Knockdown of FOXRED2 restrains proliferation, invasion and migration of human melanoma cells.

Objectives: This experiment investigated the role of the FAD-dependent oxidoreductase domain-containing 2 (FOXRED2) in the development of cutaneous malignant melanoma. Methods: We explored the expression and prognostic effects of FOXRED2 in cutaneous malignant melanoma by performing bioinformatics analyses and immunohistochemical staining experiments and verified the biological influence of FOXRED2 on human melanoma cells using in vitro experiments. Results: FOXRED2 expression was significantly higher in cutaneous malignant melanoma compared to normal skin and nevus tissues and closely associated with prognosis. The expression levels of FOXRED2 mRNA and protein were significantly upregulated in human melanoma cell lines, and knocking down FOXRED2 expression inhibits proliferation, invasion, and migration, promotes apoptosis, and alters tumor cell biology in A2058 and A375 cells. Conclusion: FOXRED2 may play a crucial role in the development and progression of cutaneous malignant melanoma.

Prospective study of efficacy and safety of non-ablative 1927†nm fractional thulium fiber laser in Asian skin photoaging.

Background and Objective: Photoaging manifests as deeper wrinkles and larger pores. It has been tried to rejuvenate photoaging skin using a variety of lasers, including fractionated lasers, which are a popular photorejuvenation treatment. A new breakthrough for skin rejuvenation is the 1927 nm fractional thulium fiber laser (FTL), a laser and light-based treatment option. Clinical data regarding the FTL for treating photoaging are limited despite its effectiveness and safety. This study is aim to evaluate FTL' clinical effectiveness and safety. Methods: Fitzpatrick skin types II-IV subjects with mild to moderate photoaging signs were enrolled in this prospective study. At intervals of one month, patients received three full face treatments. Wrinkles, spots, texture, pores, melanin index, erythema index (MI and EI), skin elasticity and hydration were measured with non-invasive tool. The epidermal thickness and dermal density on ultrasonography were compared between baseline and one month after all treatment sessions. The Global Score for Photoaging scale (GSP) was rated by two independent evaluators at the baseline and final follow-up visit. Secondary outcomes included patient-rated pain on a 10-point visual analog scale (VAS), as well as overall satisfaction. Following each treatment, adverse events were noted. Results: Totally 27 subjects (24 females and 3 males) with Fitzpatrick skin types II to IV and a mean age of 44.41 (range33-64) were enrolled. Results suggests that the epidermal thickness has significantly improved after treatment. Statistically significant improvements in melanin index, skin elasticity and wrinkles were noted. An analysis of 12 subjects' reports (44%) suggested their skin felt brighter. No post-inflammatory hyperpigmentation changes or adverse events were observed. 70% patients reporting "satisfied" or "extremely satisfied". Conclusions: In this study, FTL was found to be a safe and effective treatment option for treating photoaging.

Mechanism of a new photosensitizer (TBZPy) in the treatment of high-risk human papillomavirus-related diseases.

BACKGROUND: High-risk human papillomavirus infection is closely related to the development of several diseases, including cervical cancer and condyloma acuminatum. We recently designed a new photosensitizer, 1-triphenylaminebenzo[c][1,2,5]thiadiazole-4-yl)styryl)-1-methylpyridin-1-ium iodide salt (TBZPy), which shows good photodynamic properties. In this study, we explored the mechanism of action of the TBZPy photosensitizer and its potential application in the treatment of high-risk human papillomavirus-related diseases. METHODS: HeLa cells (infected by the high-risk human papillomavirus strain HPV18) were treated with TBZPy-photodynamic therapy (PDT). Cell viability, production of reactive oxygen species, apoptosis, and mitochondrial membrane depolarization were evaluated using cell counting kit-8, immunofluorescence, and flow cytometry assays, respectively. Expression levels of the anti-apoptotic proteins Bcl-2 and Bcl-XL; pro-apoptotic proteins Bax, cytochrome C, cleaved caspase 3, and cleaved caspase 9; and the mitochondrial stress protein heat shock protein 60 were examined by western blotting. RESULTS: TBZPy-PDT inhibited the viability and promoted reactive oxygen species production, lactate dehydrogenase release, and apoptosis of HeLa cells in vitro. TBZPy-PDT also promoted the loss of mitochondrial membrane potential, downregulated the expression of anti-apoptotic proteins, and upregulated the expression of pro-apoptotic proteins. Moreover, TBZPy-PDT downregulated the expression of the human papillomavirus E6 and E7 proteins. CONCLUSION: Our study demonstrates the effectiveness of TBZPy-PDT against human papillomavirus-related diseases. These findings provide a foundation for using this novel photosensitizer to treat diseases associated with high-risk human papillomavirus infection.

Endogenous SO2 Controls Cell Apoptosis: The State-of-the-Art.

SO2, previously known as the product of industrial waste, has recently been proven to be a novel gasotransmitter in the cardiovascular system. It is endogenously produced from the metabolism pathway of sulfur-containing amino acids in mammalians. Endogenous SO2 acts as an important controller in the regulation of many biological processes including cardiovascular physiological and pathophysiological events. Recently, the studies on the regulatory effect of endogenous SO2 on cell apoptosis and its pathophysiological significance have attracted great attention. Endogenous SO2 can regulate the apoptosis of vascular smooth muscle cells, endothelial cells, cardiomyocytes, neuron, alveolar macrophages, polymorphonuclear neutrophils and retinal photoreceptor cells, which might be involved in the pathogenesis of hypertension, pulmonary hypertension, myocardial injury, brain injury, acute lung injury, and retinal disease. Therefore, in the present study, we described the current findings on how endogenous SO2 is generated and metabolized, and we summarized its regulatory effects on cell apoptosis, underlying mechanisms, and pathophysiological relevance.

[Identification of variants in TNNI3 gene in two children with restrictive cardiomyopathy].

OBJECTIVE: To identify the pathogenesis in two patients of restrictive cardiomyopathy (RCM) using high-throughput sequencing. METHODS: Peripheral blood samples from the two patients and their parents were collected and genomic DNAs were extracted to conduct targeted next generation sequencing or whole exome sequencing. Bioinformation analysis was performed to identify the pathogenic variants in genes associated with cardiomyopathy, which were further validated by Sanger sequencing. RESULTS: By high throughput sequencing, we detected a de novo heterozygous variant c.549+1G>T in TNNI3 gene in patient 1. The variant has not been reported previously and was predicted to be pathogenic in line with American College of Medical Genetics and Genomics (ACMG) guidelines (PVS1+PS2+PM2). Another heterozygous variant c.433C>T (p.Arg145Trp) in TNNI3 gene was identified in patient 2 and his father. The variant had been reported as pathogenic variant in Clinvar and HGMD databases; based on ACMG guidelines, the variant was predicted to be likely pathogenic (PS3+PM1+PP3). CONCLUSION: TNNI3 variants may be the causative gene responsible for restrictive cardiomyopathy in the two patients. High throughput sequencing results provide bases for the diagnosis of restrictive cardiomyopathy.

The mechanism of 5-aminolevulinic acid photodynamic therapy in promoting endoplasmic reticulum stress in the treatment of HR-HPV-infected HeLa cells.

BACKGROUND: 5-aminoketovaleric acid, as a precursor of the strong photosensitizer protoporphyrin IX (PpIX), mainly enters the mitochondria after entering the cell, and the formed PpIX is also mainly localized in the mitochondria. So at present the research on the mechanism of 5-aminoketovalerate photodynamic therapy (ALA-PDT) mainly focuses on its impact on mitochondria. There are few reports on whether ALA-PAT can affect the endoplasmic reticulum and trigger endoplasmic reticulum stress (ERS). AIMS/OBJECTIVES: Here we investigated the effects of ALA-PDT on endoplasmic reticulum and its underlying mechanisms in high-risk human papillomavirus (HR-HPV) infection. MATERIALS AND METHODS: The human cervical cancer cell line HeLa (containing whole genome of HR-HPV18) was treated with ALAPDT, and cell viability, ROS production, the level of Ca2+ in the cytoplasm and apoptosis were evaluated by CCK8, immunofluorescence and flow cytometry, respectively. The protein expression of the markers of ERS and autophagy and CamKKß-AMPK pathway was examined by western blot. RESULTS: The results showed that ALA-PDT inhibited cell viability of HeLa cells in vitro; ALA-PDT induced autophagy in HeLa cells ; ALA-PDT induced autophagy via the Ca2+-CamKKß-AMPK pathway, which could be suppressed by the inhibition of ERS;ALA-PDT induced ERS-specific apoptosis via the activation of caspase 12. CONCLUSIONS: Our study demonstrated that ALA-PDT could exert a killing effect by inducing HeLa cell apoptosis, including endoplasmic reticulum-specific apoptosis. Meanwhile, ERS via the Ca2+ -CamKKß-AMPK pathway promoted the occurrence of autophagy in HeLa cells. Inhibition of autophagy could increase the apoptosis rate of HeLa cells after ALA-PDT, suggesting that autophagy may be one of the mechanisms of PDT resistance; The Ca2+-CamKKß-AMPK pathway and autophagy may be targets to improve the killing effect of ALA-PDT in treating HR-HPV infection.

Dihydroartemisinin administration improves the effectiveness of 5-aminolevulinic acid-mediated photodynamic therapy for the treatment of high-risk human papillomavirus infection.

AIMS AND BACKGROUND: High-risk human papillomavirus (HR-HPV) infection has been confirmed to be highly related to diseases such as Bowenoid papulosis, cervical cancer, and cervical intraepithelial neoplasia. 5-aminolevulinic acid-mediated PDT (ALA-PDT) has been used in a variety of HR-HPV infection-related diseases. Dihydroartemisinin (DHA) is one of artemisinin derivatives, and has inhibitory effects on a variety of cancer cells. For now, there is no published study focusing on the combination use of ALA-PDT with DHA to improve clinical efficacy of HR-HPV infection-related diseases. So in this study, we will examine the effectiveness of combined treatment of ALA-PDT and DHA for HR-HPV infection as well as its underlying mechanism. METHODS: The human cervical cancer cell line HeLa (containing whole genome of HR-HPV18) was treated with ALA-PDT or/and DHA, and cell viability, long proliferation, ROS production and apoptosis were evaluated by CCK8, colony-forming assay, immunofluorescence and flow cytometry, respectively. The protein expression of NF-κB-HIF-1α-VEGF pathway and NRF2-HO-1 pathway was examined by western blot. RESULTS: The results showed that DHA could enhance the effect of ALA-PDT on cell viability long proliferation, ROS production and apoptosis in HeLa cells. We also found that DHA inhibited NF-κB-HIF-1α-VEGF pathway which was activated by ALA-PDT. Besides, ALA-PDT combined with DHA activated NRF2-HO-1 pathway. CONCLUSION: Although the NRF2 - NO-1 pathway as a resistance mechanism remains unresolved, DHA has the potential to enhance the effect of ALA-PDT for HPV infection-related diseases through inhibiting NF-κB - HIF-1α - VEGF pathway.

The recent effects of small dose of folic acid on lipoprotein-associated phospholipase A2 and systolic blood pressure variability in coronary heart disease patients with hyperhomocysteinemia: A single-center prospective cohort study.

ABSTRACT: To Investigate the recent effects of small dose of folic acid on lipoprotein-associated phospholipase A2 (LP-PLA2) and systolic blood pressure variability in coronary heart disease (CHD) patients with hyperhomocysteinemia.In this prospective cohort study, a total of 167 CHD patients with hyperhomocysteinemia were consecutively enrolled, and they were divided into Group A (without folic acid intervention, n = 99), Group B (with 0.4 mg of folic acid intervention, n = 34), Group C (0.8 mg of folic acid intervention, n = 34). General information, fasting blood glucose, and blood lipid, folic acid, homocysteine, Lp-PLA2, and blood pressure variability were compared among 3 groups. The above indicators were reviewed after 3 months of treatment.There were no statistically significant differences of age, gender, blood pressure, incidence of type 2 diabetes mellitus, fasting blood glucose, folic acid, homocysteine, Lp-PLA2, total cholesterol, 3 acyl glycerin, apolipoprotein B, lipoprotein (a), high density lipoprotein cholesterol, and low density lipoprotein cholesterol were found among 3 groups (P > .05); however, after being treated for 3 months, there was statistically significant difference in folic acid among 3 groups (P < .05), there was statistically significant difference in apolipoprotein A between Group A and Group B (t = 0.505, P = .039), and also between Group A and Group C (t = 0.052, P = .017). There were statistically significant differences in Lp-PLA2 (t = 24.320, P = .016) and systolic blood pressure variability (t = 0.154, P = .018) between Group A and Group C.For CHD patients with hyperhomocysteinemia, the higher dose (0.8 mg) of folic acid supplement was beneficial for increasing the apolipoprotein A, reducing the Lp-PLA2, and improving the systolic blood pressure variation, which might help to improve the prognosis in these patients.

Whole-exome sequencing reveals two de novo variants in the RBM20 gene in two Chinese patients with left ventricular non-compaction cardiomyopathy.

IMPORTANCE: Pathogenic variants in the RBM20 gene are associated with aggressive dilated cardiomyopathy (DCM). Recently, RBM20 was found to be associated with left ventricular non-compaction cardiomyopathy (LVNC). Thus far, only five families with LVNC have been reported to carry variants in RBM20. It remains unknown whether the variants in RBM20 associated with DCM can also cause LVNC. OBJECTIVE: To elucidate the causative RBM20 variant in two unrelated patients with both LVNC and DCM, and to identify the clinical characteristics associated with variants in RBM20. METHODS: Trio whole-exome sequencing (WES) was performed. Variants were filtered and classified in accordance with the guidelines of the American College of Medical Genetics and Genomics (ACMG). RESULTS: We identified two distinct de novo variants in RBM20 (one per patient) in these two patients with LVNC. Both variants have been reported in patients with DCM, without the LVNC phenotype. Patient 1 was an 11-year-old girl who had DCM, LVNC, and heart failure; the ratio of noncompacted-to-compacted myocardium was 2.7:1. A de novo heterozygous variant c.1907G>A (p.Arg636His) in exon 9 was identified in this patient. Patient 2 was a 13-year-old boy who had clinical phenotypes identical to those of Patient 1; the ratio of noncompacted-to-compacted myocardium was 3.2:1 in this patient. WES revealed a de novo heterozygous variant c.1909A>G (p.Ser637Gly) in exon 9. Both variants were previously characterized as pathogenic, and our study classified them as pathogenic variants based on the ACMG guidelines. INTERPRETATION: We found that two patients with LVNC had variants in RBM20. Our results extended the clinical spectrum of the two RBM20 variants and illustrated that the same variant in RBM20 can cause DCM, with or without the LVNC phenotype.

Evaluation of the efficacy of 5-aminolevulinic acid photodynamic therapy for the treatment of vulvar lichen sclerosus.

BACKGROUND: This study aimed to evaluate the effects of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) on the improvement of symptoms and recurrence rate in patients with vulvar lichen sclerosus (VLS) and observe its side effects. METHODS: The symptom scores before and after photodynamic therapy (PDT) in 13 enrolled patients with VLS were analyzed retrospectively. All patients were followed-up for at least 6 months to evaluate the recurrence rate after PDT. The patients were treated with PDT only during the study period. During the PDT treatment, a 20 % 5-aminolevulinic acid solution was applied to the lesions and marginal areas for 3 h, and the entire area was then irradiated with 635 nm red light of 80 J/cm2 at 80 mW/cm2 for 30 min. RESULTS: In this study, the effective rate of PDT was 92.31 %. Lesions recurred in two patients at 6 months after PDT. Post-treatment, the total subjective, total objective, and the Dermatological Life Quality Index scores changed from 11.4, 4.3, and 13.4 at baseline to 4.9, 2, and 5.9, respectively. The difference was statistically significant (p <0.05). PDT was mildly toxic in most patients. CONCLUSIONS: ALA-PDT is a safe and effective method for the treatment of VLS, and the therapeutic effects can be maintained for at least 3 months. The therapeutic effects may decrease during the 3-6-month period after PDT.

Microwave-assisted synthesis of anatase TiO(2) nanorods with mesopores.

Pure anatase TiO(2) nanorods with mesopores were synthesized by a simple and low cost microwave-assisted method when tri-block copolymer was used as a structure stabilization agent and TiCl(4) as metal precursor. TEM investigation showed that larger nanorods were assembled by pearl-necklace-shaped nanorods following an oriented attachment mechanism in a specific direction. A proposed hypothetical scheme showed that the formation of lyotropic titania liquid crystal (TLC) serves a key role in the stabilization of nanorods, and the mesopores on nanorods are derived from the vacancy of inter-particles of nanorods and regions lacking inorganic precursors in the TLC structure. Control experiments showed that microwave treatment plays a key role in the maintenance of original morphologies and mesostructures free from destruction even under high temperature calcinations.

[Chronotropic incompetence predicts angiographic severity in patients with coronary artery disease].

OBJECTIVE: To investigate the relationship between the chronotropic incompetence and angiographic severity in patients with coronary artery disease (CAD). METHODS: Coronary angiography was performed in 130 patients suspected for CAD and angiographic severity of coronary artery was quantitated by Duke score and Gensini score. Patients were divided to 4 groups: non-CAD group (39 patients), CAD group with one coronary artery involved (CHD1 group, 30 patients), CHD group with two coronary arteries involved (CHD2 group, 31 patients) and CAD group with three coronary arteries involved (CHD3 group, 30 patients). One month before coronary angiography, symptom-limited exercise treadmill tests were made and the ratio of heart rate reserve (HRR) and the percent maximal age-predicted heart rate achieved (rHR) were measured. RESULTS: rHR and HRR were significantly lower in CHD2 group (rHR 0.79+/-0.08, HRR 0.63+/-0.11) and CHD3 (rHR 0.78+/-0.07, HRR 0.59+/-0.12) than that in non-CHD group (rHR 0.89+/-0.06, HRR 0.80+/-0.10) and CHD1 group (rHR 0.86+/-0.08, HRR 0.74+/-0.15, all P<0.05). rHR and HRR also significantly correlated with Duke score (r=-0.554, -0.578, all P<0.01) and Gennisi score (r=-0.453, -0.467, all P<0.01). CHD incidence rate was 75% in patients with positive rHR (or HRR) but without ST lowering during exercise. CONCLUSION: Chronotropic incompetence are negatively related to angiographic coronary severities and thus predict angiographic coronary severities. There is a high CAD incidence in patients with positive rHR (or HRR) but no ST lowering during symptom-limited exercise treadmill tests.