Causal effects of genetically determined metabolites on androgenetic alopecia: A two-sample Mendelian randomization analysis.

BACKGROUND: Androgenic alopecia (AGA) is the most common non-scarring alopecia disorder. Given its increasing incidence and onset during adolescence, AGA significantly impacts both the physical and psychological well-being of affected individuals. Emerging evidence suggests a pivotal role of metabolites in AGA. This study aims to elucidate the causal relationship between metabolites and AGA using Mendelian randomization (MR) analysis. METHODS: We conducted a two-sample Mendelian randomization (TSMR) analysis based on a genome-wide association study (GWAS) to assess the causality of 452 metabolites on AGA. The main approach employed for inferring causal effects was inverse variance weighted (IVW), which was complemented by MR-Egger regression, weighted median, as well as MR pleiotropy residual sum and outlier (MR-PRESSO) approaches. Additionally, sensitivity analyses were performed to ensure result robustness. Single nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) in GWAS dataset comprising 452 metabolites. RESULTS: Notably, we identified Scyllo-inositol and Alpha-ketoglutarate as the most potent protective factors against AGA, while Heme* and 2-palmitoylglycerophosphocholine* emerged as significant risk factors for AGA. Furthermore, sensitivity analysis revealed no heterogeneity in these findings. CONCLUSIONS: Overall, our research suggests a potential causal link between metabolites and AGA, offering a more comprehensive insight into the pathogenesis of AGA and present additional strategies for prevention and treatment.

Expert consensus on perioperative integrated skincare for noninvasive energy-based device aesthetic procedures in clinical practice in China.

BACKGROUND: Noninvasive energy-based device (NI-EBD) aesthetic procedures has recently gained widespread usage for treating various skin conditions, enhancing skin texture and performing rejuvenation-related procedures. However, practically all NI-EBD procedures result in variable degrees of damage to the skin barrier, inducing pathological and physiological processes such as oxidative stress and inflammation, and only a small percentage of individuals possess the innate ability to restore it. OBJECTIVE: To introduce the concept of integrated skincare and establish standardized operational procedures for perioperative integrated skincare, and furnish a theoretical basis for clinical diagnosis and treatment performed by professional medical aestheticians. METHODS: The author leveraged domestic and international guidelines, clinical practice expertise and evidence-based research, adapting them to suit the specific circumstances in China. RESULTS: The consensus were provided four parts, including concept and essence of integrated skincare, integrated skincare significance during the perioperative phase of NI-EBD procedures, active ingredients and functions of effective skincare products, standardized perioperative skincare procedure for NI-EBD procedures and precautions. For the standardized perioperative skincare procedure, four recommendations were listed according to different stages during NI-EBD procedures. CONCLUSION: These recommendations create the 'Expert Consensus on Perioperative Integrated Skincare for Noninvasive Energy-Based Device Aesthetic Procedures in Clinical Practice in China'.

Isolation, identification and transcriptome analysis of triadimefon-degrading strain Enterobacter hormaechei TY18.

Triadimefon, a type of triazole systemic fungicide, has been extensively used to control various fungal diseases. However, triadimefon could lead to severe environmental pollution, and even threatens human health. To eliminate triadimefon residues, a triadimefon-degrading bacterial strain TY18 was isolated from a long-term polluted site and was identified as Enterobacter hormaechei. Strain TY18 could grow well in a carbon salt medium with triadimefon as the sole nitrogen source, and could efficiently degrade triadimefon. Under triadimefon stress, a total of 430 differentially expressed genes (DEGs), including 197 up-regulated and 233 down-regulated DEGs, were identified in strain TY18 using transcriptome sequencing (RNA-Seq). Functional classification and enrichment analysis revealed that these DEGs were mainly related to amino acid transport and metabolism, carbohydrate transport and metabolism, small molecule and pyrimidine metabolism. Interestingly, the DEGs encoding monooxygenase and hydrolase activity acting on carbon-nitrogen were highly up-regulated, might be mainly responsible for the metabolism in triadimefon. Our findings in this work suggest that strain E. hormaechei TY18 could efficiently degrade triadimefon for the first time. They provide a great potential to manage triadimefon biodegradation in the environment successfully.

Effect and mechanism of coexistence of microplastics on arsenate adsorption capacity in water.

Arsenic pollution control technology in water was important to ensure environmental health and quality safety of agricultural products. Therefore, the adsorption performance of three adsorbents for chitosan, sepiolite, and Zeolitic Imidazolate Framework-8 (ZIF-8) were investigated in arsenate contaminated water. The results revealed that the adsorption capacity of ZIF-8 was higher than that of chitosan and sepiolite. The analysis of adsorption isotherm models showed that the behavior of ZIF-8 was more consistent with the Langmuir model. Furthermore, the adsorption mechanisms of three adsorbents for arsenate were investigated by Fourier-transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). The analysis of FTIR showed that ZIF-8 maintained the stability of the interaction with arsenate by forming As-O chemical bonds. However, the effect of chitosan and sepiolite with arsenate was mainly physical adsorption. The analysis of XPS showed that the absorption of ZIF-8 with arsenate involved metal sites and nitrogen through the characteristic peak and the change of the binding energy. Furthermore, the impact of microplastics as a widespread coexistence pollutant in the water on adsorbent performance was investigated. The results indicated that the adsorption capacity of ZIF-8 was almost not affected by microplastics. The maximum adsorption amount of arsenate was changed from 73.45 mg/g to 81.89 mg/g. However, the maximum adsorption amount of chitosan and sepiolite decreased by 31.4 % and 11.6 %, respectively. The analysis of FTIR and XPS revealed that ZIF-8 enhances arsenate adsorption by forming N-O-As bonds in the presence of microplastics. This study provides scientific evidence for the management of arsenate pollution in water bodies, especially in complex water bodies containing microplastics.

A randomized, double-blind, placebo-controlled phase II study to evaluate the efficacy and safety of ivarmacitinib (SHR0302) in adult patients with moderate-to-severe alopecia areata.

BACKGROUND: Alopecia areata (AA) is a CD8+ T cell-mediated autoimmune disease characterized by nonscarring hair loss. Ivarmacitinib, which is a selective oral Janus kinase 1 inhibitor, may interrupt certain cytokine signaling implicated in the pathogenesis of AA. OBJECTIVE: To evaluate the efficacy and safety of ivarmacitinib in adult patients with AA who have ≥25% scalp hair loss. METHODS: Eligible patients were randomized 1:1:1:1 to receive ivarmacitinib 2, 4, or 8 mg once daily or placebo for 24 weeks. The primary end point was the percentage change from baseline in the Severity of Alopecia Tool score at week 24. RESULTS: A total of 94 patients were randomized. At week 24, the least squares mean difference in the percentage change from baseline in the Severity of Alopecia Tool score for ivarmacitinib 2, 4, and 8 mg and placebo groups were -30.51% (90% CI, -45.25, -15.76), -56.11% (90% CI, -70.28, -41.95), -51.01% (90% CI, -65.20, -36.82), and -19.87% (90% CI, -33.99, -5.75), respectively. Two serious adverse events-follicular lymphoma and COVID-19 pneumonia-were reported. LIMITATIONS: A small sample size limits the generalizability of the results. CONCLUSION: Treatment with ivarmacitinib 4 and 8 mg doses in patients with moderate and severe AA for 24 weeks was efficacious and generally tolerated.

Transcription factor FOXC1 positively regulates SFRP1 expression in androgenetic alopecia.

Androgenetic alopecia (AGA) is the most common type of hair loss dysfunction. Secreted frizzled related protein 1 (SFRP1) is found to be associated with hair loss, but its role in AGA and the regulation mechanism of its transcription level is unclear. The aim of our study is to explore the expression of SFRP1 in AGA samples and its transcriptional mechanism. Male frontal and occipital scalp hair follicles from AGA patients were collected, and human dermal papilla cells (DPCs) were isolated and cultured. SFRP1 gene was cloned and constructed into recombinant plasmids to perform dual-luciferase reporter assay. Transcription factor binding sites were predicted through the Jaspar website and further confirmed by the chromatin immunoprecipitation (ChIP) assay. Expression of genes in DPCs was determined by immunofluorescence (IF) staining, quantitative real-time PCR (qRT-PCR) and western blotting. Our findings showed that SFRP1 was highly expressed in DPCs of AGA patients. The core promoter region of SFRP1 was from -100 to +50 bp and was found to be positively regulated by forkhead box C1 (FOXC1), a transcription factor related to hair growth, both at mRNA and protein level in DPCs. Our study suggests that FOXC1 plays an important role in regulating SFRP1 transcription, which may provide new insights into the development of therapeutic strategies for the treatment of AGA.

Characterization of Volatile Organic Compounds Produced by Bacillus siamensis YJ15 and Their Antifungal Activity Against Botrytis cinerea.

To develop an effective and environmentally safe strategy to control postharvest gray mold caused by Botrytis cinerea, Bacillus siamensis strain YJ15 isolated from blueberry was used to test the biocontrol potential. It is interesting to find that the volatile organic compounds (VOCs) emitted from strain YJ15 exhibited significant antifungal activity against Botrytis cinerea as well as 11 other plant-pathogenic fungi, with a percentage of mycelial growth inhibition from 74.96 to 92.81%. Additionally, VOCs from strain YJ15 could reduce significantly the disease incidence and lesion diameter with the increasing of fermentation time, indicating great biocontrol potential for controlling blueberry postharvest gray mold. Furthermore, the VOCs were collected by using headspace solid-phase microextraction fiber, and the composition of VOCs was further revealed by using gas chromatography coupled with quadruple mass spectrometry. In total, 24 kinds of VOCs, including 5 alkanes, 2 aldehydes, 3 ketones, 5 alcohols, 1 alkene, 5 acids and esters, 2 aromatic compounds, and 1 sulfur compound, were emitted at 1, 3, 5, and 7 days after inoculation. Among these VOCs, eight antifungal VOCs could inhibit mycelial growth of B. cinerea. It is important to highlight that, although 1-butanol and 3-methyl-1-butanol were the most abundant compounds, 2-ethylhexanol, 1-heptanol, and 1,3-xylene have proved to be more toxic to B. cinerea than 3-methyl-1-butanol, propanethioic acid, 2,2-dimethyl-, ethyl 2-methylbutyrate, 2-heptanone, and 1-butanol, which provide new, promising biofumigants for the control of postharvest gray mold caused by B. cinerea.

Effective biodegradation of pentachloronitrobenzene by a novel strain Peudomonas putida QTH3 isolated from contaminated soil.

To eliminate pentachloronitrobenzene (PCNB) residue in PCNB-contaminated environment, the degradation potential of Pseudomonas putida QTH3 to PCNB was evaluated in this study. Peudomonas putida QTH3 could grow well in mineral salt medium (MSM) containing PCNB as sole carbon and was able to degrade PCNB efficiently, whereas the degradation rate of P. putida QTH3 to PCNB increased gradually, and reached 49.84% in 35 days. The degradation rates of P. putida QTH3 to 13 tested organochlorine compounds found to be 10.85%-42.51% after 14 days. The metabolites during PCNB biodegradation by P. putida QTH3 were identified as catechol, 2, 3, 5, 6-tetrachloroaniline (TCA), 2, 3, 4, 5- TCA, 2, 3, 4, 5, 6-pentachloroaniline (PCA) and pentachlorothioanisole (PCTAs). Furthermore, possible degradation pathway of PCNB by P. putida QTH3 was proposed. The degradation rates of intracellular enzyme and extracellular enzyme were 44.73% and 8.93% after incubation with 100 mg L-1 PCNB for 30 min, respectively. Thus, intracellular enzyme is a major enzyme responsible for PCNB degradation. The results indicate that P. putida QTH3 can be a suitable organism for the degradation of PCNB, and facilitate its potential for the bioremediation of the environments contaminated with major organochlorine compounds used during this study.

Platelet-Rich Plasma for Treating Androgenic Alopecia: A Systematic Review.

BACKGROUND: Platelet-rich plasma (PRP) contains a variety of growth factors and proteins that can accelerate tissue repair. Androgenic alopecia is a genetic disorder characterized by atrophy of hair follicles and hair loss. At present, PRP injections for hair restoration have become a popular though controversial practice. We conducted a meta-analysis to compare the differences between patients treated with local injections of PRP and control group subjects to explore the effectiveness of PRP treatment for androgenic alopecia. MATERIALS AND METHODS: We searched PubMed, EMBASE and the Cochrane Library until Jan 2019 for human studies evaluating the efficacy of PRP for the treatment of androgenic alopecia. RESULTS: We retrieved 132 papers; 11 articles matched our inclusion criteria and comprised 262 androgenic alopecia patients. Through a meta-analysis, we found a significantly locally increased hair number per cm2 after PRP injections in the treatment group versus the control group (mean difference 38.75, 95% CI 22.22-55.28, P < .00001). Similarly, a significantly increased terminal hair density was found in the PRP group compared with the control group (mean difference 22.83, 95% CI 0.28-45.38, P = 0.05). CONCLUSION: Most studies suggest that subcutaneous injection of PRP is likely to reduce hair loss, increase hair diameter and density in patients with androgenic alopecia. Because of the low quality of the studies, small sample sizes, different treatment regimens and possible publication bias, the results of this meta-analysis should be interpreted with caution. Furthermore, more randomized controlled studies should be performed. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Identification of volatile compounds and odour activity values in quinoa porridge by gas chromatography-mass spectrometry.

BACKGROUND: Quinoa porridge is becoming popular among Asian for its nutritional values; hence, it is important to understand its aroma characteristics. RESULTS: Volatile compounds in porridge of 30 quinoa varieties were determined by gas chromatography-mass spectrometry combined with headspace-solid phase micro-extraction. In total, 53 volatile compounds were detected and grouped into 14 alkanals, four alcohols, seven ketones, 10 alkanes, 10 acids and esters, and eight heterocycles. The relative content of alkanes (22.97%), acids and esters (44.33%) was comparatively high, although alkanals (11.75%) may dominate the aroma. Most of the compounds were similar with respect to types and numbers, although they varied in amount, whereas 11 compounds varied significantly among different varieties. The 30 varieties could be divided into eight groups based on the concentrations of volatile compounds, although the same varieties would be divided into four groups if based on the relative odour activity values of twelve variable aroma compounds. CONCLUSION: Nine compounds were identified as the main contributors to the quinoa porridge aroma, including hexanal, 1-octen-3-ol, 2-pentylfuran, nonanal, (E,E)-2,4-decadienal and 6,10-dimethyl-5,9-undecadien-2-one. Heptanal, benzeneacetaldehyde and decanal may play roles in harmonizing the overall aroma. It is also interesting to note that 6,10,14-trimethyl-2-pentadecanone, with a slightly fatty aroma, showed a high content in all varieties. © 2019 Society of Chemical Industry.

Causal Effects of Lipids-Related Metabolites on Androgenic Alopecia: A Mendelian Randomization Study.

Purpose: To investigate whether increased levels of lipids-related metabolites (LRMs) result in androgenic alopecia (AGA). Patients and Methods: A two-sample Mendelian randomization (MR) study was designed, and single nucleotide polymorphisms (SNPs) respectively related to nine LRMs were selected from the genome-wide association study (GWAS) dataset. An MR analysis was performed to assess the causal association between LRMs and AGA. Results: Through the fixed-effect inverse variance weighting (IVW) method, MR analysis indicated that Apolipoprotein B (ApoB), low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL) had a causal relationship with AGA. No obvious heterogeneity or pleiotropy was observed. Conclusion: The risk of AGA increases significantly when the serum levels of ApoB, LDL, and VLDL increase. This causal relationship is solid and free of interference from confounding factors.

Effectiveness and safety of baricitinib in patients with moderate-to-severe refractory alopecia areata in real world: An open-label, single-center study.

PURPOSE: Baricitinib is a small-molecular drug that selectively inhibits the Janus Kinase (JAK) 1 and 2. However, it showed various efficiency and safety in treating moderate-to-severe alopecia areata (AA). This study was to describe the real-world effectiveness of baricitinib in treating moderate-to-severe refractory AA. METHODS: Patients who were affected by moderate-to-severe AA and reported no shrinkage in the alopecia area after 6 months of conventional treatment were enrolled in the retrospective study. The patients were treated with baricitinib orally for at least 24 weeks. The severity of alopecia was evaluated at the end of 4, 12, and 24 weeks of treatment. RESULTS: The 32 patients included 23 females and nine males, with a median duration of AA of 14.5 months. Among them, 28 patients received baricitinib 2 mg per day for 24 weeks while the other four patients increased the daily dose from 2 to 4 mg after the first 12 weeks due to the unobvious hair restoration. SALT value showed a significant decrease from baseline at week 12 and 24 (64.45 [44.68-100.00] vs. 26.80 [13.40-62.32], p < 0.0001 and 64.45 [44.68-100] vs. 9.40 [4.85-34.95], p < 0.0001). After 24 weeks of treatment, 50% of patients had an improvement of ≥2 points in IGA scores from the baseline, and IGA scores of 68.75% of patients were less than 2. CONCLUSION: This 24-week research showed that baricitinib had favorable clinical efficacy and safety in treating moderate-to-severe AA, which is worthy of attention and expectation.

Photodynamic therapy for the treatment of port-wine stains in phakomatosis pigmentovascularis.

BACKGROUND: Phakomatosis pigmentovascularis (PPV) is a rare congenital syndrome. Only a few studies have reported the treatment of PPV, including a case using photodynamic therapy (PDT) to treat PPV-associated port-wine stains (PWS). OBJECTIVE: To investigating the efficacy and adverse effects of hemoporfin-PDT in PPV-associated PWS. METHODS: The efficacy and adverse effects in patients with PPV who underwent two sessions of hemoporfin-PDT from January 2019 to December 2022 were retrospectively analyzed. RESULTS: Twenty patients were included (13 females, 7 males, age range: 2-31 years; mean: 8.20 ± 8.92 years). Two, nine, seven, and two patients had PPV types Ia, IIa, IIb, and IIIa, respectively. After two treatments, the visual evaluation indicated the color of the PWS in 4, 5, 6, and 5 patients showed poor, fair, good, and excellent improvements, respectively. The combined good and excellent improvement rates in patients with PWS and pigmentary nevus overlapping in the same treatment area and in patients with PWS in the treatment areas only were 33.3% versus 87.5%, respectively, and were significantly different (p = 0.02). Minor side effects, such as edema, scabbing, hyperpigmentation, and blistering, were observed in some patients after PDT. CONCLUSION: Hemoporfin-PDT is an effective treatment for PPV-associated PWS. Patients with PWS and pigmentary nevus overlapping in the same treatment area showed poorer efficacy than patients with PWS in the treatment areas only.

Efficacy of hemoporfin-mediated photodynamic therapy in treating Sturge-Weber syndrome associated port-wine stains: A retrospective study.

Background Sturge-Weber syndrome (SWS) is a rare condition associated with a GNAQ gene mutation, which affects neural crest cells. A pulsed dye laser (PDL) is a first-line therapy for SWS, but its outcomes are worse than those in patients with port-wine stains (PWS). Photodynamic therapy (PDT) is a promising therapeutic option for PWS. However, its use for PWS associated with SWS has rarely been studied. Aims To investigate the therapeutic and adverse effects of photodynamic therapy in treating SWS-associated PWS. Methods Patients with SWS and matched patients with large size facial PWS were included in this study. Both colorimetric assessment and visual evaluation were conducted to evaluate patients' responses to treatment. Results Colorimetric assessment (blanching rate) and visual evaluation (scores of colour improvement) showed that after two PDT treatments, the SWS and PWS groups had similar treatment responses (21.2% vs. 29.8%; 3.39 vs. 3.65; P = 0.18, P = 0.37). However, there was a significant difference in efficacy between patients with SWS with and without a treatment history (12.4 and 34.9%, respectively; P = 0.02), as well as between patients with lesions located on the central and lateral faces (18.5 and 36.8%, respectively; P = 0.01). Both the SWS and PWS groups experienced minor adverse effects, and the frequency of these effects was not significantly different between the two groups. Limitation The study was limited by a small sample size and the possibility of later onset of glaucoma. In addition, false-negative magnetic resonance imaging screening results for SWS could not be ruled out due to the young age of some participants. Conclusion Photodynamic therapy is a safe and effective therapeutic option for SWS-associated PWS. Patients without a treatment history, and lesions on the lateral face, responded well, demonstrating good efficacy.

The Efficacy and Safety of Oral and Topical Spironolactone in Androgenetic Alopecia Treatment: A Systematic Review.

Introduction: Androgenetic alopecia (AGA) has negative impacts on both men and women in terms of appearance and mental stress. Spironolactone is a synthetic aldosterone receptor antagonist known to stimulate hair growth and has been widely used by dermatologists to treat AGA. Objective: To conduct a systematic review evaluating the efficacy and safety of topical and oral spironolactone in AGA treatment. Methods: We searched PubMed, Embase, the Cochrane Library, and the Web of Science until October 23rd, 2022, for human studies evaluating the efficacy of spironolactone for the treatment of AGA, regardless of doses and routes. Results: We retrieved 784 papers and ultimately 7 articles matched our inclusion criteria and comprised 618 AGA patients (65 men, 553 women), 414 of them received spironolactone treatment. Oral spironolactone doses ranged from 25mg to 200mg daily, with the vast majority between 80mg and 110 mg. Dosage forms for topical spironolactone use include gels of 1% and solutions of 5% twice daily. Both oral and topical spironolactone have been shown efficacy for alopecia recovery, but topical use has significantly fewer side effects and is suitable for any gender. It showed better efficacy in combination with other therapies such as oral or topical minoxidil compared with monotherapy. Conclusion: Spironolactone is an effective and safe treatment of androgenic alopecia which can enhance the efficacy when combined with other conventional treatments such as minoxidil. Topical spironolactone is safer than oral administration and is suitable for both male and female patients, and is expected to become a common drug for those who do not have a good response to minoxidil. Furthermore, more high-quality clinical randomized controlled studies should be performed.

The role of telomerase in hair growth and relevant disorders: A review.

BACKGROUND: Hair diseases may present with hair loss, hirsutism, hair melanin abnormalities and other manifestations. Hair follicles are known as mini-organs that undergo periodic remodeling, and their constant regeneration in vivo reflects interesting anti-aging functions. Telomerase prevents cellular senescence by maintaining telomere length, but its excessive proliferation in cancer cells may also induce cancer. However, the effects of telomerase in hair growth have rarely been reported. METHODS: In this study, we reviewed the role of telomerase in hair growth and the effects of hair disorders through literature search and analysis. RESULTS: There is growing evidence that telomerase plays an important role in maintaining hair follicle function and proliferation. Changes in telomerase levels in hair follicles have also been found in a variety of hair disorders. CONCLUSION: Telomerase plays a positive role in hair growth and is expected to become a new target for the treatment of alopecia or other hair diseases in the future.

Physiological and transcriptomic analyses reveal that phytohormone pathways and glutathione metabolism are involved in the arsenite toxicity response in tomatoes.

The main forms of inorganic arsenic (As) in soil are arsenate [As(V)] and arsenite [As(III)]. Both forms inhibit plant growth. Here, we investigate the effects of As(III) toxicity on the growth of tomatoes by integrating physiological and transcriptomic analyses. As(III) toxicity induces oxidative damage, inhibits photosynthetic efficiency, and reduces soluble sugar levels. As(III) toxicity leads to reductions in auxin, cytokinin and jasmonic acid contents by 29 %, 39 % and 55 %, respectively, but leads to increases in the ethylene precursor 1-amino-cyclopropane carboxylic acid, abscisic acid and salicylic acid contents in roots, by 116 %, 79 % and 39 %, respectively, thereby altering phytohormone signalling pathways. The total glutathione, reduced glutathione (GSH) and oxidized glutathione (GSSG) contents are reduced by 59 %, 49 % and 94 % in roots; moreover, a high GSH/GSSG ratio is maintained through increased glutathione reductase activity (increased by 214 %) and decreased glutathione peroxidase activity (decreased by 40 %) in the roots of As(III)-treated tomato seedlings. In addition, As(III) toxicity affects the expression of genes related to the endoplasmic reticulum stress response. The altered expression of aquaporins and ABCC transporters changes the level of As(III) accumulation in plants. A set of hub genes involved in modulating As(III) toxicity responses in tomatoes was identified via a weighted gene coexpression network analysis. Taken together, these results elucidate the physiological and molecular regulatory mechanism underlying As(III) toxicity and provide a theoretical basis for selecting and breeding tomato varieties with low As(III) accumulation. Therefore, these findings are expected to be helpful in improving food safety and to developing sustainable agricultural.

1α,25(OH)2D3(VD3) promotes Raddeanin A-induced anti-proliferative effects on HeLa cell apoptosis and autophagy through negative regulation of HPV18E6-E7/PD-L1/VDR axis.

Raddeanin A (RA) has indicated suppressive effects on various human tumor cells, and insufficient vitamin D was associated with human papillomavirus (HPV) persistence and gynecological tumors. However, combined effects of RA and vitamin D on HPV-positive cells remain elusive. Herein, we aimed to investigate the combined effects of RA and 1ɑ,25(OH)2D3 (VD3) on cellular viability and modulation of HPV18E6/E7, programmed cell death 1 ligand (PD-L1) and vitamin D receptor (VDR) expression in HeLa cells in vitro. HeLa cells were treated with RA alone or VD3 combined with RA. Cell viability was measured using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT), and apoptosis was detected by flow cytometry. Real-time PCR (qRT-PCR) and Western blot were used to determine the gene/protein expression levels. The autophagosomes were observed by Transmission electron microscopy (TEM). The result showed that cell viability was inhibited by RA, and apoptosis in HeLa cells treated with RA was elevated accordingly. The expression of Bax, Cleaved-caspase-3, Cleaved-caspase-9 and Cleaved-PARP increased, and Bcl-2 decreased. The autophagy was induced by RA, as evidenced by elevated autophagosomes and the increased LC3-II/I ratio and Beclin-1. The expression of HPV18E6/E7, PD-L1 and VDR was reduced by RA. Moreover, RA combined with VD3 had a stronger effect on HeLa cells than RA alone. In conclusion, RA inhibits HeLa proliferation and induces apoptosis and autophagy via suppressing HPV18E6/E7, PD-L1 and VDR, and VD3 showed reinforced effects of RA on HeLa cells. Therefore, combined usage of VD3 with RA might be a potential novel immunotherapy strategy for HPV-related diseases.

The JAK2/STAT3 pathway inhibitor, AG490, suppresses the abnormal behavior of keloid fibroblasts in vitro.

AG490 is a selective inhibitor of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. The present study examined its effects on the abnormal behavior of human keloid fibroblasts (HKFs) and evaluated its potential use in the treatment of keloids. Human normal fibroblasts (HNFs) and HKFs were treated with increasing concentrations of AG490. The proliferation of HNFs and HKFs was inhibited by AG490 in both a time­ and concentration­dependent manner by increasing apoptosis and inducing G1 cell cycle arrest. The downregulation of cyclin D1 and connective tissue growth factor (CTGF) expression was associated with a decrease in STAT3 expression in response to AG490. The effects of AG490 on TGF­ß­stimulated fibroblasts, including HNFs, HKFs and hypertrophic scar fibroblasts (HSFs) were also evaluated. The TGF­ß1­stimulated excessive proliferation and CTGF production were markedly inhibited by the application of AG490 in the HNFs, HSFs and HKFs. In addition, the STAT3­specific decoy oligodeoxynucleotides (SODNs) were transfected into HKFs. The invasive ability of the SODN­transfected HKFs was determined and the expression of extracellular matrix components was quantified. Similarly, SODNs blocked the constitutive activation of STAT3. SODNs inhibited the invasion and progression of HKFs, possibly via the upregulation of the expression of tissue inhibitor of metalloproteinase­2 (TIMP­2), and the downregulation of the expression of matrix metalloproteinase­2 (MMP­2) and vascular endothelial growth factor (VEGF). On the whole, the findings of the present study demonstrate that STAT3­specific elimination, such as the application of AG490 and decoy ODNs, may serve as promising therapeutic strategies for the treatment of keloids.