Hair Formula Plus

CLINICAL STUDIES ON THE FOLLOWING INGREDIENTS:

Zinc

Hair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis

Abstract

Hair thinning and loss are prominent aging phenotypes but have an unknown mechanism. We show that hair follicle stem cell (HFSC) aging causes the stepwise miniaturization of hair follicles and eventual hair loss in wild-type mice and in humans. In vivo fate analysis of HFSCs revealed that the DNA damage response in HFSCs causes proteolysis of type XVII collagen (COL17A1/BP180), a critical molecule for HFSC maintenance, to trigger HFSC aging, characterized by the loss of stemness signatures and by epidermal commitment. Aged HFSCs are cyclically eliminated from the skin through terminal epidermal differentiation, thereby causing hair follicle miniaturization. The aging process can be recapitulated by Col17a1 deficiency and prevented by the forced maintenance of COL17A1 in HFSCs, demonstrating that COL17A1 in HFSCs orchestrates the stem cell-centric aging program of the epithelial mini-organ.

Source: Matsumura H, Mohri Y, Binh NT, Morinaga H, Fukuda M, Ito M, Kurata S, Hoeijmakers J, Nishimura EK. “Hair follicle aging is driven by transepidermal elimination of stem cells via COL17A1 proteolysis.” Science. (2016);351(6273).

Zinc may increase bone formation through stimulating cell proliferation, alkaline phosphatase activity and collagen synthesis in osteoblastic MC3T3-E1 cells

Abstract

Zinc is an essential trace element required for bone formation, however not much has been clarified yet for its role in osteoblast. We hypothesized that zinc would increase osteogenetic function in osteoblasts. To test this, we investigated whether zinc treatment enhances bone formation by stimulating osteoblast proliferation, bone marker protein alkaline phosphatase activity and collagen synthesis in osteoblastic MC3T3-E1 cells. MC3T3-E1 cells were cultured and treated with various concentrations of zinc (0, 1, 3, 15, 25 uM) along with a normal osteogenic medium (OSM) as control for 1, 5, 10 days. As measured by MTT assay for mitochondrial metabolic activity, cell proliferation was stimulated even at low zinc treatment (1-3 µM) compared to OSM, and it was stimulated in a zinc concentration-dependent manner during 5 and 10 days, with the most pronounced effect at 15 and 25 uM Zn. Cellular (synthesized) alkaline phosphatase (ALP) activity was increased in a zinc concentration-dependent manner, so did medium (secreted) ALP activity. Cellular collagen concentration was increased by zinc as time went by, therefore with the maximum zinc stimulatory effect in 10 days, and medium collagen concentration showed the same pattern even on 1 and 5 day. This zinc stimulatory effect of collagen synthesis was observed in cell matrix collagen staining. The study results imply that zinc can increase osteogenic effect by stimulating cell proliferation, ALP activity and collagen synthesis in osteoblastic cells.

Source: Seo HJ, Cho YE, Kim T, Shin HI, Kwun IS. “Zinc may increase bone formation through stimulating cell proliferation, alkaline phosphatase activity and collagen synthesis in osteoblastic MC3T3-E1 cells.” Nutr Res Pract. 2010 Oct;4(5):356-61.

The Therapeutic Effect and the Changed Serum Zinc Level after Zinc Supplementation in Alopecia Areata Patients Who Had a Low Serum Zinc Level

Abstract

Background: It has been reported that some alopecia areata patients have zinc deficiency. There have also been several reports published concerning oral zinc sulfate therapy, with encouraging results, in some alopecia areata patients.

Objective: The purpose of this study was to evaluate the therapeutic effects of oral zinc supplementation for twelve weeks in alopecia areata patients who had a low serum zinc level.

Methods: Oral zinc gluconate (50 mg/T/day) supplementation was given to alopecia areata patients without any other treatment for twelve weeks. The serum zinc level was measured before and after zinc supplementation. A four-point scale of hair regrowth was used to evaluate the therapeutic effect of oral zinc supplementation in these patients.

Results: Fifteen alopecia areata patients were enrolled in this study. After the therapy, the serum zinc levels increased significantly from 56.9 µg/ to 84.5 µg/dl. Positive therapeutic effects were observed for 9 out of 15 patients (66.7%) although this was not statistically significant. The serum zinc levels of the positive response group increased more than those of the negative response group (p=0.003).

Conclusion: Zinc supplementation needs to be given to the alopecia areata patients who have a low serum zinc level. We suggest that zinc supplementation could become an adjuvant therapy for the alopecia areata patients with a low serum zinc level and for whom the traditional therapeutic methods have been unsuccessful.

Source: Park H, Kim CW, Kim SS, Park CW. “The therapeutic effect and the changed serum zinc level after zinc supplementation in alopecia areata patients who had a low serum zinc level.” Ann Dermatol. 2009 May;21(2):142-6.

Ashwagandha

Corticosterone inhibits GAS6 to govern hair follicle stem-cell quiescence

Abstract

Chronic, sustained exposure to stressors can profoundly affect tissue homeostasis, although the mechanisms by which these changes occur are largely unknown. Here we report that the stress hormone corticosterone—which is derived from the adrenal gland and is the rodent equivalent of cortisol in humans—regulates hair follicle stem cell (HFSC) quiescence and hair growth in mice. In the absence of systemic corticosterone, HFSCs enter substantially more rounds of the regeneration cycle throughout life. Conversely, under chronic stress, increased levels of corticosterone prolong HFSC quiescence and maintain hair follicles in an extended resting phase. Mechanistically, corticosterone acts on the dermal papillae to suppress the expression of Gas6, a gene that encodes the secreted factor growth arrest specific 6. Restoring Gas6 expression overcomes the stress-induced inhibition of HFSC activation and hair growth. Our work identifies corticosterone as a systemic inhibitor of HFSC activity through its effect on the niche, and demonstrates that the removal of such inhibition drives HFSCs into frequent regeneration cycles, with no observable defects in the long-term.

Source: Choi S, Zhang B, Ma S, Gonzalez-Celeiro M, Stein D, Jin X, Kim ST, Kang YL, Besnard A, Rezza A, Grisanti L, Buenrostro JD, Rendl M, Nahrendorf M, Sahay A, Hsu YC. “Corticosterone inhibits GAS6 to govern hair follicle stem-cell quiescence.” Nature. 2021 Apr;592(7854):428-432.

A Prospective, Randomized Double-Blind, Placebo-Controlled Study of Safety and Efficacy of a High-Concentration Full-Spectrum Extract of Ashwagandha Root in Reducing Stress and Anxiety in Adults

Abstract

Context: Stress is a state of mental or emotional strain or tension, which can lead to underperformance and adverse clinical conditions. Adaptogens are herbs that help in combating stress. Ayurvedic classical texts, animal studies and clinical studies describe Ashwagandha as a safe and effective adaptogen.

Aims: The aim of the study was to evaluate the safety and efficacy of a high-concentration full-spectrum extract of Ashwagandha roots in reducing stress and anxiety and in improving the general well-being of adults who were under stress.

Settings and Design: Single center, prospective, double-blind, randomized, placebo-controlled trial.

Materials and Methods: A total of 64 subjects with a history of chronic stress were enrolled into the study after performing relevant clinical examinations and laboratory tests. These included a measurement of serum cortisol, and assessing their scores on standard stress-assessment questionnaires. They were randomized to either the placebo control group or the study drug treatment group, and were asked to take one capsule twice a day for a period of 60 days. In the study drug treatment group, each capsule contained 300 mg of high-concentration full-spectrum extract from the root of the Ashwagandha plant. During the treatment period (on Day 15, Day 30 and Day 45), a follow-up telephone call was made to all subjects to check for treatment compliance and to note any adverse reactions. Final safety and efficacy assessments were done on Day 60.

Statistical Analysis: t-test, Mann-Whitney test.

Results: The treatment group that was given the high-concentration full-spectrum Ashwagandha root extract exhibited a significant reduction (P<0.0001) in scores on all the stress-assessment scales on Day 60, relative to the placebo group. The serum cortisol levels were substantially reduced (P=0.0006) in the Ashwagandha group, relative to the placebo group. The adverse effects were mild in nature and were comparable in both the groups. No serious adverse events were reported.

Conclusion: The findings of this study suggest that a high-concentration full-spectrum Ashwagandha root extract safely and effectively improves an individual's resistance towards stress and thereby improves self-assessed quality of life.

Source: Chandrasekhar K, Kapoor J, Anishetty S. “A prospective, randomized double-blind, placebo-controlled study of safety and efficacy of a high-concentration full-spectrum extract of ashwagandha root in reducing stress and anxiety in adults.” Indian J Psychol Med. 2012 Jul;34(3):255-62.

Preparation and Evaluation of Hair Growth Formulations of Indian Ginseng (Withania somnifera) for Alopecia

Abstract

Background and Objective: Hair loss or alopecia or baldness, a dermatological disorder, affects the personality of an individual, psychologically and sociologically. There is a flood of drugs claiming to be useful in the treatment of alopecia but none seems to be developed with a proper rational strategy. The study aims to investigate the hair growth promoting activity of herbal formulations prepared from fruits extract of Withania somnifera (family- Solanaceae) collected from two different locations (from Rajasthan, WSR and from Uttarakhand WSU) on healthy male Wistar rats.

Materials and Methods: The methanolic fruit extracts were sub fractionated into ethyl acetate, butanol and water fractions. All extracts were evaluated for their total phenolic content (TPC), total flavonoid content (TFC) and in vitro anti-oxidant activity (by two different methods). Aloe vera based herbal formulations were prepared from ethyl acetate fraction of the plant extracts. The prepared herbal formulations were subjected to primary skin irritation test and in vivo hair growth activity in healthy male Wistar rats. All the formulations were observed for hair growth initiation (HGIT) and hair growth completion time (HCIT). The histological study of skin samples was also performed at the end of study to study hair growth at follicular level.

Results: Ethyl acetate fraction showed high TPC as well as TFC in both WSR and WSU in general. The extracts (particularly ethyl acetate extract) showed significant anti-oxidant activity in DPPH free radical scavenging activity and hydrogen peroxide scavenging assay. Primary skin irritation test showed that the prepared herbal formulations were non-irritating and non-toxic to the skin without any erythema or oedema at the end of 48 h of formulation application on denuded skin of rats. In vivo study showed early hair growth initiation and completion time in test group of animals as compared to the control group and the effect was comparable to that of standard group. The histology showed good growth of hair follicle in WSU as compared to WSR, control and standard with visible maximum anagenic population of hair.

Conclusion: It was concluded that WSU formulation showed good in vivo hair growth activity and was well supported by follicular/histological study.

Source: Mukesh Pandey, Lokesh Adhikari, Rupali Kotiyal, Ajay Semalty and Mona Semalty. “Preparation and Evaluation of Hair Growth Formulations of Indian Ginseng (Withania somnifera) for Alopecia.” Asian Journal of Biological Sciences (2019), 12: 524-532.

Ashwagandha root in the treatment of non-classical adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) is a well-characterised family of disorders of the adrenal cortices, resulting in varying degrees of cortisol, aldosterone and androgen deficiency or androgen excess, depending on the enzyme(s) affected and the degree of quantitative or functional enzyme deficit. Withania somnifera (WS), commonly known as Ashwagandha, is a medicinal plant that has been employed for centuries in ayurvedic medicine. Preclinical studies have shown that WS increases circulating cortisol levels and improves insulin sensitivity. We report the case of a 57-year-old woman with non-classical adrenal hyperplasia due to both 3-β-ol dehydrogenase deficiency and aldosterone synthase deficiency who was self-treated with WS for 6 months. After 6 months of treatment her serum 18-OH-hydroxycorticoserone, 17-OH-pregnenolone, corticosterone and 11-deoxycortisol decreased by 31%, 66%, 69% and 55%, respectively. The biochemical improvement was accompanied by a noticeable reduction in scalp hair loss.

Source: Kalani A, Bahtiyar G, Sacerdote A. Ashwagandha root in the treatment of non-classical adrenal hyperplasia. BMJ Case Rep. 2012 Sep 17;2012:bcr2012006989.

Ju Zhong

Determination of the potency of a novel saw palmetto supercritical CO2 extract (SPSE) for 5α-reductase isoform II inhibition using a cell-free in vitro test system

Abstract

Background: The nicotinamide adenine dinucleotide phosphate-dependent membrane protein 5α-reductase catalyses the conversion of testosterone to the most potent androgen – 5α-dihydrotestosterone. Two 5α-reductase isoenzymes are expressed in humans: type I and type II. The latter is found primarily in prostate tissue. Saw palmetto extract (SPE) has been used extensively in the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia (BPH). The pharmacological effects of SPE include the inhibition of 5α-reductase, as well as anti-inflammatory and antiproliferative effects. Clinical studies of SPE have been inconclusive – some have shown significant results, and others have not – possibly the result of varying bioactivities of the SPEs used in the studies.

Purpose: To determine the in vitro potency in a cell-free test system of a novel SP supercritical CO2 extract (SPSE), an inhibitor of the 5α-reductase isoenzyme type II.

Materials and methods: The inhibitory potency of SPSE was compared to that of finasteride, an approved 5α-reductase inhibitor, on the basis of the enzymatic conversion of the substrate androstenedione to the 5α-reduced product 5α-androstanedione.

Results: By concentration-dependent inhibition of 5α-reductase type II in vitro (half-maximal inhibitory concentration 3.58±0.05 μg/mL), SPSE demonstrated competitive binding toward the active site of the enzyme. Finasteride, the approved 5α-reductase inhibitor tested as positive control, led to 63%–75% inhibition of 5α-reductase type II.

Conclusion: SPSE effectively inhibits the enzyme that has been linked to BPH, and the amount of extract required for activity is comparatively low. It can be confirmed from the results of this study that SPSE has bioactivity that promotes prostate health at a level that is superior to that of many other phytotherapeutic extracts. The bioactivity of SPSE corresponds favorably to that reported for the hexane extract used in a large number of positive BPH clinical trials, as well as to finasteride, the established standard of therapy among prescription drugs. Future in vitro and clinical trials involving SPEs would be useful for elucidating their comparative differences, as well as appropriate patient selection for their use.

Source: Pais P, Villar A, Rull S. “Determination of the potency of a novel saw palmetto supercritical CO2 extract (SPSE) for 5α-reductase isoform II inhibition using a cell-free in vitro test system” Res Rep Urol. 2016 Apr 21;8:41-9.

Treatment of male androgenetic alopecia with topical products containing Serenoa repens extract

Abstract

Background/objectives: Male androgenetic alopecia (AGA) is a common hair problem. Serenoa repens extract has been shown to inhibit both types of 5-α reductase and, when taken orally, has been shown to increase hair growth in AGA patients. The aim of this study was to assess the efficacy of topical products containing S. repens extract for the treatment of male AGA.

Methods: This was a pilot, prospective, open, within-subject comparison limited to 24 weeks using no placebo controls. In all, 50 male volunteers aged between 20 and 50 years received topical S. repens products for 24 weeks. The primary end-point was a hair count in an area of 2.54 cm(2) at week 24. Secondary end-points included hair restoration, investigators' photographic assessment, patients' evaluation and discovering adverse events.

Results: The average hair count and terminal hair count increased at weeks 12 and 24 compared to baseline. Some of these positive results levelled off at week 24, presumably because the concentrated topical product containing S. repens extract was stopped after 4 weeks. The patients were satisfied with the products and the side-effects were limited.

Conclusions: The topical application of S. repens extract could be an alternative treatment in male pattern baldness in male patients who do not want or cannot tolerate the side-effects of standard medications, but the use of a concentrated S. repens product beyond 4 weeks may be necessary for sustained efficacy.

Source: Wessagowit V, Tangjaturonrusamee C, Kootiratrakarn T, Bunnag T, Pimonrat T, Muangdang N, Pichai P. “Treatment of male androgenetic alopecia with topical products containing Serenoa repens extract.” Australas J Dermatol. 2016 Aug;57(3):e76-82.

A randomized, double-blind, placebo-controlled trial to determine the effectiveness of botanically derived inhibitors of 5-alpha-reductase in the treatment of androgenetic alopecia

Abstract

Background: Androgenetic alopecia (AGA) is characterized by the structural miniaturization of androgen-sensitive hair follicles in susceptible individuals and is anatomically defined within a given pattern of the scalp. Biochemically, one contributing factor of this disorder is the conversion of testosterone (T) to dihydrotestosterone (DHT) via the enzyme 5-alpha reductase (5AR). This metabolism is also key to the onset and progression of benign prostatic hyperplasia (BPH). Furthermore, AGA has also been shown to be responsive to drugs and agents used to treat BPH. Of note, certain botanical compounds have previously demonstrated efficacy against BPH. Here, we report the first example of a placebo-controlled, double-blind study undertaken in order to examine the benefit of these botanical substances in the treatment of AGA.

Objectives: The goal of this study was to test botanically derived 5AR inhibitors, specifically the liposterolic extract of Serenoa repens (LSESr) and beta-sitosterol, in the treatment of AGA.

Subjects: Included in this study were males between the ages of 23 and 64 years of age, in good health, with mild to moderate AGA.

Results: The results of this pilot study showed a highly positive response to treatment. The blinded investigative staff assessment report showed that 60% of (6/10) study subjects dosed with the active study formulation were rated as improved at the final visit.

Conclusions: This study establishes the effectiveness of naturally occurring 5AR inhibitors against AGA for the first time, and justifies the expansion to larger trials.

Source: Prager N, Bickett K, French N, Marcovici G. “A randomized, double-blind, placebo-controlled trial to determine the effectiveness of botanically derived inhibitors of 5-alpha-reductase in the treatment of androgenetic alopecia.” J Altern Complement Med. 2002 Apr;8(2):143-52.

Bioperine

Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers

Abstract

The medicinal properties of curcumin obtained from Curcuma longa L. cannot be utilised because of poor bioavailability due to its rapid metabolism in the liver and intestinal wall. In this study, the effect of combining piperine, a known inhibitor of hepatic and intestinal glucuronidation, was evaluated on the bioavailability of curcumin in rats and healthy human volunteers. When curcumin was given alone, in the dose 2 g/kg to rats, moderate serum concentrations were achieved over a period of 4 h. Concomitant administration of piperine 20 mg/kg increased the serum concentration of curcumin for a short period of 1-2 h post drug. Time to maximum was significantly increased (P < 0.02) while elimination half life and clearance significantly decreased (P < 0.02), and the bioavailability was increased by 154%. On the other hand in humans after a dose of 2 g curcumin alone, serum levels were either undetectable or very low. Concomitant administration of piperine 20 mg produced much higher concentrations from 0.25 to 1 h post drug (P < 0.01 at 0.25 and 0.5 h; P < 0.001 at 1 h), the increase in bioavailability was 2000%. The study shows that in the dosages used, piperine enhances the serum concentration, extent of absorption and bioavailability of curcumin in both rats and humans with no adverse effects.

Source: Shoba G, Joy D, Joseph T, Majeed M, Rajendran R, Srinivas PS. “Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers.” Planta Med. 1998 May;64(4):353-6.

Iron and Physical Activity: Bioavailability Enhancers, Properties of Black Pepper (Bioperine®) and Potential Applications

Abstract

Black pepper (Piper nigrum L.) has been employed in medicine (epilepsy, headaches, and diabetes), where its effects are mainly attributed to a nitrogen alkaloid called piperidine (1-(1-[1,3-benzodioxol-5-yl]-1-oxo-2,4 pentenyl) piperidine). Piperine co-administered with vitamins and minerals has improved its absorption. Therefore, this study aimed to describe the impact of the joint administration of iron (Fe) plus black pepper in physically active healthy individuals. Fe is a micronutrient that aids athletic performance by influencing the physiological functions involved in endurance sports by improving the transport, storage, and utilization of oxygen. Consequently, athletes have risk factors for Fe depletion, Fe deficiency, and eventually, anemia, mainly from mechanical hemolysis, gastrointestinal disturbances, and loss of Fe through excessive sweating. Declines in Fe stores have been reported to negatively alter physical capacities such as aerobic capacity, strength, and skeletal muscle recovery in elite athletes. Thus, there is a need to maintain Fe storage, even if Fe intake meets the recommended daily allowance (RDA), and Fe supplementation may be justified in physically active individuals, in states of Fe deficiency, with or without anemia. Females, in particular, should monitor their Fe hematological profile. The recommended oral Fe supplements are ferrous or ferric salts, sulfate, fumarate, and gluconate. These preparations constitute the first line of treatment; however, the high doses administered have gastrointestinal side effects that reduce tolerance and adherence to treatment. Thus, a strategy to counteract these adverse effects is to improve the bioavailability of Fe. Therefore, piperine may benefit the absorption of Fe through its bioavailability enhancement properties. Three research studies of Fe associated with black pepper have reported improvements in parameters related to the metabolism of Fe, without adverse effects. Although more research is needed, this could represent an advance in oral Fe supplementation for physically active individuals.

Source: Fernández-Lázaro D, Mielgo-Ayuso J, Córdova Martínez A, Seco-Calvo J. “Iron and Physical Activity: Bioavailability Enhancers, Properties of Black Pepper (Bioperine®) and Potential Applications.” Nutrients. 2020 Jun 24;12(6):1886.

 

References:

1. https://pubmed.ncbi.nlm.nih.gov/26010505/
2. https://www.medicalnewstoday.com/articles/325307
3. https://www.advdermatology.com/blog/non-scarring-types-hair-loss/
4. https://www.drugwatch.com/propecia/side-effects/
5. https://www.mskcc.org/cancer-care/patient-education/finasteride
6. https://www.newswise.com/articles/survey-shows-patient-satisfaction-with-hair-restoration-surgery-has-increased
7. https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1006594
8. https://en.wikipedia.org/wiki/Non_scarring_hair_loss
9. https://www.forhims.com/blog/scarring-alopecia
10. https://health.clevelandclinic.org/why-do-men-go-bald-and-is-there-anything-you-can-really-do-about-it/
11. https://www.mayoclinic.org/diseases-conditions/hair-loss/expert-answers/preventing-hair-loss-in-women/faq-20452842
12. https://www.science.org/doi/10.1126/science.aad4395
13. Ibid.
14. Ibid.
15. https://www.scientificamerican.com/article/why-does-skin-wrinkle-wit/
16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1606623/
17. https://diannehales.com/casanova-in-the-italian-language/
18. https://www.upi.com/Odd_News/2005/03/24/Casanova-was-right-on-about-oysters/92811111692358/#:~:text=Casanova%20reportedly%20ate%2050%20raw,rats%20with%20them%20proved%20it.
19. https://healthyeating.sfgate.com/minerals-aid-collagen-production-9485.html
20. https://academic.oup.com/cdn/article/4/Supplement_2/1854/5845783
21. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861201/
22. https://www.healthline.com/nutrition/zinc-overdose-symptoms#:~:text=Taking%20more%20zinc%20than%20the,zinc%20toxicity%20can%20be%20difficult.
23. https://www.nature.com/articles/s41586-021-03417-2
24. Ibid.
25. Ibid.
26. Ibid.
27. Ibid.
28. Ibid.
29. https://news.harvard.edu/gazette/story/2021/03/researchers-discover-how-chronic-stress-leads-to-hair-loss/#:~:text=Harvard%20University%20researchers%20have%20identified,might%20lead%20to%20hair%20loss.
30. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3573577/
31. https://www.researchgate.net/publication/331047259_Preparation_and_Evaluation_of_Hair_Growth_Formulations_of_Indian_Ginseng_Withania_somnifera_for_Alopecia
32. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4543599/
33. https://www.webmd.com/skin-problems-and-treatments/hair-loss/hair-loss-causes-women
34. https://www.healthline.com/health/dht
35. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4847595/
36. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4847595/
37. https://pubmed.ncbi.nlm.nih.gov/26010505/
38. https://pubmed.ncbi.nlm.nih.gov/26010505/
39. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2840915/
40. https://www.healthline.com/nutrition/saw-palmetto-benefits#:~:text=Saw%20palmetto%20is%20a%20species,and%20enhance%20urinary%20tract%20function.
41. https://www.ncbi.nlm.nih.gov/books/NBK526128/
42. https://bioperine.com/researchhighlight/#:~:text=Resveratrol,)%20was%20increased%20by%201544%25.
43. https://pubmed.ncbi.nlm.nih.gov/9619120/