Paeoniflorin regulates RhoA/ROCK1 and Nrf2 pathways in PDLIM1-dependent or independent manners in oxidative stressed melanocytes.

BACKGROUND: The adhesive properties of vitiligo melanocytes have decreased under oxidative stress., cytoskeleton proteins can control cell adhesion. Paeoniflorin (PF) was proved to resist hydrogen peroxide (H2O2)-induced oxidative stress in melanocytes via nuclear factorE2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. OBJECTIVES: This study was to investigate whether PF exerts anti-oxidative effect through influencing cytoskeleton markers or potential signaling pathway. METHODS: Human Oxidative Stress Plus array was used to identify the differentially expressed genes between H2O2 + PF group and H2O2 only group, in PIG1 and PIG3V melanocyte cell lines respectively. Western blotting was used to verify the PCR array results and to test the protein expression levels of cytoskeleton markers including Ras homolog family member A (RhoA), Rho-associated kinase 1 (ROCK1) and antioxidative marker Nrf2. Small interfering RNA was used to knock down PDZ and LIM domain 1 (PDLIM1). RESULTS: PF increased the expressions of PDLIM1, RhoA and ROCK1 in H2O2-induced PIG1, in contrast, decreased the expressions of PDLIM1 and ROCK1 in H2O2-induced PIG3V. Knockdown of PDLIM1 increased the expressions of RhoA and Nrf2 in PF-pretreated H2O2-induced PIG1, and ROCK1 and Nrf2 in PF-pretreated H2O2-induced PIG3V. CONCLUSIONS: PF regulates RhoA/ROCK1 and Nrf2 pathways in PDLIM1-dependent or independent manners in H2O2-induced melanocytes. In PIG1, PF promotes PDLIM1 to inhibit RhoA/ROCK1 pathway or activates Nrf2/HO-1 pathway, separately. In PIG3V, PF directly downregulates ROCK1 in PDLIM1-independent manner or upregulates Nrf2 dependent of PDLIM1.

Antioxidant effects of Paeoniflorin and relevant molecular mechanisms as related to a variety of diseases: A review.

Paeoniflorin (PF), which is the main component of the Paeonia lactiflora Pall extract, is one of the traditional Chinese medicines. The pharmacological effects associated with PF include antioxidant, immunomodulatory, anti-inflammatory, anticancer, antidepressant-like and neuroprotective effects. Our previous studies had revealed that PF protected melanocytes and inhibited photodamage through the suppression of oxidative stress (OS). As OS plays a vital role in the progression of a variety of diseases, the capacity for PF to suppress OS may exert important effects upon them. However, no review exists on these antioxidant effects of PF as related to various diseases. Therefore, in this review we summarized studies involved with examining the antioxidant effects and molecular mechanisms of PF. Through its capacity to inhibit OS, PF has been shown to exert beneficial effects upon several systems including nervous, cardiac/vascular, digestive, and respiratory as well as specific diseases such as diabetes, autoimmune, pregnancy related, ocular, kidney, dermatology, along with suppression of distal flap necrosis, postoperative adhesions, and hearing loss. Such findings provide new insights and directions for future research directed at the development of PF as a natural antioxidant for the treatment of clinical diseases.

Artificial intelligence-driven microbiome data analysis for estimation of postmortem interval and crime location.

Microbial communities, demonstrating dynamic changes in cadavers and the surroundings, provide invaluable insights for forensic investigations. Conventional methodologies for microbiome sequencing data analysis face obstacles due to subjectivity and inefficiency. Artificial Intelligence (AI) presents an efficient and accurate tool, with the ability to autonomously process and analyze high-throughput data, and assimilate multi-omics data, encompassing metagenomics, transcriptomics, and proteomics. This facilitates accurate and efficient estimation of the postmortem interval (PMI), detection of crime location, and elucidation of microbial functionalities. This review presents an overview of microorganisms from cadavers and crime scenes, emphasizes the importance of microbiome, and summarizes the application of AI in high-throughput microbiome data processing in forensic microbiology.

The African killifish: A short-lived vertebrate model to study the biology of sarcopenia and longevity.

Sarcopenia, the age-related decline in muscle function, places a considerable burden on health-care systems. While the stereotypic hallmarks of sarcopenia are well characterized, their contribution to muscle wasting remains elusive, which is partly due to the limited availability of animal models. Here, we have performed cellular and molecular characterization of skeletal muscle from the African killifish-an extremely short-lived vertebrate-revealing that while many characteristics deteriorate with increasing age, supporting the use of killifish as a model for sarcopenia research, some features surprisingly reverse to an "early-life" state in the extremely old stages. This suggests that in extremely old animals, there may be mechanisms that prevent further deterioration of skeletal muscle, contributing to an extension of life span. In line with this, we report a reduction in mortality rates in extremely old killifish. To identify mechanisms for this phenomenon, we used a systems metabolomics approach, which revealed that during aging there is a striking depletion of triglycerides, mimicking a state of calorie restriction. This results in the activation of mitohormesis, increasing Sirt1 levels, which improves lipid metabolism and maintains nutrient homeostasis in extremely old animals. Pharmacological induction of Sirt1 in aged animals was sufficient to induce a late life-like metabolic profile, supporting its role in life span extension in vertebrate populations that are naturally long-lived. Collectively, our results demonstrate that killifish are not only a novel model to study the biological processes that govern sarcopenia, but they also provide a unique vertebrate system to dissect the regulation of longevity.

Histone acetylation gene-based biomarkers as novel markers of the immune microenvironment in glioblastoma.

BACKGROUND: Glioblastoma (GBM) is a primary malignant tumour with high intracranial morbidity, high malignancy and poor prognosis. Abnormal changes in histone acetylation are closely related to the occurrence and development of cancer. However, there is still a lack of systematic research on histone acetylation in GBM. METHODS: Whole-transcriptome sequencing data and clinical data of GBM patients were obtained through the TCGA database. Single-cell RNA-sequencing (scRNA-seq) data from GBM patients were obtained from GSE146711 in the Gene Expression Omnibus database. Cell descending fractionation was first performed for scRNA-seq on GBM. The CellChat and PROGENy scores explore the impact of the histone acetylation pathway in GBM on intercellular chat and tumour pathways. The AddModuleScore function evaluates the enrichment score of histone acetylation in cells and divides them into high-histone acetylation and low-histone acetylation groups. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed on the differential genes between different histone acetylation states, and the biological processes and pathways that may be affected by histone acetylation were evaluated. Based on this, a prognostic model was constructed using least absolute shrinkage and selection operator (LASSO) analysis, and survival analysis was performed to evaluate its prognostic performance. Finally, we also analysed the main effects of the constructed histone acetylation-related model on GBM immune infiltration by multiple methods, and analysed the main mutation data of its different subgroups. RESULTS: GBM samples mainly include seven large cell populations: oligodendrocyte precursor cells (OPCs), myeloid, neoplastic, oligodendrocytes, astrocytes, vascular and neurons. Cellchat and ProgenY scores revealed that in GBM tumours, histone acetylation interacts closely with multiple immune cells and tumour pathways. GO and KEGG analyses revealed the main impact proteins and pathway correlates of histone acetylation. Five histone acetylation genes were screened using LASSO analysis and a prognostic model was constructed. The results revealed that prognostic models were significant in the prognostic stratification of patients in both the training and validation groups of GBM patients. Immune infiltration analysis revealed that the mechanism of histone acetylation in GBM may be related to the immune infiltration of multiple effector immune cells. CONCLUSIONS: Our histone acetylation-based biomarkers are closely associated with immune microenvironmental infiltration and functional mutations in multiple tumour pathways in GBM. This suggests that histone acetylation may reveal microscopic alterations in the tumour microenvironment, and may provide potential evidence and a research basis for the development of novel therapeutic targets for GBM. On this basis, a novel perspective on the spatial biology and immunological understanding of GBM is provided.

Investigation of optimal energy or density of a fractional CO2 laser system in the treatment of stable non-segmental vitiligo.

BACKGROUND: Fractional carbon dioxide (CO2) laser has been considered to be an add-on to conventional treatments of vitiligo. OBJECTIVE: This study aimed to evaluate the optimal energy and density of the fractional CO2 laser system in stable non-segmental vitiligo (NSV) patients. METHOD: 48 patients were treated with fractional CO2 laser and sequential phototherapies of narrowband ultraviolet B (NB-UVB), after the CO2 laser treatment, a compound betamethasone solution was topically applied. For the fractional CO2 laser, coverages of 8% and 12.6% were set as low density (Ld) and high density (Hd), and energies of 60 mJ and 80 mJ were set as low energy (Le) and high energy (He), respectively. The patients were randomly assigned to Group A (HeHd), Group B (HeLd) or Group C (LeLd). RESULTS: Either after 3 or 6 months of enrollment, the efficacy of Group C was better than Group B (p < 0.05). No difference was seen between Group A and Group B or Group A and Group C (p > 0.05). More patients complained higher pain score in Group A as compared with Group C (p < 0.05). CONCLUSION: The optimal parameters of the fractional CO2 laser were energy at 60 mJ and density at 8%.

Toxic epidermal necrosis associated with afatinib: A case report and literature review.

Objective: To report a case of afatinib-induced toxic epidermal necrosis (TEN), in a patient with metastatic non-small cell lung cancer (NSCLC) and compare these findings with that of evaluate similarities and differences to other cases reported in the literature. Methods: With use of the algorithm of drug causality for epidermal necrolysis (ALDEN), the effects of afatinib were evaluated in a NSCLC patient who developed TEN. In addition, previous case reports on this topic were included to provide a review of patients' clinical characteristics, treatment regimens and therapy outcomes in response to afatinib treatment. Results: In our case, toxic epidermal necrolysis was observed at five days after afatinib therapy, while other Stevens-Johnson syndrome/toxic epidermal necrolysis responses, as associated with afatinib, did not seem to be induced until a latency period of over thirty days post-afatinib. Treatment with corticosteroids resulted in significant improvements of these clinical symptoms, and eventually to a complete remission. Conclusion: Afatinib can result in grade four cutaneous adverse effects like SJS/TEN, with an uncertain latency period. The skin lesions which appear during this period of afatinib treatment should be closely monitored.

Identification of novel candidate genes in rosacea by bioinformatic methods.

BACKGROUND: Rosacea is a chronic inflammatory skin disease whose psychological consequences severely affect patient's quality of life. OBJECTIVE: To identify candidate genes of rosacea for potential development of new target therapies. METHODS: Gene Expression Omnibus datasets were retrieved to obtain differentially expressed genes (DEGs) between rosacea patients and healthy controls. Gene ontology (GO) analyses were used to identify functions of candidate genes. Related signaling pathways of DEGs were analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set enrichment analysis. Protein-protein interaction (PPI) networks were applied using search tools for the retrieval of interacting genes/proteins and modulations involving PPI networks were evaluated with use of the MCODE app. RESULTS: Samples from 19 rosacea patients and 10 healthy controls of dataset GSE65914 were enrolled. A total of 215 DEGs, 115 GO terms and 6 KEGG pathways were identified. A total of 182 nodes and 456 edges were enriched in PPI networks. Maximal clusters showed 15 central nodes and 96 edges. The toll-like receptor (TLR) signaling pathway was the most significant pathway detected and 5 DEGs were identified as candidate genes which included TLR2, C-C motif chemokine (CCL) 5, C-X-C motif chemokine ligand (CXCL) 9, CXCL10 and CXCL11. The results were verified in rosacea patients with use of real-time polymerase chain reaction and immunohistochemistry. Cell-type enrichment analysis revealed 8 lymphocytes that were enriched in rosacea patients. CONCLUSIONS: The results suggest that both innate and adaptive immune responses were involved in the etiology of rosacea. Five DEGs in the TLR signaling pathway may serve as potential therapeutic target genes.

UVA influenced the SIRT1-miR-27a-5p-SMAD2-MMP1/COL1/BCL2 axis in human skin primary fibroblasts.

Both SIRT1 and UVA radiation are involved in cellular damage processes such as apoptosis, senescence and ageing. MicroRNAs (miRNAs) have been reported to be closely related to UV radiation, as well as to SIRT1. In this study, we investigated the connections among SIRT1, UVA and miRNA in human skin primary fibroblasts. Our results showed that UVA altered the protein level of SIRT1 in a time point-dependent manner. Using miRNA microarray, bioinformatics analysis, we found that knocking down SIRT1 could cause up-regulation of miR-27a-5p and the latter could down-regulate SMAD2, and these results were verified by qRT-PCR or Western blot. Furthermore, UVA radiation (5 J/cm2 ), knocking down SIRT1 or overexpression of miR-27a-5p led to increased expression of MMP1, and decreased expressions of COL1 and BCL2. We also found additive impacts on MMP1, COL1 and BCL2 under the combination of UVA radiation + Sirtinol (SIRT1 inhibitor), or UVA radiation + miR-27a-5p mimic. SIRT1 activator resveratrol could reverse damage changes caused by UVA radiation. Besides, absent of SIRT1 or overexpression of miR-27a-5p increased cell apoptosis and induced cell arrest in G2/M phase. Taken together, these results demonstrated that UVA could influence a novel SIRT1-miR-27a-5p-SMAD2-MMP1/COL1/BCL2 axis in skin primary fibroblasts, and may provide potential therapeutic targets for UVA-induced skin damage.

UVA Induced Oxidative Stress Was Inhibited by Paeoniflorin/Nrf2 Signaling or PLIN2.

Photodamages caused by UVA radiation induced oxidative injuries are closely related to photoaging and skin cancer. Paeoniflorin (PF), extracted from the root of Paeonia lactiflora, has been reported to be an effective antioxidant. PLIN2, known as adipose differentiation-related protein, has been previously involved in the regulation of oxidative stress. In this study, we were sought to investigate the photo-protective property of PF and PLIN2 in UVA-radiated human dermal fibroblasts (HDFs). HDFs were pre-treated with PF (800 µM) followed by UVA radiation (22.5 J/cm2). MTS activity, cell apoptosis, ROS, MDA, and SOD were detected, respectively. The expressions of Nrf2, HO-1, NQ-O1, and PLIN2 were determined using RT-qPCR or western blot. Nrf2 was silenced by siRNA, and PLIN2 was overexpressed via lentiviral transduction. Comparing to the UVA radiation, PF pre-treatment could prominently increase the MTS activity, decrease cell apoptosis, reduce the generations of ROS and MDA, increase the activity of SOD and increase the expression of Nrf2 and its target genes HO-1 and NQ-O1. When Nrf2 was knocked down, PF lost above protective properties. In addition, UVA induced oxidative stress led to upregulation of PLIN2 and the latter could be decreased by PF. Overexpression of PLIN2 improved MTS activity and reduced MDA level in HDFs. The combination of PLIN2 overexpression and PF pre-treatment corporately inhibited UVA-induced injury. Besides, we also found that PF and PLIN2 had a compensatory protection against UVA induced oxidative stress. In conclusion, our study demonstrated that UVA induced photodamages could be inhibited by PF via Nrf2/HO-1/NQ-O1 signaling pathway or by PLIN2, and the combination of PLIN2 overexpression and PF played additive effects against UVA-related oxidative stress.

Paeoniflorin Resists H2O2-Induced Oxidative Stress in Melanocytes by JNK/Nrf2/HO-1 Pathway.

Paeoniflorin (PF) possesses multiple biological functions including anti-oxidization. PF is the major bioactive ingredient of total glycosides of paeony (TGP), which could promote re-pigmentation of vitiligo. The study was sought to investigate the effects and potential signaling pathways of PF on hydrogen peroxide (H2O2)-induced oxidative stress in melanocytes. The results showed that pretreatment with 50 µM PF significantly inhibited cell apoptosis, enhanced cell viability, and suppressed reactive oxygen species (ROS) accumulation by enhancing the productions of superoxide dismutase (SOD) and antioxidant enzymes catalase (CAT). Furthermore, PF activated c-Jun amino terminal kinase (JNK) and the nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway to counteract H2O2-induced oxidative damage in PIG1 and PIG3V. Taken together, our study firstly demonstrates that PF resists H2O2-induced oxidative stress in melanocytes probably by activating JNK/Nrf2/HO-1 signaling, suggesting a potential therapeutic application of PF on vitiligo.

Formation of Enamines via Catalytic Dehydrogenation by Pincer-Iridium Complexes.

Di-isopropylphosphino-substituted pincer-ligated iridium catalysts are found to be significantly more effective for the dehydrogenation of simple tertiary amines to give enamines than the previously reported di-t-butylphosphino-substituted species. It is also found that the di-isopropylphosphino-substituted complexes catalyze dehydrogenation of several ß-functionalized tertiary amines to give the corresponding 1,2-difunctionalized olefins. The di-t-butylphosphino-substituted species are ineffective for such substrates; presumably, the marked difference is attributable to the lesser crowding of the di-isopropylphosphino-substituted catalysts. Experimentally determined kinetic isotope effects in conjunction with DFT-based analysis support a dehydrogenation mechanism involving initial pre-equilibrium oxidative addition of the amine α-C-H bond followed by rate-determining elimination of the ß-C-H bond.

A decade retrospective study of light/laser devices in treating nasal rosacea.

Background: Large-scale retrospective studies of light/laser in treating nasal rosacea were lacking.Objective: The study was aimed to perform a decade retrospection of the patients with nasal rosacea who were treated with light/laser devices.Methods: A study between 2008 and 2017 was performed retrospectively. Categorization of rosacea type (erythema/telangiectasia, ET; papules/pustules, PP; rhinophyma, RP) was made according to the photographs. Device settings, treatment regimens and treatment sessions of light/laser facilities were summarized. Efficacy was evaluated using a grading scale.Results: In all, 807 patients received light/laser treatments. The subtypes of nasal rosacea were ET (n = 196), PP (n = 95), RP (n = 42), ET + PP (n = 334), ET + RP (n = 15), PP + RP (n = 88), and ET + PP + RP (n = 37). The lesions of ET or PP were mainly treated with noninvasive devices (Intense pulsed light, IPL; Dye pulse light, DPL; Dual wavelength laser system, DW) and those of RP were treated with the Fractional carbon dioxide (FCO2) laser. For the mixed subtypes, the general disposal orders of lesions were ET, PP, and later RP, and the fundamental orders of devices application were IPL, DPL, DW, and FCO2 laser. For all types of rosacea except for RP (2-4 sessions), most of the patients received 4-6 sessions of treatments. Of all subtypes of ET, PP, RP, ET + PP, ET + RP, PP + RP, and ET + PP + RP, the patients who achieved more than 50% improvement accounted for 74.5%, 58.3%, 83.3%, 69.2%, 73.3%, 61.4%, and 51.4%, respectively.Conclusion: The multiple, sequential light/laser devices can be safely used in nasal rosacea with various degrees efficacies based on different types.

The Prevalence of Thyroid Disorders in Patients With Vitiligo: A Systematic Review and Meta-Analysis.

Background: Associations between vitiligo and thyroid disorders have been suggested, However, the prevalence of thyroid disorders in vitiligo vary widely. Purpose: To conduct a systematic review and meta-analysis assessing the prevalence of thyroid disorders in patients with vitiligo. Method: The PubMed, Cochrane Library, EMBASE, CNKI (China National Knowledge Infrastructure), Chongqing VIP database, and Wanfang database from inception to August 2, 2018 were systematically searched. The pooled prevalence and its 95% confidence interval (CI) were calculated. Results: A total of 77 eligible studies were identified and included, published from 1968 to 2018. Six thyroid disorders including subclinical hyperthyroidism, overt hyperthyroidism, subclinical hypothyroidism, overt hypothyroidism, Graves disease, and Hashimoto thyroiditis were described. The numbers of relative studies were 54 in overt hypothyroidism, 50 in overt hyperthyroidism, 25 in subclinical hypothyroidism, 19 in Hashimoto thyroiditis, 16 in Graves disease, and 10 in subclinical hyperthyroidism. The highest prevalence was 0.06 (95% CI: 0.04-0.07) in subclinical hypothyroidism, and the lowest was 0.01 in subclinical hyperthyroidism (95% CI: 0.00-0.01) or Graves disease (95% CI: 0.01-0.02). Conclusion: Six thyroid disorders showed various prevalence in vitiligo. The highest prevalence was in subclinical hypothyroidism, and the lowest was in subclinical hyperthyroidism or Graves disease. Screening vitiligo patients for thyroid disorders seem plausible, in an effort to detect potential thyroid diseases or to assess the risk of future onset.

[Effects and mechanism of Sibiraea angustata on lipid metabolism in hight-fatted rats].

OBJECTIVE: To investigate the effect and mechanism of Sibiraea angustata on lipid metabolism in hight-fatted SD rats. METHODS: After the obese model was built,Sibiraea angustata was administrated intragastrically to obese rats for 8 weeks. Peeled off fat around kidneys and made pathological tissue sections. The number and size of adipocytes were detected. The levels of adiponectin, adipoR2, AMPK, and PPARgamma mRNA in adipose tissue were detected by RT-PCR. AMPK protein expression in adipose tissue were detected by Western Blot. RESULTS: Compared with the model group, the diameter of adipocytes were reduced while the number increased after adminiseration of Sibiraea angustata for 8 weeks. The levels of adiponectin, adipoR2, AMPK and PPARgamma mRNA were increased siginficantly. The expression of AMPK protein was also up-regulated significantly. CONCLUSION: Sibiraea angustata has anti-obesity effect. The mechanism may be related to the adiponectin signal transduction pathway.

A novel two-carbon homologation with N-vinylacetamides and ethyl vinyl ether as acetaldehyde anion equivalents in the synthesis of 9H-xanthene, 9H-thioxanthene, and 9,10-dihydro-9-acridine carboxaldehydes.

An efficient synthesis of 9H-xanthene-9-carboxaldehyde (3a), 9H-thioxanthene-9-carboxaldehyde (3b), and 9,10-dihydro-10-methyl-9-acridinecarboxaldehyde (3c) by a novel two-carbon homologation of xanthydrol (1a), thioxanthydrol (1b), and 9,10-dihydro-10-methyl-9-acridinol (1c), respectively, using N-vinylacetamides (2a,b) or ethyl vinyl ether (2c) as acetaldehyde anion equivalents, is described.