Submitted Successfully!
To reward your contribution, here is a gift for you: A free trial for our video production service.
Thank you for your contribution! You can also upload a video entry or images related to this topic.
Version Summary Created by Modification Content Size Created at Operation
1
Sunil Pareek
 + 1837 word(s) 1837 2021-03-16 03:11:09 |
2 format correct
Bruce Ren
Meta information modification 1837 2021-03-23 01:55:55 |

Video Upload Options

Do you have a full video?
Send video materials Upload full video

Confirm

Are you sure to Delete?
Yes No
Cite
If you have any further questions, please contact Encyclopedia Editorial Office.
Pareek, S. β-Carotene within Loaded Delivery Systems. Encyclopedia. Available online: https://encyclopedia.pub/entry/8164 (accessed on 28 April 2024).
Pareek S. β-Carotene within Loaded Delivery Systems. Encyclopedia. Available at: https://encyclopedia.pub/entry/8164. Accessed April 28, 2024.
Pareek, Sunil. "β-Carotene within Loaded Delivery Systems" Encyclopedia, https://encyclopedia.pub/entry/8164 (accessed April 28, 2024).
Pareek, S. (2021, March 22). β-Carotene within Loaded Delivery Systems. In Encyclopedia. https://encyclopedia.pub/entry/8164
Pareek, Sunil. "β-Carotene within Loaded Delivery Systems." Encyclopedia. Web. 22 March, 2021.
β-Carotene within Loaded Delivery Systems
Edit
This entry is adapted from the peer-reviewed paper 10.3390/antiox10030426

Nanotechnology has opened new opportunities for delivering bioactive agents. Their physiochemical characteristics, i.e., small size, high surface area, unique composition, biocompatibility and biodegradability, make these nanomaterials an attractive tool for β-carotene delivery. Delivering β-carotene through nanoparticles does not only improve its bioavailability/bioaccumulation in target tissues, but also lessens its sensitivity against environmental factors during processing. Regardless of these benefits, nanocarriers have some limitations, such as variations in sensory quality, modification of the food matrix, increasing costs, as well as limited consumer acceptance and regulatory challenges. This research area has rapidly evolved, with a plethora of innovative nanoengineered materials now being in use, including micelles, nano/microemulsions, liposomes, niosomes, solidlipid nanoparticles, nanostructured lipids and nanostructured carriers. These nanodelivery systems make conventional delivery systems appear archaic and promise better solubilization, protection during processing, improved shelf-life, higher bioavailability as well as controlled and targeted release. 

beta-carotene bioavailability delivery system encapsulation engineered nanomaterial SLNs NLCs

1. Introduction

Vitamin A deficiency is one of the most diagnosed micronutrient deficiency disorders worldwide, especially in developing countries. However, its magnitude is more widespread in the vegetarian population [1]. Across the globe, approximately 250 million preschool children are estimated to be affected by vitamin A deficiency [2]. Furthermore, occurrence of disease has an intimate relationship with a low antioxidant load in the daily diet. Furthermore, lifestyle (exercise, smoking, drinking and high consumption of meat-based and processed foods), environment (emotional and social stress), and cultural constraints trigger the expression of housekeeping genes to adopting genes to retain the cellular, organ or body homeostasis [3]. The aforesaid stimuli also cause the generation of reactive oxygen species (ROS), resulting in oxidative homoeostasis imbalance at cellular and tissue levels, thus generating oxidative stress [4]. Oxidative stress can be defined as a phenomenon triggered by an imbalance between the generation and accumulation of ROS. In general, ROS, including organic hydro peroxides, hydrogen peroxide, nitric oxide, hydroxyl radicals and superoxide, are generated as by-products of oxygen metabolism; in addition, these environmental stimuli (UV, pollutants, heavy metals, and xenobiotics (including antiblastic drugs, antiallergic drugs, immunosuppressant drugs) equally contribute to ROS production, thus causing oxidative stress [5]. Accruing scientific evidence is accumulating on the involvement of oxidative stress in the occurrence of several health complications, which are attributed to inactivation of metabolic enzymes and damage vital cellular components, oxidization the nucleic acids, resulting in eye disorders, atherosclerosis, cardiovascular diseases, joint and bone disorders, neurological diseases (amyotrophic lateral sclerosis, Parkinson’s disease and Alzheimer’s disease) and misfunctioning of different organ including lung, kidney, liver and reproductive system [6]. ROS are primarily generated in mitochondria under both pathological as well as physiological conditions [7]. Cells activate an antioxidant defensive system which primarily includes enzymatic components such as superoxide dismutase, glutathione peroxidase, and catalase in order to minimize the oxidative stress cell [8].

2. Oxidative Stress and Antioxidants

ROS generation is attributed to both nonenzymatic and enzymatic reactions. Enzymatic processes that have intricate involvement in the respiratory chain, phagocytosis, prostaglandins biosynthesis, and cytochrome P450 system are responsible for ROS generation. Superoxide radicals produced as the result of enzymatic action of NADPH oxidase, peroxidases and xanthine oxidase initiate the chain reaction for ROS formation including hydrogen peroxide, hydroxyl radicals, peroxynitrite, hypochlorous acid and so on [9]. Hydroxyl radicals (OH•) are considered as the most reactive among all ROS in vivo and are produced as a result of catalysis of H2O2 in the presence of Fe2+ or Cu+ (Fenton reactions).

In addition, some nonenzymatic processes also contribute to ROS generation, especially when oxygen is either exposed to ionizing radiations or reacts with organic compounds. ROS are produced due to exogenous and endogenous sources. Exogenous sources of ROS include inflammation, immune cell activation, infection, ischemia, cancer, mental stress, excessive exercise and aging [4][10]. Exogeneous ROS generation relies on exposure to radiation, heavy metals [11], environmental pollutants [12], certain drugs (bleomycin, cyclosporine, gentamycin, tacrolimus) [13], toxic chemical and solvents [13], food processing (used oil and fat and smoked meat) [14], cigarette smoking and alcohol consumption, among other [10]. ROS are essential part of several biological processes when they remain at low or moderate concentrations. For instance, these ROS are obligatory for synthesis of some cellular structures, which have vital role in the host defense system, i.e. in the defence of pathogens [14][15]. In fact, macrophages synthesize and store ROS to kill pathogenic microbes [16]. The critical role of ROS in the immune system is well recognized as patients unable to produce ROS are more prone to pathological infections [17]. In addition, ROS are also integrated in an array of cellular signaling pathways as they play a regulatory role in intracellular signaling cascades, including endothelial cells, fibroblasts, cardiac myocytes, vascular smooth muscle cells and thyroid tissue. Nitric oxide (NO) is considered as a key cell-to-cell messenger, which plays a vital role in cell signaling and is intricately involved in several processes, such as blood flow modulation, thrombosis and normal neural functioning [18]. Nitric oxide also demonstrates close association with nonspecific host defense in eliminating the tumor cells, as well as intracellular pathogens [19]. In addition to beneficial effects, ROS also pose several negative impacts by affecting cellular structure, including plasma membrane, proteins, lipoprotein, proteins and nucleic acids (deoxyribonucleic acid, DNA; ribonucleic acid, RNA). Oxidative stress is a result of ROS imbalance between its rate of generation and rate of clearance within the cell [20]. These excess ROS thus cause damage in the plasma membrane by lipid peroxidation and form malondialdehyde and conjugated dienes which are cytotoxic and mutagenic in nature. Being a chain reaction cascade, lipid peroxidation spreads very rapidly, damaging a significant number of lipids, proteins and nucleic acids, hence hampering their functionalities [21]. In summary, ROS impart beneficial effects when they are maintained at low or moderate concentrations while they negatively affect several cellular structures at higher concentrations.

The human body adopts several strategies to combat the negative effects generated due to oxidative stress, including enzymatic (superoxide dismutase, glutathione peroxidase and catalase) or nonenzymatic (L-arginine, glutathione, coenzyme Q10 and lipoic acid) antioxidant molecules. In addition to the aforesaid molecules, several exogenous antioxidants molecules from animal or plant origins are deliberately incorporated, i.e. fortified, into the diet [5].

3. Mode of Action of β-Carotene against Oxidative Stress

β-Carotene, a key member of the carotenoid family, is recognized as one of the most potent antioxidants [22] and the major provitamin A carotenoid available in the human diet. The health benefits of β-carotene are attributed to its given biological properties [21]: (a) as antioxidants that scavenge and quench ROS of oxidative metabolism, (b) as provitamin A compounds that activate retinol-mediated pathways, (c) as electrophiles that boost endogenous antioxidant systems, (d) by hampering inflammation-related processes mediated by nuclear factor κ-light-chain-enhancer of activated B cell (NF-κB) pathway, and/or (e) by directly binding nuclear receptors (NRs) and other transcription factors in target cells.

Retinoic acid acts as ligand for the retinoid X receptors (RXRs) and canonical retinoid acid receptors (RARs), which influence the expression of a number of responsive genes and have intimate relationships with fatty acid, cholesterol, Ca2+ and phosphate homeostasis [23]. β-Carotene also demonstrated tumor cell suppression activity and enhanced intercellular communication at gap junctions [3]. It is believed that consumption of β-carotene may cause low incidence of hepatic oxidative stress and lipid oxidation. The assumption was supported by a mice model study where expression of 1207 genes (approximately 4% genes) of a total of 30,855 genes in a hepatic transcriptome was influenced when mice were fed with β-carotene as compared to control mice [24]. Remarkably, numerous differentially expressed genes were intimately involved in energy metabolism, lipid metabolism, and mitochondrial redox homeostasis.

β-Carotene is the main contributor to vitamin A in human beings, if preformed vitamin A intake is insufficient. It acts as a precursor of vitamin A, with the potential to yield two retinal molecules following cleavage by beta-carotene oxygenase 1 in the intestine, as compared to other carotenoids which generally yield only one retinal molecule. Despite its indispensable role in vision, it may furthermore play a role as a bioactive compound, due to its potential antioxidant effects [25], and its interaction with nuclear receptors, mainly RAR/RXR, which is important for cell differentiation and immunity [26]. These properties make β-carotene one of the most investigated biological molecules, both in academia and industry. Though its multifunctionality in humans is yet to be fully understood, several epidemiologic studies have demonstrated its relationship to a decreased incidence of chronic diseases such as blindness [27], xerophthalmia [28], cancer [29], cardiovascular diseases [30], diabetes [31] and premature death [32] and found to have an antioxidant component.

4. Challenges Associated with β-Carotene Food Fortification

β-Carotene is naturally found in various foods and is also commonly used as a natural pigment in food, pharmaceutical and cosmetic industries. This lipophilic molecule is characterized by the presence of a polyene structure with 11 conjugated double bonds with two β-ionone rings. Under environmental stress (temperature, humidity, pH, ionic strength and radiation), β-carotene may undergo transformation, resulting in the formation of different isomers such as 15-cis-β-carotene, 13-cis-β-carotene and 9-cis-β-carotene and several trans-β-carotenes [33][34]. Cis-isomers have bent structures and are likely to be more readily solubilized and adsorbed compared to trans-β-carotene which possesses a linear and rigid structure and has a high tendency to crystallize and aggregate as compare to the cis-isomers [35][36]. The unsaturated structure makes β-carotene prone to oxidation, resulting in the loss of its vitamin A functionality. Furthermore, β-carotene is also susceptible to isomerization when confronted with acidic conditions, high-salt, temperature, metal ions, peroxides and radiation during food processing and storage before consumption [36]. In addition, naturally occurring β-carotene is often complexed with protein molecules which limit its solubility and distribution in the food matrix, as well as its adsorption in human body [37].

Currently, β-carotene is one of the most exploited carotenoids and is usedto develop functional foods [38], formulate pharmaceutical supplements and prepare cosmetic products. However, food fortification, i.e., incorporating β-carotene within functional foods, is recognized as the most natural, appropriate and safe methods as compared to other drug administration routes including intravenous, intramuscular and subcutaneous ones [39]. However, within these functional food products, β-carotene is prone to physicochemical degradation during the production, processing and storage before food consumption. These limiting factors, in addition to its low bioavailability within the human gastrointestinal tract, make β-carotene difficult to incorporate into the food matrix and hence significantly impact its efficacy as a health beneficial plant compound.

Nanotechnology seems to be a logical solution to address these limiting factors, as it has demonstrated its potential to encapsulate, protect and delivery bioactive compounds using several delivery systems to improve their physicochemical stability, solubility, dispersibility and bioavailability upon ingestion [40][41][42][43][44]. Researchers have nanoengineered various kinds of delivery systems, such as microemulsion, liposomes, solid lipid carriers, nanostructured lipid carriers, nanocapsules and nanospheres to encapsulate and deliver bioactive compounds. These delivery systems are capable of improving stability, dispersity and bioavailability of bioactive compounds within the target food matrix. Although several excellent reports have already been published emphasizing the factors affecting the chemical stability of carotenoids [45], encapsulation techniques to protect them against environmental stress [46], production methods to prepare nanoengineered delivery systems [47] and delivery systems to improve their solubility or bioavailability [48], there is lack of reviews regarding β-carotene delivery systems, in particular with food applications.

References

  1. McLaren, D.S.; Kraemer, K. Manual on Vitamin A Deficiency Disorders (VADD); Karger Medical and Scientific Publishers: Basel, Switzerland, 2012.
  2. Unit, N.; World Health Organization. Global Prevalence of Vitamin A Deficiency; World Health Organization: Geneva, Switzerland, 1995.
  3. Rodriguez-Concepcion, M.; Avalos, J.; Bonet, M.L.; Boronat, A.; Gomez-Gomez, L.; Hornero-Mendez, D.; Limon, M.C.; Meléndez-Martínez, A.J.; Olmedilla-Alonso, B.; Palou, A. A global perspective on carotenoids: Metabolism, biotechnology, and benefits for nutrition and health. Prog. Lipid Res. 2018, 70, 62–93.
  4. Shibata, M.; Sato, H.; Shimizu, T.; Shibata, S.; Toriumi, H.; Kuroi, T.; Ebine, T.; Iwashita, T.; Funakubo, M.; Akazawa, C. Differential cellular localization of antioxidant enzymes in the trigeminal ganglion. J. Headache Pain 2013, 14, P83.
  5. Adwas, A.A.; Elsayed, A.; Azab, A.E.; Quwaydir, F.A. Oxidative stress and antioxidant mechanisms in human body. J. Appl. Biotechnol. Bioeng. 2019, 6, 43–47.
  6. Giustarini, D.; Dalle-Donne, I.; Tsikas, D.; Rossi, R. Oxidative stress and human diseases: Origin, link, measurement, mechanisms, and biomarkers. Crit. Rev. Clin. 2009, 46, 241–281.
  7. Adam-Vizi, V.; Chinopoulos, C. Bioenergetics and the formation of mitochondrial reactive oxygen species. Trends Pharmacol. Sci. 2006, 27, 639–645.
  8. Lenaz, G. Mitochondria and reactive oxygen species. Which role in physiology and pathology? Adv. Mitochondrial. Med. 2012, 93–136.
  9. Auten, R.L.; Davis, J.M. Oxygen toxicity and reactive oxygen species: The devil is in the details. Pediatr. Res. 2009, 66, 121–127.
  10. Sharifi-Rad, M.; Anil Kumar, N.V.; Zucca, P.; Varoni, E.M.; Dini, L.; Panzarini, E.; Rajkovic, J.; Tsouh Fokou, P.V.; Azzini, E.; Peluso, I. Lifestyle, oxidative stress, and antioxidants: Back and forth in the pathophysiology of chronic diseases. Front. Physiol. 2020, 11, 694.
  11. Engwa, G.A.; Ferdinand, P.U.; Nwalo, F.N.; Unachukwu, M.N. Mechanism and health effects of heavy metal toxicity in humans. In Poisoning in the Modern World-New Tricks for an Old Dog? IntechOpen: London, UK, 2019; pp. 77–100.
  12. Leni, Z.; Künzi, L.; Geiser, M. Air pollution causing oxidative stress. Curr. Opin. Toxicol. 2020, 20, 1–8.
  13. Klawitter, J.; Klawitter, J.; Pennington, A.; Kirkpatrick, B.; Roda, G.; Kotecha, N.C.; Thurman, J.M.; Christians, U. Cyclophilin D knockout protects the mouse kidney against cyclosporin A-induced oxidative stress. Am. J. Physiol. Ren. Physiol. 2019, 317, F683–F694.
  14. Wu, S.-C.; Yen, G.-C. Effects of cooking oil fumes on the genotoxicity and oxidative stress in human lung carcinoma (A-549) cells. Toxicol. In Vitro 2004, 18, 571–580.
  15. Bardaweel, S.K.; Gul, M.; Alzweiri, M.; Ishaqat, A.; Alsalamat, H.A.; Bashatwah, R.M. Reactive oxygen species: The dual role in physiological and pathological conditions of the human body. Eurasian J. Med. 2018, 50, 193.
  16. Chen, Q.; Wang, Q.; Zhu, J.; Xiao, Q.; Zhang, L. Reactive oxygen species: Key regulators in vascular health and diseases. Br. J. Pharmacol. 2018, 175, 1279–1292.
  17. Franchina, D.G.; Dostert, C.; Brenner, D. Reactive oxygen species: Involvement in T cell signaling and metabolism. Trends Immunol. 2018, 39, 489–502.
  18. Martina, A.; Jana, P.; Anna, S.; Tomas, B. Nitric oxide—Important messenger in human body. J. Mol. Integr. Physiol. 2012, 2, 98–106.
  19. Hezel, M.P.; Weitzberg, E. The oral microbiome and nitric oxide homoeostasis. Oral Dis. 2015, 21, 7–16.
  20. Belhadj Slimen, I.; Najar, T.; Ghram, A.; Dabbebi, H.; Ben Mrad, M.; Abdrabbah, M. Reactive oxygen species, heat stress and oxidative-induced mitochondrial damage. A review. Int. J. Hyperth. 2014, 30, 513–523.
  21. Kaulmann, A.; Bohn, T. Carotenoids, inflammation, and oxidative stress—implications of cellular signaling pathways and relation to chronic disease prevention. Nutr. Res. 2014, 34, 907–929.
  22. Kawata, A.; Murakami, Y.; Suzuki, S.; Fujisawa, S. Anti-inflammatory activity of β-carotene, lycopene and tri-n-butylborane, a scavenger of reactive oxygen species. In Vivo 2018, 32, 255–264.
  23. Evans, R.M.; Mangelsdorf, D.J. Nuclear receptors, RXR, and the big bang. Cell 2014, 157, 255–266.
  24. Palczewski, G.; Widjaja-Adhi, M.A.; Amengual, J.; Golczak, M.; Von Lintig, J. Genetic dissection in a mouse model reveals interactions between carotenoids and lipid metabolism. J. Lipid Res. 2016, 57, 1684–1695.
  25. Krinsky, N.I.; Johnson, E.J. Carotenoid actions and their relation to health and disease. Mol. Aspects Med. 2005, 26, 459–516.
  26. Czarnewski, P.; Das, S.; Parigi, S.M.; Villablanca, E.J. Retinoic acid and its role in modulating intestinal innate immunity. Nutrients 2017, 9, 68.
  27. Al Binali, H.A.H. Night blindness and ancient remedy. Heart Views 2014, 15, 136.
  28. Biradar, S.T.; Ankitha, C.S.; Pasha, S.M. An Ayurvedic insight to keratoconus-A case report. J. Ayurveda Integr. Med. 2020, 5, 412–416. Available online: (accessed on 26 February 2021).
  29. Balaji, S.; Roy, A. Beta-carotene--A versatile antioxidant in oral cancer: A review. Drug Invent. Today 2020, 13, 398–403.
  30. Miller, A.P.; Coronel, J.; Amengual, J. The role of β-carotene and vitamin A in atherogenesis: Evidences from preclinical and clinical studies. Biochim. Biophys. Acta Mol. Cell Biol. Lipids 2020, 158635.
  31. Csepanyi, E.; Czompa, A.; Szabados-Furjesi, P.; Lekli, I.; Balla, J.; Balla, G.; Tosaki, A.; Bak, I. The effects of long-term, low-and high-dose beta-carotene treatment in Zucker diabetic fatty rats: The role of HO-1. Int. J. Mol. Sci. 2018, 19, 1132.
  32. Stevens, G.A.; Bennett, J.E.; Hennocq, Q.; Lu, Y.; De-Regil, L.M.; Rogers, L.; Danaei, G.; Li, G.; White, R.A.; Flaxman, S.R. Trends and mortality effects of vitamin A deficiency in children in 138 low-income and middle-income countries between 1991 and 2013: A pooled analysis of population-based surveys. Lancet Glob. Health 2015, 3, e528–e536.
  33. Imsic, M.; Winkler, S.; Tomkins, B.; Jones, R. Effect of storage and cooking on β-carotene isomers in carrots (Daucus carota L. cv. ‘Stefano’). J. Agric. Food Chem. 2010, 58, 5109–5113.
  34. Knockaert, G.; Lemmens, L.; Van Buggenhout, S.; Hendrickx, M.; Van Loey, A. Changes in β-carotene bioaccessibility and concentration during processing of carrot puree. Food Chem. 2012, 133, 60–67.
  35. Schieber, A.; Carle, R. Occurrence of carotenoid cis-isomers in food: Technological, analytical, and nutritional implications. Trends Food Sci. Technol. 2005, 16, 416–422.
  36. Rodriguez-Amaya, D.B. Food Carotenoids: Chemistry, Biology and Technology; John Wiley & Sons: Hoboken, NJ, USA, 2015.
  37. Erdman, J.W., Jr.; Bierer, T.L.; Gugger, E.T. Absorption and transport of carotenoids. Ann. N. Y. Acad. Sci. 1993, 691, 76–85.
  38. Nagarajaiah, S.B.; Prakash, J. Nutritional composition, acceptability, and shelf stability of carrot pomace-incorporated cookies with special reference to total and β-carotene retention. Cogent Food Agric. 2015, 1, 1039886.
  39. Kaya-Celiker, H.; Mallikarjunan, K. Better nutrients and therapeutics delivery in food through nanotechnology. Food Eng. Rev. 2012, 4, 114–123.
  40. Gul, K.; Tak, A.; Singh, A.; Singh, P.; Yousuf, B.; Wani, A.A. Chemistry, encapsulation, and health benefits of β-carotene-A review. Cogent Food Agric. 2015, 1, 1018696.
  41. Teng, Z.; Xu, R.; Wang, Q. Beta-lactoglobulin-based encapsulating systems as emerging bioavailability enhancers for nutraceuticals: A review. RSC Adv. 2015, 5, 35138–35154.
  42. Chen, L.; Bai, G.; Yang, R.; Zang, J.; Zhou, T.; Zhao, G. Encapsulation of β-carotene within ferritin nanocages greatly increases its water-solubility and thermal stability. Food Chem. 2014, 149, 307–312.
  43. Gutiérrez, F.J.; Albillos, S.M.; Casas-Sanz, E.; Cruz, Z.; García-Estrada, C.; García-Guerra, A.; García-Reverter, J.; García-Suárez, M.; Gatón, P.; González-Ferrero, C.; et al. Methods for the nanoencapsulation of β-carotene in the food sector. Trends Food Sci. Technol. 2013, 32, 73–83.
  44. Zhu, F.; Du, B.; Xu, B. Anti-inflammatory effects of phytochemicals from fruits, vegetables, and food legumes: A review. Crit. Rev. Food Sci. Nutr. 2018, 58, 1260–1270.
  45. Boon, C.S.; McClements, D.J.; Weiss, J.; Decker, E.A. Factors influencing the chemical stability of carotenoids in foods. Crit. Rev. Food Sci. Nutr. 2010, 50, 515–532.
  46. Dos Santos, P.P.; de Aguiar Andrade, L.; Flôres, S.H.; de Oliveira Rios, A. Nanoencapsulation of carotenoids: A focus on different delivery systems and evaluation parameters. J. Food Sci. Technol. 2018, 55, 3851–3860.
  47. Rehman, A.; Tong, Q.; Jafari, S.M.; Assadpour, E.; Shehzad, Q.; Aadil, R.M.; Iqbal, M.W.; Rashed, M.M.A.; Mushtaq, B.S.; Ashraf, W. Carotenoid-loaded nanocarriers: A comprehensive review. Adv. Colloid Interface Sci. 2020, 275, 102048.
  48. Mao, L.; Wang, D.; Liu, F.; Gao, Y. Emulsion design for the delivery of β-carotene in complex food systems. Crit. Rev. Food Sci. Nutr. 2018, 58, 770–784.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
Upload a video for this entry
Information
Subjects: Food Science & Technology
Contributor MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Sunil Pareek
View Times: 367
Revisions: 2 times (View History)
Update Date: 23 Mar 2021
Table of Contents
    1000/1000
    Hot Most Recent
    Feedback