Piperine

Piperine is an alkaloid naturally found in the fruits ofPiper nigrum (black pepper) and Piper longum(long pepper), plants belonging to the Piperaceae family. It is the compound primarily responsible for the characteristic pungency and spicy flavor of black pepper. Historically, piperine has been a significant component in traditional medicine systems, particularly Ayurveda, where it was valued for its diverse therapeutic properties.^[1]

Biological Basis

At a biological level, piperine exerts its effects through several mechanisms. It is known to modulate drug-metabolizing enzymes, notably the cytochrome P450 enzyme system, which plays a crucial role in the metabolism of various compounds in the liver and intestines.^[2]By inhibiting these enzymes, piperine can influence the pharmacokinetics and bioavailability of other substances. Furthermore, research indicates that piperine interacts with various cellular signaling pathways, contributing to its observed anti-inflammatory and antioxidant activities.^[3]

Clinical Relevance

Clinically, piperine is most recognized for its unique ability to enhance the bioavailability of other compounds. It can significantly improve the absorption and efficacy of certain nutrients, drugs, and phytochemicals—such as curcumin, coenzyme Q10, and resveratrol—by reducing their metabolic breakdown and increasing their uptake in the gastrointestinal tract.^[4]Beyond this pharmacokinetic influence, studies suggest that piperine itself possesses a range of potential health benefits, including anti-inflammatory, antioxidant, neuroprotective, and even some anticancer properties.^[3]

Social Importance

Piperine is widely consumed globally as a staple spice in black pepper, integral to countless cuisines and dietary traditions. Its role in enhancing the flavor and preserving foods has been important for centuries. In modern contexts, due to its well-documented bioavailability-enhancing effects and other potential health benefits, piperine has become a popular ingredient in dietary supplements. It is frequently combined with other nutraceuticals to maximize their therapeutic potential, reflecting its continued relevance from traditional medicine to contemporary health practices.

Limitations

Methodological and Statistical Considerations

Research into the effects and metabolism of piperine often faces methodological and statistical hurdles that can influence the interpretation of findings. Many initial studies, particularly those exploring genetic associations, may involve relatively small sample sizes, which can limit statistical power to detect genuine effects or lead to inflated effect sizes for observed associations. This can result in findings that are difficult to replicate in larger, independent cohorts, highlighting the need for more robust, well-powered studies to validate initial discoveries. Consequently, the generalizability and reliability of some reported associations with piperine’s biological activities or metabolism may be uncertain until further validation.

The design of studies also presents challenges, with potential for cohort biases if participant selection is not carefully controlled. For instance, observational studies might inadvertently include groups with confounding lifestyle factors, making it difficult to isolate the specific impact of piperine. Furthermore, the complexity of biological systems means that simple statistical models might not fully capture intricate interactions, potentially leading to an incomplete understanding of piperine’s multifaceted roles. These limitations underscore the necessity for rigorous study designs, comprehensive statistical analyses, and independent replication efforts to build a more definitive evidence base.

Population Diversity and Phenotypic Heterogeneity

A significant limitation in understanding piperine’s impact stems from issues of generalizability across diverse populations and the inherent variability in human phenotypes. Many studies are conducted within specific ancestral groups, which can restrict the applicability of findings to broader, more genetically diverse populations. Genetic variations, including polymorphisms in genes related to drug metabolism or nutrient absorption, can differ substantially across ancestries, meaning that observed effects in one group may not translate directly to another. This lack of diverse representation can lead to an incomplete picture of how piperine interacts with human biology globally.

Moreover, the precise measurement and definition of phenotypes related to piperine consumption or its biological effects can be inconsistent across studies. Whether assessing metabolic markers, physiological responses, or disease outcomes, variations in measurement protocols, assay sensitivities, and diagnostic criteria introduce heterogeneity. This phenotypic variability makes it challenging to compare results across different research endeavors and to draw clear conclusions about consistent effects. Addressing these issues requires standardized measurement practices and inclusive study designs that account for both genetic and phenotypic diversity.

Environmental and Genetic Complexity

The interplay between genetic predispositions and environmental factors represents a complex challenge in fully elucidating piperine’s effects, contributing to remaining knowledge gaps. Dietary habits, lifestyle choices, and exposure to other environmental compounds can significantly modify how individuals respond to piperine, often confounding attempts to identify isolated genetic influences. Gene-environment interactions are likely to play a substantial role, where certain genetic variants may only manifest their effects on piperine metabolism or efficacy under specific environmental conditions, making it difficult to pinpoint direct genetic causality.

This intricate web of interactions also contributes to the phenomenon of missing heritability, where identified genetic variants explain only a fraction of the observed variability in traits related to piperine. The remaining unexplained heritability suggests that many genetic factors, possibly rare variants or complex polygenic interactions, are yet to be discovered, or that epigenetic mechanisms and other non-genetic factors are more influential than currently appreciated. A comprehensive understanding requires advanced analytical approaches capable of modeling these complex interactions and integrating multi-omics data to bridge existing knowledge gaps.

Variants

The ARID3B (AT-rich interaction domain 3B) gene encodes a transcription factor, a type of protein that regulates the activity of other genes. . These proteins are essential for controlling when and how genes are expressed by binding to specific DNA sequences, particularly AT-rich regions, thereby orchestrating various cellular processes. . The variant rs8041357 is located within an intronic region of the ARID3Bgene. While this means it does not directly alter the amino acid sequence of the protein, intronic variants can influence gene expression by affecting messenger RNA splicing, stability, or the function of regulatory elements within the gene.

ARID3B plays a critical role in several fundamental biological pathways, including cell proliferation, differentiation, and programmed cell death (apoptosis). . It is particularly significant during embryonic development, contributing to neurogenesis and the proper formation of the nervous system. . Variations within the ARID3B gene, such as rs8041357 , could subtly modify these intricate processes. Such modifications might lead to altered levels of the ARID3B protein or impact its binding efficiency to target DNA sequences, consequently influencing the expression of numerous downstream genes involved in development and cellular homeostasis.

The broad regulatory functions of ARID3Bin cell growth and differentiation suggest its potential involvement in various health conditions where cellular dysregulation is a factor. . Piperine, a bioactive alkaloid found in black pepper, is recognized for its diverse pharmacological properties, including anti-inflammatory, antioxidant, and potential anti-proliferative effects..^[5] While a direct mechanistic link between rs8041357 and piperine’s actions is complex, variant-mediated changes inARID3B’s influence on critical cellular pathways could theoretically modulate an individual’s physiological response to compounds like piperine, especially in contexts related to cellular stress, inflammation, or abnormal cell growth.

Key Variants

RS ID	Gene	Related Traits
rs8041357	ARID3B	IGA glomerulonephritis piperine measurement

Definition and Chemical Identity

Piperine is precisely defined as a naturally occurring alkaloid, specifically an amide of piperidine and piperic acid, with the chemical formula C17H19NO3.^[6] This compound is primarily responsible for the characteristic pungent taste of fruits from the Piperaceae family, most notably black pepper (Piper nigrum) and long pepper (Piper longum). ^[6] Operationally, its presence is a key diagnostic criterion for the authenticity and quality of pepper-derived products, often serving as a marker for the active constituents of these spices.

The systematic nomenclature for piperine is (2E,4E)-1-[5-(1,3-benzodioxol-5-yl)penta-2,4-dienoyl]piperidine, which accurately describes its chemical structure. While this IUPAC name provides specific detail for chemical classification, “piperine” remains the universally recognized and standardized term in both scientific and commercial contexts. Historically, it has been identified simply as the “active principle” or “pungent principle” of pepper, highlighting its long-recognized biological activity prior to its complete chemical characterization.

Classification and Biological Significance

Piperine is classified primarily as an alkaloid, which is a diverse group of naturally occurring organic compounds containing basic nitrogen atoms, often exhibiting significant physiological effects.^[7]Within the broader classification of natural products, it is further categorized as a pungent amide, distinguishing it by its sensory property. A crucial conceptual framework for understanding piperine’s biological role is its classification as a “bioenhancer” or “bioavailability enhancer.” This functional classification refers to its ability to increase the absorption and systemic availability of various co-administered drugs, nutrients, and phytochemicals by modulating metabolic enzymes and efflux transporters within the body.^[7]

This bioenhancing property places piperine in a unique pharmacological category, contributing significantly to its scientific and potential clinical significance. It is not classified as a disease-modifying agent itself but rather as an adjunct that can potentiate the effects of other substances. Its role as a bioavailability enhancer is a key aspect of its contemporary understanding, distinguishing it from other pungent compounds and highlighting its utility in pharmaceutical and nutritional applications.

Measurement and Functional Criteria

The measurement of piperine concentration in plant extracts, dietary supplements, or biological matrices is typically achieved through precise analytical approaches. High-Performance Liquid Chromatography (HPLC) coupled with ultraviolet (UV) detection is a widely accepted and standardized method for its quantification, relying on the compound’s specific absorbance characteristics.^[6]Gas Chromatography-Mass Spectrometry (GC-MS) offers an alternative or complementary method for both identification and quantification, providing highly specific molecular information. These methods utilize pure piperine as a reference standard to establish calibration curves, ensuring accurate and reproducible results.

Diagnostic and research criteria for evaluating piperine’s effects often extend beyond mere quantification of the compound itself. For instance, its bioenhancing activity is assessed through pharmacokinetic studies, where the primary criteria include measuring changes in the area under the curve (AUC) or maximum plasma concentration (Cmax) of a co-administered substance when taken with piperine. A statistically significant increase in these pharmacokinetic parameters, compared to the substance administered alone, serves as a key research criterion for confirming piperine’s bioenhancing effect.

Biological Background

Molecular and Cellular Mechanisms of Action

Piperine exerts its biological effects through diverse molecular and cellular pathways, often by interacting with critical enzymes and signaling molecules. One well-documented mechanism involves its capacity to inhibit key drug-metabolizing enzymes, particularly cytochrome P450 isoforms likeCYP3A4, and efflux transporters such as P-glycoprotein (ABCB1). This inhibition alters the pharmacokinetics of various compounds, leading to enhanced bioavailability by reducing their first-pass metabolism and increasing absorption across cellular membranes. ^[8]Furthermore, piperine can modulate intracellular signaling cascades, influencing cellular functions related to inflammation, proliferation, and apoptosis by affecting transcription factors and protein kinase activities.^[9]

The compound’s interaction with transient receptor potential (TRP) channels, specifically TRPV1 (vanilloid receptor 1), is another significant molecular pathway. Activation of TRPV1by piperine can lead to a sensation of heat and pain, and it plays a role in its analgesic and anti-inflammatory properties by modulating calcium influx and subsequent cellular responses.^[10]These interactions highlight piperine’s role as a broad-spectrum modulator, affecting cellular permeability, enzymatic activity, and receptor-mediated signaling, thereby influencing a wide array of physiological processes.

Pharmacokinetic Modulation and Systemic Effects

Piperine’s impact on pharmacokinetics extends beyond the cellular level to influence tissue and organ-specific biology, particularly within the gastrointestinal tract and liver. By inhibiting intestinal and hepaticCYP3A4 and ABCB1, piperine significantly affects the absorption and systemic exposure of co-administered drugs and nutrients, thereby enhancing their therapeutic efficacy or nutritional uptake.^[5] This systemic consequence is crucial for its application as a bioavailability enhancer, as it allows for lower doses of certain compounds to achieve desired physiological concentrations and effects.

At the organ level, the liver’s role in detoxification and metabolism is directly influenced, altering the metabolic fate of various xenobiotics and endogenous substances. ^[11] Such modulation can have profound systemic consequences, impacting not only drug metabolism but also the overall homeostatic balance of the body. The altered processing of substances can lead to modified systemic concentrations, affecting target organ exposure and potentially influencing the efficacy and toxicity profiles of other compounds.

Anti-inflammatory and Antioxidant Processes

Piperine demonstrates significant anti-inflammatory and antioxidant properties, which are crucial in mitigating pathophysiological processes related to oxidative stress and chronic inflammation. It achieves its anti-inflammatory effects primarily by inhibiting the activation of the nuclear factor kappa B (NF-κB) pathway, a central regulator of inflammatory gene expression. ^[12]This inhibition leads to a reduction in the production of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, as well as enzymes like COX-2 and iNOS, which are key mediators of inflammation and pain.

In terms of antioxidant activity, piperine directly scavenges free radicals and reactive oxygen species, protecting cellular components from oxidative damage.^[13]Beyond direct scavenging, it also enhances the activity of endogenous antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), thereby bolstering the body’s natural defense mechanisms against oxidative stress. These combined actions contribute to its potential therapeutic utility in conditions characterized by chronic inflammation and oxidative damage, such as certain neurodegenerative diseases and metabolic disorders.

Metabolic and Neurobiological Regulation

Piperine plays a role in metabolic regulation and exhibits neurobiological effects, influencing key biomolecules and signaling pathways in various tissues. In metabolic contexts, studies indicate piperine’s potential to improve glucose and lipid metabolism, suggesting a modulatory effect on enzymes involved in glucose uptake and fatty acid synthesis.^[14] This can contribute to better glycemic control and lipid profiles, potentially ameliorating aspects of metabolic syndrome and related homeostatic disruptions. Its influence on metabolic pathways extends to systemic consequences, impacting energy balance and nutrient utilization.

Neurobiologically, piperine has been observed to interact with neurotransmitter systems and neuronal receptors, affecting brain function and potentially offering neuroprotective benefits. It can modulate the activity of monoamine oxidases and influence the levels of neurotransmitters such as serotonin and dopamine, impacting mood and cognitive functions.^[15]Furthermore, its anti-inflammatory and antioxidant actions within the central nervous system contribute to protecting neuronal cells from damage, highlighting its multifaceted role in maintaining neurological health and function.

Pathways and Mechanisms

Receptor Modulation and Intracellular Signaling

Piperine exerts its biological effects by interacting with various cellular receptors and influencing key intracellular signaling cascades. A prominent mechanism involves the activation of the transient receptor potential vanilloid 1 (TRPV1) channel, a ligand-gated ion channel primarily known for its role in nociception and thermoregulation. Upon binding to TRPV1, piperine induces calcium influx, triggering downstream signaling events that contribute to its analgesic and anti-inflammatory properties. This receptor activation initiates complex intracellular signaling pathways, influencing cellular responses to various stimuli.

Beyond direct receptor activation, piperine significantly modulates transcription factor activity, most notably the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). It inhibits the phosphorylation and degradation of IκB (inhibitor of NF-κB), thereby preventing NF-κBtranslocation to the nucleus and subsequent transcription of pro-inflammatory genes. Additionally, piperine has been shown to interact with peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor that plays a crucial role in lipid metabolism, glucose homeostasis, and inflammation. Activation ofPPARγby piperine can lead to the expression of anti-inflammatory and insulin-sensitizing genes, highlighting its broad regulatory influence on cellular physiology.

Pharmacokinetic Regulation and Metabolic Flux

A well-documented mechanism of piperine involves its ability to modulate drug metabolism and enhance the bioavailability of various compounds. Piperine acts as an inhibitor of drug-metabolizing enzymes, particularly cytochrome P450 (CYP) enzymes such as CYP3A4, which are critical for the phase I metabolism of many xenobiotics and endogenous substances. By reducing the activity of these enzymes, piperine can decrease the breakdown of co-administered drugs or nutrients, leading to higher systemic concentrations and prolonged therapeutic effects. This inhibition represents a crucial regulatory mechanism impacting the metabolic flux of a wide array of compounds in the body.

Furthermore, piperine interferes with drug efflux transporters, such as P-glycoprotein (P-gp), encoded by the ABCB1 gene. P-gpis an ATP-dependent efflux pump that actively expels various substrates from cells, playing a significant role in drug resistance and limiting drug absorption and distribution. By inhibitingP-gpactivity, piperine enhances the intestinal absorption and reduces the efflux of its substrates, thereby increasing their bioavailability. This regulatory action on both metabolic enzymes and efflux transporters underscores piperine’s systems-level integration into the body’s pharmacokinetic machinery, influencing the overall disposition and efficacy of numerous bioactive molecules.

Transcriptional Control and Anti-inflammatory Pathways

Piperine exerts profound regulatory control over gene expression, particularly in pathways related to inflammation and cellular stress. Its inhibitory effect on theNF-κB signaling pathway directly translates into altered transcriptional profiles, leading to a downregulation of genes encoding pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6, as well as enzymes like inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). This transcriptional repression is a key mechanism underlying piperine’s anti-inflammatory properties, preventing the perpetuation of inflammatory responses at the genetic level.

Beyond NF-κB, piperine’s influence extends to other regulatory mechanisms, including the modulation of protein modification and post-translational regulation. It can affect the phosphorylation status of signaling proteins, thereby altering their activity or stability. For instance, its interaction withPPARγ can influence the expression of genes involved in lipid metabolism, such as CD36 and FABP4, through direct transcriptional regulation. These intricate regulatory mechanisms, spanning from gene transcription to protein activity, collectively contribute to piperine’s diverse biological effects, impacting cell survival, proliferation, and differentiation.

Systems-Level Integration and Disease Relevance

The diverse molecular targets and pathways influenced by piperine demonstrate a significant degree of systems-level integration and pathway crosstalk. Its ability to modulate both drug metabolism viaCYP enzymes and drug transport via P-gphighlights a hierarchical regulation that impacts the pharmacokinetics of a broad spectrum of compounds, from pharmaceuticals to dietary components. This interaction can lead to emergent properties, where the combined effect of piperine with other substances is greater than the sum of their individual effects, particularly in enhancing bioavailability and therapeutic efficacy.

These mechanisms are highly relevant to various disease states, positioning piperine as a compound with therapeutic potential. Its anti-inflammatory actions, mediated throughTRPV1 and NF-κBinhibition, are beneficial in chronic inflammatory conditions, while its ability to modulate drug metabolism and efflux pumps offers strategies to overcome drug resistance in cancer chemotherapy or improve drug delivery for other conditions. Piperine’s influence onPPARγfurther suggests roles in metabolic disorders like diabetes and obesity. The dysregulation of these pathways in disease underscores piperine’s potential as a therapeutic agent that targets multiple compensatory mechanisms and signaling nodes to restore cellular homeostasis.

Clinical Relevance

Pharmacokinetic Modulation and Therapeutic Enhancement

Research indicates that piperine may significantly influence the pharmacokinetics of various compounds, primarily by inhibiting drug-metabolizing enzymes such as cytochrome P450 enzymes and P-glycoprotein. This modulatory effect has substantial clinical relevance for optimizing drug bioavailability and efficacy, particularly for medications with low oral absorption or rapid metabolism.^[4] Understanding these interactions is crucial for treatment selection and developing personalized medicine approaches, allowing clinicians to potentially reduce drug dosages while maintaining therapeutic levels, thereby minimizing side effects and improving patient adherence. This aspect holds prognostic value in predicting an individual’s response to co-administered drugs and guiding long-term therapeutic strategies, especially in managing complex polypharmacy regimens in vulnerable populations. ^[16]

Anti-inflammatory and Antioxidant Applications

Piperine’s demonstrated anti-inflammatory and antioxidant properties suggest its potential clinical utility as an adjunctive therapeutic agent in conditions characterized by chronic inflammation and oxidative stress. Studies have explored its role in mitigating inflammatory pathways relevant to diseases such as arthritis, inflammatory bowel disease, and neurodegenerative disorders.^[7]These properties contribute to its potential in risk assessment and prevention strategies, particularly for individuals predisposed to chronic inflammatory states or those experiencing age-related oxidative damage. Integrating piperine into patient care could involve monitoring inflammatory markers and assessing disease progression, potentially offering a complementary approach to improve outcomes and reduce the burden of related comorbidities.^[17]

Metabolic Regulation and Disease Prevention

The association of piperine with metabolic regulation highlights its relevance in addressing conditions like obesity, type 2 diabetes, and dyslipidemia. Research suggests that piperine can influence glucose and lipid metabolism, potentially improving insulin sensitivity and reducing fat accumulation.^[18]This makes it a candidate for risk stratification, identifying individuals at higher risk for metabolic syndrome or its complications, and exploring its role in personalized prevention strategies. Furthermore, its potential to modulate neurological pathways suggests associations with neurodegenerative conditions, offering insights into overlapping phenotypes and potential for early intervention. Monitoring metabolic parameters and neurological function could be part of a comprehensive strategy leveraging piperine’s effects to improve long-term health outcomes and mitigate disease progression.^[19]

References

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[2] Mehmood, M. H., et al. “Piperine inhibits the growth of human colon cancer cells via G2/M cell cycle arrest and induction of apoptosis.”Journal of Agricultural and Food Chemistry, vol. 60, no. 31, 2012, pp. 7642-7649.

[3] Surendran, S., et al. “Piperine, a major component of black pepper, modulates antioxidant and inflammatory responses in diabetic rats.”Food Chemistry, vol. 141, no. 4, 2013, pp. 3144-3151.

[4] Shoba, G., et al. “Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers.”Planta Medica, vol. 64, no. 4, 1998, pp. 353-356.

[5] Amrutkar, Amol, et al. “Piperine: A Comprehensive Review of its Pharmacological Properties and Therapeutic Potential.”Journal of Ethnopharmacology, vol. 280, 2021, pp. 114467.

[6] Damanhouri, Zakiya A., and Abdulaziz Ahmad. “Piperine in the Treatment of Cancer: A Review.”Journal of Applied Pharmaceutical Science, vol. 6, no. 03, 2016, pp. 165-171.

[7] Butt, M. S., et al. “Piperine: A review of its biological effects.”Critical Reviews in Food Science and Nutrition, vol. 53, no. 6, 2013, pp. 581-591.

[8] Johnson, Mark, et al. “Piperine Enhances the Bioavailability of Curcumin by Inhibiting Glucuronidation and P-glycoprotein.”Journal of Pharmacology and Experimental Therapeutics, vol. 327, no. 3, 2008, pp. 680-686.

[9] Sharma, Rahul, and Virendra Singh. “Piperine: A Natural Bioenhancer for Drug Delivery.”Current Drug Metabolism, vol. 16, no. 2, 2015, pp. 113-125.

[10] Lee, Sang-Ho, and Ji-Hye Kim. “Piperine Activates TRPV1 Channels and Induces Calcium Influx in PC12 Cells.”Neuroscience Letters, vol. 468, no. 2, 2010, pp. 127-130.

[11] Kumar, Vivek, et al. “Piperine: A Review of Its Pharmacological Effects and Potential Applications.”Phytotherapy Research, vol. 34, no. 10, 2020, pp. 2576-2591.

[12] Sun, Ling, et al. “Piperine Inhibits NF-κB Pathway and Attenuates Inflammation in LPS-Induced RAW264.7 Macrophages.”Inflammation, vol. 37, no. 4, 2014, pp. 1295-1302.

[13] Singh, Rakesh, and Anamika Gupta. “Piperine: An Overview of Its Pharmacological Activities.”International Journal of Pharmaceutical Sciences Review and Research, vol. 4, no. 1, 2010, pp. 168-175.

[14] Jain, Aruna, et al. “Piperine: A Potential Candidate for the Treatment of Diabetes Mellitus.”Mini-Reviews in Medicinal Chemistry, vol. 18, no. 1, 2018, pp. 19-32.

[15] Bang, Jong-Seok, et al. “Anti-inflammatory and Antiarthritic Effects of Piperine in Human Fibroblast-like Synoviocytes and in Vivo Models.”Journal of Ethnopharmacology, vol. 121, no. 1, 2009, pp. 114-118.

[16] Dudhat, P. D., et al. “Piperine: A Review on its Pharmacological Activities.”Journal of Pharmaceutical Research International, vol. 33, no. 31, 2021, pp. 110-125.

[17] Khan, M. A., et al. “Piperine: A natural alkaloid with versatile pharmacological activities.”Journal of Ethnopharmacology, vol. 279, 2021, p. 114382.

[18] Kim, S. H., et al. “Piperine enhances insulin signaling and reduces the expression of genes involved in adipogenesis and inflammation in 3T3-L1 adipocytes.”Journal of Nutritional Biochemistry, vol. 24, no. 11, 2013, pp. 1926-1933.

[19] Oladipupo, A. R., et al. “Therapeutic Potentials of Piperine: A Review of its Neuroprotective and Cognitive Enhancing Effects.”Pharmacological Research - Modern Chinese Medicine, vol. 1, 2021, p. 100008.