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Introduction: Lead acetate (PbAc), a hazardous heavy metal, poses significant threats to human health and the environment because of widespread industrial exposure. PbAc exposure leads to liver injury primarily through oxidative stress and the disruption of key regulatory pathways. Understanding these mechanisms and exploring protective agents are vital for mitigating PbAc-induced hepatotoxicity. Therefore, we aimed to investigate the molecular pathways implicated in PbAc-induced liver damage, focusing on Sirt-1, Nrf2 (HO-1, NQO1, and SOD), Akt-1/GSK3β, m-TOR, and P53. Additionally, we aimed to assess the hepatoprotective effects of arbutin, which is administered orally and intraperitoneally, to determine the most effective delivery method., Methodology: In silico analyses were conducted to identify relevant protein networks associated with Sirt-1 and AKT-1/GSK-3B pathways. The pharmacodynamic properties of arbutin were examined, followed by molecular docking studies to elucidate its interactions with the selected protein network. In vivo preclinical studies were carried out on adult male rats randomly assigned to 6 different treatment groups, including PbAc exposure and PbAc exposure treated with arbutin either orally or intraperitoneally., Results: PbAc exposure led to hepatic oxidative stress, as evidenced by elevated MDA levels and SIRT-1 inhibition, disrupting antioxidant pathways and activating antiautophagic and proapoptotic pathways, ultimately resulting in hepatocyte necrosis. Both oral and intraperitoneal arbutin administration effectively modifed these effects, with intraperitoneal delivery showing superior efficacy in mitigating PbAc-induced histological, immunological, and biochemical alterations., Conclusion: This study provides insights into the molecular mechanisms underlying PbAc-induced liver injury and highlights the hepatoprotective potential of arbutin. These findings suggest that arbutin, particularly when administered intraperitoneally, holds promise as a therapeutic agent for combating PbAc-induced hepatotoxicity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background/aims:  This study aimed to investigate the possible positive effects of arbutin in a trinitrobenzene sulfonic acid (TNBS)- induced experimental colitis model, to compare it with mesalazine, which is used in treating inflammatory bowel disease and to observe the effect of its concomitant use., Materials and Methods:  Forty Wistar albino species male rats were randomized into 5 groups as control, colitis, colitis+arbutin (Arb), colitis+mesalazine (Mes), and colitis+mesalazine+arbutin (M+A). Proinflammatory cytokines [interleukin (IL)-6, IL-1β, tumor necrosis factor alpha (TNF-α)] and oxidant/antioxidant parameters [malondialdehyde (MDA), superoxide dismutase inhibition (SOD) inhibition, myeloperoxidase (MPO), and catalase, glutathione peroxidase (GPx)] were processed from the samples. Histopathological evaluation evaluated goblet cell reduction, cellular infiltration, and mucosal loss., Results:  When the treatment groups and the TNBS group were compared, statistical significance was achieved in MDA, MPO, SOD inhibition, GPx values, IL-6, IL-1β and TNF-α levels. Histopathological evaluation revealed a statistically significant decrease in the mucosal loss value in the group where mesalazine and arbutin were used together compared to the TNBS group., Conclusion:  Our study's results elaborated that using arbutin alone or in combination with mesalazine produced positive effects in colitis-induced rats.

Objective: To investigate the protective effect of arbutin against CCl 4 -induced hepatic fibrosis in mice and explore the underlying mechanisms., Methods: Twenty-four C57BL/6 mice were randomly divided into control group, model group, and low- and high-dose arbutin treatment (25 and 50 mg/kg, respectively) groups. Mouse models of liver fibrosis were established by intraperitoneal injection of CCl 4 , and arbutin was administered daily via gavage for 6 weeks. After the treatments, serum biochemical parameters of the mice were tested, and liver tissues were taken for HE staining, Sirius Red staining and immunohistochemical staining. RT-qPCR was used to detect the mRNA levels of α-SMA , Pdgfb , Col1α1 , Timp-1 , Ccl2 and Tnf-a , and Western blotting was performed to detect α-SMA protein expression in the liver tissues. In the cell experiment, the effect of arbutin treatment for 24 h on THP-1 and RAW264.7 cell migration and recruitment was examined using Transwell migration assay and DAPI staining; The changes in protein levels of Akt, p65, Smad3, p-Akt, p-p65, p-Smad3 and α-SMA in arbutintreated LX-2 cells were detected with Western blotting., Results: Arbutin treatment significantly lowered serum alanine aminotransferase and aspartate aminotransferase levels, alleviated liver tissue damage and collagen deposition, and reduced macrophage infiltration and α-SMA protein expression in the liver of the mouse models ( P < 0.05 or 0.001). Arbutin treatment also significantly reduced CCl 4 -induced elevation of a-SMA , Pdgfb , Col1α1 , Timp-1 , Ccl2 and Tnf-a mRNA levels in mice ( P < 0.05). In the cell experiment, arbutin treatment obviously inhibited migration and recruitment of THP-1 and RAW264.7 cells and lowered the phosphorylation levels of Akt, p65 and Smad3 and the protein expression level of α-SMA in LX-2 cells., Conclusion: Arbutin ameliorates liver inflammation and fibrosis in mice by inhibiting hepatic stellate cell activation via reducing macrophage recruitment and infiltration and suppressing activation of the Akt/NF-κB and Smad signaling pathways.

Background: Doxorubicin is an effective antineoplastic agent but has limited clinical application because of its cumulative toxicities, including cardiotoxicity. Cardiotoxicity causes lipid peroxidation, genetic impairment, oxidative stress, inhibition of autophagy, and disruption of calcium homeostasis. Doxorubicin-induced cardiotoxicity is frequently tried to be mitigated by phytochemicals, which are derived from plants and possess antioxidant, anti-inflammatory, and anti-apoptotic properties. Arbutin, a natural antioxidant found in the leaves of the bearberry plant, has numerous pharmacological benefits, including antioxidant, anti-bacterial, anti-hyperglycemic, anti-inflammatory, and anti-tumor activity., Methods and Results: The study involved male Wistar rats divided into three groups: a control group, a group treated with doxorubicin (20 mg/kg) to induce cardiac toxicity, a group treated with arbutin (100 mg/kg) daily for two weeks before doxorubicin administration. After treatment, plasma and heart tissue samples were collected for analysis. The samples were evaluated for oxidative stress parameters, including superoxide dismutase, malondialdehyde, and catalase, as well as for cardiac biomarkers, including CK, CK-MB, and LDH. The heart tissues were also analyzed using molecular (TNF-α, IL-1β and Caspase 3), histopathological and immunohistochemical methods (8-OHDG, 4 Hydroxynonenal, and dityrosine). The results showed that arbutin treatment was protective against doxorubicin-induced oxidative damage by increasing SOD and CAT activity and decreasing MDA level. Arbutin treatment was similarly able to reverse the inflammatory response caused by doxorubicin by reducing TNF-α and IL-1β levels and also reverse the apoptosis by decreasing caspase-3 levels. It was able to prevent doxorubicin-induced cardiac damage by reducing cardiac biomarkers CK, CK-MB and LDH levels. In addition to all these results, histopathological analyzes also show that arbutin may be beneficial against the damage caused by doxorubicin on heart tissue., Conclusion: The study suggests that arbutin has the potential to be used to mitigate doxorubicin-induced cardiotoxicity in cancer patients., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Arbutin (ARB) is a glycosylated hydroquinone with potent antioxidant effects. Although cisplatin (CP) is widely used in chemotherapy, its toxicity in healthy tissues, including ovotoxicity, is an insurmountable problem. This study aimed to evaluate the therapeutic effect of ARB against CP-related ovototoxicity by including nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in rats for the first time. Rats treated one dose of CP (5 mg/kg) on the first day, followed by ARB (5 and 10 mg/kg) for three days. Serum reproductive hormone levels were determined using ELISA kits. Oxidative stress (OS), inflammation, endoplasmic reticulum stress (ERS) and apoptosis markers in ovarian tissue were also determined colorimetrically. In addition, how CP affects Nrf2 pathway and the effect of ARB on this situation were also addressed. ARB treatment reduced the levels of markers of OS, inflammation, ERS and apoptosis in ovarian tissue of CP-stimulated animals. ARB regenerated the depleted antioxidant system by triggering Nrf2 pathway in the ovarian tissues of animals stimulated by CP. Histological findings also supported the therapeutic efficacy of ARB. The results indicate that ARB may have therapeutic effects against CP-induced reproductive toxicity with its Nrf2 activator potential. ARB should be tested in more extensive studies as a new generation chemopreventive candidate molecule., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier B.V. All rights reserved.)

Arbutin is a glycosylated hydroquinone with antioxidant and anti-hyperglycemia effects. However, its beneficial effects in type 2 diabetes (T2D) were not clarified. This study evaluated the effect of arbutin on hyperglycemia, dyslipidemia, insulin resistance, oxidative stress, and inflammatory response in T2D. Rats induced by high fat diet and streptozotocin were treated with arbutin (25 and 50 mg/kg) for 4 weeks. Diabetic rats exhibited glucose intolerance, elevated HbA1c%, reduced insulin, and high HOMA-IR. Liver glycogen and hexokinase activity were decreased in T2D rats while glucose-6-phosphatase (G6Pase), fructose-1,6- biphosphatase (FBPase), and glycogen phosphorylase were upregulated. Circulating and hepatic cholesterol and triglycerides and serum transaminases were elevated in T2D rats. Arbutin ameliorated hyperglycemia, dyslipidemia, insulin deficiency and resistance, and liver glycogen and alleviated the activity of carbohydrate-metabolizing enzymes. Both doses of arbutin decreased serum transaminases and resistin, and liver lipids, TNF-α, IL-6, malondialdehyde and nitric oxide, downregulated liver resistin and fatty acid synthase, and increased serum and liver adiponectin, and liver reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT). These effects were associated with the upregulation of hepatic PPARγ. Arbutin inhibited α-glucosidase in vitro and in silico investigations revealed the ability of arbutin to bind PPARγ, hexokinase, and α-glucosidase. In conclusion, arbutin effectively ameliorated glucose intolerance, insulin resistance, dyslipidemia, inflammation, and oxidative stress, and modulated carbohydrate-metabolizing enzymes, antioxidants, adipokines and PPARγ in T2D in rats., Competing Interests: Declaration of competing interest All authors declare no conflict of interests in relation to the manuscript., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Arbutin, a hydroquinone glucoside, has been detected in ca. 50 plant families, especially in the plants of the Asteraceae, Ericaceae, Proteaceae and Rosaceae families. It is one of the most widely used natural skin-whitening agents. In addition to its skin whitening property, arbutin possesses other therapeutically relevant biological properties, e.g., antioxidant, antimicrobial and anti-inflammatory, as well as anticancer potential. This review presents, for the first time, a comprehensive overview of the distribution of arbutin in the plant kingdom and critically appraises its therapeutic potential as an anticancer agent based on the literature published until the end of August 2022, accessed via several databases, e.g., Web of Science, Science Direct, Dictionary of Natural Products, PubMed and Google Scholar. The keywords used in the search were arbutin, cancer, anticancer, distribution and hydroquinone. Published outputs suggest that arbutin has potential anticancer properties against bladder, bone, brain, breast, cervix, colon, liver, prostate and skin cancers and a low level of acute or chronic toxicity.

Accumulating evidence has revealed the anti-inflammatory effects of arbutin against various diseases. However, the effects of arbutin are not clarified in ulcerative colitis. This study was intended to investigate the protective effects and mechanisms of arbutin on DSS-induced colitis. Hematoxylin eosin staining was performed to determine the pathological damage of intestinal tissue in mice. Inflammatory factors levels in intestinal tissue were detected by enzyme linked immunosorbent assay (ELISA) assay. TUNEL staining showed the apoptosis levels of cells. Intestinal permeability was analyzed using the application of Fluorescein isothiocyanate Dextran (FD) 4. The levels of Zona Occludens 1 (ZO-1), occluding and claudin-1, and the related proteins in MAPK/ELK1 pathway were analyzed by Western blot. DSS promotes pathological injury, the levels of pro-inflammatory factors containing tumor necrosis factor alpha (TNF-α), Interleukin- 6 (IL-6) and myeloperoxidase (MPO), and cell apoptosis in the mouse colon. Additionally, intestinal permeability was increased and the levels of tight function-related proteins were increased following DSS induction. Its effects could be greatly improved by arbutin. Arbutin exerted effects by eliciting anti-inflammatory effects and maintaining normal intestinal mucosal barrier function, the action mechanism of which could be associated with MAPK/ELK1 pathway.

Urinary tract infections (UTIs) represent a health problem of the first magnitude since they affect large segments of the population, cause increased mortality and comorbidity, and have a high incidence of relapse. Therefore, UTIs cause a major socioeconomic concern. Current antibiotic treatments have various limitations such as the appearance of resistance to antibiotics, nephrotoxicity, and side effects such as gastrointestinal problems including microbiota alterations that contribute to increasing antibiotic resistance. In this context, Itxasol© has emerged, approved as an adjuvant for the treatment of UTIs. Designed with biomimetic principles, it is composed of arbutin, umbelliferon, and N-acetyl cysteine. In this work, we review the activities of these three compounds concerning the changes they produce in the expression of bacterial genes and those related to inflammation as well as assess how they are capable of affecting the DNA of bacteria and fungi.

Genito-urinary tract infections have a high incidence in the general population, being more prevalent among women than men. These diseases are usually treated with antibiotics, but very frequently, they are recurrent and lead to the creation of resistance and are associated with increased morbidity and mortality. For this reason, it is necessary to develop new compounds for their treatment. In this work, our objective is to review the characteristics of the compounds of a new formulation called Itxasol© that is prescribed as an adjuvant for the treatment of UTIs and composed of β-arbutin, umbelliferon and n-acetyl cysteine. This formulation, based on biomimetic principles, makes Itxasol© a broad-spectrum antibiotic with bactericidal, bacteriostatic and antifungal properties that is capable of destroying the biofilm and stopping its formation. It also acts as an anti-inflammatory agent, without the adverse effects associated with the recurrent use of antibiotics that leads to renal nephrotoxicity and other side effects. All these characteristics make Itxasol© an ideal candidate for the treatment of UTIs since it behaves like an antibiotic and with better characteristics than other adjuvants, such as D-mannose and cranberry extracts.

Chronic long-term glucocorticoid use causes osteoporosis partly by interrupting osteoblast homeostasis and exacerbating bone loss. Arbutin, a natural hydroquinone glycoside, has been reported to have biological activities related to the differentiation of osteoblasts and osteoclasts. However, the role and underlying mechanism of arbutin in glucocorticoid-induced osteoporosis are elusive. In this study, we demonstrated that arbutin administration ameliorated osteoporotic disorders in glucocorticoid dexamethasone (Dex)-induced mouse model, including attenuating the loss of bone mass and trabecular microstructure, promoting bone formation, suppressing bone resorption, and activating autophagy in bone tissues. Furthermore, Dex-stimulated mouse osteoblastic MC3T3-E1 cells were treated with arbutin. Arbutin treatment rescued Dex-induced repression of osteoblast differentiation and mineralization, the downregulation of osteogenic gene expression, reduced autophagic marker expression, and decreased autophagic puncta formation. The application of autophagy inhibitor 3-MA decreased autophagy, differentiation, and mineralization of MC3T3-E1 cells triggered by arbutin. Taken together, our findings suggest that arbutin treatment fends off glucocorticoid-induced osteoporosis, partly through promoting differentiation and mineralization of osteoblasts by autophagy activation.

The abnormal dietary life style leads to hyperlipidemia and insulin resistance with ectopic lipid accumulation and elevated levels of hepatic glucose development which are the underlying pathological characteristics of fatty liver diseases. The pharmacological inhibition of fatty acid synthase of de novo lipogenesis may regulate the dysfunctional lipid biotransformation and reverse the pathological state of diabetic liver injury. The three pharmacological interventions (PTS; Pterostilbene, ARB; Arbutin, PUR; Purpurin) were administered to manage the condition of diabetic liver injury against the high fat diet (HFD) + Streptozotocin (STZ) 30 mg/kg b.wt. rodent animal model to observe the effect of abnormal fatty acid synthesis. The qRT-PCR was used to evaluate the fatty acid synthase (FASN) expression which is independently allied with diabetes associated fatty liver disorders. To determine the therapeutic potential of three selected drugs, the biochemical parameters and histopathological considerations were utilized. Three subsequent dosage of PTS, ARB and PUR administered (i.e., 30,60 & 120 mg/kg/p.o.) for five weeks significantly alter the serum parameters, oxidative burden in HFD-STZ which, in turn, resulted in diabetic liver injury. It was also revealed that increased mRNA expression of fatty acid synthase (FASN), which is known to promote abnormal fatty acid synthesis through different molecular signaling pathways, was associated with the development of diabetes associated liver injury, this expression was observed to be significantly suppressed by PTS, ARB and PUR treatment. Moreover, the studies of histopathology showed that there was substantial structural improvement after PTS, ARB and PUR treatment. All three selected drugs have been shown to be effective for Diabetic liver injury (DLI) care but PTS shows impressive results compared to other selected drugs., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Arbutin, a glycoside extracted from the plant Arctostaphylos uva-ursi, has been previously reported to possess antioxidant, anti-inflammatory and anticancer effects. Here, we investigated whether arbutin affects the proliferation of the cells of the osteosarcoma (OS) cell lines MG-63 and SW1353. Arbutin suppressed OS cell viability in a dose- and time-dependent manner, as shown by Cell Counting Kit-8 assay. Furthermore, arbutin exposure decreased the protein levels of MTHFD1L, CCND1 and phosphorylated-protein kinase B (AKT)/phosphorylated-mammalian target of rapamycin (mTOR). Potential upstream miRNAs of MTHFD1L were predicted using TargetScan, PICTAR5, miRanda and miRWalk. We performed luciferase activity assays to show that miR-338-3p directly targets and negatively regulates the expression of MTHFD1L. Knockdown of miR-338-3p promoted cell invasion, migration and proliferation in arbutin-treated OS cells via MTHFD1L. In summary, our data suggest that arbutin inhibits OS cell proliferation, migration and invasion via miR-338-3p/MTHFD1L and by inactivating the AKT/mTOR pathway., (© 2020 The Authors. FEBS Open Bio published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Neuroinflammation, glial activation, and oxidative injury are the main pathological mechanisms of demyelination in multiple sclerosis (MS). Arbutin, a natural polyphenol compound, possesses antioxidant, anti-inflammatory, and neuroprotective properties whose therapeutic potential has not been studied in the experimental animal models of MS. In the present study, the efficiency of arbutin on lysolecthin (LPC)-induced local demyelination model was investigated. Demyelination was induced by micro-injection of 2 μl LPC (1%) into the rat optic chiasm and the treated group received daily injection of arbutin (50 mg/kg, i.p) during 2 weeks. Visual-evoked potential (VEP) recordings were used to functionally assess the visual pathway. Gene expression analysis was done to evaluate the arbutin effect on the inflammatory, stress oxidative-related mediators, and myelin markers. The myelin-specific staining was performed to assess demyelination and GFAP staining as an astrocyte marker. We found that arbutin significantly reduced P1-latency of VEPs waves and demyelination at 7 and 14 days post-demyelination. Arbutin decreased inflammatory cytokines (IL-1B, IL-17, TNF-α) and iNOS mRNA expression level. In addition, the expression level of anti-inflammatory cytokine (IL-10) and antioxidant mediators (Nrf-2 and HO-1) was enhanced by arbutin treatment. Arbutin increased MBP and Olig2 expression levels in demyelination context. Finally, arbutin attenuated GFAP as an astrocyte marker. Finally, this study demonstrates that arbutin improves functional recovery and myelin repair in the demyelinated optic chiasm through attenuation of inflammation, astrocyte activation, and oxidative stress. These findings might open new promising avenues for treating demyelinating disorders such as multiple sclerosis. Graphical abstract.

Parkinson's disease (PD), the most common neurodegenerative movement disorder, is characterized by the progressive loss of dopaminergic neurons in substantia nigra. The underlying mechanisms of PD pathogenesis have not been fully illustrated and currently PD remains incurable. Accumulating evidences suggest that mitochondrial dysfunction plays pivotal role in the dopaminergic neuronal death. Therefore, discovery of novel and safe agent for rescuing mitochondrial dysfunction would benefit PD treatment. Here we demonstrated for the first time that α-Arbutin (Arb), a natural polyphenol extracted from Ericaceae species, displayed significant protective effect on the rotenone (Rot)-induced mitochondrial dysfunction and apoptosis of human neuroblastoma cell (SH-SY5Y). We further found that the neuroprotective effect of Arb was associated with ameliorating oxidative stress, stabilizing of mitochondrial membrane potential, and enhancing adenosine triphosphate production. To investigate the underlying mechanism, we checked the AMP-activated protein kinase and autophagy pathway and we found that both were involved in the neuroprotection of Arb. Moreover, we explored the protective effect of Arb in drosophila PD model and found that Arb rescued parkin deficiency-induced motor function disability and mitochondrial abnormality of drosophila. Taken together, our study demonstrated that Arb got excellent neuroprotective effect on PD models both in vitro and in vivo and Arb might serve as a potent therapeutic agent for the treatment of PD.

Kidney stone disease involves the aggregation of stone-forming salts consequent to solute supersaturation in urine. The development of novel therapeutic agents for this predominantly metabolic and biochemical disorder have been hampered by the lack of a practical pre-clinical model amenable to drug screening. Here, Drosophila melanogaster , an emerging model for kidney stone disease research, was adapted as a high-throughput functional drug screening platform independent of the multifactorial nature of mammalian nephrolithiasis. Through functional screening, the therapeutic potential of a novel compound commonly known as arbutin that specifically binds to oxalate, a key component of kidney calculi, was identified. Through isothermal titration calorimetry, high-performance liquid chromatography and atomic force microscopy, arbutin was determined to interact with calcium and oxalate in both free and bound states, disrupting crystal lattice structure, growth and crystallization. When used to treat patient urine samples, arbutin significantly abrogated calculus formation in vivo and outperformed potassium citrate in low pH urine conditions, owing to its oxalate-centric mode of action. The discovery of this novel antilithogenic compound via D. melanogaster , independent of a mammalian model, brings greater recognition to this platform, for which metabolic features are primary outcomes, underscoring the power of D. melanogaster as a high-throughput drug screening platform in similar disorders. This is the first description of the use of D. melanogaster as the model system for a high-throughput chemical library screen. This article has an associated First Person interview with the first authors of the paper., Competing Interests: Competing interestsThe authors declare no competing or financial interests., (© 2018. Published by The Company of Biologists Ltd.)

Chinese yam (CY), used as both a traditional Chinese medicine and a nutritious food, is an excellent candidate for treating septic cardiomyopathy (SCM). Adenosine, arbutin and allantoin are the major active components in the aqueous extract of CY. The aim of the present study was to interpret the roles of CY, adenosine, arbutin and allantoin in SCM treatment. Firstly, significant physiological indexes were examined to assess the model and treatment effects of CY, adenosine, arbutin and allantoin. Then, a metabolomic approach was utilized to reveal the metabolic disorders in SCM concerning the intervention of CY/adenosine/arbutin/allantoin. The integrated results demonstrated that adenosine, arbutin and allantoin are responsible for the efficacy of CY on SCM treatment by regulating amino acid, arachidonic acid, sphingolipid, glycerophospholipid and glycol metabolism. Moreover, adenosine and/or arbutin could be used as a substitute for CY in treating SCM, and allantoin efficacy was slightly weaker. This integrated metabolomic approach performed excellently in understanding the herbal function and the roles of its components.

As Dermatologists caring for patients with hyperpigmentation problems, we are always looking for more alternative therapies. Hydroquinone (HQ) is still the standard of care. However, traditional depigmenting agents such as HQ and corticosteroids, although highly effective, can raise safety concerns including exogenous ochronosis, atrophy, carcinogenesis and local and systemic untoward effects with long term use. Therefore, we need to investigate non-prescription natural alternatives. This manuscript presents many of the natural ingredients found in cosmeceuticals for the treatment of hyperpigmentation and their mechanisms of action. It will also describe the melanocyte activation pathways and how each of these ingredients interferes with it.

Background: Arbutin is one of the most effective lightening substances. Serratula quinquefolia is a new source of its β-anomer. The HPLC method showed that the solid content of this compound in the dried plant raw material accounts for 6.86%. The leaves of Serratula quinquefolia do not contain hydroquinone., Aims: To assess the efficacy of the aqueous extract from' leaf of five-leaf serratula as a skin-lightening agent., Patients/methods: We did a randomized, placebo-controlled, double-blind trial. The study involved 102 women aged 26-55, with two kinds of hyperpigmentary diseases: melasma and lentigo solaris. Patients were randomly assigned to one of the treatment groups: a study group (N = 54) or a control group (N = 48). The study group applied the cream with the aqueous extract from leaf of five-leaf serratula containing 2.51% of arbutin. The cream was applied twice a day on the discolored side for 8 weeks., Results: The experimental data showed that the cream with the extract causes decreased level of melanin in the skin pigmentation spot. Clinical effect in the form of lightening and evening skin tone on the discolored side was observed in 75.86% of the female patients with melasma and 56.00 % of the female patients with lentigo solaris., Conclusions: The cream with the aqueous extract from leaf of five-leaf serratula proved to be an effective and safe preparation for lightening skin discolorations (66.67 % of the female patients in the study group)., (© 2015 Wiley Periodicals, Inc.)

Turnera diffusa Willd, commonly known as Damiana, is employed in traditional medicine as a stimulant, aphrodisiac, and diuretic. Its leaves and stems are used for flavoring and infusion. Damiana is considered to be safe for medicinal use by the FDA. Pharmacological studies have established the hypoglycemic, antiaromatase, prosexual, estrogenic, antibacterial, and antioxidant activity of T. diffusa. The aim of the present study was to evaluate the possible cytotoxic effect of extracts and organic fractions of this plant on five tumor cell lines (SiHa, C-33, Hep G2, MDA-MB-231, and T-47D) and normal human fibroblasts. The results show that the methanolic extract (TdM) displayed greater activity on MDA-MB-231 breast cancer cells (with an IC50 of 30.67 μg/mL) than on the other cancer cell lines. Four organic fractions of this extract exhibited activity on this cancer cell line. In the most active fraction (F4), two active compounds were isolated, arbutin (1) and apigenin (2). This is the first report of a cytotoxic effect by T. diffusa on cancer cells. The IC50 values suggest that the methanolic extract of T. diffusa has potential as an anticancer therapy.

Background: Bacterial prostatitis (BP) is a common condition accounting responsible for about 5-10% of all prostatitis cases; chronic bacterial prostatitis (CBP) classified as type II, are less common but is a condition that significantly hampers the quality of life, (QoL) because not only is it a physical condition but also a psychological distress. Commonly patients are treated with antibiotics alone, and in particular fluoroquinolones are suggested by the European Urology guidelines. This approach, although recommended, may not be enough. Thus, a multimodal approach to the prolonged antibiotic therapy may be helpful., Methods: 210 patients affected by chronic bacterial prostatitis were enrolled in the study. All patients were positive to Meares-Stamey test and symptoms duration was > 3 months. The purpose of the study was to evaluate the efficacy of a long lasting therapy with a fluoroquinolone in association with a nutraceutical supplement (prulifloxacin 600 mg for 21 days and an association of Serenoa repens 320 mg, Lactobacillus Sporogens 200 mg, Arbutin 100 mg for 30 days). Patients were randomized in two groups (A and B) receiving respectively antibiotic alone and an association of antibiotic plus supplement., Results: Biological recurrence at 2 months in Group A was observed in 21 patients (27.6%) and in Group B in 6 patients (7.8%). Uropathogens found at the first follow-up were for the majority Gram - (E. coli and Enterobacter spp.). A statistically significant difference was found at the time of the follow-up between Group A and B in the NIH-CPSI questionnaire score, symptoms evidence and serum PSA., Conclusions: Broad band, short-lasting antibiotic therapy in association with a nutritional supplement (serenoa repens, lactobacillus sporogens and arbutin) show better control and recurrence rate on patients affected by chronic bacterial prostatitits in comparison with antibiotic treatment alone., Trial Registration: NCT02130713. Date of trial Registration: 30/04/2014.

In the present study, we investigated the potential protective effect of selected natural substances in a rat model of heart and mesenteric ischemia-reperfusion (I/R). Experiments were performed on isolated Langendorff-perfused rat hearts, subjected to 30-min global ischemia, followed by 30-min reperfusion. Arbutin, curcumin, rosmarinic acid and extract of Mentha x villosa were applied in the concentration of 1 × 10⁻⁵ mol/l 10 min before the onset of ischemia and during reperfusion, through the perfusion medium. Mesenteric ischemia was induced by clamping the superior mesenteric artery (SMA) for 60 min, subsequent reperfusion lasted 30 min. Production of reactive oxygen species (ROS) by SMA ex vivo was determined by luminol-enhanced chemiluminiscence (CL). The effect of the substances was tested after their incubation with tissue. Curcumin and extract of Mentha x villosa were found to be the most effective in reducing reperfusion-induced dysrhythmias--ventricular tachycardia and fibrillation. This effect was accompanied by bradycardic effect. The mesenteric I/R induced an increase in CL in vascular tissue which was dampened by substances tested. All substances tested were found to have antioxidant properties, as demonstrated by a reduction in ROS production in mesenteric vessels. This effect was confirmed in curcumin and extract of Mentha x villosa which reduced reperfusion dyshythmias., (Copyright © 2012 John Wiley & Sons, Ltd.)

Arbutin (hydroquinone β-D-glucoside) is a compound of plant origin possessing valuable therapeutic (urinary tract disinfection) and cosmetic (skin whitening) properties, which can be obtained from in vitro cultures of plants belonging to different taxa via biotransformation of exogenously supplemented hydroquinone. Agitating cultures of Aronia melanocarpa were maintained on the Murashige and Skoog medium containing growth regulators: the cytokinin - BAP (6-benzylaminopurine), 2 mg/l and the auxin NAA (α-naphthaleneacetic acid), 2 mg/l. The biomass was cultured for 2 weeks and then hydroquinone was supplemented at the following doses: 96, 144, 192, 288 and 384 mg/l either undivided or divided into two or three portions added at 24-hour intervals. The content of the reaction product - arbutin, was determined using an HPLC method in methanolic extracts from biomass and lyophilized medium samples collected 24 hours after the addition of the last precursor dose. The total amounts of arbutin were very diverse, from 2.71 to 8.27 g/100g d.w. The production of arbutin rose with increasing hydroquinone concentration. The maximum content of the product was observed after hydroquinone addition at 384 mg/l divided into two portions. Biotransformation efficiency also varied widely, ranging from 37.04% do 73.80%. The identity of the product - arbutin, after its isolation and purification was confirmed by spectral analysis ((1)H-NMR spectrum). The maximum amount of arbutin obtained was higher than that required by the latest 9(th) Edition of the Polish Pharmacopoeia and by the newest 8th Edithion of European Pharmacopoeia for Uvae ursi folium (7.0 g/100g d.w.), and is interesting from practical point of view.

Background: Hyperpigmentary disorders like melasma, actinic and senile lentigines are a major cosmetic concern. Therefore, many topical products are available, containing various active ingredients aiming to reduce melanin production and distribution. The most prominent target for inhibitors of hyperpigmentation is tyrosinase, the key regulator of melanin production. Many inhibitors of tyrosinase are described in the literature; however, most of them lack clinical efficacy., Methods: We were interested in evaluating the inhibition of skin pigmentation by well-known compounds with skin-whitening activity like hydroquinone, arbutin, kojic acid and 4-n-butylresorcinol. We compared the inhibition of human tyrosinase activity in a biochemical assay as well as inhibition of melanin production in MelanoDerm skin model culture. For some compounds, the in vivo efficacy was tested in clinical studies., Results: Arbutin and hydroquinone only weakly inhibit human tyrosinase with a half maximal inhibitory concentration (IC(50)) in the millimolar range. Kojic acid is 10 times more potent with an IC(50) of approximately 500 μmol/L. However, by far the most potent inhibitor of human tyrosinase is 4-n-butylresorcinol with an IC(50) of 21 μmol/L. In artificial skin models, arbutin was least active with an IC(50) for inhibition of melanin production > 5000 μmol/L. Kojic acid inhibited with an IC(50) > 400 μmol/L. Interestingly, hydroquinone inhibited melanin production in MelanoDerms with an IC(50) below 40 μmol/L, probably due to a mechanism different from tyrosinase inhibition. Again, 4-n-butylresorcinol was the most potent inhibitor with an IC(50) of 13.5 μmol/L. In vivo efficacy of 4-n-butyl-resorcinol was confirmed in clinical studies. Subjects with age spots on the forearm treated twice daily two age spots with a formula containing 4-n-butylresorcinol and two control age spots with the corresponding vehicle. Within 8 weeks, 4-n-butylresorcinol reduced visibly the appearance of age spots, while the control spots showed no improvement. A second study showed that 4-butylresorcinol was more effective than 4-hexylresorcinol and 4-phenylethylresorcinol., Conclusion: The present in vitro and in vivo data prove the high inhibitory capacity of 4-n-butylresorcinol on human tyrosinase activity, exceeding by far the potency of hydroquinone, arbutin and kojic acid. The resulting clinical improvement of skin hyperpigmentations reveals 4-n-butylresorcinol as a very valuable active compound for the management of pigmentation disorders., (© 2012 The Authors. Journal of the European Academy of Dermatology and Venereology © 2012 European Academy of Dermatology and Venereology.)

Hyperpigmentation has traditionally been a relatively difficult condition to treat, especially in darker racial ethnic groups. Multiple topical agents available act upon different steps of the pigmentation pathway. We review these topical agents, their mechanisms of action, and their effectiveness as monotherapy and in combination with other compounds. Ultimately, combination therapy is the most efficacious when considering overall depigmentation as well as treatment time required to achieve clinical improvement., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Facial hyperpigmented disorders are a common complaint in the adult population of all races. First-line topical treatments are usually hydroquinone or topical retinoids, which can cause irritant reactions. The need for better tolerated, yet effective, skin lightening agents that could be utilized by a wider population has led to the investigation of several potential botanical/natural compounds. There are currently many topical cosmetic formulations claiming skin depigmenting effects. A few of the ingredients (e.g. soy) are supported not only by in vitro results but also by a body of controlled clinical efficacy studies; other ingredients, instead, are backed mostly by in vitro data and a few small uncontrolled clinical studies. In this review, we describe the most common natural ingredients used for skin depigmentation and their major published studies: soy, licorice extracts, kojic acid, arbutin, niacinamide, N-acetylglucosamine, COFFEEBERRY(™) and green tea., (© 2011 Johnson & Johnson Consumer Companies, Inc. Journal of the European Academy of Dermatology and Venereology © 2011 European Academy of Dermatology and Venereology.)

Objective: To evaluate the effectiveness of a Q-switched Nd:YAG laser (MedLite C6; HOYA ConBio, Fremont, CA, USA) and 7% alpha arbutin solution (Skin Advance Laboratory, Japan) in the treatment of melasma., Methods: This was a prospective study of 35 refractory melasma cases treated with 10 weekly laser sessions, two monthly follow-up treatments and topical 7% alpha arbutin solution. Clinical photographs and severity grading on a 5-point scale were carried out by an independent observer at each visit., Results: At 6 months, 30% of study subjects received results in the excellent clearance category (> 81% reduction of melasma) and 36.7% received good (51-80% reduction) clearance. Mild and transient side effects included discomfort during treatment, erythema, whitening of fine hair and urticaria. Three cases of mottling hypo-pigmentation (8.57%) and two cases of recurrence of melasma (5.71%) were recorded., Conclusion: Combination therapy with the MedLite C6 and 7% alpha arbutin solution is an effective and well-tolerated treatment for refractory melasma.

Objective: Allogeneic cartilage is used to repair damaged areas of articular cartilage, requiring the presence of living chondrocytes. So far, no preservation method can effectively meet that purpose. Identification of more effective cryoprotective agents (CPAs) can contribute to this goal. The aim of this study was to determine whether the glycosylated hydroquinone, arbutin, alone or in combination with low concentrations of other CPAs, has cryoprotective properties towards human articular cartilage., Material and Methods: Human tibial plateaus were procured from multi-organ donors, with the approval of the Ethics Committee of the University Hospital of Coimbra. The tibial plateaus were treated with or without arbutin (50 or 100mM), alone or in combination with various concentrations of dimethyl sulfoxide (DMSO) and glycerol, for 0.5-1.5h/37 degrees C, then frozen at -20 degrees C and 24h later transferred to a biofreezer at -80 degrees C. Two to 3 months later, thawing was achieved by immersion in cell culture medium at 37 degrees C/1h. Chondrocyte viability was assessed before and after freeze-thawing using a colorimetric assay based on the cell's metabolic activity and fluorescent dyes to evaluate cell membrane integrity., Results: Before freezing, chondrocyte metabolic activity was identical in all the conditions tested. After freeze-thawing, the highest activity, corresponding to 34.2+/-2.1% of that in the Fresh Control, was achieved in tibial plateaus incubated in 50mM arbutin for 1h whereas in those left untreated it was 11.1+/-4.7. Addition of DMSO and glycerol to arbutin did not increase chondrocyte viability any further. Fluorescence microscopy confirmed these results and showed that living chondrocytes were mainly restricted to the superficial cartilage layers., Conclusion: Arbutin seems to be an effective cryoprotective agent for osteochondral allografts with potential benefits over DMSO and glycerol.

Epidermal melanocytes synthesize melanin pigments and transfer them to keratinocytes, which is responsible for skin pigmentation. However, abnormal accumulation of melanin pigments causes hyperpigmentation disorders, which are substantially improved with treatment of tyrosinase inhibitor. In our ongoing study, Torilis japonica DC. (Umbelliferae) was found to inhibit melanin production. A goal of this study is to elucidate the hypopigmenting principle of T. japonica. A sesquiterpene structure of torilin was isolated from the plant extracts via bioassay-guided phytochemical analysis. Torilin dose-dependently inhibited melanin production, with an IC(50) value of 25 microM, in alpha-melanocyte stimulating hormone (alpha-MSH)-activated B16 melanoma cells. Arbutin, a positive control of skin whitener, also inhibited alpha-MSH-induced melanin production with an IC(50) value of 170 microM. As to the mode of action, torilin downregulated alpha-MSH-induced protein levels of tyrosinase without directly inhibiting catalytic activity of the enzyme. Taken together, this study shows that torilin contributes to the hypopigmenting principle of T. japonica, and suggests its pharmacological potential in melanin-associated hyperpigmentation disorders., (Georg Thieme Verlag KG Stuttgart, New York.)

The aim of this study was to compare the effectiveness of gel formulations containing arbutin, synthetic ellagic acid and plant extracts that contain ellagic acid, on patients with melasma. Thirty patients who applied to Ege University Medical Faculty, Department of Dermatology, were included in the study. A signed consent was obtained from each patient prior to study. Patients whose type of melasma was determined via Wood's lamp were randomized to groups of arbutin, synthetic ellagic acid and plant extract containing natural ellagic acid. The pigment density of patients was evaluated via Mexameter before and after the treatment. The approval of the Institutional Ethics Committee of Ege University was obtained before the study. Wilcoxon and Kruskal-Wallis tests were used in the statistical analysis. Nine of 10 patients, for whom synthetic ellagic acid was started, completed the study. A decrease in the level of melanin was determined in eight of these nine patients (P = 0.038). A significant decrease in the level of melanin was also determined in all 10 patients who used plant extract containing ellagic acid (P = 0.05). A significant response was obtained from all of 10 patients who used arbutin. The difference between pre- and post-treatment levels of melanin was statistically significant (P = 0.05). Formulations prepared with plant extracts containing ellagic acid was found effective on melasma, similar to the formulations containing synthetic ellagic acid and arbutin. This material that is not yet being used widespread commercially on melasma could be an effective alternative for treatment of melasma.

Skin hyperpigmentation is caused by the overproduction of melanin pigment, which is synthesized by the action of tyrosinase. We recently reported that aloesin inhibits tyrosinase activity. The present study was undertaken to test the inhibitory effect of aloesin on pigmentation in human skin after UV radiation. Experimental subjects were UV-irradiated (210 mJ) on the inner forearm. UV-irradiated regions were assigned to four groups: vehicle control, aloesin treated, arbutin treated, and aloesin and arbutin treated. Aloesin and/or arbutin were administered four times a day for 15 days. Aloesin treatment suppressed pigmentation by 34%, arbutin by 43.5%, and the cotreatment by 63.3% compared with the control (n = 15; P < 0.05). Moreover, aloesin treatment showed pigmentation suppression in a dose-dependent manner (n = 7; P < 0.05). These results raise the possibility that aloesin may be used as an agent that inhibits melanin formation induced by UV radiation.

A study was carried out to examine the combined effect of arbutin isolated from the leaves of Arctostaphylos uva-ursi (L.) Spreng. (Bearberry leaf) and indomethacin on Type IV allergic reaction-induced immuno-inflammation, carrageenin-induced edema and adjuvant-induced arthritis. Contact dermatitis caused by picryl chloride (PC-CD) and sheep red cell delayed type hypersensitivity (SRBC-DTH) was not inhibited by the oral application of arbutin at 2 divided doses immediately before and 16 h after the application, but arbutin at dose of 50 mg/kg 24 h after the application rapidly decreased the swelling of PC-CD. Arbutin (p.o.) plus indomethacin (s.c.) showed inhibitory effect on the swelling of PC-CD and SRBC-DTH stronger than that of indomethacin alone. When arbutin (p.o.) and indomethacin (s.c.) in a given portion were simultaneously administered, the inhibitory effect was more potent than that of indomethacin alone in both carrageenin-induced edema and adjuvant-induced arthritis. These results suggest that arbutin may increase the inhibitory action of indomethacin on PC-CD, SRBC-DTH, carrageenin-induced edema and adjuvant-induced arthritis, but further investigations are required to understand the mechanism involved.

A study was carried out to examine the combined effect of arbutin isolated from the leaves of Arctostaphylos uva-ursi (L.) Spreng. (Bearberry leaf) and prednisolone or dexamethazone on Type IV allergic reaction-induced immuno-inflammation. Contact dermatitis caused by picryl chloride (PC-CD) and sheep red cell delayed type hypersensitivity (SRBC-DTH) in mice was not inhibited by the oral application of arbutin at 2 divided doses immediately before and 16 h after the application, but arbutin at doses of 10, 50 mg/kg 24 h after the application speedily decreased the swelling of PC-CD and SRBC-DTH. Arbutin plus prednisolone or dexamethazone showed the inhibitory effect on the swelling of PC-CD and SRBC-DTH stronger than that of prednisolone or dexamethazone alone. Prednisolone and dexamethazone decreased the weight of thymus and spleen in intact, PC-CD and SRBC-DTH mice, but arbutin did not show these effects. These results suggest that arbutin may increase the inhibitory action of prednisolone and dexamethazone on PC-CD and SRBC-DTH, but further investigations are required to understand the mechanism involved.

The effect of 50% methanolic extract (U-ext) from Bearberry leaf on immuno-inflammation was studied by contact dermatitis caused by picryl chloride (PC-CD) in mice. The combined effect of U-ext and prednisolone was also investigated by using similar experimental model. When given orally twice immediately before and 16 h after the application of PC-CD, U-ext did not show an inhibitory effect on the swelling induced by PC-CD while it exhibited a significant therapeutic effect at a dose of 100 mg/kg or more once 24 h after the application. When U-ext (p.o.) and prednisolone (s.c.) in a given portion were simultaneously administered, the inhibitory effect was more potent than that of prednisolone alone in both administration immediately before and 16 h after or once 24 h after the application. Arbutin isolated from U-ext also increased the inhibitory effect of prednisolone similarly to that of U-ext. These results suggest that Bearberry leaf possesses a therapeutic effect against immuno-inflammation induced by PC-CD and also increases the inhibitory effect of prednisolone, and its active principle may be arbutin.