Comparative genomics of the medicinal plants Lonicera macranthoides and L. japonica provides insight into genus genome evolution and hederagenin-based saponin biosynthesis.

Lonicera macranthoides (LM) and L. japonica (LJ) are medicinal plants widely used in treating viral diseases, such as COVID-19. Although the two species are morphologically similar, their secondary metabolite profiles are significantly different. Here, metabolomics analysis showed that LM contained ~86.01 mg/g hederagenin-based saponins, 2000-fold higher than LJ. To gain molecular insights into its secondary metabolite production, a chromosome-level genome of LM was constructed, comprising 9 pseudo-chromosomes with 40 097 protein-encoding genes. Genome evolution analysis showed that LM and LJ were diverged 1.30-2.27 million years ago (MYA). The two plant species experienced a common whole-genome duplication event that occurred ∼53.9-55.2 MYA before speciation. Genes involved in hederagenin-based saponin biosynthesis were arranged in clusters on the chromosomes of LM and they were more highly expressed in LM than in LJ. Among them, oleanolic acid synthase (OAS) and UDP-glycosyltransferase 73 (UGT73) families were much more highly expressed in LM than in LJ. Specifically, LmOAS1 was identified to effectively catalyse the C-28 oxidation of ß-Amyrin to form oleanolic acid, the precursor of hederagenin-based saponin. LmUGT73P1 was identified to catalyse cauloside A to produce α-hederin. We further identified the key amino acid residues of LmOAS1 and LmUGT73P1 for their enzymatic activities. Additionally, comparing with collinear genes in LJ, LmOAS1 and LmUGT73P1 had an interesting phenomenon of 'neighbourhood replication' in LM genome. Collectively, the genomic resource and candidate genes reported here set the foundation to fully reveal the genome evolution of the Lonicera genus and hederagenin-based saponin biosynthetic pathway.

Efficacy of topical acidified aliphatic ester for treatment of axillary osmidrosis by rebalancing skin microecology.

This study investigated the mechanism and efficacy of topical acidified aliphatic ester for treatment of axillary osmidrosis (AO). A total of 32 AO patients were enrolled in this study. In the initial pilot study, 20 patients were double-blindly, randomly divided into acidified aliphatic ester or aliphatic ester treatment groups, followed by efficacy evaluation after 4 weeks. Then, all patients (n = 32) were treated with topical acidified aliphatic ester for 16 weeks. Efficacy was evaluated at every 4 weeks, and at 3- and 6-month follow-ups. Changes of pH values and microecology at targeting sites were analyzed. In the first cohort (n = 20) of pilot study, acidified aliphatic ester showed significantly higher curative rate (60% vs 10%, P < .05) and effective rate (90% vs 30%; P < .05) than aliphatic ester. For the next 16 weeks, 25 of 32 cases completed treatment. Curative rate showed gradual and significant increases from 64% to 96% during the treatment courses (P = .001); it slightly but insignificantly decreased at 3- and 6- month follow-ups. Abundance of Corynebacterium and Anaerobic bacteria decreased while Staphylococcus increased after treatments. Axillary pH values negatively correlated with Staphylococcus abundance (r = -.40, P = .01) and positively with Corynebacterium abundance (r = .64, P = .01). We concluded that topical acidified aliphatic ester could effectively alleviate conditions of AO patients by reducing value of axillary pH and rebalancing axillary microecology.

Characterization of Laser-Resistant Port Wine Stain Blood Vessels Using In Vivo Reflectance Confocal Microscopy.

BACKGROUND AND OBJECTIVES: Port wine stain (PWS) is a congenital vascular malformation of the human skin. Laser is the treatment of choice for PWS. Laser-resistant PWS is one crucial factor accounting for inadequate treatment outcome, which needs to be fully characterized. This study aims to quantitatively characterize the morphology of laser-resistant PWS blood vessels in the upper papillary dermis using in vivo reflectance confocal microscopy (RCM). STUDY DESIGN/MATERIALS AND METHODS: A total of 42 PWS subjects receiving laser treatment from August 2016 through July 2018 were enrolled into this study. Thirty-three subjects had facial PWS; nine had extremity PWS. All subject's PWS received multiplex 585/1,064 nm laser treatment. RCM images were taken before and after treatment. The density, diameter, blood flow, and depth of PWS blood vessels were analyzed. RESULTS: We found 44.4% PWS on the extremities (four out of nine subjects) were laser-resistant, which was significantly higher (P < 0.001) when compared with those PWS on the face (15.2%, 5 out of 33 subjects). The laser-resistant facial PWS blood vessels had significantly higher blood flow (1.35 ± 0.26 U vs. 0.89 ± 0.22 U, P < 0.001), larger blood vessel diameters (109.60 ± 18.24 µm vs. 84.36 ± 24.04 µm, P = 0.033) and were located deeper in the skin (106.01 ± 13.87 µm vs. 87.82 ± 12.57 µm, P < 0.001) in the skin when compared with laser-responsive PWS on the face. The average PWS blood vessel density (17.01 ± 4.63/mm2 vs. 16.61 ± 4.44/mm2 , P = 0.857) was not correlated to the laser resistance. CONCLUSIONS: Laser-resistant PWS blood vessels had significantly higher blood flow, larger diameters, and were located deeper in the skin. RCM can be a valuable tool for a prognostic evaluation on laser-resistant lesions before treatment, thereby providing guidance for tailored laser treatment protocols, which may improve the therapeutic outcome. The limitations for this study include relative small sample size and acquisitions of different blood vessels before and after 2 months of treatment. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Serum interleukin-31 level and pruritus in atopic dermatitis: A Meta-analysis.

OBJECTIVE: To investigate associations of interleukin-31 (IL-31) and pruritus in atopic dermatitis (AD) with Meta-analysis.
 Methods: Materials were extracted from the citations listed in the following databases: PubMed, Science Direct, Web of Science and Cochrane. Key search terms included: atopic dermatitis, pruritus, and IL-31. The Meta-analysis was used to analyze the correlation between pruritws in AD and IL-31 expression level.
 Results: The Meta-analysis showed that serum IL-31 levels were higher in AD patients than those in the healthy controls. The levels of IL-31 were higher in severe AD patients than those in the mild and moderate AD patients. Moreover, a positive correlation between serum IL-31 levels and severity of pruritus was identified.
 Conclusion: Increased serum levels of IL-31 generally exist in the AD patients, and it may accelerate the pruritus in the AD patients.

[Bactericidal effect of ozonated camellia oil on Staphylococcus aureus in vitro].

OBJECTIVE: To explore a new method for detecting the bactericidal effect of oiling agent in vitro, and to determine the disinfectant effecacy of ozonated camellia oil on Staphylococcus aureus.
 Methods: Suspension of Staphylococcus aureus was prepared and innoculated on the LB plate by plate scribing method. After culture overnight, 21 bacterial monoclones with the same diameter were selected and divided into 3 groups: A negative control group, a baseoil (camellia oil) group and an ozonated camellia oil group. We used a ring to isolate the single clone and added oil inside the ring, cultured the whole plate over night, picked out each single clone (with gel) to 5 mL LB medium and cultured it for 12 h. The final concentration of the LB medium was detected by plate count method and turbidimetry.
 Results: According to the plate count method and turbidimetry, the bacterial concentration in the ozonated camellia oil group was lower than that in the negative control group and base oil group (P<0.001).
 Conclusion: Bacterial monoclone culture method shows that ozonated camellia oil can significantly kill Staphylococcus aureus, and this method is an effective method for evaluating the bactericidal function of the oiling agent in vitro.

[Attenuation rules and germicidal efficacy of ozoneted water].

OBJECTIVE: To determine initial concentrations of ozonated water under different temperatures, attenuation rules of ozonated water under the room temperature (25 ℃), and to inspect the effects of ozonated water under different concentrations on common microorganisms.
 Methods: The online test method and the plate cultivation method were employed to check the concentrations and killing rates on common microorganisms of ozonated water produced by HZ-2601 B Ozone Water Generating Instrument.
 Results: The initial concentrations of ozonated water at 20, 25, 30, 35, and 40 ℃ were 4.38, 4.26, 3.12, 2.76, and 1.31 mg/L, respectively. The ozonated water was rapidly attenuated at first 10 min. The concentration of ozonated water still remained at 1.06 mg/L and 0.37 mg/L at 25 and 30 ℃ after 30 min. The average killing rates for Pseudomonas aeruginosa, Escherichia coli, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and Candida albicans in 1.0 mg/L ozonated water for 1 min were 99%, 100%, 100%, 100%, and 100%, respectively. The average killing rates of Escherichia coli, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans in 0.3 mg/L ozonated water for 1 min were 100%, 100%, 100%, 95%, and 92%, respectively.
 Conclusion: The initial concentrations of ozonated water produced by HZ-2601 B Ozone Water Generating Instrument decrease with the increase of temperature. Ozonated water under 20-30 ℃ has good sterilization effect on common microorganisms.

Efficacy of combination of ozonated water with oil for treatment of tinea pedis.

OBJECTIVE: To evaluate efficacy of combined therapy with ozonated water and oil on patients with tinea pedis.
 Methods: A total of 60 patients with tinea pedis were divided into 2 groups in a randomized and blinded test. Patients in a control group were treated with naftinfine hydrochloride and ketoconazole cream once a day. Patients in an ozone group were treated with ozonated water bath and then ozonated oil topical application once a day. Patients in the 2 groups were treated for 4 weeks. Clinical and laboratory data were collected for both groups at the end of the 1st week, the 2nd week, and the 4th week. The Pearson chi-square was performed to compare scores of the clinical signs and symptoms (CSS) and the mycological result between the 2 groups. Independent samples T-test was performed to compare the curative effect between the 2 groups.
 Results: After 4 weeks' treatment, 6 patients were positive in the control group determined by mycological examination while 1 patient was positive in the ozone group, with no significant difference between the 2 groups (P>0.05). Changes in CSS at the end of the 1st week, 2nd week, and 4th week were obtained and showed no significant difference between the 2 groups at the 3 different time points (P>0.05). No side effects were observed.
 Conclusion: Combination of ozonated water with oil is effective on treatment of tinea pedis and it shows no side effects.

[Topical ozone therapy: An innovative solution to patients with herpes zoster].

OBJECTIVE: To observe the clinical efficacy and safety of topical ozone therapy for patients with herpes zoster by reflectance confocal microscopy (RCM).
 Methods: A total of 60 patients with herpes zoster were divided into a control group and an ozone treatment group (n=30). In the control group, patients took oral valacyclovir tablets or granules (0.3 g per day, three times a day) and they were subjected to local weak laser irradiation treatment plus topical 2% mupirocin ointment twice a day. In the ozone group, the treatment is same as the control group except mupirocin ointment was replaced with topical ozone treatment (hydrotherapy every day plus ozonated oil twice a day). The clinical symptoms, discoid cell and adverse reactions were observed and taken records at day 0, 3, 7 and 14. Statistical analysis was performed to compare the clinical efficacy between the 2 groups. 
 Results: On the seventh day of treatment, the discoid cells of the ozone group disappeared, and the difference between the control group and the ozone group was statistically significant (P<0.05). The difference of decreased percentage of pain scores at each time point between the 2 groups was statistically significant (P<0.05). The clinical efficacy was 100% in the ozone group and 86.7% in the control group, with significant difference between the 2 groups (P<0.05).
 Conclusion: Topical ozone therapy in patients with herpes zoster is helpful in relieving pain, shortening the course as well as improving the clinical efficacy without obvious adverse reactions. It is worth to be popularized.

[Safety evaluation for medical ozone oil on skin].

OBJECTIVE: To evaluate skin irritation, acute toxicity, and allergy of medical ozone oil for clinical application.
 Methods: In contrast to their left and right side irritation, one or more skin irritation tests were performed on the intact and damaged skins of guinea pigs. With the maximum concentration, acute skin toxicity test was applied on the intact and damaged skins of rats.Active cutaneous anaphylaxis was applied to the guinea pigs.
 Results: High concentration (ozone consumption: 150 g/L) of medical ozone oil showed a slight irritation on the broken skin of guinea pigs, while low concentrations did not show skin irritation.Medical ozone oil had no obvious acute toxicity to rats. The medical ozone oil and base oil showed mildallergy for the skin of guinea pig.
 Conclusion: The irritation of medical ozone oil is related to its concentration. With appropriateconcentration and duration of treatment, medical ozone oil is safe.

[Effect of ozone on Staphylococcus aureus colonization in patients with atopic dermatitis].

OBJECTIVE: To verify the effect of ozone on Staphylococcus aureus (S. aureus) colonization in patients with atopic dermatitis (AD) and its correlation with the patient's status.
 Methods: A total of 12 patients with moderate or severe AD, aged from 6 to 65 years, were recruited from outpatient of the Third Xiangya Hospital. The treatment sides were showered with ozonated water and smeared with ozonated oil for 7 days (twice a day), while the control sides were washed with warm running water and smeared with base oil. At different time points, the severity scoring of atopic dermatitis (SCORAD) scores, sleep and pruritus scores were assessed and compared between the two sides. Meanwhile, plate cultivation was used to quantitatively detect the changes of S. aureus colonization in skin lesions.
 Results: After 7 days treatment, erythema and pimples were decreased in the treatment sides. The clear skin texture, smooth skin, improved skin lesions were also observed by dermoscopic examination. The results of reflectance confocal microscopy (RCM) demonstrated that the parakeratosis was improved, the structures were clearer, and the inflammatory cells infiltration was reduced after ozone treatment for 7 days. After ozone treatment for 3 and 7 days, the S. aureus colonization in the treatment sides decreased by (75.55±21.81)% and (97.24±2.64)% respectively. Compared to that of control sides, the percentage of S. aureus colony after ozone treatment for 7 days decreased significantly (P<0.01). After ozone treatment for 7 days, the SCORAD scores, sleep and pruritus scores were significantly decreased (all P<0.01). There was a linear correlation between the decreasing percentage of S. aureus colony and the declining percentage of SCORAD scores in AD patients.
 Conclusion: Topical ozone therapy can effectively reduce S. aureus colony in skin lesions and alleviate the severity of AD patients with moderate to severe degree.

[Topical ozone application: An innovative therapy for infantile atopic dermatitis].

OBJECTIVE: To evaluate the clinical efficacy and safety of the innovative topical ozone therapy for infantile atopic dermatitis.
 Methods: Sixty children with atopic dermatitis were divided into a treatment group and a control group. The treatment group was showered with ozonated water (3-5 times a week) and smeared with ozonated oil (twice a day), while the control group was washed with warm running water and smeared with base oil, adding moisturizer if necessary. The treatment course was 2 weeks. Efficacy and side effect were evaluated.
 Results: The skin exudation was reduced and erosion was healing after 3-5 days topical ozone therapy for infantile atopic dermatitis. The effective rates were 80.0% and 20.0% in the treatment group and control group for 1 week, and 89.6% and 30.7% for 2 weeks, respectively, with significant difference between the 2 groups (P<0. 001).
 Conclusion: Innovative treatment of infantile atopic dermatitis with topical ozone application is safe and effective, which is worth popularizing in clinic.

Epicutaneous sensitization with ovalbumin, staphylococcal enterotoxin B and vitamin D analogue induces atopic dermatitis in mice.

OBJECTIVE: To illuminate a method for establishment of a cost-efficient atopic dermatitis (AD) mouse model by topical application of ovalbumin (OVA), super-antigen staphylococcal enterotoxin B (SEB), and calcipotriene ointment (CO) on the back of BALB/c mice.
 Methods: Experimental mice were topically treated with OVA/SEB or OVA/SEB/CO every other day during 15 days of induction. Clinical alterations on the skin area were monitored every other day. Epidermal thickness were measured by reflectance confocal microscope (RCM) before harvest. Inflammatory cells in skin biopsies were marked by hematoxylin-eosin (HE) staining. Blood sample and skin biopsies were measured by ELISA and quantitative real-time PCR to detect the expression of IL-2, IL-4, IL-31, interferon (IFN)-γ, tumor necrosis factor (TNF)-α pruritus-associated nerve growth factor (NGF), and serum IgE.
 Results: Human AD-like cutaneous local inflammatory reaction was characterized by the accumulation of inflammatory cells, increased epidermal thickness and serum IgE levels as well as Th1 cell-associated cytokines (IFN-γ, TNF-α), Th2 cell-associated cytokines (IL-4, IL-31), and NGF in the OVA/SEB/CO group compared with that in the normal control group or the OVA/SEB group.
 Conclusion: OVA/SEB/CO can induce an AD-like mouse model with lower economic and time consumption.

Bacillomycin L and surfactin contribute synergistically to the phenotypic features of Bacillus subtilis 916 and the biocontrol of rice sheath blight induced by Rhizoctonia solani.

The antagonistic activity of lipopeptides in Bacillus subtilis 916 has been well documented, yet relatively little is known about their mechanism in biofilm formation and environmental colonization. This study sought to examine the interaction of B. subtilis 916 on Rhizoctonia solani-infected rice sheath to elucidate the mechanism of colonization on plant leaves. Results showed that the mutants Δbac, Δsrf, and Δsrf + bac of B. subtilis 916, deficient in bacillomycin L and surfactin production, respectively, not only altered colony morphology but also changed swarming motility, reduced antagonistic activity, and decreased biofilm formation. In particular, biofilm formation in mutant Δbac, not Δsrf or Δsrf + bac, were restored with addition of surfactin and bacillomycin L at 10 and 50 µg/mL, respectively. Moreover, surfactin and bacillomycin L were able to restore or enhance swarming motility in the corresponding mutants at 10 µg/mL, respectively. With the aid of green fluorescent protein tagging, it was demonstrated that B. subtilis 916 formed a robust biofilm on the rice sheath blight lesion and colonized well on R. solani-infected rice sheath, while its corresponding mutants performed poorly. These observations also correlated with the rice cultivar pot experiments, in which B. subtilis 916 exhibited greater biocontrol than its mutants. Our results suggest that surfactin and bacillomycin L contribute differently but synergistically to the biocontrol of rice sheath blight in B. subtilis 916 through its antifungal activity, biofilm formation, and colonization.

Topical Ozone Accelerates Diabetic Wound Healing by Promoting Re-Epithelialization through the Activation of IGF1R-EGFR Signaling.

Ozonated oil increases the healing of chronic diabetic wounds, but the underlying mechanisms remain unclear. We investigated the effect of topical ozonated oil on wound healing in mice with diabetes with diet-induced obesity and further elucidated the role of EGFR and IGF1R signaling in diabetic wound healing. We found that topical ozonated oil accelerated wound healing; increased phosphorylation of IGF1R, EGFR, and VEGFR; and improved vascularization at the wound leading edge in mice with diabetes with diet-induced obesity. Exposure of normal epidermal keratinocytes to ozonated medium (20 µM for 2 hours daily) increased cell proliferation and migration distance by increasing phosphorylation of IGF1R and EGFR and downstream phosphoinositide 3-kinase, protein kinase B, and extracellular signal-regulated kinase. These findings shed light on the mechanism for topical ozone action in chronic wounds and support its potential therapeutic application.

Increased IRF9-STAT2 Signaling Leads to Adaptive Resistance toward Targeted Therapy in Melanoma by Restraining GSDME-Dependent Pyroptosis.

Melanoma is the leading cause of cutaneous malignancy death. BRAF inhibitors (BRAFis) have been developed as target therapies because nearly half of patients with melanoma have activating alterations in the BRAF oncogene. However, the fast-developed resistance to BRAFis limits their treatment efficacy. Understanding the molecular mechanism of resistance is vital to increase the success of clinical treatment. We searched three datasets (GSE42872, GSE52882, and GSE106321) from the Gene Expression Omnibus database, which analyzed the mRNA expression profile of melanoma cells under BRAFis treatment, and the differentially expressed genes were identified. Among all the differentially expressed genes, the increased expression of IRF9 and STAT2 was prominent and verified to be upregulated in BRAFis-treated melanoma cells. Furthermore, IRF9 or STAT2 overexpression led to less sensitivity, whereas IRF9 or STAT2 knockdown increased sensitivity to BRAFis treatment. In a subcutaneous xenograft tumor model, we showed that IRF9 or STAT2 overexpression slowed BRAFis-induced tumor shrinking, but IRF9 or STAT2 knockdown led to BRAFis-induced tumor shrinking more quickly. Interestingly, we discovered that IRF9-STAT2 signaling controlled GSDME-dependent pyroptosis by restoring GSDME transcription. These results suggest that targeting IRF9/STAT2 may lead to more promising effective treatments to prevent melanoma resistance to BRAFis by inducing pyroptosis.

Reduced expression of Collagen 17A1 in naturally aged, photoaged, and UV-irradiated human skin in vivo: Potential links to epidermal aging.

Collagen 17A1 (COL17A1) is a transmembrane structural component of the hemidesmosome that mediate adhesion of keratinocytes to the underlying membrane. Recent work in mouse showed that COL17A1 deficiency leads to premature skin aging. Although the role COL17A1 in skin aging is becoming recognized in mouse models, its connection to human skin natural aging/photoaging/ultraviolet (UV)-irradiated human skin has received little attention. To determine COL17A1 expression in naturally aged and photoaged as well as acutely UV irradiated human skin, skin samples were obtained from: (1) young (N = 10, 26.7±1.3 years) and aged (N = 10, 84.0 ± 1.7 years) sun-protected buttock skin; (2) photoaged extensor forearm and subject matched sun-protected underarm skin (N = 6, 56.0 ± 3.4 years); (3) solar-simulated UV-irradiated buttock skin (N = 6, 51.2 ± 3.6 years). COL17A1 levels were determined by immunohistology and RT-PCR, and the potential role of COL17A1 in epidermal aging was investigated by immunostaining of the marker for interfollicular epidermal stem cells and keratinocytes proliferation. We found that COL17A1 is specifically expressed in interfollicular epidermal stem cell niches, and that significantly reduced in naturally aged, photoaged, and acute UV-irradiated human skin in vivo. COL17A1 is identified as keratinocyte-specific collagen, and UV irradiation significantly downregulates COL17A1 expression in keratinocytes. Reduced expression of COL17A1 is positively correlated with impaired regeneration of keratinocytes and reduced dermal-epidermal junction as well as thin epidermis in aged human skin (epidermal aging). We also confirmed that keratinocyte-specific integrin ß4 (ITGB4), which interacts with COL17A1, is reduced in aged human skin. Mechanistically, we found that matrix metalloproteinases (MMPs) are responsible for UV-mediated COL17A1 degradation in both in vitro keratinocytes and in vivo mouse skin. These data suggest the possible links between reduced expression of COL17A1 and epidermal aging in human skin.

DNA methylation regulatory patterns and underlying pathways behind the co-pathogenesis of allergic rhinitis and chronic spontaneous urticaria.

Background: Allergic rhinitis (AR) and chronic spontaneous urticaria (CSU) are often concurrent in patients. Changes in DNA methylation affect T cell biological processes, which may explain the occurrence and progression of comorbidity. However, downstream regulatory pathways of DNA methylation in two diseases and the underlying mechanisms have not been fully elucidated. Methods: The GSE50101, GSE72541, GSE50222 and OEP002482 were mined for the identification of differentially expressed genes (DEGs) or co-expressed genes and differentially methylated genes (DMGs) in AR and CSU patients. We applied GO analysis and consensus clustering to study the potential functions and signal pathways of selected genes in two diseases. GSVA and logistic regression analysis were used to find the regulatory pathway between DNA methylation and activation patterns of CD4+ T cells. Besides, we used the Illumina 850k chip to detect DNA methylation expression profiles and recognize the differentially methylated CpG positions (DMPs) on corresponding genes. Finally, we annotated the biological process of these genes using GO and KEGG pathway analysis. Result: The AR-related DEGs were found closely related to the differentiation and activation of CD4+ T cells. The DEGs or co-expressed genes of CD4+ T cells in AR and CSU patients were also clustered using GO and KEGG analysis and we got 57 co-regulatory pathways. Furthermore, logistic regression analysis showed that the regulation of cellular component size was closely related to the activation of CD4+ T cells regulated by DNA methylation. We got self-tested data using the Illumina 850k chip and identified 98 CpGs that were differentially methylated in patients. Finally, we mapped the DMPs to 15 genes and found that they were mainly enriched in the same CD4+T cell regulating pathway. Conclusion: Our study indicated that DNA methylation affected by pollen participated in the activation patterns of CD4 + T cells, providing a novel direction for the symptomatic treatment of the co-occurrence of AR and CSU.

IPL irradiation rejuvenates skin collagen via the bidirectional regulation of MMP-1 and TGF-ß1 mediated by MAPKs in fibroblasts.

The efficacy of intense pulsed light (IPL) in remodeling the extracellular matrix of aged skin had been proven by an increasing number of clinical trials. However, because of the lack of research about the underlying molecular and signaling mechanisms, its efficiency had not been accepted universally. A potential mechanism of IPL rejuvenation effects is due to its different effects on diverse cytokines, the impact of IPL on them may determine the phenotype and prognosis of the aged skin. We designed this study to evaluate the impact of IPL on the secretion of matrix metalloproteinase-1 (MMP-1), transforming growth factor-ß1 (TGF-ß1), and the mitogen-activated protein kinase (MAPK) signaling pathway in human skin fibroblasts, and tried to study the respective functions of MAPKs as mediators of the MMP-1, TGF-ß1 secretion. Results showed that the MMP-1 secretion was only enhanced by IPL at 10 J/cm(2); while the TGF-ß1 secretion was inhibited by IPL when the fluence was below 36 J/cm(2), but enhanced at 72 J/cm(2). Meanwhile, ERK inhibitor PD98059 decreased MMP-1 secretion, but did not show a significant influence on TGF-ß1; JNK inhibitor SP600125 increased the secretion of MMP-1 and decreased the TGF-ß1 secretion; P38 inhibitor SB203580 had no significant influence on MMP-1 but increased the secretion of TGF-ß1. Our findings indicated that the bidirectional influence of IPL on the secretion of MMP-1 and TGF-ß1 is a potential mechanism of its skin rejuvenation effect; and the secretion of these two cytokines can be mediated by MAPKs.

[Propranolol in the treatment of problematic infantile hemangiomas].

OBJECTIVE: To evaluate the short-term efficacy and safety of propranolol for problematic infantile hemangiomas. METHODS: Oral propranolol was administered to 68 infants with heamngiomas diagnosed by clinical evaluation and adjuvant examination at 1.0~2.0 mg per kilogram of body weight per day, divided to 2 or 3 times. The patients revisited once a month. The changes of the tumor size, texture, and color were monitored and recorded at a regular interval.The adverse effects after medication were observed and managed accordingly.The short-term results were evaluated using a 4-grade system. RESULTS: All the 68 infants were followed up for 3-13 months, except that 1 infants combined with other diseases and 4 withdrew.The overall response was Scale 1 in 8 infants, Scale II in 13, Scale III in 29, and Scale IV in 13. No serious adverse effects were seen, but none cured entirely as well. CONCLUSION: Oral propranolol is safe and effective for infantile heamngioma with good short-term result. It could be used as the primary drug for problematic infantile hemangiomas at the rapid growth stage of hemangiomas.

Integrative Omics Analyses Reveal the Effects of Copper Ions on Salvianolic Acid Biosynthesis.

Salvianolic acids, a group of secondary metabolites produced by Salvia miltiorrhiza, are widely used for treating cerebrovascular diseases. Copper is recognized as a necessary microelement and plays an essential role in plant growth. At present, the effect of copper on the biosynthesis of SalAs is unknown. Here, an integrated metabolomic and transcriptomic approach, coupled with biochemical analyses, was employed to dissect the mechanisms by which copper ions induced the biosynthesis of SalAs. In this study, we identified that a low concentration (5 µM) of copper ions could promote growth of S. miltiorrhiza and the biosynthesis of SalAs. Results of the metabolomics analysis showed that 160 metabolites (90 increased and 70 decreased) were significantly changed in S. miltiorrhiza treated with low concentration of copper ions. The differential metabolites were mainly involved in amino acid metabolism, the pentose phosphate pathway, and carbon fixation in photosynthetic organisms. The contents of chlorophyll a, chlorophyll b, and total chlorophyll were significantly increased in leaves of low concentration of copper-treated S. miltiorrhiza plants. Importantly, core SalA biosynthetic genes (laccases and rosmarinic acid synthase), SalA biosynthesis-related transcription factors (MYBs and zinc finger CCCH domain-containing protein 33), and chloroplast proteins-encoding genes (blue copper protein and chlorophyll-binding protein) were upregulated in the treated samples as indicated by a comprehensive transcriptomic analysis. Bioinformatics and enzyme activity analyses showed that laccase 20 contained copper-binding motifs, and its activity in low concentration of copper ions-treated S. miltiorrhiza was much higher than that in the control. Our results demonstrate that enhancement of copper ions of the accumulation of SalAs might be through regulating laccase 20, MYBs, and zinc finger transcription factors, and photosynthetic genes.