Discovery of psoralen as a quorum sensing inhibitor suppresses Pseudomonas aeruginosa virulence.

Pseudomonas aeruginosa is a common opportunistic pathogen with growing resistance and presents heightened treatment challenges. Quorum sensing (QS) is a cell-to-cell communication system that contributes to the production of a variety of virulence factors and is also related to biofilm formation of P. aeruginosa. Compared to traditional antibiotics which kill bacteria directly, the anti-virulence strategy by targeting QS is a promising strategy for combating pseudomonal infections. In this study, the QS inhibition potential of the compounds derived from the Traditional Chinese Medicines was evaluated by using in silico, in vitro, and in vivo analyses. The results showed that psoralen, a natural furocoumarin compound derived from Psoralea corylifolia L., was capable of simultaneously inhibiting the three main QS regulators, LasR, RhlR, and PqsR of P. aeruginosa. Psoralen had no bactericidal activity but could widely inhibit the production of extracellular proteases, pyocyanin, and biofilm, and the cell motilities of the model and clinical P. aeruginosa strains. RNA-sequencing and quantitative PCR analyses further demonstrated that a majority of QS-activated genes in P. aeruginosa were suppressed by psoralen. The supplementation of psoralen could protect Caenorhabditis elegans from P. aeruginosa challenge, especially for the hypervirulent strain PA14. Moreover, psoralen showed synergistic antibacterial effects with polymyxin B, levofloxacin, and kanamycin. In conclusions, this study identifies the anti-QS and antibiofilm effects of psoralen against P. aeruginosa strains and sheds light on the discovery of anti-pseudomonal drugs among Traditional Chinese Medicines. KEY POINTS: • Psoralen derived from Psoralea corylifolia L. inhibits the virulence-related phenotypes of P. aeruginosa. • Psoralen simultaneously targets the three core regulators of P. aeruginosa QS system and inhibits the expression of a large part of downstream genes. • Psoralen protects C. elegans from P. aeruginosa challenge and enhances the susceptibility of P. aeruginosa to antibiotics.

Phytochemical and Pharmacological Aspects of Psoralen - A Bioactive Furanocoumarin from Psoralea corylifolia Linn.

Since long ago, medicinal plants have played a vital role in drug discovery. Being blessed and rich in chemovars with diverse scaffolds, they have unique characteristics of evolving based on the need. The World Health Organization also mentions that medicinal plants remain at the center for meeting primary healthcare needs as the population relies on them. The plant-derived natural products have remained an attractive choice for drug development owing to their specific biological functions relevant to human health and also the high degree of potency and specificity they offer. In this context, one such esteemed phytoconstituent with inexplicable biological potential is psoralen, a furanocoumarin. Psoralen was the first constituent isolated from the plant Psoralea corylifolia, commonly known as Bauchi. Despite being a life-saver for psoriasis, vitiligo, and leukoderma, it also showed immense anticancer, anti-inflammatory, and anti-osteoporotic potential. This review brings attention to the possible application of psoralen as an attractive target for rational drug design and medicinal chemistry. It discusses the various methods for the total synthesis of psoralen, its extraction, the pharmacological spectrum of psoralen, and the derivatization done on psoralen.

Unveiling hepatotoxicity distinction of coumarin-related compounds from glycosides to aglycones in Fructus Psoraleae by integrating UPLC-Q-TOF-MS and high content analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Fructus Psoraleae (FP), the dried and ripe fruit of Cullen corylifolium (L.) Medik., is widely used due to its various clinical pharmacological effects, but its hepatotoxicity restricts its clinical application. So far, its hepatotoxic components and their underlying mechanism have not been systematically elucidated. AIM OF THE STUDY: This study was undertaken to reveal the hepatotoxicity distinction of coumarin-related compounds from glycosides to aglycones in FP and elucidate their potential mechanism. METHODS: Rats were administrated with the aqueous extract of Fructus Psoraleae (AEFP), in which eight coumarin-related compounds were focused. Subsequently, compounds exposed in rats' livers were detected by UPLC-Q-TOF-MS, and the identified hepatotoxic compounds were evaluated to elaborate their possible mechanism by the aid of high content analysis (HCA). RESULTS: Eight coumarin-related compounds were identified, among which psoralenoside (PO), isopsoralenoside (IPO), psoralen (P), and isopsoralen (IP) were the principally exposed compounds in rats' livers. Furocoumarinic acid glucoside (FAG), (E)-3-(4-(((2S, 3R, 4S, 5S, 6R)-3,4,5-trihydroxy-6-(hydroxymethyl) tetrahydro-2H-pyran-2-yl) oxy) benzofuran-5-yl) acrylic acid (isofurocoumarinic acid glucoside, IFAG), furocoumarinic acid (FA), and (E)-3-(4-hydroxybenzofuran-5-yl) acrylic acid (isofurocoumarinic acid, IFA) were also detected in low abundance. P, IP, FA, and IFA were identified as the hepatotoxic compounds, while their glycosides were almost non-hepatotoxic. The HCA's results showed that hepatotoxic compounds disrupted the balance in reactive oxygen species (ROS), nuclear area, and mitochondrial membrane potential of HepG2 cells, leading to the occurrence of hepatotoxicity. CONCLUSIONS: P, IP, FA, and IFA were identified as hepatotoxic compounds, from which P and IP were proposed as the important risk components for hepatotoxicity. The conversion from glycosides to aglycones played an essential role in FP-induced hepatotoxicity.

A Metabolic Driven Bio-Responsive Hydrogel Loading Psoralen for Therapy of Rheumatoid Arthritis.

Overexpressed matrix metalloproteinases, hypoxia microenvironment, and metabolic abnormality are important pathological signs of rheumatoid arthritis (RA). Designing a delivery carrier according to the pathological characteristics of RA that can control drug release in response to disease severity may be a promising treatment strategy. Psoralen is the main active ingredient isolated from Psoralea corylifolia L. and possesses excellent anti-inflammatory activities as well as improving bone homeostasis. However, the specific underlying mechanisms, particularly the possible relationships between the anti-RA effects of psoralen and related metabolic network, remain largely unexplored. Furthermore, psoralen shows systemic side effects and has unsatisfactory solubility. Therefore, it is desirable to develop a novel delivery system to maximize psoralen's therapeutic effect. In this study, a self-assembled degradable hydrogel platform is developed that delivers psoralen and calcium peroxide to arthritic joints and controls the release of psoralen and oxygen according to inflammatory stimulation, to regulate homeostasis and the metabolic disorder of the anoxic arthritic microenvironment. Therefore, the hydrogel drug delivery system based on the responsiveness of the inflammatory microenvironment and regulation of metabolism provides a new therapeutic strategy for RA treatment.

Psoralen prevents the inactivation of estradiol and treats osteoporosis via covalently targeting HSD17B2.

ETHNOPHARMACOLOGICAL RELEVANCE: Psoralea corylifolia L. seeds (P. corylifolia), popularly known as Buguzhi in traditional Chinese medicine, are often used to treat osteoporosis in China. Psoralen (Pso) is the key anti-osteoporosis constituent in P. corylifolia, however, its targets and mechanism of action are still unclear. AIM OF THE STUDY: The purpose of this study was to explore the interaction between Pso and 17-ß hydroxysteroid dehydrogenase type 2 (HSD17B2), an estrogen synthesis-related protein that inhibits the inactivation of estradiol (E2) to treat osteoporosis. MATERIALS AND METHODS: Tissue distribution of Pso was analyzed by in-gel imaging after oral administration of an alkynyl-modified Pso probe (aPso) in mice. The target of Pso in the liver was identified and analyzed using chemical proteomics. Co-localization and cellular thermal shift assays (CETSA) were used to verify the key action targets. To detect the key pharmacophore of Pso, the interaction of Pso and its structural analogs with HSD17B2 was investigated by CETSA, HSD17B2 activity assay, and in-gel imaging determination. Target competitive test, virtual docking, mutated HSD17B2 activity, and CETSA assay were used to identify the binding site of Pso with HSD17B2. A mouse model of osteoporosis was established by ovariectomies, and the efficacy of Pso in vivo was confirmed by micro-CT, H&E staining, HSD17B2 activity, and bone-related biochemical assays. RESULTS: Pso regulated estrogen metabolism by targeting HSD17B2 in the liver, with the α, ß-unsaturated ester in Pso being the key pharmacophore. Pso significantly suppressed HSD17B2 activity by irreversibly binding to Lys236 of HSD17B2 and preventing NAD+ from entering the binding pocket. In vivo studies in ovariectomized mice revealed that Pso could inhibit HSD17B2 activity, prevent the inactivation of E2, increase levels of endogenous estrogen, improve bone metabolism-related indices, and play a role in anti-osteoporosis. CONCLUSIONS: Pso covalently binds to Lys236 of HSD17B2 in hepatocytes to prevent the inactivation of E2, thereby aiding in the treatment of osteoporosis.

Psoralen induces liver injury and affects hepatic bile acids metabolism in female and male C57BL/6J mice.

Psoralen is a major component of Fructus Psoraleae that could induce liver injury. In this study, C57BL/6J mice were administered with psoralen at doses of 80 mg/kg for 3, 7 and 14 days. Blood and liver samples were collected for serum biochemistry and histopathology examinations, respectively. Psoralen led to liver injury with significantly increased liver weight and liver coefficient and up regulated serum ALT, AST and TG but down regulated serum TC and TP. The expression of bile acid-associated transporters and enzymes was detected by western blot, and the results showed that psoralen significantly down-regulates the expressions of CYP7A1, CYP27A1, BSEP and OSTα protein while up-regulates the expressions of HMGCR and FASN, resulting in the obstacles of bile acid efflux in the liver. The contents of 24 kinds of bile acids in the liver were measured by LC-MS/MS, and the results showed that psoralen led to the accumulation of unconjugated bile acids in the liver, such as ALCA and CA, which were more severe in male mice than female mice. It was indicated that psoralen may disrupt the balance of bile acid metabolism by inhibiting the expression of the efflux transporter, which then leads to liver damage.

Ingenious application of ethylenediaminetetraacetic acid disodium to improve the extraction yield of psoralen in fig (Ficus carica L.) leaves.

In this study, ethylenediaminetetraacetic acid (EDTA) disodium was first chosen as catalyst to convert psoralenoside (PO) to psoralen (PSO) for increasing the extraction yield of PSO. An efficient continuous system for synchronous transformation and extraction of PSO from fig leaves applying microwave-assisted EDTA disodium (MAE-EDTA) was developed. The optimal MAE-EDTA condition was obtained: EDTA disodium concentration of 0.07 mol·L-1, ethanol volume fraction of 56%, extraction time of 16 min, and extraction temperature of 70 °C by single factor experiments and response surface method (RSM). Under the optimal condition, the yield of PSO reached 27.24 mg·g-1. Compared with microwave-assisted ethanol extraction (MAE) and reflux extraction (RE), the yield of PSO by MAE-EDTA is 2.03-fold higher than RE and 1.70-fold higher than MAE. Therefore, MAE-EDTA is an efficient method for extracting PSO from fig leaves, and it might provide references for the extraction of PSO from other medicinal plants.

Individual and combined effects of chromium and ultraviolet-B radiation on defense system, ultrastructural changes, and production of secondary metabolite psoralen in a medicinal plant Psoralea corylifolia L.

The present study focuses on the effects of individual and combined stress of chromium (Cr) and ultraviolet-B (UV-B) radiation on Psoralea corylifolia L. The experiment comprised four sets: (i) control, (ii) eUV-B (elevated UV-B i.e., ambient + 7.2 kJ m-2 day-1 UV-B), (iii) Cr (chromium; 30 mg kg-1 soil), and (iv) Cr + eUV-B (chromium and elevated UV-B; Cr 30 mg kg-1 and ambient + 7.2 kJ m-2 day-1 UV-B). The eUV-B and Cr individually and in combination showed the variable responses on ultrastructure, physiology and biomass however, the impact was more prominent under individual Cr treatment followed by Cr + eUV-B and eUV-B. Higher bioconcentration factor and the lowered translocation factor consequently led to a higher reduction in the below ground biomass and the lesser reduction in above ground biomass under Cr + eUV-B treatment as compared to individual Cr treatment. In addition, higher induction in the enzymatic (glutathione reductase, ascorbate peroxidase, superoxide dismutase, and glutathione-S-transferase) and non-enzymatic antioxidants (glutathione reduced) were found to be responsible for efficient scavenging of hydrogen peroxide and superoxide radical leading to lowered MDA content under combined treatment as compared to Cr treatment. Deposition of Cr as electron dense granules in the cytoplasm, vacuoles, and cell wall under Cr and Cr + eUV-B is contemplated as one of the cellular mechanisms of P. corylifolia against the toxicity of Cr. Psoralen increased under all treatments with a maximum increase under Cr + eUV-B treatment. Taken together our results accentuated that P. corylifolia can be grown in an area contaminated with Cr and has a higher influx of UV-B for the attainment of psoralen considering its pharmaceutical perspectives.

Transcriptomics and metabolomics reveal the role of CYP1A2 in psoralen/isopsoralen-induced metabolic activation and hepatotoxicity.

Psoralen and isopsoralen are the pharmacologically important but hepatotoxic components in Psoraleae Fructus. The purpose of this study was to reveal the underlying mechanism of psoralen/isopsoralen-induced hepatotoxicity. Initially, we applied integrated analyses of transcriptomic and metabolomic profiles in mice treated with psoralen and isopsoralen, highlighting the xenobiotic metabolism by cytochromes P450 as a potential pathway. Then, with verifications of expression levels by qRT-PCR and western blot, affinities by molecular docking, and metabolic contributions by recombinant human CYP450 and mouse liver microsomes, CYP1A2 was screened out as the key metabolic enzyme. Afterwards, CYP1A2 induction and inhibition models in HepG2 cells and mice were established to verify the role of CYP1A2, demonstrating that induction of CYP1A2 aggravated the hepatotoxicity, and conversely inhibition alleviated the hepatotoxic effects. Additionally, we detected glutathione adducts with reactive intermediates of psoralen and isopsoralen generated by CYP1A2 metabolism in biosystems of recombinant human CYP1A2 and mouse liver microsomes, CYP1A2-overexpressed HepG2 cells, mice livers and the chemical reaction system using UPLC-Q-TOF-MS/MS. Ultimately, the high-content screening presented the cellular oxidative stress and relevant hepatotoxicity due to glutathione depletion by reactive intermediates. In brief, our findings illustrated that CYP1A2-mediated metabolic activation is responsible for the psoralen/isopsoralen-induced hepatotoxicity.

Concentrations of metalloproteinase-1 in patients with morphea treated with phototherapy: a preliminary study.

Introduction: Morphea (localized scleroderma) is a rare, chronic, inflammatory connective tissue disease, characterized by immune system dysfunction, vasculopathy and skin fibrosis. One of the most effective treatments is phototherapy. Phototherapy has been found to be effective in treating localized scleroderma by inducing the expression of metalloproteinase-1. Aim: To compare the concentrations of metalloproteinase (MMP-1) before psoralen and ultraviolet A (PUVA) and ultraviolet A1 (UVA1) treatments in the serum of patients with morphea. Material and methods: The observational study was conducted in one research centre and included patients with generalised morphea who were treated with PUVA and UVA1 phototherapies. The mean age of all morphea patients included in the study was 55.7 years. The levels of MMP-1 were examined by ELISA (The Biorbyt Human MMP-1 ELISA - Enzyme-Linked Immunosorbent Assay). Results: The study showed that patients treated with PUVA and UVA1 had an improvement based on clinical measures, resulting in a reduction of clinical score. However, we did not observe statistically significant differences in MMP-1 concentrations before and after treatment. Limitations: The study sample was relatively small. Further studies on a larger group of patients would be beneficial. Conclusions: Our data suggest that there is a possible correlation between MMP-1 concentrations and phototherapy. MMP-1 levels were found to be increased following phototherapy treatment, which may suggest a correlation with better response to treatment in patients with morphea. However, further research is needed.

Psoralen and isopsoralen from Psoraleae Fructus aroused hepatotoxicity via induction of aryl hydrocarbon receptor-mediated CYP1A2 expression.

ETHNOPHARMACOLOGICAL RELEVANCE: Psoraleae Fructus (PF), a traditional Chinese medicine, has long been used to treat diseases such as cancer, osteoporosis and leukoderma. Psoralen and isopsoralen are main bioactive ingredients of PF with anti-tumor, anti-inflammatory, estrogen-like neuroprotection, etc., meanwhile they are also representative hepatotoxic components of PF. Hepatic CYP1A2 has been reported to be the important metabolic enzymes involved in psoralen and isopsoralen-induced hepatotoxicity. However, the relationship between the hepatotoxicity and CYP1A2 expression, and the underlying mechanism of regulating CYP1A2 expression remain unclear. AIM OF STUDY: The aim of this study was to explore the associated mechanism between psoralen or isopsoralen induced hepatotoxicity and activated aryl hydrocarbon receptor (AhR)-mediated transcriptional induction of CYP1A2 in vitro and in vivo. MATERIALS AND METHODS: Psoralen and isopsoralen at different doses were treated on HepG2 cells (10, 25, 50, 100, 200 µM for 2, 12, 24, 36, 48 h) and mice (20, 80, 160 mg/kg for 3, 7, 14 days) for different time, to assess the correlation of induced hepatotoxicity and CYP1A2 mRNA and protein expression in vivo and in vitro, as well as the effect on CYP1A2 enzyme activity evaluated by phenacetin metabolism. In addition, the potential mechanism of the regulation of CYP1A2 expression mediated by AhR was explored through nucleocytoplasmic shuttling, immunofluorescence, cellular thermal shift assay and molecular docking, etc. RESULTS: Psoralen and isopsoralen induced cytotoxicity in HepG2 cells, and hepatomegaly, biochemicals disorder and tissue pathological impairment in mice, respectively in dose- and time-dependent manners. Simultaneously accompanied with elevated levels of CYP1A2 mRNA and protein in the same trend, and the CYP1A2 activity was remarkably inhibited in vitro but significantly elevated overall in vivo. Besides, psoralen and isopsoralen bound to AhR and activated translocation of AhR from the cytoplasm to the nucleus, leading to the transcriptional induction of target gene CYP1A2. CONCLUSIONS: Hepatotoxicities in HepG2 cells and mice aroused by psoralen and isopsoralen were related to the induction of CYP1A2 expression and activity, whose underlying mechanism might be psoralen or isopsoralen activated AhR translocation and induced increase of CYP1A2 transcriptional expression. Hopefully, these finding are conductive to propose an alert about the combined usage of psoralen or isopsoralen and AhR ligands or CYP1A2 substrates in clinical practice.

Prognosis in early stage cutaneous T-cell lymphoma treated with psoralen plus ultraviolet A irradiation and low-dose interferon-α: Long-term efficacy and survival according to conventional and emerging clinical endpoints.

Patients with early stage cutaneous T cell lymphoma (CTCL) usually have a benign and chronic disease course, characterized by temporally response to conventional skin directed therapies and intrinsic possibility to evolve. Using the combination of psoralen plus ultraviolet A irradiation (PUVA) and low-dose interferon-α (INF), the principal treatment goal is to keep confined the disease to the skin, preventing disease progression. Among 87 patients with early stage IA to IIA MF treated with low-dose IFN-α2b and PUVA in our center, complete remission (CR) were reported in 70 patients (80.5%) and the overall response rate (ORR) was 97.8% (n = 85), with a median time to best response to therapy of 5 months (range, 1-30). Among the responders, only the 8% of patients had a relapse with major event. The median follow-up was 207 months (range, 6-295). Survival data showed a median overall survival (OS) not reached (95% CI; 235-NR months), a disease free survival (DFS) of 210 months (95% CI; 200-226 months) and a median time to next treatment (TTNT) of 38.5 months (95% CI, 33-46 months). The long follow up of this study verifies our preliminary results already published in 2006 and confirms the efficacy of INF-PUVA combination therapy in a real world setting, according conventional (OS and DFS) and emerging (TTNT) clinical endpoint of treatment efficacy.

[Biotransformation of psoralenoside and isopsoralenoside in Psoraleae Fructus incubated with human intestinal bacteria flora in vitro].

Absorption is crucial to the resultant efficacy of oral drugs where the intestinal bacteria flora functions as one of the first-pass effects.The present study investigated the biotransformation of psoralenoside and isopsoralenoside in Chinese medicine Psoraleae Fructus(the dried fruit of Psoralea corylifolia) with the internationally recognized human intestinal bacteria flora model in vitro.Pso-ralenoside and isopsoralenoside were anaerobically incubated with human intestinal bacteria flora at 37 ℃, respectively, and biotransformation products were analyzed and identified using high-performance liquid chromatography-tandem mass spectrometry(HPLC-MS) and comparison with reference standards.The main biotransformation products of psoralenoside were psoralen and a small amount of 6,7-furano-hydrocoumaric acid, and the main biotransformation products of isopsoralenoside were isopsoralen and a small amount of 5,6-furano-hydrocoumaric acid.

A new strategy for the rapid identification and validation of direct toxicity targets of psoralen-induced hepatotoxicity.

The interaction between small-molecule compounds of traditional Chinese medicine and their direct targets is the molecular initiation event, which is the key factor for toxicity efficacy. Psoralen, an active component of Fructus Psoraleae, is toxic to the liver and has various pharmacological properties. Although the mechanism of psoralen-induced hepatotoxicity has been studied, the direct target of psoralen remains unclear. Thus, the aim of this study was to discover direct targets of psoralen. To this end, we initially used proteomics based on drug affinity responsive target stability (DARTS) technology to identify the direct targets of psoralen. Next, we used surface plasmon resonance (SPR) analysis and verified the affinity effect of the 'component-target protein'. This method combines molecular docking technology to explore binding sites between small molecules and proteins. SPR and molecular docking confirmed that psoralen and tyrosine-protein kinase ABL1 could be stably combined. Based on the above experimental results, ABL1 is a potential direct target of psoralen-induced hepatotoxicity. Finally, the targets Nrf2 and mTOR, which are closely related to the hepatotoxicity caused by psoralen, were predicted by integrating proteomics and network pharmacology. The direct target ABL1 is located upstream of Nrf2 and mTOR, Nrf2 can influence the expression of mTOR by affecting the level of reactive oxygen species. Immunofluorescence experiments and western blot results showed that psoralen could affect ROS levels and downstream Nrf2 and mTOR protein changes, whereas the ABL1 inhibitor imatinib and ABL1 agonist DPH could enhance or inhibit this effect. In summary, we speculated that when psoralen causes hepatotoxicity, it acts on the direct target ABL1, resulting in a decrease in Nrf2 expression, an increase in ROS levels and a reduction in mTOR expression, which may cause cell death. We developed a new strategy for predicting and validating the direct targets of psoralen. This strategy identified the toxic target, ABL1, and the potential toxic mechanism of psoralen.

Bath Psoralen Plus UVA Therapy Suppresses Keratinocyte-Derived Chemokines in Pathogenetically Relevant Cells.

Psoriasis is a chronic inflammatory proliferative skin disease involving various types of chemokines regulating immune cell migration, localization, and activation. Bath psoralen plus UVA (PUVA) treatment is an established phototherapy for psoriasis, but its effects on chemokine levels remain unknown. We investigated the levels of 22 serum chemokines in 20 patients with psoriasis first treated with bath PUVA therapy between 2007 and 2011 in a single center and analyzed the associations between the chemokines and disease severity (PASI) before and after therapy to investigate the mechanisms of action of bath PUVA therapy. Before bath PUVA therapy, the PASI scores correlated with the serum levels of CCL17 (r = 0.581), CCL18 (r = 0.462), CCL19 (r = 0.477), and CXCL16 (r = 0.524). After bath PUVA, the serum levels of CCL17, CCL22, CXCL1, and CXCL9 were significantly decreased. Heatmap clustering and network analysis based on statistically significant Spearman correlations among the chemokines showed distinctive changes in the chemokine signature. Our findings revealed that the levels of several chemokines correlated with the disease state of psoriasis. Furthermore, bath PUVA therapy reduced the secretion of keratinocyte-derived chemokines that induce the migration of immune cells important for psoriasis pathogenesis, partly revealing the mechanism of the therapeutic activity.

A Retrospective Study of 3,000 Indian Patients with Vitiligo Treated with Phototherapy or Topical Monotherapy.

BACKGROUND: Vitiligo-affected individuals, especially patients with darker skin tones, can suffer from negative psychosocial impacts due to unpredictable development of the condition and perceived cosmetic concerns. However, given that spontaneous repigmentation can be gained in vitiligo, many patients ask for treatment due to these cosmetic concerns. In the literature, only a few studies have been documented focusing on the outcome of various treatment modalities for vitiligo. OBJECTIVE: This article highlights the retrospective response of various treatment modalities in Indian patients with vitiligo. METHODS: A retrospective chart review was performed from July 2017 to August 2018 at our private dermatology clinic. A total of 3,000 patients were enrolled in this observational study. Patient characteristics and details of phototherapy (psoralen and ultraviolet A, narrow-band ultraviolet B, excimer laser) were noted as per a predefined format. The clinical response was evaluated as a marked response, defined as repigmentation in more than 75% of the initial lesional area. RESULTS: Of those included in this retrospective analysis, 1,996 patients received phototherapy and 1,004 patients were treated with topical monotherapy. Patients treated with phototherapy only and those treated with a combination of phototherapy and topical agents showed significantly higher clinical response rates relative to patients treated with topical monotherapy only (marked response rate: 47.8% vs. 8.7%; P<0.001 and 23.4% vs. 8.7%; P<0.001). Disease subtype predominately affected the treatment response. CONCLUSION: In Indian patients with vitiligo, phototherapy appears to be an effective treatment option for both focal and vitiligo vulgaris. Due to its reliability and minimal side effects, it can be considered a preferable treatment modality for vitiligo.

The addition of topical calcipotriol to phototherapy enhance the efficacy of treatment in patients with vitiligo: A systematic review and meta-analysis.

BACKGROUND: Treatment of vitiligo has several challenges. Phototherapy and topical calcipotriol have been reported to be effective in combination with other therapies, but there is no consensus on the combination use. OBJECTIVE: To perform a systematic review and meta-analysis that elucidates the efficacy of the combination of phototherapy and topical calcipotriol. METHODS: This systematic review was performed by searching PubMed, EMBASE, Web of Science, Cochrane Library databases, Chinese National Knowledge Infrastructure (CNKI), WanFang and VIP databases for relevant publications till February 28, 2021. Relative risk (RR) and its 95% confidence interval (CI) were used to evaluate the data. Bias assessment, heterogeneity and sensitivity analysis were conducted in this meta-analysis. RESULTS: After screening, nine studies with 700 participants were included. The meta-analysis indicated that the combination of phototherapy and topical calcipotriol showed significantly higher effective rate (RR 1.11, 95% CI 1.02-1.22; p < 0.05) and apparent effective rate (RR 1.35, 95% CI 1.15-1.59; p < 0.01) than phototherapy monotherapy in the treatment of vitiligo. In addition, the side effects were minor, transient and tolerable. CONCLUSIONS: This meta-analysis provides evidence supporting phototherapy combined with topical calcipotriol as a valuable treatment modality for patients with vitiligo, which has better efficacy than monotherapy.

Potential of Ficus carica extracts against Euschistus heros: Toxicity of major active compounds and selectivity against beneficial insects.

BACKGROUND: Using plant-based extracts and their constituents has been suggested as an alternative tool to replace or integrate with the synthetic compounds used to manage insect pests. Here, we evaluated the potential of extracts obtained from Ficus carica Linn (Moraceae) branches and leaves against the Neotropical brown stink bug, Euschistus heros, one of the most prevalent insect pests in soybean fields. We further isolated and evaluated the toxicity of the extracts' major components against E. heros. Additionally, by using computational docking analysis and toxicological approaches, we assessed the physiological basis for the selectivity of these extracts against beneficial insects such as pollinator bees (i.e. Apis mellifera and the Neotropical stingless bee Partamona helleri), ladybeetles (Eriopis connexa and Coleomegilla maculata), and lacewings (Chrysoperla externa). RESULTS: Our results demonstrate that branch (LC50  = 5.9 [4.7-7.1] mg mL-1 ) and leaf (LC50  = 14.1 [12.5-15.4] mg mL-1 ) extracts exhibited similar toxicity against E. heros. Our phytochemical analysis revealed psoralen and bergapten furanocoumarins as the major components of the extract. Based on our computational predictions, these molecules' differential abilities to physically interact with the acetylcholinesterases of E. heros and beneficial insects play relevant roles in their selectivity actions. The estimated LC90 values of branch (30.0 mg mL-1 ) and leaf (30.0 mg mL-1 ) extracts killed less than 12% of the beneficial insects. CONCLUSION: Overall, our findings revealed that furanocoumarin-rich extracts obtained from F. carica extracts have the potential to be used as alternative tools in the integrated management of stink bug pests. © 2021 Society of Chemical Industry.

Phototherapy as a treatment of early-stage mycosis fungoides and predictive factors for disease recurrence: A 17-year retrospective study.

BACKGROUND: Mycosis fungoides is the most common form of cutaneous T-cell lymphoma. Narrowband ultraviolet B and psoralen and ultraviolet A are effective treatment options, but studies of their treatment efficacy and disease relapse remain limited. OBJECTIVES: This study aimed (1) to determine the efficacy of narrowband ultraviolet B and psoralen and ultraviolet A as a treatment for early-stage mycosis fungoides and explore the predictive factors for complete remission and (2) to determine the relapse rate and analyze their predictive factors, including the utility of maintenance therapy. METHODS: This was a retrospective cohort study consisting of 61 patients with early-stage mycosis fungoides (IA - IB) treated with narrowband ultraviolet B or psoralen and ultraviolet A as the first-line therapy from January 2002 to December 2018 at the Division of Dermatology, Ramathibodi Hospital, Bangkok, Thailand. Cox regression analysis and Kaplan-Meier survival curve were performed for the main outcomes. RESULTS: A complete remission was achieved by 57 (93.5%) patients. The median time to remission was 7.80 ± 0.27 months. Types of phototherapy (narrowband ultraviolet B or psoralen and ultraviolet A), age and gender did not associate with time to remission, while the presence of poikiloderma and higher disease stage led to a longer time to remission. The cumulative incidence of relapse was 50.8%. The median time to relapse was 24.78 ± 5.48 months. In patients receiving phototherapy during the maintenance period, a treatment duration longer than six months was associated with a significantly longer relapse-free interval. CONCLUSION: Narrow-band-ultraviolet B and psoralen and ultraviolet A are effective treatment options for early-stage mycosis fungoides. Maintenance treatment by phototherapy for at least six months seems to prolong remission.

Bergamottin and 5-Geranyloxy-7-methoxycoumarin Cooperate in the Cytotoxic Effect of Citrus bergamia (Bergamot) Essential Oil in Human Neuroblastoma SH-SY5Y Cell Line.

The plant kingdom has always been a treasure trove for valuable bioactive compounds, and Citrus fruits stand out among the others. Bergamottin (BRG) and 5-geranyloxy-7-methoxycoumarin (5-G-7-MOC) are two coumarins found in different Citrus species with well-acknowledged pharmacological properties. Previously, they have been claimed to be relevant in the anti-proliferative effects exerted by bergamot essential oil (BEO) in the SH-SY5Y human neuroblastoma cells. This study was designed to verify this assumption and to assess the mechanisms underlying the anti-proliferative effect of both compounds. Our results demonstrate that BRG and 5-G-7-MOC are able to reduce the proliferation of SH-SY5Y cells, inducing apoptosis and increasing cell population in sub-G0/G1 phase. Moreover, we demonstrated the pro-oxidant activity of the two coumarins that increased reactive oxygen species and impaired mitochondrial membrane potential. From a molecular point of view, BRG and 5-G-7-MOC were able to modulate apoptosis related factors at both protein and gene levels. Lastly, we evaluated the synergistic effect of their combination, finding that the highest synergy was observed at a concentration ratio similar to that occurring in the BEO, supporting our initial hypothesis. Taken together, our results deepen the knowledge regarding the effect of BRG and 5-G-7-MOC in SH-SY5Y cells, emphasizing the relevance of their cooperation in achieving this effect.