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International Journal of Cosmetic... Feb 2022To demonstrate the synergistic effect of 4-hexylresorcinol (4-HR) with niacinamide in boosting anti-melanogenic efficacy in vitro and establish the in vivo efficacy and... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
To demonstrate the synergistic effect of 4-hexylresorcinol (4-HR) with niacinamide in boosting anti-melanogenic efficacy in vitro and establish the in vivo efficacy and safety of the combination in a human trial.
METHODS
Primary human epidermal melanocytes and 3D pigmented skin equivalents were treated with 4-HR, niacinamide, and their combinations for their effect on pigmentation. This was followed by a randomized, double-blind, split-face clinical study in Chinese subjects, and effects on skin tone, hyperpigmentation, fine lines and wrinkles, hydration, and skin firmness were measured for a 12-week study period.
RESULTS
In vitro tyrosinase enzyme activity studies showed that 4-HR is one of the most potent tyrosinase inhibitors. The combination of 4-HR and niacinamide showed a synergistic reduction in melanin production in cultured melanocytes and lightened the 3D skin equivalent model. In vitro as well as in the human trial, the combination of 4-HR and niacinamide showed significantly improved efficacy over niacinamide alone on hyperpigmentation spots as measured by L*, the visual appearance of fine lines and wrinkles in crow's feet and perioral area and skin firmness, with no product-related adverse events.
CONCLUSIONS
A formulation containing a combination of 4-HR and niacinamide delivered superior skin tone and anti-ageing benefits significantly better than niacinamide alone with no adverse events. This study demonstrates that a product designed to affect multiple pathways of melanogenesis, inflammation, and ageing may provide an additional treatment option, beyond hydroquinone and retinoids, for hyperpigmentation and ageing.
Topics: Aging; Hexylresorcinol; Humans; Hyperpigmentation; Niacinamide; Skin Pigmentation
PubMed: 34958693
DOI: 10.1111/ics.12759 -
Maxillofacial Plastic and... Feb 20224-Hexylresorcinol (4HR) is amphiphilic organic chemical and auto-regulator for micro-organism. As 4HR administration induces the stress on the endoplasmic reticulum, 4HR... (Review)
Review
4-Hexylresorcinol (4HR) is amphiphilic organic chemical and auto-regulator for micro-organism. As 4HR administration induces the stress on the endoplasmic reticulum, 4HR changes protein folding. The application of 4HR inhibits NF-κB signal pathway and TNF-α production. In addition, 4HR administration increases VEGF, TGF-β1, and calcification associated proteins. As a consequence, 4HR administration increases angiogenesis and bone formation in wounded area. Strong anti-inflammatory reaction and capillary regeneration in diabetic model demonstrate that 4HR can be applied on many types of surgical wound.
PubMed: 35103875
DOI: 10.1186/s40902-022-00334-w -
Maxillofacial Plastic and... Dec 2020Immunomodulation is a technique for the modulation of immune responses against graft material to improve surgical success rates. The main target cell for the... (Review)
Review
Immunomodulation is a technique for the modulation of immune responses against graft material to improve surgical success rates. The main target cell for the immunomodulation is a macrophage because it is the reaction site of the graft and controls the healing process. Macrophages can be classified into M1 and M2 types. Most immunomodulation techniques focus on the rapid differentiation of M2-type macrophage. An M2 inducer, 4-hexylresorcinol, has been recently identified and is used for bone grafts and dental implant coatings.
PubMed: 32206664
DOI: 10.1186/s40902-020-00249-4 -
Veterinary World Dec 2022Secondary bioactive compounds of medicinal plants exert anti-inflammatory, antimicrobial, antioxidant, and metabolism-modulating effects. This study aimed to investigate...
Effect of feeding bioactive compounds identified from plant extracts (4-hexylresorcinol, 7-hydroxycoumarin, and gamma-octalactone) on the productivity and quality of broiler meat.
BACKGROUND AND AIM
Secondary bioactive compounds of medicinal plants exert anti-inflammatory, antimicrobial, antioxidant, and metabolism-modulating effects. This study aimed to investigate the effect of feeding 4-hexylresorcinol, as well as its combinations with gamma-octalactone and 7-hydroxycoumarin, on the digestibility of dietary nutrients, weight gain, and quality characteristics of the meat and liver of Arbor Acres broiler chickens.
MATERIALS AND METHODS
The following feeding scheme was applied on the chickens: Control, basal diet (BD); I experimental, BD + 4-hexylresorcinol at 0.5 mg/kg of live weight per day; II experimental, BD + 4-hexylresorcinol + gamma-octalactone at 0.4 mg/kg of live weight per day; III experimental, BD + 4-hexylresorcinol + 7-hydroxycoumarin at 0.1 and 0.15 mg/kg of live weight per day; and IV experimental, BD + 4-hexylresorcinol + gamma-octalactone + 7-hydroxycoumarin at 0.05, 0.15, and 0.01 mg/kg of live weight per day.
RESULTS
Chickens in I, II, and IV experimental groups at the age of 35 days showed superior live weight than chickens in the control group. Supplementation with all the tested additives, except the combination 4-hexylresorcinol + 7-hydroxycoumarin, significantly increased the digestibility coefficients of dietary nutrients. Supplementation with the combinations 4-hexylresorcinol + gamma-octalactone and 4-hexylresorcinol + gamma-octalactone + 7-hydroxycoumarin significantly increased the amount of fat in the pectoral muscles. However, the mass fraction of fat in the thigh muscles of broiler chickens decreased in II, III, and IV experimental groups. The pectoral muscles of broiler chickens in experimental Group IV contained small amounts of lysine, tyrosine, histidine, leucine-isoleucine, methionine, valine, proline, threonine, serine, alanine, and glycine. Supplementation with pure 4-hexylresorcinol significantly reduced the levels of lysine, phenylalanine, histidine, leucine-isoleucine, methionine, valine, proline, threonine, and alanine in the thigh muscles. However, supplementation with pure 4-hexylresorcinol significantly increased the concentrations of P, Fe, Se, Zn, and B and decreased the concentrations of I, Ni, V, Al, and Pb in the pectoral muscles. Supplementation with the combination 4-hexylresorcinol + gamma-octalactone + 7-hydroxycoumarin resulted in the accumulation of Ca, Co, Fe, Mn, Se, Zn, and Li and a decrease in the concentrations of K, Mg, and V.
CONCLUSION
Supplementation with all the tested additives, except the combination 4-hexylresorcinol + 7-hydroxycoumarin, exerted a positive effect on the indicators of live weight gain and dietary nutrient digestibility in broiler chickens. Supplementation with the combinations 4-hexylresorcinol + gamma-octalactone and 4-hexylresorcinol + gamma-octalactone + 7-hydroxycoumarin increased the amount of fat in the pectoral muscles but decreased it in the thigh muscles. Supplementation with all the tested additives decreased the concentrations of I in the pectoral muscles and Zn in the thigh muscles in all the experimental groups compared with those in the control group.
PubMed: 36718328
DOI: 10.14202/vetworld.2022.2986-2996 -
The Protein Journal Feb 2004The effects of hexylresorcinol and dodecylresorcinol on the monophenolase and diphenolase activity of mushroom tyrosinase have been studied. The results show that...
The effects of hexylresorcinol and dodecylresorcinol on the monophenolase and diphenolase activity of mushroom tyrosinase have been studied. The results show that hexylresorcinol and dodecylresorcinol can inhibit both monophenolase and diphenolase activity of the enzyme. The lag period of the enzyme was obviously lengthened, and the steady-state activity of the enzyme decreased sharply. Two microM of hexylresorcinol and dodecylresorcinol can lengthen the lag period from 98 s to 260 and 275 s, respectively. Both hexylresorcinol and dodecylresorcinol can lead to reversible inhibition of the enzyme. The IC50 values of hexylresorcinol and dodecylresorcinol were estimated as 1.24 and 1.15 microM for monophenolase and as 0.85 and 0.80 microM for diphenolase, respectively. A kinetic analysis shows that hexylresorcinol and dodecylresorcinol are competitive inhibitors. The apparent inhibition constant for hexylresorcinol and dodecylresorcinol binding with free enzyme has been determined to be 0.443 and 0.405 microM for diphenolase, respectively.
Topics: Agaricales; Catechol Oxidase; Enzyme Inhibitors; Hexylresorcinol; Inhibitory Concentration 50; Monophenol Monooxygenase; Oxidoreductases; Resorcinols
PubMed: 15106879
DOI: 10.1023/b:jopc.0000020080.21417.ff -
Journal of Cosmetic Dermatology Dec 2020Effective skin lightening remains an unmet need in over-the-counter formulations.
BACKGROUND
Effective skin lightening remains an unmet need in over-the-counter formulations.
AIMS
This research examined a topical facial formulation containing hexylresorcinol, silymarin, 20% vitamin C, and 5% vitamin E in a proprietary anhydrous vehicle in skin explants for UVB photoprotective effects and clinical benefits.
PATIENTS/METHOD
In vitro investigation examined 12 skin explants to assess the test product and vehicle. Six skin explants received 10 μL of the study product, and six skin explants received the 10 μL of the vehicle. After 96 hours, half the skin samples were exposed to 250 mJ/cm of UVB radiation while the other half unexposed. Clinically, 42 female subjects with normal or dry skin 35-55 years with skin types I-VI were enrolled possessing discoloration, uneven skin tone, and fine lines. The dermatologist investigator evaluated brightening, evenness, fine lines, wrinkles, and global appearance.
RESULTS
Explants treated with the study product experienced no significant change in gene marker expression of pro-collagen and pro-inflammatory gene markers upon UVB exposure. In contrast, skin explants treated with the vehicle experienced significant decreases in pro-collagen expression and significant increases in pro-inflammatory gene marker expression. Clinically, the greatest improvement as compared to baseline was seen at week 12 (P < .001) with 45% improvement in brightening, 27% improvement in evenness, 25% improvement in lines, and 25% improvement in global facial appearance.
CONCLUSION
Hexylresorcinol, silymarin, 20% vitamin C, and 5% vitamin E in a proprietary anhydrous vehicle are effective in decreasing UVB-induced photodamage in skin explants while clinically producing skin brightness improvement.
Topics: Excipients; Female; Humans; Skin; Skin Aging; Skin Pigmentation; Technology; Ultraviolet Rays
PubMed: 32985076
DOI: 10.1111/jocd.13741 -
PloS One 2020Ever decreasing efficiency of antibiotic treatment due to growing antibiotic resistance of pathogenic bacteria is a critical issue in clinical practice. The two...
Ever decreasing efficiency of antibiotic treatment due to growing antibiotic resistance of pathogenic bacteria is a critical issue in clinical practice. The two generally accepted major approaches to this problem are the search for new antibiotics and the development of antibiotic adjuvants to enhance the antimicrobial activity of known compounds. It was therefore the aim of the present study to test whether alkylresorcinols, a class of phenolic lipids, can be used as adjuvants to potentiate the effect of various classes of antibiotics. Alkylresorcinols were combined with 12 clinically used antibiotics. Growth-inhibiting activity against a broad range of pro- and eukaryotic microorganisms was determined. Test organisms did comprise 10 bacterial and 2 fungal collection strains, including E. coli and S. aureus, and clinical isolates of K. pneumoniae. The highest adjuvant activity was observed in the case of 4-hexylresorcinol (4-HR), a natural compound found in plants with antimicrobial activity. 50% of the minimal inhibitory concentration (MIC) of 4-HR caused an up to 50-fold decrease in the MIC of antibiotics of various classes. Application of 4-HR as an adjuvant revealed its efficiency against germination of bacterial dormant forms (spores) and prevented formation of antibiotic-tolerant persister cells. Using an in vivo mouse model of K. pneumoniae-induced sepsis, we could demonstrate that the combination of 4-HR and polymyxin was highly effective. 75% of animals were free of infection after treatment as compared to none of the animals receiving the antibiotic alone. We conclude that alkylresorcinols such as 4-HR can be used as an adjuvant to increase the efficiency of several known antibiotics. We suggest that by this approach the risk for development of genetically determined antibiotic resistance can be minimized due to the multimodal mode of action of 4-HR.
Topics: Adjuvants, Pharmaceutic; Animals; Anti-Bacterial Agents; Disease Models, Animal; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Escherichia coli; Female; Hexylresorcinol; Humans; Klebsiella Infections; Klebsiella pneumoniae; Mice; Microbial Sensitivity Tests; Polymyxins; Sepsis; Staphylococcus aureus
PubMed: 32960928
DOI: 10.1371/journal.pone.0239147 -
National Toxicology Program Technical... May 19884-Hexylresorcinol, which is used as an anthelmintic and antiseptic, was nominated by the National Cancer Institute for study. Toxicology and carcinogenesis studies were...
4-Hexylresorcinol, which is used as an anthelmintic and antiseptic, was nominated by the National Cancer Institute for study. Toxicology and carcinogenesis studies were conducted by administering 4-hexylresorcinol (greater than 99% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Sixteen-Day and Thirteen-Week Studies: In the 16-day studies, groups of five rats and five mice of each sex were administered 0, 31.3, 62.5, 125, 250, or 500 mg/kg 4-hexylresorcinol. Survival was not affected. Decreased body weights were seen in male rats that received 250 or 500 mg/kg 4-hexylresorcinol. No other effects were observed. In the 13-week studies, groups of 10 rats and 10 mice of each sex were administered 0, 62.5, 125, 250, 500, or 1,000 mg/kg of the chemical, 5 days per week. All rats and male mice and 9/10 female mice that received 1,000 mg/kg died before the end of the studies. Final mean body weights of male rats that received 250 or 500 mg/kg were 22% or 38% lower than that of the vehicle controls; final mean body weights of female rats that received 250 or 500 mg/kg were 16% or 9% lower. No compound-related gross or microscopic pathologic effects were observed in rats. No body weight effects were observed for mice. Mild to moderate nephropathy was dose related in male and female mice. Based on these results, 2-year toxicology and carcinogenesis studies of 4-hexylresorcinol were conducted by administering 0, 62.5, or 125 mg/kg to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex, 5 days per week. Body Weight and Survival in the Two-Year Studies: Mean body weights of high dose male rats were 7%-11% lower than those of the vehicle controls throughout the study. Mean body weights of low dose male and dosed female rats were similar to those of the vehicle controls. The body weights of dosed male and dosed female mice were comparable to those of vehicle controls except during the last 16 weeks of the studies, when body weights were 6%-16% lower in the dosed groups. No significant differences in survival were observed between any groups of rats or mice of either sex (male rats: vehicle control, 30/50; low dose, 29/50; high dose, 33/50; female rats: 28/50; 32/50; 30/50; male mice: 36/50; 26/50; 30/50; female mice: 35/50; 32/50; 35/50). Nonneoplastic and Neoplastic Lesions in the Two-Year Studies: Two astrocytomas and an oligodendroglioma were observed in high dose male rats, a glioma was observed in one low dose male rat, and an oligodendroglioma was observed in one vehicle control male rat. These neoplasms were not considered to be related to 4-hexylresorcinol administration. Focal medullary hyperplasia of the adrenal gland was observed at increased incidences in dosed male mice (5/50; 16/50; 10/49). Pheochromocytomas in male mice occurred with a marginal upward trend (1/50; 2/50; 5/49). Historically, these neoplasms are observed in about 1% of corn oil vehicle control B6C3F1 male mice. The incidences of neoplasms of the harderian gland in male mice were slightly increased over those in the vehicle controls (adenomas or carcinomas, combined: 0/50; 4/50; 3/50). Decreases were observed in the incidences of mononuclear cell leukemia in dosed male (12/49; 7/50; 1/50) and female (16/50; 3/50; 2/50) rats, hepatocellular adenomas or carcinomas (combined) in dosed male mice (21/50; 9/50; 9/50), and circulatory system tumors in male (10/50; 4/50; 2/50) and female (6/50; 2/49; 0/50) mice. These decreased incidences of tumors in rats and mice are considered to be possibly related to 4-hexylresorcinol administration. The incidences and severity of nephropathy (male: 39/50; 43/50; 47/50; female: 7/50; 40/49; 47/50) and incidences of osteosclerosis (male: 5/50; 5/50; 15/50; female: 21/50; 25/49; 40/50) were increased in both dosed male and female mice and are considered to be related to chemical exposure. Genetic Toxicology: 4-Hexylresorcinol was not mutagenic for Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without S9 metabolic activation. 4-Hexylre, TA1535, or TA1537 with or without S9 metabolic activation. 4-Hexylresorcinol induced forward mutations at the TK locus in mouse L5178Y cells in the presence of S9; no response was observed in the absence of metabolic activation. In cytogenetic assays with cultured Chinese hamster ovary (CHO) cells, 4-hexylresorcinol caused an increase in the frequency of sister chromatid exchanges (SCEs) in the absence of metabolic activation; no induction of SCEs was observed in the presence of S9. Chromosomal aberrations were not induced in CHO cells with or without metabolic activation. Data Audit: The data, documents, and pathology materials from the 2-year studies of 4-hexylresorcinol were audited at the NTP Archives. The audit findings show that the conduct of the studies is documented appropriately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of 4-hexylresorcinol for male or female F344/N rats given doses of 62.5 or 125 mg/kg. There was equivocal evidence of carcinogenic activity of 4-hexylresorcinol for male B6C3F1 mice, as shown by marginally increased incidences of pheochromocytomas (and hyperplasia) of the adrenal medulla and of harderian gland neoplasms. There was no evidence of carcinogenic activity for female B6C3F1 mice given doses of 62.5 or 125 mg/kg 4-hexylresorcinol. Decreased incidences of three tumors types were considered related to 4-hexylresorcinol administration: mononuclear cell leukemia in male and female rats, hepatocellular neoplasms in male mice, and circulatory system tumors in male and female mice. Synonyms: 4-hexyl-1,3-benzenediol; 4-hexyl-1,3-dihydroxybenzene
PubMed: 12732906
DOI: No ID Found -
International Journal of Molecular... Aug 20214-Hexylresorcinol (4HR) has been used as a food additive, however, it has been recently demonstrated as a Class I histone deacetylase inhibitor (HDACi). Unlike other...
4-Hexylresorcinol (4HR) has been used as a food additive, however, it has been recently demonstrated as a Class I histone deacetylase inhibitor (HDACi). Unlike other HDACi, 4HR can be taken through foods. Unfortunately, some HDACi have an influence on craniofacial growth, therefore, the purpose of this study was to evaluate the effects of 4HR on craniofacial growth. Saos-2 cells (osteoblast-like cells) were used for the evaluation of HDACi and its associated activities after 4HR administration. For the evaluation of craniofacial growth, 12.8 mg/kg of 4HR was administered weekly to 4 week old rats (male: 10, female: 10) for 12 weeks. Ten rats were used for untreated control (males: 5, females: 5). Body weight was recorded every week. Serum and head samples were collected at 12 weeks after initial administration. Craniofacial growth was evaluated by micro-computerized tomography. Serum was used for ELISA (testosterone and estrogen) and immunoprecipitation high-performance liquid chromatography (IP-HPLC). The administration of 4HR (1-100 μM) showed significant HDACi activity ( < 0.05). Body weight was significantly different in male rats ( < 0.05), and mandibular size was significantly smaller in 4HR-treated male rats with reduced testosterone levels. However, the mandibular size was significantly higher in 4HR treated female rats with increased growth hormone levels. In conclusion, 4HR had HDACi activity in Saos-2 cells. The administration of 4HR on growing rats showed different responses in body weight and mandibular size between sexes.
Topics: Animals; Anthelmintics; Bone and Bones; Facial Bones; Female; Hexylresorcinol; Male; Maxillofacial Development; Osteoblasts; Rats
PubMed: 34445640
DOI: 10.3390/ijms22168935 -
Head & Face Medicine Jun 20224-Hexylresorcinol (4HR) is a food additive and class I histone deacetylase inhibitor. In this study, we examined the effects of 4HR administration on the submandibular...
BACKGROUND
4-Hexylresorcinol (4HR) is a food additive and class I histone deacetylase inhibitor. In this study, we examined the effects of 4HR administration on the submandibular gland in a growing rat model.
METHODS
Four-week-old rats were used in this study. The experimental group (nine males and eight females) received 12.8 mg/kg of 4HR weekly for 12 weeks. Ten rats (five males and five females) were used as controls. The submandibular glands of rats were collected 12 weeks after the first administration of 4HR. The weight of the glands was measured. Histological analysis, immunoprecipitation-high-performance liquid chromatography (IP-HPLC), and western blotting were performed.
RESULTS
The weights of the rat submandibular glands were higher in the experimental groups than in the control group, especially in male rats (P < 0.05). The vascular endothelial growth factor (VEGF) and testosterone in the submandibular glands were more highly expressed in 4HR-treated male rats than in untreated rats, as detected by both western blotting and immunohistochemistry. The IP-HPLC results demonstrated that the expression levels of Ki67, epidermal growth factor, and testosterone in the submandibular glands were higher in 4HR-treated male rats than in untreated rats.
CONCLUSIONS
This study demonstrated that the systemic administration of 4HR increased the weight of submandibular glands in male rats. In addition, the testosterone and VEGF expression levels in the submandibular glands increased owing to 4HR administration.
Topics: Animals; Blotting, Western; Female; Hexylresorcinol; Humans; Male; Rats; Submandibular Gland; Testosterone; Vascular Endothelial Growth Factor A
PubMed: 35668488
DOI: 10.1186/s13005-022-00320-7