Angelicin: A leading culprit involved in fructus Psoraleae liver injury via inhibition of VKORC1.

ETHNOPHARMACOLOGICAL RELEVANCE: The adverse effects of Fructus Psoraleae (FP), especially liver injury, have attracted wide attention in recent years. AIM OF THE STUDY: To establish a system to explore potential hepatotoxic targets and the chief culprit of liver injury based on clinical experience, network pharmacological method, molecular docking, and in vitro and in vivo experiments. MATERIALS AND METHODS: Clinical applications and adverse reactions to FP were obtained from public literatures. Components absorbed in the blood were selected as candidates to search for potential active targets (PATs) of FP. Subsequently, potential pharmacological core targets (PPCTs) were screened through the "drug targets-disease targets" network. Non-drug active targets (NPATs) were obtained by subtracting the PPCTs from the PATs. The potential hepatotoxic targets (PHTs) of FP were the intersection targets obtained from Venn analysis using NPATs, hepatotoxic targets, and adverse drug reaction (ADR) targets provided by the databases. Then, potential hepatotoxic components and targets were obtained using the "NPATS-component" network relationship. Molecular docking and in vitro and in vivo hepatotoxicity experiments were performed to verify the targets and related components. RESULTS: Overall, 234 NPATs were acquired from our analysis, and 6 targets were identified as PHTs. Results from molecular docking and in vitro and in vivo experiments showed that angelicin is the leading cause of liver injury in FP, and VKORC1 plays an important role. CONCLUSION: The results indicate that six targets, especially VKORC1, are associated with the PHTs of FP, and angelicin is the leading culprit involved in FP liver injury via inhibition of VKORC1.

Angelicin Alleviates Maternal Isoflurane Exposure-Induced Offspring Cognitive Defects Through the Carbonic Anhydrase 4/Aquaporin-4 Pathway.

An increasing number of studies reveal the deleterious effects of isoflurane (Iso) exposure during pregnancy on offspring cognition. However, no effective therapeutic strategy for Iso-induced deleterious effects has been well developed. Angelicin exerts an anti-inflammatory effect on neurons and glial cells. This study investigated the roles and mechanism of action of angelicin in Iso-induced neurotoxicity in vitro and in vivo. After exposing C57BL/6 J mice on embryonic day 15 (E15) to Iso for 3 and 6 h, respectively, neonatal mice on embryonic day 18 (E18) displayed obvious anesthetic neurotoxicity, which was revealed by the elevation of cerebral inflammatory factors and blood-brain barrier (BBB) permeability and cognitive dysfunction in mice. Angelicin treatment could not only significantly reduce the Iso-induced embryonic inflammation and BBB disruption but also improve the cognitive dysfunction of offspring mice. Iso exposure resulted in an increase of carbonic anhydrase (CA) 4 and aquaporin-4 (AQP4) expression at both mRNA and protein levels in vascular endothelial cells and mouse brain tissue collected from neonatal mice on E18. Remarkably, the Iso-induced upregulation of CA4 and AQP4 expression could be partially reversed by angelicin treatment. Moreover, GSK1016790A, an AQP4 agonist, was used to confirm the role of AQP4 in the protective effect of angelicin. Results showed that GSK1016790A abolished the therapeutic effect of angelicin on Iso-induced inflammation and BBB disruption in the embryonic brain and on the cognitive function of offspring mice. In conclusion, angelicin may serve as a potential therapeutic for Iso-induced neurotoxicity in neonatal mice by regulating the CA4/AQP4 pathway.

Phytophotodermatitis as a clinical problem and as a therapeutic option: Case report and review of the literature.

BACKGROUND: Phytophotodermatitis is a contact photodermatitis to furocoumarins, which act as sensitizing psoralens, from certain plants, especially citrus and fig trees. This photosensitizing effect has traditionally been used for the treatment of cutaneous viral warts, a reflection of traditional medicine. However, there are hardly any studies that support this fact. Otherwise, on certain occasions, especially in extensive exposures, they can cause a generalized severe condition that can even put the patient's life at risk. CASE PRESENTATION: We report the case of a 28-year-old man with severe phytophotodermatitis after generalized photoexposure with the manipulation of a fig tree, which required hospital management in a burn unit. RESULTS: A traditional method for the treatment of warts in some rural areas, especially in Iran, comprises the use of fig tree (ficus carica) latex as a local treatment; however, there is no scientific evaluation of its efficacy. It bases its effectiveness on physical destruction due to the sensitizing effect of furocoumarins. Though, in generalized exposures of this tree, as the case of our patient, can cause fatal symptoms. The essential therapeutic pillar is the avoidance of exposure to this tree and of sun exposure. Symptomatically, topical corticosteroids and systemic antihistamines are used. In severe cases, admission to a burn unit may be necessary. CONCLUSION: In conclusion, we highlight the importance the importance of early detection of phytophotodermatitis, an entity that can be caused by the daily handling of trees, including fig trees, a traditional remedy for viral warts and which, without adequate supervision in its application, can cause severe generalized symptoms.

Bergamottin alleviates LPS-induced acute lung injury by inducing SIRT1 and suppressing NF-κB.

Acute lung injury (ALI) is associated with a high mortality due to inflammatory cell infiltration and lung edema. The development of ALI commonly involves the activation of NF-κB. Since bergamottin is a natural furanocoumarin showing the ability to inhibit the activation of NF-κB, in this study we aimed to determine the effect of bergamottin on ALI. RAW264.7 mouse macrophages were pre-treated with bergamottin and then stimulated with LPS. Macrophage inflammatory responses were examined. Bergamottin (50 mg/kg body mass) was intraperitoneally administrated to mice 12 h before injection of LPS, and the effect of bergamottin on LPS-induced ALI was evaluated. Our results showed that LPS exposure led to increased production of TNF-α, IL-6, and monocyte chemoattractant protein-1 (MCP-1), which was impaired by bergamottin pre-treatment. In vivo studies confirmed that bergamottin pre-treatment suppressed LPS-induced lung inflammation and edema and reduced the levels of pro-inflammatory cytokines in lung tissues and bronchoalveolar lavage fluids. Mechanistically, bergamottin blocked LPS-induced activation of NF-κB signaling in lung tissues. Additionally, bergamottin treatment reduced NF-κB p65 protein acetylation, which was coupled with induction of SIRT1 expression. In conclusion, our results reveal the anti-inflammatory property of bergamottin in preventing ALI. Induction of SIRT1 and inhibition of NF-κB underlies the anti-inflammatory activity of bergamottin.

Intake of Furocoumarins and Risk of Skin Cancer in 2 Prospective US Cohort Studies.

BACKGROUND: In prior studies, higher citrus consumption was associated with higher risk of cutaneous malignant melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC). Furocoumarins, compounds with phototoxicity and photocarcinogenicity in citrus, may be responsible for the association. OBJECTIVES: The objective of the study was to investigate the association between furocoumarin intake and skin cancer risk. METHODS: A total of 47,453 men from the Health Professionals Follow-Up Study (HPFS) and 75,291 women from the Nurses' Health Study (NHS) with diet data collected every 2-4 y in the 2 prospective cohort studies were included. A furocoumarin food composition database for 7 common furocoumarins [bergaptol, psoralen, 8-methoxypsoralen, bergapten, 6',7'-dihydroxybergamottin (6'7'-DHB), epoxybergamottin, and bergamottin] was developed and used to calculate participants' cumulative average and energy-adjusted furocoumarin intake. Multivariate HRs and 95% CIs of the associations between furocoumarin intake and skin cancer risk were estimated using Cox proportional hazards models. Analyses were performed separately in each cohort as well as pooled using a fixed-effects model. RESULTS: Throughout follow-up (1984-2012 in the NHS and 1986-2012 in the HPFS), we identified 1593 melanoma, 4066 SCC, and 28,630 BCC cases. Higher intake of total furocoumarins was associated with an increased risk of BCC; the pooled HR comparing the top with the bottom quintile was 1.16 (95% CI: 1.11, 1.21; P-trend = 0.002). Higher intakes of bergaptol, bergapten, 6'7'-DHB, and bergamottin were also significantly associated with increased BCC risk. No significant associations were found between intake of total furocoumarins and the risks of SCC or melanoma. CONCLUSIONS: Intakes of total furocoumarins as well as some individual furocoumarins were associated with an increased risk of skin cancer, especially BCC, in 2 cohorts of US health professionals.

Relationship between Furocoumarin Intake and Melanoma History among US Adults in the National Health and Nutrition Examination Survey 2003-2012.

Furocoumarins are a group of phototoxic compounds found in numerous edible plants. Data from cohort studies have suggested that consumption of certain furocoumarin-rich foods may increase skin cancer risk. However, no study has specifically tested this hypothesis by estimating furocoumarin intake and assessing its relationship with skin cancer. This study aimed to estimate average daily furocoumarin intake of US adults using the National Health and Nutrition Examination Survey (NHANES) 2003-2012 and to examine the relationship between furocoumarin intake and melanoma history. A database of the contents of seven furocoumarins in 29 popular foods was linked to dietary data in NHANES 2003-2012. Mean total intake of the selected furocoumarins among US adults was 81.4 µg/day (standard error = 5.5). A total of 75 participants reported a history of melanoma. Using non- and low consumers (<50th percentile) as a reference, and after adjusting for potential confounders, OR (with 95% confidence interval) of melanoma history for the top 10 percent, 80-90th percentiles, and 50-80th percentiles were 1.75 (0.43-7.20), 1.66 (0.39-7.16), and 0.90 (0.45-1.78), respectively. Furocoumarins are widely consumed among US adults, and a trend towards higher odds of melanoma history was observed among those with higher furocoumarin intake, although this relationship was not statistically significant.

Amotosalen-inactivated fresh frozen plasma is comparable to solvent-detergent inactivated plasma to treat thrombotic thrombocytopenic purpura.

BACKGROUND: Therapeutic Plasma Exchange (TPE) is the primary therapy of immune-mediated Thrombotic Thrombocytopenic Purpura (iTTP). Efficacy and safety data for TPE of iTTP have been assessed with Quarantine and Solvent-Detergent inactivated (SD) plasma. Here, amotosalen-UVA pathogen inactivated (AI) plasma, also in routine use, was evaluated in iTTP. METHODS: We conducted a retrospective review of iTTP cases prospectively reported to the French national registry (2010-2013). Cases reviewed underwent TPE with ≥70% of either AI or SD plasma. The primary endpoint was time to platelet count recovery; secondary endpoints were related to follow-up (sustained remission, relapses, flare-ups and refractoriness). RESULTS: 30 Test patients were identified in the AI group which could be timely matched to 40 Control patients in the SD group. The groups were fairly comparable for clinical presentation. Major findings were: (i) iTTP patients were exposed to lower plasma volumes in the AI group than in the SD group; (ii) Recovery rates were comparable between the groups. Median time to platelet count recovery (>150 × 109/L) trended to be shorter in the AI group though non significantly. Tolerance of AI vs SD plasma was of comparable frequency and severity in either group. CONCLUSION: TPE with Amotosalen-inactivated plasma demonstrated therapeutic efficacy and tolerability for iTTP patients. In view of the retrospective design, confirmation of these results is required in larger prospective studies.

Effects of imperatorin in the cardiovascular system and cancer.

Patients with cancer survivors are at increased risk of cardiovascular disease(CVD). Cardio-oncology has developed as a new discipline with the advances in cancer treatment. There are many new challenges for the clinician and a new frontier for research and investigation. There is an urgent need for further study on the prevention of cardiovascular toxicity. Imperatorin (IMP) is a natural form of coumarin and extract from several plants with diver's pharmacokinetic effects, including antioxidant and anti-inflammatory properties. This review focus on the molecular mechanisms and pharmacological effects of Imperatorin maybe provide potential cancer and cardiovascular protection that targets IMP. Further studies are required to elucidate the entire spectrum of cytotoxic activities of these compounds to validate and expand their preclinical and clinical applications and to clarify the potential role of IMP.

La piel en el campo / The skin in the field

No disponible

Photoonycholysis: new findings.

First described in 1961, photoonycholysis (PO) is a rare nail alteration that may result from drug intake, from topical aminolevulinate photodynamic therapy or from photosensitive conditions such as porphyria or pseudoporphyria. Spontaneous PO is rare. This review updates the numerous causes of PO and highlights some new ways producing this condition. Four different types of PO are clearly recognized without relationship with the responsible drug. An updated list of potential inducing drug is provided. Some practical points on PO have been raised. The inability to reproduce photoonycholysis experimentally should be emphasized, and the pathogenesis of PO still needs to be clarified.

Dietary furocoumarins and skin cancer: A review of current biological evidence.

Furocoumarins are a class of compounds produced by several plant species, including some popularly consumed by humans. Furocoumarins are known to be well absorbed from food sources, and can be rapidly distributed into several tissues including the skin. In human skin, when exposed to UV radiation, furocoumarins may become photoactivated and form interstrand crosslinks with DNA, thereby disrupting DNA transcription. Because of this property, furocoumarins have been combined as topical or oral agents with UV irradiation as a phototherapy to treat multiple skin conditions, yet these treatments have been shown to increase risk of both melanoma and non-melanoma skin cancer. Whether or not dietary furocoumarin exposure may confer the same risk is not yet known. This review summarizes the current evidence regarding the activities of ingested furocoumarins, with particular focus on how dietary furocoumarins are absorbed, metabolized, and distributed throughout the body, and their interactions with various cellular components that may underlie a potential relationship with skin cancer.

Lemons in the Arizona Sunshine: The Effects of Furocoumarins Leading to Phytophotodermatitis and Burn-like Injuries.

INTRODUCTION: Phytophototoxic dermatitis is a strong phototoxic reaction to ultraviolet A (UV-A) radiation exposure after cutaneous contact with citrus fruit containing furocoumarins, leading to skin injury. At the Arizona Burn Center (Phoenix, AZ), the majority of these injuries are managed in the outpatient setting. CASE REPORT: The authors present a pediatric admission for burn-like injuries following prolonged cutaneous exposure to lemons while playing in the Arizona sunshine. A 7-year-old girl playing in her backyard squeezed lemon juice onto her skin while in the hot Arizona sunshine; within 24 hours, the child experienced pain, erythema, and blistering to multiple areas of her skin. She was admitted to the authors' burn center for wound care and pain control. She had scattered first-degree and second-degree burn-like lesions to her face, neck, and chest as well as bilateral forearms, hands, lower extremities, and feet. After blister debridement, appropriate dressing care, and pain medication, the patient was discharged home after 4 days of hospitalization with appropriate clinical follow-up. CONCLUSIONS: Burn-like lesions caused by furocoumarins after cutaneous absorption and UV-A exposure are known clinical entities in Arizona. The sequential progression from erythema to blisters equivalent to second-degree burn-like lesions to cutaneous hyperpigmentation is a well-described clinical triad. Meticulous wound care and pain control for the treatment of these burn-like lesions are essential as is the need for the wound care specialist to be well versed on this topic to quickly identify the etiology of the injury, thereby avoiding misdiagnosing the patient with nonaccidental traumatic injuries.

[Sosnowsky's hogweed - toxicology and threat to health]. / Barszcz Sosnowskiego ­ toksykologia a zagrozenie dla zdrowia.

Sosnowsky's hogweed (Heracleum sosnowskyi Manden.) is a genus of plants in the family Apiaceae which also includes Giant Hogweed (Heracleum mantegazzianum Sommier and Levier). They are both found in Central Europe, mainly in neglected green areas or riversides. Sosnowsky's hogweed was brought to Poland from the Soviet Union in the 1950s to be used in animal feed production. Intended goals couldn't be achieved and the plant spread throughout grounds distant to the primarily cultivated lands. Sosnowsky's hogweed is especially hazardous in direct contact with human skin. It results from the content of photoallergic substances called furanocoumarins in its essential oil. Clinically it is presented as burns, mainly of 2nd and 3rd degree. They mostly occur on the face, upper and lower limbs. Typical symptoms include pain, redness, swelling and heat in the area of exposure. Their extent depends on burn's depth and area and also on time of exposure to plant's toxins. In this article we present Sosnowsky's hogweed's activity and its influence on human health.