused elevation of miR‐383 and decrease of RP105/PI3K/AKT pathway were reverted by PIP treatment. Luciferase reporter assay confirmed RP105 as a miR‐383 target. miR‐383 knockdown ameliorated but miR‐383 overexpression facilitated pyroptosis and MIRI. Moreover, the anti‐pyroptotic effect from miR‐383 silencing was verified to be relied on the RP105/PI3K/AKT signalling pathway. Additionally, our present study further indicated the miR‐383/RP105/AKT‐dependent approach resulting from PIP administration against pyroptosis in MIRI. Therefore, PIP treatment attenuates MIRI and pyroptosis by regulating miR‐383/RP105/AKT pathway, and it may provide a therapeutic manner for the treatment of MIRI.

Piperine: Chemical, biological and nanotechnological applications.

Piperine (PIP) is an alkaloid present in several species of piper, mainly Piper nigrum Linn. and P. longum, among other species. The present article provides a comprehensive review of PIP research in the last years concerning its chemical properties, synthesis, absorption, metabolism, bioavailability and toxicity. The reviewed PIP literature has shown many pharmacological properties, such as antidiabetic, antidiarrheal, antioxidant, antibacterial, and anti-parasitic activity of PIP. However, its low solubility and absorption make its application challenging. This review also includes advances in the development of nanosystems containing PIP, including liposomes, micelles, metal nanoparticles, nanofibers, polymeric nanoparticles, and solid-lipid nanoparticles. Finally, we discuss different in vitro and in vivo studies to evaluate the biological activity of this drug, as well as some methods for the synthesis of nanosystems and their physical characteristics.