A Review of the Applications of Vitamin C to Treat Human Diseases

Abstract

Vitamin C, a ubiquitous water-soluble vitamin, has been demonstrated to have several biological activities, including the promotion of collagen production, enhancement of immunity, facilitation of iron absorption, and improvement of fat metabolism. Thus, it has a multitude of applications in the medical field, such as whitening, antioxidation, and the prevention of a wide range of diseases. Conversely, its lack of stability and low permeability limit its applicability. This review presents a summary of the physicochemical properties, delivery strategies, and biological activities of vitamin C. Additionally, this review provides an overview of its preventive and therapeutic effects on diseases such as cataracts, tumors, and cardiovascular conditions. Finally, this review explores the prospective applications of vitamin C as a pharmaceutical agent. A variety of vitamin C derivatives and delivery systems have been developed to overcome the instability and low permeability of vitamin C. However, several challenges persist, including the uncertain efficacy of derivatives and the complexities associated with the implementation of delivery systems. It is anticipated that future advancements will facilitate the development of delivery forms and the utilization of vitamin C in novel applications.

Keywords

vitamin C - ascorbic acid - free radicals - antioxidant - biological activities

Introduction

Vitamin C (VC), also known as L-ascorbic acid (AA), one of the water-soluble vitamins, is an essential substance for maintaining the normal physiological state of the human body. VC plays a critical role in physiological functions such as promoting collagen production, enhancing immunity, and improving fat metabolism. Therefore, VC has a wide range of applications in the medical field.

In nature, VC can be synthesized by most animals and plants, but the gene for L-gluconolactone oxidase, which synthesizes VC, is mutated in humans, resulting in the inability to synthesize VC.[1] The primary source of VC for humans is through the daily diet. Approximately 90% of the daily intake of VC in the general population is derived from fruits and vegetables. The VC content of common fruits and vegetables is listed in [Table 1].[2] A plasma concentration of VC below 10 μmol/L is associated with the development of scurvy, which presents with symptoms such as impaired wound healing, gingivitis, and ecchymosis.[3] [4] [5] The deficiency of VC is mainly caused by inadequate dietary intake, although other factors, including smoking, pregnancy, age, genetic susceptibility, and some metabolic diseases such as hypertension and diabetes, also contribute to its prevalence.[3] [6] The recommended dietary allowance for women and men is 75 and 90 mg/d, respectively.[7] For most adults, 200 mg/d is the optimal intake.[6] [8]

Table 1 Food sources of vitamin C

Fruit
Source (portion size)	Vitamin C content (mg)
Strawberries (1 cup, sliced)	95
Papaya (1 cup, cubes)	85
Kiwi (1 medium)	75
Orange (1 medium)	70
Cantaloupe (1/4 medium)	60
Honeydew melon (1/8 medium)	40
Fresh grapefruit (1/2 fruit)	40
Vegetables
Source (portion size)	Vitamin C content (mg)
Raw pepper, red or green (1/2 cup)	65
Broccoli, cooked (1/2 cup)	60
Kale, cooked (1 cup)	55
Fresh snow peas, cooked (1/2 cup)	40
Mustard greens, cooked (1 cup)	35
Baked sweet potato (1 medium)	30
Cauliflower, raw or cooked (1/2 cup)	25

Source: Reproduced with permission from Levine et al,[2] copyright 1999 American Medical Association.

Due to its strong water solubility and electronegativity, VC cannot penetrate the lipid bilayer easily. Therefore, the absorption of VC does not depend on simple diffusion, but rather on facilitated diffusion mediated by glucose transporters (GLUT) and active transport mediated by sodium-dependent VC transporter (SVCT).[9] In the intestine, VC can be oxidized to dehydroascorbic acid (DHA), which is then immediately reduced to AA after it is transported into the cell via GLUT.[10] [11] This process is known as the AA cycle.[12] Two distinct forms of SVCT are present in the human body: SVCT1 and SVCT2. These transporters facilitate the uptake of AA into cells.[9] SVCT1 is subject to feedback inhibition by AA concentration,[13] [14] whereas SVCT2 is responsive to changes in intracellular AA levels, which may be crucial for maintaining intracellular AA homeostasis.[14] [15]

When the daily intake of VC exceeds 400 mg, the plasma concentration of VC is fully saturated, resulting in a steady-state plasma concentration of ∼80 μmol/L.[16] Excessive VC is usually excreted in the urine. VC is well tolerated by the human body; however, short-term supplementation of VC has been associated with gastrointestinal adverse reactions, including abdominal distension, flatulence, diarrhea, and abdominal pain. At the same time, VC participates in the metabolic process, whereby it produces oxalic acid. Consequently, the risk of developing kidney stones is elevated when individuals consume a substantial amount of VC over an extended period. In addition, the ingestion of large quantities of VC may also result in relative deficiencies of other vitamins in the body.[3] [17]

This article will provide an overview of the physicochemical properties, biological activities, and delivery mode of VC. In conjunction with developments in clinical and research practice, this article will examine the preventive and therapeutic effects of VC in the management of skin conditions, cataracts, tumors, cardiovascular diseases (CVDs), and other diseases.

Overview

The Structure and Properties of Vitamin C

VC is an acidic polyhydroxyl compound comprising carbon, hydrogen, and oxygen with a molecular formula of C₆H₈O₆ and an IUPAC name of 2,3,4,5,6-pentahydroxy-2-hexenoide-4-lactone, with a molecular weight of 176.1 g/mol. The structural formula is shown in [Fig. 1].

Fig. 1 The structure of vitamin C.

The structure of VC contains enediol groups, of which C₃–OH exhibits strong acidity. This is influenced by the conjugation effect (pK_a = 4.17). In contrast, C₂–OH is weakly acidic due to intramolecular hydrogen bonding (pK_a = 11.75). Accordingly, VC exists in the form of anion under physiological conditions.[14] The structure of VC contains conjugated structures, which result in ultraviolet absorption. The maximum absorption wavelength is ∼245 nm, which provides a method for the detection of VC content. The double bond between C₂ and C₃ yields two electrons, which are subsequently lost by VC to generate AA free radicals (semi-hydroascorbic acid). The majority of these free radicals have a lifetime of less than a millisecond and exhibit reduced activity.[18] When VC loses its second electron, it forms a substance that is more stable than the ascorbate radical: DHA. Both AA free radicals and DHA can be reduced to AA. Once the five-membered loop of DHA is hydrolyzed and broken to produce 2,3-diketo-1-gulonic acid (this process is irreversible), the reduction of DHA to AA is no longer possible. The detailed oxidation process of VC is shown in [Fig. 2].

Fig. 2 Oxidation of ascorbic acid.

Some biological processes within the human body may result in the production of highly reactive and potentially harmful free radicals, and these free radicals can be removed by VC. In this process, VC itself is converted to less active ascorbate radicals. These results indicate that AA is an effective antioxidant and free radical scavenger.[19]

Commercially Available Formulations and Delivery Systems for VC

Most VC-related dosage forms are oral preparations, external dosage forms, and injections. A large number of VC products are approved by the National Medical Products Administration (NMPA) annually. The VC-related preparations approved by NMPA from 2021 to 2023 are shown in [Table 2]. To reduce VC degradation, achieve targeted drug delivery, and improve therapeutic efficacy, researchers have developed different drug delivery systems to deliver VC, such as polymeric nanoparticles, liposomes, microemulsions, and micelles ([Fig. 3]).

Table 2 Approved vitamin C commercial formulations from 2021 to 2023

Dosage form	Drug name	Active agent	Specification	Number of manufacturers of the same type	The most recent approval date	Indications
Tablets	Vitamin C tablets	Vitamin C	25 mg; 50 mg; 100 mg;	584	2023-03-27	Scurvy; chronic iron poisoning; idiopathic methemoglobinemia; liver cirrhosis; acute hepatitis
Tablets	Vitamin C Yinqiao tablets	Vitamin C; acetaminophen; chlorpheniramine maleate	Each tablet contains 49.5 mg of vitamin C, 105 mg of acetaminophen, and 1.05 mg of chlorpheniramine maleate	292	2022-07-22	Influenza caused by exogenous wind-heat
Tablets	Vitamin E and C chewable tablets	Vitamin C; vitamin E	Each tablet contains 100 mg of vitamin E and 200 mg of vitamin C	3	2021-10-11	Prevent and treat disease caused by vitamin E and vitamin C deficiency
Tablets	Aspirin vitamin C enteric-coated tablets	Aspirin; vitamin C	Each tablet contains 0.25 g of aspirin and 25 mg of vitamin C	10	2023-02-24	Used to relieve fever, headache, and body aches caused by cold or flu
Tablets	Compound rutin tablets	Rutin; vitamin C	Each tablet contains 20 mg of rutin and 50 mg of vitamin C	60	2022-05-09	Used for capillary hemorrhage with increased fragility, and also used for adjuvant treatment of hypertensive encephalopathy
Tablets	Diavitamin and glucuronolactone tablets	Glucuronide; vitamin C; vitamin B	Each tablet contains 5 mg of glucuronide, 10 mg of vitamin C, 110 mg of vitamin B	8	2021-03-29	Used for adjuvant treatment of liver damage in acute and chronic hepatitis and chronic poisoning such as arsenic, mercury, lead, benzene
Tablets	Vitamin C effervescent tablets	Vitamin C	0.5 g; 1g	13	2022-06-28	Infectious diseases; scurvy
Tablets	Vitamin C chewable tablets	Vitamin C	50 mg; 0.1 g	39	2021-02-26	Scurvy; infectious diseases; purpura
Tablets	Aspirin and vitamin C effervescent tablets	Aspirin; vitamin C	Each tablet contains 0.4 g of aspirin and 24 mg of vitamin C	3	2023-04-18	Used for heating, including cold caused by fever, headache, sore throat, toothache, and other pain, etc.
Tablets	Paracetamol and vitamin C dispersible tablets	Paracetamol; vitamin C	Each tablet contains 330 mg of paracetamol and 200 mg of vitamin C	2	2023-02-21	Antipyretic and analgesic
Tablets	Paracetamol and vitamin C effervescent tablets	Paracetamol; vitamin C	Each tablet contains 330 mg of paracetamol and 200 mg of vitamin C	3	2023-01-03	Antipyretic and analgesic
Tablets	Paracetamol vitamin C tablets	Paracetamol; vitamin C	Each tablet contains 330 mg of paracetamol and 200 mg of vitamin C	1	2022-09-14	Antipyretic and analgesic
Tablets	Compound trivitamin and calcium hydrogen phosphate tablets	Calcium hydrogen phosphate; calcium lactate; vitamin B1; vitamin B2; vitamin C	Each tablet contains 75 mg of calcium hydrogen phosphate, 45 mg of calcium lactate, 0.05 mg of vitamin B1, 0.0015 mg of vitamin B2, and 12 mg of vitamin C	5	2021-01-13	Used for calcium supplementation in children and pregnant women
Injections	Vitamin C injection	Vitamin C	2 mL: 0.5 g; 10 mL: 1 g; 5 mL: 0.5 g; 20 mL: 2.5 g; 2 mL: 0.1 g; 2 mL: 0.25 g; 5 mL: 0.5 g	214	2023-06-26	Scurvy; chronic iron poisoning; idiopathic methemoglobinemia
Injections	Vitamin C for injection	Vitamin C	0.25 g; 0.5 g; 1.0 g;	17	2022-9-14	Scurvy; chronic iron poisoning; idiopathic methemoglobinemia
Injections	Water-soluble vitamin for injection	Thiamine nitrate; riboflavin sodium phosphate; nicotinamide; pyridoxine hydrochloride; sodium pantothenate; vitamin C sodium; biotin; folic acid; vitamin B12	Each bottle contains 3.1 mg of thiamine nitrate, 4.9 mg of riboflavin sodium phosphate, 40 mg of nicotinamide, 4.9 mg of pyridoxine hydrochloride, 16.5 mg of sodium pantothenate, 113 mg of vitamin C sodium, 60 μg of biotin, 0.4 mg of folic acid, and 5.0 μg of vitamin B 12	33	2022-11-03	One of the components of parenteral nutrition
Capsules	Compound trivitamin and linolic acid soft capsules Ⅰ	Linoleic acid; vitamin B6; vitamin C; inositol	Each capsule contains 350 mg of linoleic acid, 2 mg of vitamin B6, 25 mg of vitamin C, and 10 mg of inositol	26	2021-03-17	Used for adjuvant treatment and prevention of atherosclerosis
Capsules	Vitamin C granules	Vitamin C	0.1 g	12	2021-04-25	Scurvy; chronic iron poisoning; idiopathic methemoglobinemia
Capsules	Compound trivitamin and linolic acid soft capsules I	Linoleic acid; vitamin B; vitamin C; vitamin E; inositol; soy phospholipid; methyl hesperidin	Each capsule contains 0.35 g of linoleic acid, 62 mg of vitamin B, 25 mg of vitamin C, 1.67 mg of vitamin E, 10 mg of inositol, 24 mg of soy phospholipid, and 10 mg of methyl hesperidin	2	2021-03-16	Used for adjuvant treatment and prevention of atherosclerosis
Granules	Vitamin E and C granules	Vitamin C; vitamin E	Each capsule contains 0.1 g of vitamin E and 0.2 g of vitamin C	13	2021-09-23	Used to prevent and treat diseases caused by vitamin E and vitamin C deficiency
Granules	Aurantium and vitamin C granules	Vitamin C; hesperidin	Each bag (7 g) contains 100 mg of vitamin C and 60 mg of hesperidin	13	2021-08-25	Used for diseases caused by vitamin C and hesperidin deficiency
Granules	Compound bifendate granules	Bifendate; inosine; vitamin C	Each bag (10 g) contains 15 mg of bifendate, 100 mg of inosine, and 50 mg of vitamin C	13	2021-04-30	For chronic and persistent hepatitis with elevated alanine aminotransferase
Pills	Vitamin C pills	Vitamin C	50 mg; 0.1 g	16	2021-07-27	Used to prevent and treat scurvy and various acute and chronic infectious diseases or other diseases
Powders	Oral four vitamins and glucose	Vitamin B1; vitamin B2; vitamin C; vitamin D2; glucose	Each gram contains 11.2 mg of vitamin B1, 20.8 mg of vitamin B2, 20 mg of vitamin C, 23 μg of vitamin D2, and 10 g of glucose	12	2021-08-25	For nutrition and energy supplementation for patients with vitamin deficiency
Powders	Oral five vitamins and glucose	Vitamin B1; vitamin B2; vitamin C; vitamin D2; nicotinic acid; glucose	Each gram contains 0.12 mg of vitamin B, 0.08 g of vitamin B2, 2 mg of vitamin C, 0.002 mg of vitamin D2, 1 mg of nicotinic acid, and glucose appropriate	36	2022-03-11	Used in various diseases caused by vitamin deficiency
Solutions	Five vitamins and lysine hydrochloride oral solution	Vitamin A; vitamin D; vitamin C; vitamin B6; niacinamide; lysine hydrochloride	Each (10 mL) contains 3,000 units of vitamin A, 2,200 units of vitamin D, 50 mg of vitamin C, 2 mg of vitamin B6, 20 mg of niacinamide, and 60 mg of lysine hydrochloride	2	2021-03-22	Used to prevent and treat many diseases caused by the lack of multiple vitamins in children
Solutions	Tri-vitamins and cod liver oil emulsion	Cod liver oil; vitamin A; vitamin D3; vitamin C	Each gram contains 10 mg of cod liver oil, 30 units of vitamin A, 13.5 units of vitamin D3, and 1.54 mg of vitamin C	7	2022-01-04	Used for the prevention and treatment of various diseases caused by vitamin A, D, and C deficiency in adults

Note: Data in Table 2 was acquired from the National Medical Products Administration database (https://www.nmpa.gov.cn/).

Fig. 3 The delivery system of vitamin C.

Nanoparticles made of natural polymers have low toxicity, high biocompatibility, and sufficient degradability.[1] Chitosan is a kind of hydrophilic polysaccharide. Chitosan-based drug delivery systems have the following advantages: increased solubility, controlled drug release, enhanced drug targeting, and improved absorption.[20] Alishahi et al[21] adopted the ionotropic gelation method and used tripolyphosphate as a cross-linking agent to prepare VC-chitosan nanoparticles, which realized the encapsulation of VC within the nanoparticle. The obtained nanoparticles improved the stability of VC in the gastrointestinal tract and showed consistent VC release for up to 48 hours.

Liposomes are phospholipid bilayer vesicles composed of amphiphilic molecules, which can load hydrophobic and hydrophilic molecules and have the advantages of low toxicity and high biocompatibility.[22] [23] Orally administered VC is easily degraded in the gastrointestinal tract, and liposomes can provide a hydrophilic–hydrophobic interface to avoid VC degradation.[24] [25] Liposomes can also reduce gastrointestinal interference and prolong the release of VC.[26] Jiao et al[27] used chitosan-coated liposomes to deliver VC and folic acid, which improved the antioxidant efficacy of the preparation. Therefore, the use of liposome delivery technology can improve the bioavailability of VC to a certain extent and avoid the risks associated with intravenous administration.[26] [28] [29]

Microemulsion is a transparent, thermodynamically stable colloidal system formed spontaneously from oil, water, and emulsifier, with an average particle size of 10 to 100 nm. The microemulsion has low surface tension, high interfacial tension, and solubilization properties.[30] In addition to the above nano-preparations, currently, researchers use VC to develop new drug delivery systems to achieve targeted drug delivery. Sawant et al[31] used polyethylene glycol phosphatidylethanolamine to prepare palmitoyl ascorbate micelles, which improved the solubility of palmitoyl ascorbate and increased the accumulation of palmitoyl ascorbate at the tumor site through the high permeability and enhanced permeability and retention effect (EPR effect) of solid tumors, showing good antitumor activity. Xiao et al[32] used AA derivatives as liposome ligands and used VC to bind to the receptor-ligand of GLUT1 and SVCT2 to deliver drugs targeted to the brain, indicating that AA has the potential to enhance brain targeting of drugs in the central nervous system. Luo et al[33] used ascorbate-coupled polylactic acid-hydroxyethyl copolymer to promote oral drug absorption through SVCT1. Inoue et al[34] used AA derivative ascorbic acid 2-phospho-6-palmitate trisodium to form micelles and used as drug carriers to improve drug skin permeability.

In general, these drug delivery systems address the limitations of VC, namely its poor stability and strong hydrophilicity, through enhanced encapsulation and targeted drug delivery thereby improving the absorption of VC in vivo. However, the current industrial technologies impose constraints on the large-scale clinical application of these delivery systems.

Biological Activity

VC Promotes Collagen Formation

VC plays a pivotal role in the posttranslational modification of procollagen, a crucial coenzyme factor in collagen biosynthesis.[35] VC facilitates the synthesis of collagen, a fundamental protein in the extracellular matrix, by regulating the structure and secretion of procollagen.[36] Procollagen is synthesized in the endoplasmic reticulum and consists of proline-rich amino acid repeats, which are essential for its structural integrity. Specifically, proline and lysine residues undergo hydroxylation and conversion to hydroxyproline and hydroxylysine, respectively. This hydroxylation process requires VC as a cofactor.[18] Collagen has a triple helix structure, and the presence of hydroxyproline is essential to stabilize this structure.[35] Without hydroxyproline, fibroblasts cannot secrete collagen properly. Hydroxylysine is necessary for collagen cross-linking, and its absence can also lead to structural instability.[37] A computer simulation experiment was conducted to study the effect of VC on amino acid sequence and interaction forces during collagen formation.[38] In the presence of VC, collagen was synthesized, while in the absence of VC, hydroxyproline dissociates from prolyl-5-hydroxylase and the reaction stops. Therefore, VC can be considered a cofactor for prolyl-5-hydroxylase, which is responsible for the conversion of proline to hydroxyproline. VC is conducive to the hydroxylation process, which facilitates the formation of a stable triple helix structure in collagen and promotes collagen formation.

VC Promotes HIF-1 Hydroxylation

Hypoxia-inducible factor-1 (HIF-1) is a nuclear protein with transcriptional activity that plays an important role in physiological processes such as erythropoiesis, cell survival, and angiogenesis.[18] HIF-1 can induce the formation of new blood vessels around hypoxic cells and tissues thus promoting cell survival. Consequently, HIF-1 exerts a significant influence on fetal development, yet it also serves as a key promoter of a range of pathological conditions, including inflammatory diseases, lung disease, heart disease, diabetes, and cancer.[39]

HIF-1 consists of an active α subunit and a structurally expressed β subunit. Proline residues on the HIF-α subunit are hydroxylated by the prolyl hydroxylase domain (PHD) and undergo rapid degradation by ubiquitin protease under normal oxygen conditions. Under hypoxia conditions, PHD is inhibited.[40] VC plays an important role in the hydroxylation of proline residues by PHD. PHD is a nonheme iron-dependent dioxygenase, its catalytic activity can be enhanced by VC.[41] [42] In vitro experiments have shown that VC has a significant inhibition effect on HIF-1, and can block HIF-1-induced gene transcription, thereby delaying the development of the disease.[43] [44] In summary, by influencing the PHD to regulate HIF-1 levels, VC can diminish symptoms and delay the progression of the disease.

VC Enhances Immune Function

VC regulates immune function by enhancing various cellular functions of both the innate and acquired immune systems, regulating redox-sensitive cell signaling pathways, or directly protecting important cellular structural components.[45] The immune system is composed of immune organs (e.g., bone marrow, spleen, and lymph), immune cells (e.g., lymphocytes, mononuclear phagocytes, and neutrophils), and immunologically active substances (e.g., antibodies and complements) that protect the host from a range of pathogens.[46] The immune system can be divided into two categories: nonspecific immunity and specific immunity. These categories can be further delineated into three main aspects: physical barriers such as skin and mucosa, immune cells, and antibodies.[47]

VC has been shown to protect the skin from environmental oxidative stress by promoting clearance of oxidants,[48] thereby strengthening the physical skin barrier. The infiltration of neutrophils into infected tissues is the early step of innate immunity. VC can accumulate in phagocytes such as neutrophils, enhance the chemotaxis and phagocytosis of neutrophils, produce reactive oxygen species (ROS), and eventually kill microorganisms.[45] Oxidants can activate nuclear factor κB (NF-κB), which triggers a signaling cascade that leads to the continued synthesis of oxides and other proinflammatory mediators.[49] [50] VC has been shown to reduce the production of oxidants and the activation of NF-κB in dendritic cells in vitro.[51] In addition, research has demonstrated that VC enhances the immune system's response to infection by stimulating T lymphocyte proliferation, increasing cytokine production, and promoting immunoglobulin synthesis.[45] The Changxing team at West Lake University found that VC can facilitate plasma cell differentiation and humoral immune response by enhancing TET2/3-mediated DNA demethylation.[52]

A chronic deficiency of VC can lead to impaired immune function, rendering individuals more susceptible to infection. The inflammatory and metabolic demands associated with infection can significantly reduce the body's ability to absorb VC. Therefore, timely and appropriate supplementation of VC can help enhance the body's immune response.[53]

VC Improves Fat Metabolism

The fatty acids produced by the hydrolysis of fat in the human digestive tract are activated as fatty acyl CoA in the endoplasmic reticulum and the outer membrane of mitochondria. The enzymes that catalyze fatty acid oxidation are located within the mitochondrial matrix. Therefore, the activated fatty acyl CoA must enter the mitochondria to be oxidized. Long-chain fatty acyl CoA cannot penetrate the inner mitochondrial membrane and requires carnitine for transport into the mitochondria.[54]

Carnitine is a quaternary ammonium that exists in two stereoisomers, designated as D-type and L-type. The D-isomer, also known as D-carnitine, is physiologically inactive. The primary function of L-carnitine is to transfer long-chain fatty acids to the mitochondria for β-oxidation, a process by which the body derives energy.[55] Carnitine also binds to acyl residues produced by amino acid intermediate metabolism, assisting in the removal of amino acids.[54] This mechanism enables the clearance of abnormal organic acids. L-carnitine is synthesized from lysine and methionine, and the final step of the synthesis requires AA and iron ions to participate as cofactors.[55] Several in vivo experiments have proved that AA is involved in carnitine biosynthesis.[56] [57] [58] Hence, a lack of VC affects carnitine levels, which affects fat metabolism. Furthermore, Yuan et al[59] investigated the role of DNA demethylase ten-eleven translocation protein 1 (Tet1) in the development of obesity and found that VC, a cofactor of the Tet protein family, normalizes DNA methylation levels and promotes lipolysis.

VC Promotes Iron Absorption

Iron is a vital component in numerous biological processes, from oxygen transport to the synthesis of DNA. Its most important function is the transport of oxygen in hemoglobin. The primary form of dietary iron intake is iron trivalent, which is less bioavailable than ferrous iron. The absorption of iron from food is generally enhanced by the addition of iron absorption enhancers, among which AA is the most extensively studied.

The role of VC in promoting iron absorption is attributed to its ability to reduce and chelate iron. VC has the capacity to reduce trivalent iron to ferrous, thereby promoting the absorption and utilization of iron.[60] The extent of this reduction is influenced by the pH value. Studies have shown that in the range of pH 2.6 to 6.0, the reduction rate of VC decreases as the pH increases. At a pH range of 6.8 to 7.4, AA is unable to effectively reduce the trivalent iron.[61] Subsequent studies demonstrated that duodenal cytochrome B is an iron regulatory protein with iron-reductase activity, which plays a critical role in dietary iron absorption.[62] Several studies identified duodenal cytochrome B promoting iron reduction in a VC-dependent manner,[63] [64] [65] indicating that VC's primary role is in promoting iron dissolution. Furthermore, studies demonstrated that the administration of VC a few hours before the consumption of an iron-containing meal did not increase iron absorption, suggesting that VC must be taken with iron to promote iron absorption.[66] [67]

Applications in Human Diseases

VC has many preventive and therapeutic effects in the field of medicine. This section will mainly discuss its application in cataracts, cancer, CVD, and skin disease ([Fig. 4]).

Fig. 4 The applications of vitamin C.

Cataracts

Cataracts are a leading cause of vision impairment and blindness worldwide.[68] Population projections indicate that by 2025, cataracts could affect 40 million individuals.[69] The underlying mechanisms of cataract formation remain unclear, but oxidative stress is a prominent hypothesis. The free radicals generated by oxidative stress, such as glutathione (GSH), superoxide dismutase, and ROS, will damage the lens composition, resulting in lens opacity and thus lens damage.[70] Although cataract surgery is considered to be one of the safest surgeries, the prevention of cataracts has become a research focus due to the complications that can arise from the procedure, including recurrent or persistent inflammation, glaucoma, and posterior capsule opacification.[71]

The balance between antioxidants and free radicals determines the state of appropriate physiological function, if the level of free radicals rises uncontrollably, oxidative stress will appear.[72] The literature indicates that VC, as a nonenzymatic antioxidant, may have certain preventive effects on cataracts, although this is limited to nuclear cataracts.[73] Nuclear cataracts are located in the center of the lens and are usually caused by advancing age.[74] VC is present in high amounts in the aqueous humor and is therefore thought to play a role in protecting the lens from oxidative stress in the aqueous humor.[75] A statistical survey has shown that dietary intake of VC can reduce the risk of age-related cataracts.[76] Moreover, several studies and case–control studies have shown that individuals with a high dietary intake of VC exhibit a reduced risk of developing cataracts.[77] [78] [79] [80] However, it is worth noting that the VC has the potential to generate free radicals intermediates and strong oxidizers, which can inflict damage to the biological tissue.[73] It has been demonstrated that VC can facilitate the formation of advanced glycation end products, which are responsible for the chemical aging of lens proteins.[81] [82] Besides, high doses of VC have been shown to increase the prevalence of age-related cataracts in women.[73] Consequently, the effectiveness of VC for cataracts may be limited to a role in the prevention of nuclear cataracts.

Tumor Treatment

Epidemiological evidence suggests that VC or foods rich in VC may play a role in cancer prevention, as they have been shown to reduce the incidence of various tumors.[83] [84] For example, Campbell et al[85] demonstrated that administering a high dose of VC daily was able to maintain optimal levels of AA within 48 hours, while simultaneously downregulating the activity of the HIF-1 pathway within tumor tissue. Nevertheless, there is a lack of consensus regarding the efficacy of VC in treating tumors. Two previous studies yielded disparate results.[86] [87] [88] [89] Cameron and Pauling showed that high-dose VC improved the average survival rate of patients with advanced cancer. Conversely, two clinical trials by Creagan and Moertel indicated that VC did not confer a benefit in cancer treatment. A deeper examination of VC pharmacokinetics may elucidate the discrepancy in outcomes between the two administration methods. In the initial experiment, intravenous administration was used, while in the latter, oral administration alone was used. When doses of oral VC exceed 200 mg, the absorption of VC decreases, urinary excretion increases, and the bioavailability of VC decreases.[90] In contrast, intravenous administration bypasses intestinal absorption, resulting in a plasma concentration of VC that can reach pharmacological levels and thus exert efficacy.[91] Given that AA is susceptible to a pH-dependent autooxidation reaction to produce hydrogen peroxide (H₂O₂) (H₂O₂ is toxic to a variety of tumor cells[92] [93] [94]), high-dose intravenous AA can be used as a prodrug to deliver H₂O₂ to tumors, thereby treating cancer.[95] Potential mechanisms of action for VC in cancer therapy include:

• AA is an important free-radical scavenger. The oxidation of a large dose of AA to DHA has been demonstrated to increase ROS, trigger oxidative stress, and lead to the apoptosis of tumor cells.[96] Yun et al[97] have provided evidence that human colorectal cancers carrying either KRAS or BRAF mutations are sensitive to high levels of VC. As a consequence of elevated DHA intake, the uptake of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was inhibited in cells with a high glycolytic rate and a mutation in either KRAS or BRAF.

• VC can enhance immune function, thus enhancing tumor immune surveillance during cancer initiation and progression.[98] Magrì et al found that in murine cancer models such as colorectal, breast, melanoma, and pancreatic cancers, VC potentiates adaptive immune responses against cancer cells and can be effectively combined with immune checkpoint therapy.[99]

• Outside the cell, AA autooxidation produces H₂O₂. When H₂O₂ accumulates to a certain concentration, it can diffuse across cells into tumor cells and inhibit tumor growth.[100]

• Collagen in the extracellular matrix is an important component of the physical barrier against cancer cell invasion and metastasis. AA has been proven to promote collagen formation and can inhibit cancer progression by preventing cancer cell invasion at a high dose.[100]

Additionally, alternative perspectives posit that the anticancer mechanism of VC may be classified into three distinct categories: targeting redox imbalance,[101] targeting epigenetic regulators,[102] and targeting HIF-1 signaling.[103]

Intravenous administration of VC can also be used as an adjunct to chemotherapy or radiotherapy. VC has been demonstrated to stimulate the production and activation of immune cells, thereby enhancing the immunity of patients.[84] VC has been shown to improve the therapeutic effect of certain cancer drugs. For example, Lee et al[104] applied gefitinib and AA combination therapy to non-small cell lung cancer cells, resulting in an additive effect on inhibiting cell proliferation. Meanwhile, it can also mitigate the general toxicity and cardiotoxicity of Adriamycin.[105] Combination therapy helps improve a patient's quality of life and physical function and minimizes toxicity associated with chemotherapy.[106] However, the safety of high-dose intravenous VC remains a topic of contention. Complications associated with intravenous AA administration include the formation of oxalate stones and hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency.[107] Therefore, it is imperative to perform G6PD screening prior to intravenous VC administration.

Cardiovascular Disease

Several studies have shown that the incidence of coronary heart disease is inversely related to dietary VC intake, and large VC supplementation can reduce the incidence of CVD.[108] [109] [110] Nitric oxide (NO) is a potent vasodilator, mediating vascular smooth muscle relaxation and protecting endothelial function.[111] [112] The current clinical trials showed that the VC plays an important role in maintaining the NO steady state in blood vessels. A single dose of VC has been demonstrated to enhance endothelial nitric oxide synthase (eNOS) activity, thereby promoting the synthesis of NO, and facilitating vasodilation.[113] Long-term supplementation of VC has been shown to mitigate the decline in vasodilation capacity associated with endothelial injury.[114] The administration of VC has been linked to beneficial outcomes in the context of vascular endothelial function as evidenced in both healthy subjects and patients with CVD.[115]

The production of NO in endothelial cells requires a variety of cofactors, including tetrahydrobiopterin (BH4).[116] Studies have shown that VC can diminish vascular oxidative stress and augment NO-mediated endothelium-dependent relaxation, which may be achieved by chemically stabilizing BH4 to enhance the activity of nitric oxide synthase (NOS).[117] Therefore, deficiency in VC affects the reduction status of BH4 and leads to decreased NO bioavailability, thereby exacerbating the progression of CVD.

Ginter proposed that the mechanism of VC in preventing CVD may also involve cholesterol metabolism, lowering blood pressure, and antioxidant effects.[118] High cholesterol and hypertension are important risk factors for the development of CVD. A deficiency in VC over an extended period will result in a reduction in the activity of cholesterol metabolic enzymes and thus reduce the conversion of cholesterol into bile acids.[119] [120] This ultimately results in the accumulation of cholesterol in the body which can contribute to elevated cholesterol levels. Concurrently, long-term supplementation of VC has been demonstrated to reduce the risk of hypertension. The potential mechanism underlying this effect is that VC plays an antioxidant role, preventing the oxidation of low-density lipoprotein (LDL; oxidized LDL contributes to the vicious cycle of atherosclerosis [AS] by stimulating cell adhesion, producing ROS, and decreasing NO), and inhibits the proliferation of vascular smooth muscle involved in AS.[121] [122] [123] [124] Furthermore, VC may also improve chronic inflammation through nonspecific antioxidant effects (chronic vascular inflammation is a part of CVD pathophysiology[125]), thereby improving the development of CVD.[111]

VC Promotes Skin Health

As the largest organ in terms of surface area in the human body, the skin serves as a protective barrier between the external environment and the body's internal tissues. The skin functions as a barrier to the invasion of the external environment, while simultaneously providing physical and chemical protection to the internal environment. VC has been demonstrated to facilitate collagen synthesis, inhibit melanin production, and protect against ultraviolet-induced oxidative damage, thereby playing an important role in maintaining optimal dermal health.[126]

VC mainly plays a role in promoting collagen synthesis in the proline and lysine hydroxylation process; the antioxidant effect of VC is related to its structure, which can be reduced by the action of oxidants; in addition, VC can interfere with the action of tyrosinase, thereby affecting melanin production.[127] Tyrosinase is the rate-limiting enzyme in melanin synthesis, catalyzing the hydroxylation of L-tyrosine to form DOPA, which oxidizes to DOPA quinone. DOPA quinone is cyclized to dopamine, which is tautomerization to 5,6-dihydroxyindole-2-carboxylic acid (DHICA), and finally forms the DHICA-melanin subunit. VC interferes with melanin synthesis by reducing oxidized DOPA quinone, blocking the oxidation of DHICA, and interacting with copper ions in the active site of tyrosinase.[128]

Clinically, VC is commonly used in the treatment of atopic dermatitis, late-onset porphyrin skin disease, and a range of dermatological conditions including herpes zoster. Its primary role in cosmetics is to impart whitening and antiaging effects. The main ingredients of MAS063DP cream (Atopiclair) are grape seed extract, VC, vitamin E, hyaluronic acid, glycyrrhetinic acid, and shea butter.[129] Multiple clinical studies have demonstrated that this formulation is a safe, well-tolerated, and effective nonsteroidal therapy for the treatment of mild to moderate atopic dermatitis.[130] [131] [132] The drug is currently licensed in the United States and the European Union for the treatment of specific dermatological conditions, including dermatitis and contact dermatitis. In the treatment of other skin diseases, VC is employed in combination with other pharmaceutical agents or as an adjunct to physical therapy. Zinc, and clarithromycin combined with VC in the treatment of acne continue to demonstrate antibacterial efficacy against niacinomycin-induced acne, offering a novel avenue for the clinical use of antibiotics in acne therapy.[133] However, due to the issue of poor permeability, and stability,[1] [134] the application of the VC prototype in topical skin preparations is limited. In general, it is necessary to expand the application range of applications for VC by designing VC derivatives or developing suitable dosage forms.[135] [136] The emergence of microneedle technology and ion import technology has recently improved the permeability of VC, although there have been no large-scale clinical applications to date. Hence, the stability and permeability of VC must be improved to facilitate its clinical application in topical preparations.

In addition to the studies mentioned above, a joint study by the Chinese Academy of Sciences discovered that VC supplementation may impede the aging of the spinal cord.[137] By integrating transcriptomics, neurohistology, neuroelectrophysiology, and other disciplines, they identified a particular subtype of CHIT1-positive microglia in the spinal cord of older primates. These cells can activate SMAD signaling in motor neurons through paracrine CHIT1 protein, thereby contributing to the aging of the motor nerve. However, VC supplementation has been demonstrated to impede the aging and degeneration of spinal cord neurons. This study not only elucidates the potential role of VC in nervous system diseases but also indicates a novel avenue for postponing the aging of the human spinal cord and the management of geriatric diseases.

Perspectives and Conclusion

VC has a multitude of biological activities; however, its role in the field of medicine is currently in the exploratory phase, with only a limited number of large-scale clinical applications. These applications mainly focus on the role of adjuvant prevention and treatment. The primary reason for this situation lies in its extreme instability.[138] VC is easily degraded in the presence of water, oxygen, and metal ions under basic conditions, which undergoes a yellow color change.[1] Currently, the primary control measures are: controlling the oxygen content during the process, using anhydrous/nonaqueous preparations, reducing the pH value, adding antioxidants, and increasing the viscosity of the system.[134] In addition, the development of the delivery system, as well as derivatives of VC, may prove to be promising strategies to stabilize VC. The evolution of VC derivatives went through a process from binding to ionic salts to lipophilic derivatives. The structural modification improves VC's stability, but the majority of these derivatives lack direct antioxidant activity and must be converted to VC in vivo. As a hydrophilic esterified form of VC, magnesium ascorbate phosphate is currently the most common VC derivative with greater stability. However, the introduction of phosphate groups results in an increase in charge and a corresponding decrease in skin permeability.[127] [139] Additionally, a substantial number of in vitro and in vivo experiments have been conducted with VC derivatives, yielding a multitude of contradictory results.[139] Consequently, further experimentation is necessary to comprehensively assess the overall impact of each derivative. The issue of permeability can be effectively addressed through the use of carriers, especially nanocarriers. Despite the promising potential of nanocarriers, the limitations of industrial technology and e-regulatory frameworks remain a significant challenge. Further research is needed to address these issues. By considering the in vivo fate of the delivery system and focusing on the composition, size, structure, and physical state of the carrier,[24] a more sophisticated carrier structure can be developed to ensure that VC has an optimal effect concentration at the treatment site.

Furthermore, consideration should be given to the compatibility of VC with other drugs. Patients with hypertension are at an elevated risk of developing cerebral hemorrhage, and as a result, the concurrent administration of antihypertensive drugs and VC has been demonstrated to exert a protective effect against cerebral hemorrhage. The combination of VC with anticoagulants has been observed to reduce the anticoagulant effect and shorten the prothrombin time, which is incompatible.[140] Therefore, although VC is a common vitamin, the use of VC should follow the advice and guidance of physicians.

In conclusion, as a multifunctional compound, VC exhibits a range of biological activities and has been demonstrated to have preventive and therapeutic effects on a variety of diseases. The stability and permeability of VC remain limitations to its clinical application. It is anticipated that further developments in the form of new applications of VC will emerge in the future, with the potential to enhance the treatment of a range of diseases.

Conflict of Interest

None declared.

^# These authors contributed equally to this work.

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Publication History

Received: 18 September 2023

Accepted: 09 September 2024

Article published online:
21 October 2024