Why Is Vitamin C Required To Produce Collagen ~ Janis Top Nutrition

Why Is Vitamin C Required To Produce Collagen

Response of MG63 osteoblast-like cells to titanium and titanium alloy is dependent on surface roughness and composition

J. Lincks , ... Z. Schwartz , in The Biomaterials: Silver Jubilee Compendium, 1998

3.5.1 Collagen production

Collagen synthesis was also affected by surface composition and roughness ( Fig. 9). While collagen synthesis was unaffected in cells cultured on Ti-R, cells grown on Ti-S, Ti-A-R and Ti-A-S surfaces synthesized 14–30% less collagen compared to plastic. The percent collagen production by the cells was significantly decreased (15%) on rough Ti-A-R surfaces compared to Ti-R surfaces. Moreover, cells on Ti-S produced 31 % less collagen than on Ti-R, and cells on Ti-A-S produced 17% less collagen than on Ti-A-R.

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Studies in Natural Products Chemistry

Pulok K. Mukherjee , ... Birendra K. Sarkar , in Studies in Natural Products Chemistry, 2013

Collagenase Inhibitors

Collagenases, MMP-1 (fibroblast collagenase), MMP-8 (neutrophil collagenase), MMP-13 (collagenase-3), etc. are the key collagenases, which are involved in the physiological and pathological turnover of connective tissues. Their productions are significantly increased at inflammation sites due to the stimulation of pro-inflammatory cytokines [6]. These MMPs are capable of degrading triple-helical fibrillar collagens into distinctive 3/4 and 1/4 fragments which are the major components of skin, bone, and cartilage [7]. Collagenase cleaves the X-glycine bond of collagen and also synthetic peptides that contain the sequence: Proline-X-Glycine-Proline, where X is an amino acid provided that the amino terminus is blocked [8]. MMP-1 preferably degrades type III collagen, MMP-8 rather degrades type I collagen, and MMP-13 degrades type II collagen [9]. Collagenase from the bacteria Clostridium histolyticum hydrolyzes triple-helical collagen in both physiological conditions and in vitro conditions using synthetic peptides as substrates [10]. Phytoconstituents and also crude extracts from natural resources have been widely explored and found to have anticollagenase activity. Plants contain a huge variety of compounds including polyphenols such as flavonoids, terpinoids, glycosides, vitamin E, vitamin C, phenolic acids, and tannins which have been found to provide collagenase inhibitory activity.

As the age increases, collagen synthesis are reduced and collagenases level becomes higher, causing changes such as skin wrinkling and loss of elasticity [11]. There is increasing evidence that ultraviolet (UV) irradiation from sun light induces extensive generation of reactive oxygen species (ROS), which activates the mitogen-activated protein kinase (MAPK) signal-transduction pathway, which further induces the expression of activator protein-1 (AP-1)-driven genes including collagenases in the exposed skin [12]. Therefore, control of collagen metabolism and control of oxidative stress would be functional for a variety of therapeutic and cosmetic applications. Polypodium leucotomos in combination with ascorbate is beneficial to cancer management via the simultaneous inhibition of cell growth, expression of MMP-1, transforming growth factor-β (TGF-β), heat-shock proteins (HSPs), and the stimulation of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) [13]. P. leucotomos directly inhibited the activities as well as the expression of MMP-1 while stimulated the expression of types I and III collagen and TIMPs in normal fibroblasts, UV-radiated fibroblasts, and melanoma cells, respectively. This also produces stimulatory effects on TGF-β expression in nonirradiated or UV-radiated fibroblasts and inhibitory effect on TGF-β expression in melanoma cells [14]. Zeatin (1) is attributed to its more stable trans form purified from Zea mays, which is a member of the cytokinin group of plant growth factors. It has been found to inhibit UVB-induced MMP-1 expression via MAPK signaling and phosphorylation of ERK (extracellular signal-regulated kinases), JNK (jun N-terminal kinase), and p38 in human skin fibroblasts [15]. A-type cranberry proanthocyanidins have been reported to inhibit MMP-1 production with reduced phosphorylation of ERK, JNK, and p38 and the inhibition of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) p65 activity [16]. 4-Hydroxypanduratin A (2) isolated from Kaempferia pandurata has been found to reduce the MMP-1 mRNA expression through the inhibition of MAPK pathway and decrease the c-Fos expression and c-Jun phosphorylation in UV-irradiated human skin fibroblast [17]. Emblica officinalis Gaertn. (Amla) is a rich dietary source of vitamin C, minerals, amino acids, and polyphenols reported to reduce the MMP-1 level in human dermal fibroblast upon UV exposure and is useful in cosmetic applications through the control of collagen metabolism [18]. Plant flavonoids such as quercetin (3), kaempferol (4), apigenin (5), and wogonin (6) have strong MMP-1 inhibitory activity in 12-O-tetradecanoylphorbol-13-acetate-treated human dermal fibroblasts through the inhibition of MAPK [19].

Zeatin (1)	4-Hydroxypanduratin A (2)
Quercetin (3)	Kaempferol (4)
Apigenin (5)	Wogonin (6)

Magnolol (7) isolated from Magnolia ovovata is responsible for the inhibition of MMP-1 in the cells overexpressing p65 without hampering other inducible transcription factors such as AP-1 and cyclic AMP-responsive element-binding protein (CREB) [20]. Kim et al. have screened 60 plants for their MMP-1 inhibitory activity; among them Persicaria hydropiper, Filipendula glaberrima, Nymphaea tetragona, and Camellia japonica completely inhibited the expression of MMP-1 in human fibroblast cells [21]. Erythrodiol-3-acetate identified from Styrax japonica has been screened in vitro for the MMP-1 inhibitory action in UV-irradiated cultured primary old-aged human skin fibroblasts [22]. Flvonoids such as phloretin (8), 3-hydroxyphloretin (9) obtained from Malus doumeri has been proved for their anti-MMP-1 activity in human skin fibroblast cells [23]. The inhibitory effect of sativan (10) from Viola verecunda A. Gray on the expressions of MMP-1 caused by UV-irradiated cultured primary human skin fibroblasts has been reported [24]. Ho et al. isolated Aucubin (11) as the MMP-1 inhibitor from Eucommia ulmoides, which suppress the production of MMP-1 and reduces MMP-1 mRNA expression [25]. Styraxjaponoside B isolated from S. japonica S. et Z. (Styracaceae) also has been found to inhibit MMP-1 and prevented the UV-induced changes in the MMP-1 expression [26]. Acutoside A (12) (3-O-[O-β-d-glucopyranosyl-(1 → 2)-O-β-d-glucopyranosyl] oleanolic acid) obtained from Viola hondoensis W. Becker et H Boss. exhibited potent inhibitory activity against MMP-1 and prevented the UV-induced changes in the MMP-1 expression [27]. MMP-1 expression and interleukin-6 (IL-6) inhibited by luteolin (13) acquired from Zostera marina L. expected to be useful for preventing the photo aging of skin [28]. A polymethoxy flavonoid, nobiletin (14), from Citrus depressa inhibited the tumor-invasive activity of human fibrosarcoma HT-1080 cells through the suppression of pro-MMP-1/interstitial procollagenase gene expression [29].

Magnolol (7)	Phloretin (8)
3-Hydroxyphloretin (9)	Sativan (10)
Aucubin (11)	Acutoside A (12)
Luteolin (13)	Nobiletin (14)

Arthritis is one of the degenerative diseases of bone where collagenases are also responsible. Betula platyphylla var. japonica has been reported to treat osteoarthritis by decreasing the mRNA expression of MMP-1 and thereby increasing the intensity of proteoglycans in a dose-dependent manner [30]. Euphorbia hirta treated in rats using complete Freund's adjuvant (CFA) containing heat-killed Mycobacterium tuberculosis found to decrease the level of MMP-13 [31]. Siegesbeckia pubescens significantly altered the cartilage and synovial membrane degradation, inflammatory process by reducing the level of MMP-1 and MMP-13 and also increasing the proteoglycan, aggrecan, and type II collagen expression [32]. Aralia cordata inhibited the cartilage and chondrocyte destruction in osteoarthritis through the downregulation of MMP-1 and MMP-13 activities and the inhibition of proteoglycan and collagen degradation [33]. Tripterygium wilfordii hook F, a Chinese herb, suppresses the pro-inflammatory cytokine-induced expression of MMP-13 genes in articular chondrocytes of rheumatoid arthritis and osteoarthritis by inhibiting AP-1 and NF-κB activities [34]. Periodontitis is an inflammatory disease due to infection of Porphyromonas gingivalis a predominant periodontal pathogen, where MMP-1 triggers a series of host inflammatory responses that aggravate the destruction of periodontium. Polyphenols from Humulus lupulus L. (Cannabaceae) have been reported to inhibit mRMA expression of cyclooxygenase-2 (COX-2), IL-6, IL-8, and MMP-1 in response to gingival epithelial cells [35]. 2-[(2-Methylpropanoyl)-phloroglucinol]-1-O-β-d-glucopyranoside and Kaempferol 3-O-β-glucopyranoside (astragalin) present in it are the responsible compounds for these activities (15).

Kaempferol 3-O-β-glucopyranoside (astragalin) (15)

Curcumin (16)

Antitumor activity of curcumin (16) (Curcuma longa) has been found to be due to the significant reduction of MMP-1 mRNA expression in two breast cancer cell lines (MDA-MB-231 and BT-483) and also downregulation of the NFκB-inducing genes [36]. Ao et al. have screened about 13 plants for there MMP-13 inhibitory activity and found that among all plants C. longa and Curcuma aromatica due to the presence of curcumin and Ocimum basilicum due to rosmarinic acid showed highest inhibitory activity [37]. Ginkgo biloba extract suppresses the oxLDL- and 4-hydroxynonenal-induced production of MMP-1 through the inhibition of phosphorylation of ERK1/2 and platelet-derived growth-factor receptor β (PDGFR-β) activation in human coronary smooth muscle cells.

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Procollagen Assays in Cancer

Leila Risteli , ... Juha Risteli , in Advances in Clinical Chemistry, 2014

3 Fibroproliferation in Healthy Tissues and Cancer

Wound healing consists of an ordered sequence of events involving induction of collagen synthesis, deposition of collagen molecules into collagen fibers, and further maturation of these fibers. When the continuity and tensile strength of the tissue have been reestablished, the process comes to an end. Only low-level collagen synthesis remains active in the extracellular matrix at the epithelial–stromal interface.

The fibroblastic cells that migrate into a healing wound proliferate and produce type I and type III procollagens. This process can be quantified by measurement of procollagen propeptides in the extracellular fluid of the wound space [15,21]. Both type I and type III procollagens are induced simultaneously and their production follow similar kinetics. Typically, wound fluid propeptide antigens have the size of intact trimeric propeptides released en bloc from procollagen. Although fluid propeptide concentration may increase 1000-fold, corresponding blood concentration is only affected if the wound is large. For example, major abdominal surgery can increase circulating PIIINP and PICP [22] with maximal levels at 7 days and 2 months, respectively. When adequate tensile strength has been achieved, the cells become quiescent. Formation of covalent cross-links in and between fibers does, however, continue. This normal wound healing process is self-limiting.

Certain cancer treatment modalities cause tissue damage leading to wound healing. Radiotherapy of breast cancer has been found to induce skin synthesis of type I and type III collagens, a phenomenon that can persist for 2 years. Measurement of PINP and PIIINP in skin extracellular fluid supports this finding (Fig. 3.2) [23]. Intrathecal methotrexate treatment of childhood leukemia resulted in a local fibroproliferative response as demonstrated by measurement of cerebrospinal fluid PICP [24]. The effect of intensive chemotherapy on children is decreased circulating propeptides of types I and III procollagens [25,26], indicating inhibition of growth (Fig. 3.3).

Procollagen propeptides are products of cells that synthesize fibrillar collagens and thus, in cancer, are related to the reaction of the surrounding tissues to malignancy. Despite inherently poor specificity, circulating propeptides can be used as potential indicators of biologic tumor behavior.

Solid tumors typically consist of epithelial malignant cells and surrounding stroma. The properties of the latter have been shown to resemble granulation tissue of early wound healing [27]. Malignant epithelial–stromal interaction differs from its benign counterpart by resulting in the formation of an immature extracellular matrix in which the collagen molecules are not cross-linked [28]. This results in a non-self-limiting process. Interestingly, cancer has been characterized as "a wound that does not heal" [3,4].

Abnormal wound healing in tumors can lead to propeptide release into the circulation. For example, increased PIIINP has been detected in the blood from epithelial ovarian cancer patients [29,30]. In this specific disease, PIIINP is prognostic for survival and useful in treatment follow-up. Increased PIIINP is strongly suggestive of residual disease irrespective of clinical response and normalized CA 12-5 (Fig. 3.4) [29,30].

Ovarian carcinoma is characterized by a strong fibroproliferative reaction in the peritoneal cavity (Fig. 3.5) [31,32]. Despite enhanced production of both type I and type III procollagens, only PIIINP was increased in peripheral blood. It is noteworthy that serum PICP does fluctuate in advanced ovarian carcinoma, but these changes are typically within its wide reference interval [33]. In malignancy ascites, the concentration of PICP and PIIINP are 20- to > 100-fold higher than those found in serum, respectively. PIIINP concentration in ascites at the time when diagnosis is made has been found to be a strong predictor of survival [31].

Although circulating type I procollagen propeptides are not frequently increased in ovarian cancer, PINP concentration at the time of diagnosis has been reported to discriminate fast, slow, or no progression [34]. Interestingly, this was not true for PICP despite a similar origin. In fact, an aberrant PICP:PINP ratio predicted survival in early-stage ovarian cancer patients [34].

In tumors of mesenchymal origin, soft tissue sarcomas release PIIINP at concentrations that exceed the normal serum reference interval [35].

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Wound management and dressings

S. Ather , K.G. Harding , in Advanced Textiles for Wound Care, 2009

Vitamins

Vitamin A deficiency has been associated with slowed re-epithelisation, decreased collagen synthesis and stability and an increased susceptibility to infection.

Vitamin C (ascorbic acid) is an essential cofactor during collagen biosynthesis. In scurvy, the collagen formed is unhydroxylated, relatively unstable and subject to collagenolysis.

Vitamin K deficiency results in a deficiency in the production of the clotting factors (factors II, VII, IX and X) that are vitamin K dependent resulting in bleeding diathesis, hematoma formation and secondary detrimental effects on wound healing.

Iron is required to transport oxygen. Other minerals like zinc and copper are important for enzyme systems and immune systems. Zinc deficiency contributes to disruption in granulation tissue formation.

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Volume 1

Marc Peters-Golden , Katherine N. Cahill , in Encyclopedia of Respiratory Medicine(Second Edition), 2022

Fibrotic Lung Disease

By virtue of its capacity to inhibit inflammation as well as fibroblast migration, proliferation, differentiation into myofibroblasts, and collagen synthesis, PGE ₂ attenuates fibrotic responses to lung injury (Fig. 3). These actions are largely mediated via increases in cyclic AMP. In animal models of pulmonary fibrosis, pharmacologic or genetic inhibition of COX enzymes exaggerates the degree of fibrosis. Interestingly, patients with idiopathic pulmonary fibrosis have been shown to have a relative deficiency of PGE₂ in their lung lavage fluid, and impaired PGE₂ synthetic capacity has been documented in both alveolar macrophages and lung fibroblasts from such patients. PGE₂ deficiency would tend to promote an activated phenotype in fibroblasts. Activation of fibroblasts and smooth muscle cells also contributes to airway remodeling in asthma, and defective PGE₂ synthesis has also been described in these cell types from asthmatics. Taken together, these data strongly suggest that a relative deficiency of PGE₂ synthesis characterizes and may contribute to remodeling of both parenchyma and airways in chronic lung disease. Antifibrotic effects of leukotriene pathway antagonists and PGI₂ agonists in preclinical models support a complex interplay between eicosanoids in lung fibrosis. Unfortunately, modulating leukotriene and prostanoid pathways in clinical studies has not shown efficacy (Mamazhakypov et al., 2019).

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Prevention and Treatment of Aging Skin with Topical Antioxidants

Karen E. Burke , in Skin Aging Handbook, 2009

8.2.2 Actions and Efficacy

Vitamin C provides many benefits to the skin—most significantly, increased synthesis of collagen and photoprotection.

Vitamin C is absolutely essential for synthesis of collagen. Vitamin C is the essential cofactor for the two enzymes required for collagen synthesis: prolyl hydroxylase (to stabilize the collagen molecule) and lysyl hydroxylase (to give structural strength cross-linking). ¹⁰ Recent research has further demonstrated that vitamin C acts directly on DNA to increase the transcription rate and to stabilize the procollagen messenger RNA, thus regulating and maintaining the intercellular amount of collagen. ¹¹

By enhancing collagen synthesis, vitamin C also has anti-aging effects. Studies in vitro compared newborn with elderly fibroblasts (derived from newborn foreskins after circumcision and from 80–95 year-old patients, respectively). ¹² Elderly cells proliferate in vitro at only one-fifth of the rate of newborn cells. However, when vitamin C is added to the culture medium, the elderly fibroblasts increase proliferation by a factor of six to propagate even faster than normal unsupplemented newborn fibroblasts. Even the newborn fibroblasts proliferate almost four times better when exposed to vitamin C. ¹² (see Table 8.1)

Table 8.1. Anti-Aging Effects of Vitamin C in Vitro ^*

	Increase in Fibroblast Proliferation			Increase in Collagen Synthesis
	Cells × 10⁶ (day 17)			% Collagen/Total Protein
Fibroblasts	− Vit C	+ Vit C ^*	Increase	− Vit C	+ Vit C ^*	Increase
Newborn	1.0	3.7	×3.7	10.5	19.9	×1.9
Elderly	0.2	1.2	×6.0	6.2	12.4	×2.0

*: Adapted with permission from Phillips, C.L., S.B. Combs, and S.R. Pinnell. "Effects of ascorbic acid on proliferation and collagen synthesis in relation to donor age of human dermal fibroblasts." J Invest Dermatol 103:228–232, 1994.

Not only do fibroblasts increase proliferation in the presence of vitamin C, but they also synthesize more collagen. Newborn fibroblasts synthesize a larger percentage of collagen than elderly cells, but again, when elderly cells are exposed to vitamin C in vitro, they double their collagen production, outperforming normal, newborn fibroblasts. ¹² Surprisingly, even the newborn cells double the amount of collagen synthesized. ¹² (see Table 8.1)

Since vitamin C is essential for collagen synthesis, it is critical for wound healing. With vitamin C deficiency, fibroblasts produce unstable collagen, providing a weak framework for repair. It is well documented that vitamin C-deficient animals show prolonged wound healing, but whether supplemental oral vitamin C can improve wound healing is uncertain. Although severely ill patients with depleted baseline levels certainly benefit from extra vitamin C, one study showed no enhancement of wound healing. ¹³ In 20 patients with pressure ulcers, vitamin C (500 mg per day vs. placebo) did reduce the area of ulceration compared with controls. ¹⁴ Whether topical vitamin C could accelerate wound healing should certainly be further investigated.

In contrast to the increased synthesis of collagen, in vitro studies suggest that vitamin C may inhibit elastin biosynthesis by fibroblasts. ¹⁵ This may be advantageous in reducing the solar elastosis of photodamage.

Topical vitamin C has also been shown to enhance collagen production in human skin in vivo. ¹⁶ Postmenopausal women who applied 5 percent vitamin C to one arm and half of the neck with placebo to the other side showed an increase in mRNA of collagens I and III. ¹⁶ Tissue levels of the inhibitor of metalloproteinase–I (MMP-I) were also increased, thus decreasing UV-induced collagen breakdown. However, mRNA levels of elastin, fibrillin, and tissue inhibitor of MMP-2 remained unchanged. ¹⁶ Clinically, a significant decrease was observed in deep facial furrows and substantiated by silicone replicas. Histology showed elastic tissue repair.

This synthesis of collagen and inhibition of MMP-I contribute to clinical reversal of photoaging, as seen in Figure 8.2. After one year of once-daily treatment with 15 percent topical vitamin C, wrinkles were clearly reduced and mottled pigmentation resolved. The skin acquired a healthy, more youthful glow.

A new formulation of topical vitamin C (10% percent) with the lipid soluble derivative tetrahexyldecyl ascorbate (7 percent) in an anhydrous polysilicone gel base was shown to improve photoaged skin ¹⁷ in a double-blind, half-face study in ten patients. Comparing the vitamin C combination with control gel, statistically significant clinical improvement was noted on the vitamin C-treated cheeks and the perioral area after twelve weeks of treatment. Histological analysis of biopsies showed increased repair in the upper dermis ("Grenze zone") with fine, fibrillar, new collagen and increased staining for mRNA for Type I collagen in the ascorbic acid-treated side. The periorbital areas improved on both sides, which the authors attribute to improved hydration.

The second major action of topical vitamin C is that it has been proven to be photoprotective. Vitamin C is itself not a sunscreen since it has no UV absorption spectra in the UVA or UVB range; however, as an antioxidant it deactivates UV-induced free radicals and decreases UVB erythema in porcine skin by 52 percent. ⁸ In human volunteers, a less intense erythematous response to UVB was noted on the volar forearms when treated with 10% vitamin C, as compared with controls. ¹⁸ Protection by topical vitamin C from chronic UV-induced photodamage and skin cancers was demonstrated by Bisset et al ¹⁹ in mice. In another mouse study, Dunham et al ²⁰ found decreased UV-induced tumors with increased oral vitamin C. This protection was confirmed histologically: Treatment with topical 10 percent vitamin C decreased the number of abnormal 'sunburn cells' by 40–60 percent ⁸ and reduced the UV damage to DNA 8-hydroxydeoxyguanosine (8-OHdG) by 62 percent in porcine skin. ⁸

Photoprotection is enhanced by the anti-inflammatory properties of vitamin C. In vitro studies with human cells in vitamin C-enriched media demonstrated decreased activation of the transcription factor NF-κβ (nuclear factor kappa beta), the factor responsible for many pre-inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and interleukins Il-1, Il-6, and Il-8. ²¹ In fact, topical vitamin C has been used by dermatologists to treat acne and rosacea. ²² In a split-face study, Alster and West ²³ showed a significant decrease in post-CO₂-laser resurfacing erythema after eight weeks of topical treatment with a solution of vitamin C (10 percent), zinc sulfate (2 percent), and tyrosine (0.5 percent) as compared with the untreated side.

By directly decreasing inflammation, post-inflammatory hyperpigmentation is reduced. Also, vitamin C is itself an excellent depigmentating agent because it inhibits the action of the enzyme tyrosinase by reducing o-quinones, ²⁴ thereby decreasing melanin production. In the experience of this author, topical vitamin C (15 percent) demonstrated clinical lightening of melasma and solar lentigines even after only two months of daily application. Figure 8.2 shows lightening of solar lentigines and resolution of mottled, uneven pigmentation in an elderly woman after one year of daily application of 15 percent vitamin C serum.

Furthermore, Kameyama et al ²⁵ showed suppression of melanin formation by inhibition of tyrosinase in melanocytes and in melanoma cells by magnesium-L-ascorbyl-2 phosphate. When a 10 percent magnesium-L-ascorbyl-2-phosphate cream was applied to human skin, significant lightening of melasma and of lentigenes was observed in 19 of 34 patients. ²⁵

All of these proven functions of topical vitamin C contribute to reversal of the appearance of photoaging: Photoprotection over many months allows the skin to correct previous photodamage, the synthesis of collagen and inhibition of MMP-I was proven to decrease wrinkles, ¹⁶ and the inhibition of tyrosinase and anti-inflammatory activity result in depigmenting solar lentigines.

Another important action of vitamin C on the skin is that topical vitamin C increases the synthesis of several specific lipids of the skin surface. ²⁶ Thus, not only does vitamin C help the natural moisturization of the skin, but it also was shown to enhance the protective barrier function. ²⁷

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Protein Antioxidants in Thalassemia

Samir Awadallah , in Advances in Clinical Chemistry, 2013

5.2.2 Vitamin C

Vitamin C (ascorbic acid), a water-soluble vitamin, is a cofactor in many enzymatic reactions, notably hydroxylases involved in collagen synthesis. Vitamin C is widely distributed in all tissues of the body at concentration that are several-fold higher than in plasma [215]. As an electron donor, vitamin C is considered as an important free radical scavenger that protects against LPO. Neutralization of free radicals through donation of electrons from vitamin C results in its oxidation and the formation of ascorbyl radicals. Once formed, ascorbyl radicals are partially reduced back to vitamin C by several mechanisms including the glutathione system; the remaining ascorbyl radical is hydrolyzed and lost in circulation and urine [216].

Numerous studies have demonstrated decreased levels of vitamin C in thalassemic patients [77,93,113,128,137]. The exact mechanism by which vitamin C is reduced in thalassemic patients is not well explained. However, it can be postulated that vitamin C is rapidly utilized as a result of the presence of excessive amounts of free radicals [137]. In thalassemic patients, several studies have also demonstrated that decreased levels of vitamin C paralleled a decrease in the levels of vitamin E [77,128,137]. Therefore, it is also likely that much of the vitamin C is consumed while recycling other antioxidants such as vitamin E and glutathione [217]. Hence, deficiency of either vitamin may contribute to further exacerbation of the status of the other and the overall status of oxidative stress. That said, vitamin C plays a role in iron metabolism by reducing ferric iron to ferrous iron thus promoting intestinal absorption of dietary nonheme iron [23].

Vitamin C-mediated iron reduction and absorption may have deleterious consequences in thalassemia. In fact, vitamin C may exhibit a prooxidant activity in the presence of iron overload by catalyzing the formation of H₂O₂ and free radicals derived through the Fenton reaction [218,219]. In this regard, it is highly recommended that thalassemic patients should avoid taking vitamin C supplements in order not to elevate its levels in circulation.

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Fibrotic Response to Biomaterials and all Associated Sequence of Fibrosis

Kim Jones , in Host Response to Biomaterials, 2015

Regulating ECM production and catabolism

Fibrosis is essentially an imbalance between ECM production and catabolism. Altering these two processes seems like a natural approach for inhibiting fibrous capsule formation. Inhibiting enzymes involved in collagen synthesis seems a straightforward approach. Alternatively, myofibroblasts could be targeted with pro-apoptotic drugs. One enzyme that has attracted the attention of fibrosis researchers is prolyl-4-hydroxylase, since hydroxyproline is important in maintaining the triple helix structure of collagen. When released from PLGA, it significantly reduced fibrosis ( Love and Jones, 2013). As previously mentioned, the MMPs degrade components of the ECM, though their mode of action is extensive. MMP-1 in particular catabolizes collagen, so upregulating MMP-1 and downregulating TIMP-1 might reduce fibrotic tissue formation. In contrast, MMP-2, MMP-9, and MMP-12 promote fibrosis by inducing EMT and increasing vascular permeability for immune cells. Some researchers have inhibited these compounds to reduce immune cell infiltration and myofibroblast formation. Timing and location of injury are very important in targeting MMP activity.

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Tissue Engineering for Regeneration and Replacement of the Intervertebral Disc

Robby D. Bowles , ... Lori A. Setton , in Principles of Tissue Engineering (Fourth Edition), 2014

In vivo studies: other biologics

LinkN is an in vivo proteolytic degradation byproduct of proteoglycan aggregate stabilizing link protein. The effect of the intradiscal administration of the synthetic peptide of LinkN, which stimulates proteoglycan and collagen synthesis of IVD cells in vitro, was evaluated in the rabbit anular puncture model of disc degeneration and was shown to partially restore disc height, increase anabolic extracellular matrix gene expression, and reduce catabolic gene expression [170]. In a recent study in a large animal model of disc degeneration, the disc architecture and mechanical properties of surgically denucleated porcine (minipig) IVDs injected with a fibrin sealant, which promotes IVD cell proliferation and matrix synthesis, were preserved [191]. In addition, fibrin also inhibited fibrosis of the nucleus pulposus, increased proteoglycan synthesis, reduced secretion of pro-inflammatory cytokines and increased the synthesis of the pro-resolution factors, TGF-β and IL-4[191]. Nasto and co-workers have recently demonstrated that inhibition of NFκB activity via intra-peritoneal injection of Nemo Binding Domain peptide reduced proteoglycan loss in disc degeneration observed in a mouse model of accelerated aging [192].

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Tissue engineering for regeneration and replacement of the intervertebral disk

Stephen R. SloanJr., ... Lawrence A. Bonassar , in Principles of Tissue Engineering (Fifth Edition), 2020

In vivo studies: other biologics

LinkN is an in vivo proteolytic degradation byproduct of proteoglycan aggregate stabilizing link protein. The effect of the intradiscal administration of the synthetic peptide of LinkN, which stimulates proteoglycan and collagen synthesis of IVD cells in vitro, was evaluated in the rabbit anular puncture model of disk degeneration and was shown to partially restore disk height, increase anabolic ECM gene expression, and reduce catabolic gene expression [156]. In a recent study in a large animal model of disk degeneration, the disk architecture and mechanical properties of surgically denucleated porcine (minipig) IVDs injected with a fibrin sealant, which promotes IVD cell proliferation and matrix synthesis, were preserved [210]. In addition, fibrin also inhibited fibrosis of the NP, increased proteoglycan synthesis, reduced secretion of proinflammatory cytokines, and increased the synthesis of the proresolution factors, TGF-β, and IL-4. Nasto et al. have recently demonstrated that inhibition of NFκB activity via intraperitoneal injection of Nemo Binding Domain peptide reduced proteoglycan loss in disk degeneration observed in a mouse model of accelerated aging [211].

The therapeutic use of PRP treatments for the management of chronic low back pain has recently been tested in multiple preclinical [196–198,212–217] and clinical trials [199,201,218,219]. The results of these studies have been reviewed in detail elsewhere [220]. PRP is a concentrated, autologous blood product containing platelets, as well as natural concentrations of cytokines and growth factors [221,222]. The recent success of PRP therapies in the treatment of tendinopathies [223] and osteoarthritis [224] have led to increased interest in PRP treatment for low back pain and disk degeneration. In small animal models of disk degeneration, disks receiving intradiscal PRP injection have demonstrated decreased disk degeneration [196,216], increased disk height, increased disk hydration [197], and improved of disk appearance and signal in MRI imaging [216]. In clinical trials, patients receiving intradiscal PRP injection for the treatment of painful disk generation reported reduced pain [199,201,218] and improved disability scores when compared to patients in discectomy group. While findings from these clinical trials are promising, further clinical trials will be required to establish a standardized PRP treatment for painful disk degeneration.

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Why Is Vitamin C Required To Produce Collagen

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