The potential effect of Polypodium leucotomos extract on ultraviolet- and visible light-induced photoaging.

Photoaging induced by both ultraviolet and visible light has been shown to lead to increased inflammation and dysregulation of the extracellular matrix. Standardized extract of the Polypodium leucotomos fern, PLE, possesses anti-inflammatory and antioxidant properties, and has been shown to potentially mitigate photoaging through various mechanisms. This comprehensive review presents the data available on the effects of P. leucotomos extract on UV and VL-induced photoaging in vitro as well as in vivo in murine and human models.

Isolation and structural determination of flavan-3-ol derivatives from the Polypodium vulgare L. rhizomes water extract.

Polypodium vulgare L. (Polypodiaceae) is a fern used in traditional Polish medicine as an expectorant to treat cough and pertussis. Additionally, it was used as a diuretic in renal diseases, especially in chronic nephritis and pyelonephritis. In our study, a water extract was prepared from the rhizome of common polypody and subsequently fractionated on a resin column. As a result, the mixture of flavan-3-ol derivatives was obtained after the column elution with 60% methanol. Further purification by various chromatographic techniques led us to the isolation of (+)-afzelechin (1), a new previously not reported (+)-afzelechin-7-O-α-l-arabinofuranoside (2), and three other monomer flavan-3-ol glycosides: (+)-afzelechin-7-O-ß-d-apiofuranoside (3), (+)-catechin-7-O-α-l-arabinofuranoside (4) and (+)-catechin-7-O-ß-d-apiofuranoside (5). Structures of the compounds were established by HR-ESI-MS, 1D and 2D NMR spectroscopy. The HSQC and HMBC NMR techniques were used in the structure elucidation of the position of sugar attachment.

Discovery of polypodiside as a Keap1-dependent Nrf2 activator attenuating oxidative stress and accumulation of extracellular matrix in glomerular mesangial cells under high glucose.

Diabetic nephropathy (DN) is a severe microvascular complication of diabetes mellitus. High glucose has resulted in oxidative stress and following renal fibrosis as the crucial nodes of this disease. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor regulating transcription of many antioxidant genes and suppressing synthesis of extracellular matrix. To discover Nrf2 activators targeting DN, we have evaluated polypodiside using cell-based assays. The results showed polypodiside inhibited the high glucose-induced self-limited proliferation of glomerular meangial cells. Activation of Nrf2 and enhanced transcription to antioxidant response elements were observed in the presence of polypodiside. Oxidative stress and accumulation of extracellular matrix induced by high glucose in glomerular meangial cells have been ameliorated by polypodiside. Further investigations revealed the effects of polypodiside on glomerular meangial cells were associated with activation of Nrf2. Co-immunoprecipitation of Nrf2 disclosed polypodiside disrupted the Kelch-like ECH-associated protein-1 (Keap1)-Nrf2 interaction. Molecular docking elucidated polypodiside could enter the Nrf2 binding cavity of Keap1 via interacting with the residues encompassing that cavity. These findings indicate polypodiside is a Keap1-dependent Nrf2 activator affording the catabatic effects against oxidative stress and accumulation of extracellular matrix in glomerular meangial cells under high glucose.

The role of the aqueous extract Polypodium leucotomos in photoprotection.

Solar radiation in the ultraviolet (UV), visible (VIS), and infrared (IR) ranges produces different biological effects in humans. Most of these, particularly those derived from ultraviolet radiation (UVR) are harmful to the skin, and include cutaneous aging and increased risk of cutaneous diseases, particularly skin cancer. Pharmacological photoprotection is mostly topical, but it can also be systemic. Oral photoprotectives constitute a new generation of drugs to combat the deleterious effects of solar radiation. Among these, an extract of Polypodium leucotomos (PL/Fernblock®, IFC Group, Spain) contains a high content of phenolic compounds that endow it with antioxidant activity. PL can administered orally or topically and is completely safe. PL complements and enhances endogenous antioxidant systems by neutralizing superoxide anions, hydroxyl radicals, and lipoperoxides. In addition to its antioxidant activity, PL also improves DNA repair and modulates immune and inflammatory responses. These activities are likely due to its ability to inhibit the generation and release of reactive oxygen species (ROS) by UVR, VIS, and IR radiation. PL also prevents direct DNA damage by accelerating the removal of induced photoproducts and decreasing UV-induced mutations. Oral PL increases the expression of active p53, decreases cell proliferation, and inhibits UV-induced COX-2 enzyme levels. PL has been used to treat skin diseases such as photodermatoses and pigmentary disorders and recently as a complement of photodynamic phototherapy in actinic keratoses. The photoprotective capability of PL has been proven in a multitude of in vitro and in vivo studies, which include animal models and clinical trials with human subjects. Based on this evidence, PL is a new generation photoprotector with antioxidant and anti-inflammatory properties that also protects DNA integrity and enhances the immune response.

Oral Polypodium Leucotomos Extract and Its Impact on Visible Light-Induced Pigmentation in Human Subjects

BACKGROUND: Visible light (VL) has multiple effects on the skin that currently available sunscreens do not protect against. Polypodium leucotomos extract (PLE) has properties that may offer protection against VL. OBJECTIVES: To determine the effectiveness of PLE in preventing VL-induced effects. METHODS: Twenty-two subjects with Fitzpatrick skin phototype IV-VI were enrolled. On day 0, subjects were irradiated with VL. Clinical Investigator's Global Assessment (IGA) scoring and spectroscopic evaluations were performed immediately, 24 hours, and 7 days after irradiation. Subjects then received a 28-day supply of PLE (480 mg daily). Irradiation and evaluation were repeated. Three 4-mm punch biopsies were obtained for immunohistochemistry analysis: one from normal unirradiated skin and the other two twenty-four hours after irradiation, pre- and post-PLE, from sites irradiated with highest dose of VL. RESULTS: All subjects had immediate pigment darkening, persistent pigment darkening, and delayed tanning both pre- and post-PLE. For the highest VL dose (480 J/cm²) spectroscopic assessments demonstrated a statistically significant decrease in persistent pigment darkening and delayed tanning post-PLE. In addition, there was a significant decrease in cyclooxygenase-2, and a trend towards decreases in the markers for cellular damage post-PLE. While there was a trend towards lower IGA scores post-PLE, statistical significance was not reached possibly due to lack of sensitivity of the visual IGA scoring system in detecting small changes. CONCLUSIONS: Spectroscopic data and immunohistochemistry indicate an effect of PLE on visible light induced effects. As such, PLE may be used as an adjuvant to traditional means of photoprotection to protect against the effects of VL. Clinical trial registration number: NCT02904798. J Drugs Dermatol. 2019;18(12):1198-1203.

In vitro cholinesterase inhibitory activity of some plants used in Iranian traditional medicine.

In this study, in vitro evaluation of cholinesterase inhibitory (ChEI) activity of various plants including betel nuts (Areca catechu L.), clove buds (Syzygium aromaticum L.), aerial parts of dodder (Cuscuta chinensis Lam.), common polypody rhizomes (Polypodium vulgare L.) and turpeth roots (Ipomoea turpethum R. Br.) which were recommended for the treatment of AD symptoms in Iranian Traditional Medicine (ITM) is reported. Among them, aqueous extract of A. catechu L. was found as the most potent anti-AChE (IC50 = 32.00 µg/mL) and anti-BChE (IC50 = 48.81 ± 0.1200 µg/mL) agent.

Primary and Secondary Chemoprevention of Malignant Melanoma.

The incidence of malignant melanoma (MM) continues to rise in the United States. While sun protection and full body skin examinations remain the mainstay of preventative care, chemoprevention of the deadly disease has become an increasingly popular field of study. In this focused review, we discuss current findings and analyze the risks and benefits of various agents investigated for the primary and secondary chemoprevention of MM. Such agents include topical retinoids, vitamins, and supplements, Polypodium leucotomas extracts, non-steroidal anti-inflammatory agents (NSAIDs), statins, sunscreens, and field therapy with topical imiquimod for primary and secondary chemoprevention. We further identify a need for expanded high quality human research on the topic.

Fernblock (Polypodium leucotomos Extract): Molecular Mechanisms and Pleiotropic Effects in Light-Related Skin Conditions, Photoaging and Skin Cancers, a Review.

Healthier life styles include increased outdoors time practicing sports and walking. This means increased exposure to the sun, leading to higher risk of sunburn, photoaging and skin cancer. In addition to topical barrier products, oral supplementations of various botanicals endowed with antioxidant activity are emerging as novel method of photoprotection. Polypodium leucotomos extract (PL, commercial name Fernblock(®), IFC Group, Spain) is a powerful antioxidant due to its high content of phenolic compounds. PL is administered orally, with proven safety, and it can also be used topically. Its mechanisms include inhibition of the generation and release of reactive oxygen species (ROS) by ultraviolet (UV) light. It also prevents UV- and ROS-induced DNA damage with inhibition of AP1 and NF-κB and protection of natural antioxidant enzyme systems. At the cellular level, PL decreases cellular apoptosis and necrosis mediated UV and inhibits abnormal extracellular matrix remodeling. PL reduces inflammation, prevents immunosuppression, activates tumor suppressor p53 and inhibits UV-induced cyclooxygenase-2 (COX-2) enzyme expression. In agreement with increased p53 activity, PL decreased UV radiation-induced cell proliferation. PL also prevents common deletions mitochondrial DNA damage induced by UVA, and MMP-1 expression induced Visible Light and Infrared Radiation. These cellular and molecular effects are reflected in inhibitions of carcinogenesis and photoaging.

Use of Oral Polypodium Leucotomos Extract in Chronic Photoinduced Hypersensitivity Dermatitis.

A 52-year-old man with Fitzpatrick type V skin presented for evaluation of a photodistributed eruption of unknown origin. The patient reported a 20-year history of the dermatitis, with worsening severity during the past 6 years. He had required one hospital admission with intravenous methylprednisolone and two extended courses of oral prednisone (starting dose of 60 mg/d). He complained of pruritus and swelling localized to the sun-exposed areas of the forearms, face, and neck, with notable sparing of photoprotected areas of his skin. He denied new medications, and a systemic review of systems was noncontributory.

A comprehensive toxicological safety assessment of an aqueous extract of Polypodium leucotomos (Fernblock(®)).

A battery of toxicological studies was conducted in accordance with internationally accepted standards to investigate the genotoxicity and repeated-dose oral toxicity of Fernblock(®), a commercial aqueous extraction of the leaves of the tropical fern Polypodium leucotomos used for its oral and topical photoprotective properties. No evidence of mutagenicity was observed in a bacterial reverse mutation test or in vitro mammalian chromosomal aberration test nor was any genotoxic activity observed in an in vivo mouse micronucleus test. Two repeated-dose oral toxicity studies were conducted in male and female Wistar rats. In the first study, no mortality or toxic effects were observed and no target organs were identified at doses administered for 14 days by gavage up to the maximum dose of 5000 mg/kg bw/day. Based on these results, a 90-day study was conducted at 0, 300, 600, and 1200 mg/kg bw/day. No mortality or treatment-related adverse effects were observed and no target organs were identified. The NOAEL from the 90-day study was determined to be 1200 mg/kg bw/day, the highest dose tested.

Polypodium leucotomos supplementation in the treatment of scalp actinic keratosis: could it improve the efficacy of photodynamic therapy?

BACKGROUND: Actinic keratoses (AKs) are a common premalignant skin condition. Many treatments are available for AKs. Photodynamic therapy (PDT) is one of the most effective treatments. However, major concerns exist on the possibility of PDT-induced DNA-mutagenesis/immunosuppression, leading to AKs recurrence/treatment failure. An extract (PLE) from the fern polypodium leucotomos reduces UV-induced immunosuppression and mutagenesis. OBJECTIVE: To assess the ability of PLE to enhance the efficacy of PDT treatment, reducing AKs recurrence on the scalp. MATERIALS AND METHODS: Thirty-four bald patients presenting at least two AKs on the scalp were alternatively assigned to two groups. Both groups underwent two PDT-sessions one-week apart. The first group began oral PLE supplementation one week after the last PDT session. Evaluation of the effect of PLE supplementation was performed by direct inspection of the bald areas, lesions count, and photodynamic diagnosis assessment at 2 and 6 months. RESULTS: Both groups were homogeneous in terms of skin phototype and previous UV exposure. Mean age was 75.7 ± 7.8 years and 76.5 ± 5.5 years, respectively. Both treatment modalities were successful in reducing AKs number (p < .001). However, PLE supplementation increased clearance rate compared with PDT alone (p = .040). CONCLUSION: Polypodium leucotomos improves PDT clearance and decreases AK recurrence rate at 6 months, suggesting its use as a complementary agent in the treatment of field cancerization.

Polypodium leucotomos: a potential new photoprotective agent.

As the understanding of the immune system pathways, cytokine balances, and cellular interactions continues to expand, so must the potential applications of therapies that can impact the process of diseases instead of just controlling their symptoms. In the case of Polypodium leucotomos extract, which is derived from a tropical fern of the Polypodiaceae family, the future potential of applications in dermatology and beyond will be better understood as its incorporation into daily routines gives rise to the development of new regimens. Clinicians may position this agent as an option for daily maintenance, accept its use in combinations, or use it as a template for further development of oral supplementation that may evolve into a true immunomodulator. The antioxidant activity of P. leucotomos extract is primarily driven by caffeic acid and ferulic acid, resulting in the control of cutaneous responses to ultraviolet-induced erythema, in the interception of inflammatory mechanisms, and the promotion of other cytotoxic responses. Histologically, the impact of P. leucotomos extract induces an effect on the overall reduction of angiogenesis, photocarcinogenesis, and solar elastosis, while on the cellular level there are improvements in cell membrane integrity and elastin expression. Future applications for P. leucotomos extract could include the potential for photoprotective effects, and subsequent research efforts should focus on determining the optimal dosage regimen, duration of action, and utility of combinations with sunscreens, among other outcomes. Recently published data have also demonstrated how the antioxidant effects of oral P. leucotomos extract can delay tumor development in mice models, suggesting there might be a protective role that could be described with further clinical research. In addition, it is important to recognize the distinction between photoprotection and chemoprevention, in that there has yet to be any in vivo or controlled clinical trial data in human subjects that show a role for P. leucotomos extract in the prevention of carcinogenesis.

[Analysis of Volatile Components of Polypodium hastatum by GC-MS].

OBJECTIVE: To further reveal the chemical constituents of Polypodium hastatum, volatile components from this plant were investigated. METHODS: The volatile components were extracted under reflux from the whole plant of Polypodium hastatum, and then analyzed qualitatively and quantitatively by GC-MS. RESULTS: 60 volatile components were detected and of all components detected, the structures and relative contents of 34 volatile compounds were elucidated. CONCLUSION: In the volatile components identified, most are fatty acid esters, especially methyl and ethyl esters, which compose the major volatile chemical constituents of Polypodium hastatum.

Oral administration of Polypodium leucotomos delays skin tumor development and increases epidermal p53 expression and the anti-oxidant status of UV-irradiated hairless mice.

Chronic exposure to ultraviolet radiation (UVR) induces skin tumors in hairless mice. Daily oral administration of a Polypodium leucotomos (PL) extract significantly delayed tumor development in PL-treated versus non-PL-treated mice. UVR and/or PL treatment modified several oxidative stress markers. In all irradiated mice, erythrocytic glutathione S-transferase (GST) activity and glutathione disulphide (GSSG) content increased and in all PL-treated mice GSSG content decreased, specially in non-irradiated animals, and total plasma anti-oxidant capacity (ORAC) increased. In dorsolateral non-tumoral skin of all irradiated mice, glutathione reductase (GR) and glutathione peroxidase (GPx) activities increased and GSSG decreased in non-irradiated PL-treated animals. UVR induced a steep increase of p53 expression in epidermal cells. In non-tumoral skin, this increase was significantly higher in PL-treated animals than in non-treated mice and can contribute in delaying tumor development, either by repairing the damaged DNA or by increasing apoptosis. These results reinforce the usefulness of PL as systemic photoprotective agent, especially in patients highly sensitive to UVR.

Role of oral Polypodium leucotomos extract in dermatologic diseases: a review of the literature.

Polypodium leucotomos extract (PLE), derived from the tropical fern of Polypodiaceae family, has properties ranging from immunomodulatory and antioxidative to photoprotective. It is these multiple mechanisms of action, in combination with a favorable side effect profile, which makes PLE a promising adjunctive treatment for several dermatologic disorders. Studies are summarized on the use and potential applications of PLE in the treatment or management of photodermatoses, vitiligo, melasma, psoriasis, atopic dermatitis, and more recently, in minimizing infections in high-performance athletes. More data, however, with larger sample sizes are needed to confirm these benefits.

Fernblock, a nutriceutical with photoprotective properties and potential preventive agent for skin photoaging and photoinduced skin cancers.

Many phytochemicals are endowed with photoprotective properties, i.e., the capability to prevent the harmful effects of excessive exposure to ultraviolet (UV) light. These effects include photoaging and skin cancer, and immunosuppression. Photoprotection is endowed through two major modes of action: UV absorption or reflection/scattering; and tissue repair post-exposure. We and others have uncovered the photoprotective properties of an extract of the fern Polypodium leucotomos (commercial name Fernblock). Fernblock is an all-natural antioxidant extract, administered both topically (on the skin) or orally. It inhibits generation of reactive oxygen species (ROS) production induced by UV including superoxide anion. It also prevents damage to the DNA, inhibits UV-induced AP1 and NF-κB, and protects endogenous skin natural antioxidant systems, i.e., CAT, GSH, and GSSR. Its photoprotective effects at a cellular level include a marked decrease of UV-mediated cellular apoptosis and necrosis and a profound inhibition of extracellular matrix remodeling. These molecular and cellular effects translate into long-term inhibition of photoaging and carcinogenesis that, together with its lack of toxicity, postulate its use as a novel-generation photoprotective nutriceutical of phytochemical origin.

Mechanistic insights in the use of a Polypodium leucotomos extract as an oral and topical photoprotective agent.

Photoprotection is essential to prevent the deleterious effects of ultraviolet (UV) light, including skin cancer, photoaging and immunosuppression. Photoprotective agents can be classified according to their main mechanism of action. Some of them absorb or deflect UV photons (sunscreens), whereas others prevent or fix the deleterious effects of UV exposure. Here, we review recent evidence on the cellular and molecular mechanisms underlying the photoprotective effect of a Polypodium leucotomos fern extract (PL). PL is a natural mixture of phytochemicals endowed with powerful antioxidant properties. Its short-term effects include inhibition of reactive oxygen species production induced by UV radiation, DNA damage, isomerization and decomposition of trans-urocanic acid, prevention of UV-mediated apoptosis and necrosis, as well as degradative matrix remodeling, which is the main cause of photoaging. These short-term effects translate into long-term prevention of photoaging and photocarcinogenesis. A striking property is that PL can exert its effect when administered orally. Together, these effects postulate PL as a natural photoprotective agent and a potential adjuvant to phototherapy for various skin diseases.