Newly identified peptide Nigrocin-OA27 inhibits UVB induced melanin production via the MITF/TYR pathway.

Melasma is a common skin disease induced by an increase in the content of melanin in the skin, which also causes serious physical and mental harm to patients. In this research, a novel peptide (Nigrocin-OA27) from Odorrana andersonii is shown to exert a whitening effect on C57 mice pigmentation model. The peptide also demonstrated non-toxic and antioxidant capacity, and can significantly reduce melanin content in B16 cells. Topical application effectively delivered Nigrocin-OA27 to skin's epidermal and dermal layers and exhibited significant preventive and whitening effects on the UVB-induced ear pigmentation model in C57 mice. The whitening mechanism of Nigrocin-OA27 may be related to reduced levels of the microphthalmia-associated transcription factor and the key enzyme for melanogenesis-tyrosinase (TYR). Nigrocin-OA27 also inhibited the catalytic activity by adhering to the active core of TYR, thereby reducing melanin formation and deposition. In conclusion, Nigrocin-OA27 may be a potentially effective external agent to treat melasma by inhibiting aberrant skin melanin synthesis.

Global and regional epidemiology of psoriatic arthritis in patients with psoriasis: A comprehensive systematic analysis and modelling study.

OBJECTIVES: To provide a comprehensive analysis and modelling of the global epidemiology of psoriatic arthritis (PsA) in patients with psoriasis. METHODS: We reviewed and analysed PsA epidemiology studies over the past 45 years. A Bayesian hierarchical linear mixed model was developed to provide comprehensive age- and sex-specific epidemiologic estimates in different countries and regions. RESULTS: Three hundred and sixty-three studies were systematically reviewed. The incidence of PsA in patients with psoriasis varied from 2.31 per 1000 person-years in the United Kingdom to 74.00 per 1000 person-years in several Western European countries. The global prevalence of PsA in patients with psoriasis is estimated to be 17.58% (3.33%, 43.69%). Regionally, the overall prevalence of PsA in patients with psoriasis varies from 7.62% (4.18%, 12.28%) in Australasia to 26.59% (18.89%, 35.76%) in North America. The Caribbean and Central Latin America also have relatively high prevalence and are estimated at 23.14% (14.06%, 35.17%) and 22.81% (14.36%, 32.25%), respectively. The prevalence of PsA is higher in adults than children (23.93% vs 8.59%) and also slightly higher in females than males (19.14% vs 16.01%). CONCLUSIONS: This study provides valuable insights into the global epidemiology of PsA. It also serves as a useful resource for researchers in areas lacking relevant studies. These findings have important implications for clinicians managing the course of PsA and for health policymakers in resource allocation.

Peptide OM-LV20 promotes arteriogenesis induced by femoral artery ligature via the miR-29b-3p/VEGFA axis.

BACKGROUND AND AIMS: Therapeutic arteriogenesis is a promising direction for the treatment of ischemic disease caused by atherosclerosis. However, pharmacological or biological approaches to stimulate functional collateral vessels are not yet available. Identifying new drug targets to promote and explore the underlying mechanisms for therapeutic arteriogenesis is necessary. METHODS: Peptide OM-LV20 (20 ng/kg) was administered for 7 consecutive days on rat hindlimb ischemia model, collateral vessel growth was assessed by H&E staining, liquid latex perfusion, and specific immunofluorescence. In vitro, we detected the effect of OM-LV20 on human umbilical vein endothelial cells (HUVEC) proliferation and migration. After transfection, we performed quantitative real-time polymerase chain reaction, in situ-hybridization and dual luciferase reporters to assessed effective miRNAs and target genes. The proteins related to downstream signaling pathways were detected by Western blot. RESULTS: OM-LV20 significantly increased visible collateral vessels and endothelial nitric oxide synthase (eNOS), together with enhanced inflammation cytokine and monocytes/macrophage infiltration in collateral vessels. In vitro, we defined a novel microRNA (miR-29b-3p), and its inhibition enhanced proliferation and migration of HUVEC, as well as the expression of vascular endothelial growth factor A (VEGFA). OM-LV20 also promoted migration and proliferation of HUVEC, and VEGFA expression was mediated via inhibition of miR-29b-3p. Furthermore, OM-LV20 influenced the protein levels of VEGFR2 and phosphatidylinositol3-kinase (PI3K)/AKT and eNOS in vitro and invivo. CONCLUSIONS: Our data indicated that OM-LV20 enhanced arteriogenesis via the miR-29b-3p/VEGFA/VEGFR2-PI3K/AKT/eNOS axis, and highlighte the application potential of exogenous peptide molecular probes through miRNA, which could promote effective therapeutic arteriogenesis in ischemic conditions.

Hydrogel Loaded with Peptide-Containing Nanocomplexes: Symphonic Cooperation of Photothermal Antimicrobial Nanoparticles and Prohealing Peptides for the Treatment of Infected Wounds.

Current treatment for chronic infectious wounds is limited due to severe drug resistance in certain bacteria. Therefore, the development of new composite hydrogels with nonantibiotic antibacterial and pro-wound repair is important. Here, we present a photothermal antibacterial composite hydrogel fabricated with a coating of Fe2+ cross-linked carboxymethyl chitosan (FeCMCS) following the incorporation of melanin nanoparticles (MNPs) and the CyRL-QN15 peptide. Various physical and photothermal properties of the hydrogel were characterized. Cell proliferation, migration, cycle, and free-radical scavenging activity were assessed, and the antimicrobial properties of the hydrogel were probed by photothermal therapy. The effects of the hydrogel were validated in a model of methicillin-resistant Staphylococcus aureus (MRSA) infection with full-thickness injury. This effect was further confirmed by changes in cytokines associated with inflammation, re-epithelialization, and angiogenesis on the seventh day after wound formation. The MNPs demonstrated robust photothermal conversion capabilities. The composite hydrogel (MNPs/CyRL-QN15/FeCMCS) promoted keratinocyte and fibroblast proliferation and migration while exhibiting high antibacterial efficacy, effectively killing more than 95% of Gram-positive and Gram-negative bacteria. In vivo study using an MRSA-infected full-thickness injury model demonstrated good therapeutic efficacy of the hydrogel in promoting regeneration and remodeling of chronically infected wounds by alleviating inflammatory response and accelerating re-epithelialization and collagen deposition. The MNPs/CyRL-QN15/FeCMCS hydrogel showed excellent antibacterial and prohealing effects on infected wounds, indicating potential as a promising candidate for wound healing promotion.

Amphibian-derived peptide RL-RF10 ameliorates paraquat-induced pulmonary fibrosis injury.

Pulmonary fibrosis is the result of dysfunctional repair after lung tissue injury, characterized by fibroblast proliferation and massive extracellular matrix aggregation. Once fibrotic lesions develop, effective treatment is difficult, with few drugs currently available. Here, we identified a short cyclic decapeptide RL-RF10 derived from frog skin secretions as a potential novel lead molecule for the amelioration of pulmonary fibrosis. In vivo experiments indicated that RL-RF10 treatment ameliorated lung histopathological damage and fibrogenesis after paraquat (PQ) induction in a concentration-dependent manner. On day 7, bronchoalveolar lavage fluid assays performed on mice showed that RL-RF10 exerted anti-inflammatory effects by decreasing the expression of inflammation-related factors, including transforming growth factor-ß1 (TGF-ß1) and tumor necrosis factor-α, in lung tissue. In addition, RL-RF10 down-regulated the levels of collagen I, collagen III, and vimentin, while increasing the expression of E-cadherin to inhibit epithelial-mesenchymal transition. Further research demonstrated that the SMAD2/3 signaling pathway, which is strongly linked to TGF-ß1, played a critical function in enhancing the pulmonary fibrosis relief achieved by RL-RF10. Both in vivo and in vitro assays showed that RL-RF10 treatment led to a significant reduction in the phosphorylation levels of SMAD2 and SMAD3 following PQ induction. Overall, we investigated the protective effects and underlying mechanisms of the RL-RF10 peptide against pulmonary fibrosis and demonstrated its potential as a novel therapeutic drug candidate for the treatment of pulmonary fibrotic diseases.

OL-FS13 Alleviates Cerebral Ischemia-reperfusion Injury by Inhibiting miR-21-3p Expression.

BACKGROUND: OL-FS13, a neuroprotective peptide derived from Odorrana livida, can alleviate cerebral ischemia-reperfusion (CI/R) injury, although the specific underlying mechanism remains to be further explored. OBJECTIVE: The effect of miR-21-3p on the neural-protective effects of OL-FS13 was examined. METHODS: In this study, the multiple genome sequencing analysis, double luciferase experiment, RT-qPCR, and Western blotting were used to explore the mechanism of OL-FS13. RESULTS: Showed that over-expression of miR-21-3p against the protective effects of OL-FS13 on oxygen- glucose deprivation/re-oxygenation (OGD/R)-damaged pheochromocytoma (PC12) cells and in CI/R-injured rats. miR-21-3p was then found to target calcium/calmodulin-dependent protein kinase 2 (CAMKK2), and its overexpression inhibited the expression of CAMKK2 and phosphorylation of its downstream adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), thereby inhibiting the therapeutic effects of OL-FS13 on OGD/R and CI/R. Inhibition of CAMKK2 also antagonized up-regulated of nuclear factor erythroid 2-related factor 2 (Nrf-2) by OL-FS13, thereby abolishing the antioxidant activity of the peptide. CONCLUSION: Our results showed that OL-FS13 alleviated OGD/R and CI/R by inhibiting miR-21-3p to activate the CAMKK2/AMPK/Nrf-2 axis.

MYC promotes fibroblast osteogenesis by regulating ALP and BMP2 to participate in ectopic ossification of ankylosing spondylitis.

BACKGROUND: Ectopic ossification is an important cause of disability in patients with ankylosing spondylitis (AS). Whether fibroblasts can transdifferentiate into osteoblasts and contribute to ossification remains unknown. This study aims to investigate the role of stem cell transcription factors (POU5F1, SOX2, KLF4, MYC, etc.) of fibroblasts in ectopic ossification in patients with AS. METHODS: Primary fibroblasts were isolated from the ligaments of patients with AS or osteoarthritis (OA). In an in vitro study, primary fibroblasts were cultured in osteogenic differentiation medium (ODM) to induce ossification. The level of mineralization was assessed by mineralization assay. The mRNA and protein levels of stem cell transcription factors were measured by real-time quantitative PCR (q-PCR) and western blotting. MYC was knocked down by infecting primary fibroblasts with lentivirus. The interactions between stem cell transcription factors and osteogenic genes were analysed by chromatin immunoprecipitation (ChIP). Recombinant human cytokines were added to the osteogenic model in vitro to evaluate their role in ossification. RESULTS: We found that MYC was elevated significantly in the process of inducing primary fibroblasts to differentiate into osteoblasts. In addition, the level of MYC was remarkably higher in AS ligaments than in OA ligaments. When MYC was knocked down, the expression of the osteogenic genes alkaline phosphatase (ALP) and bone morphogenic protein 2 (BMP2) was decreased, and the level of mineralization was reduced significantly. In addition, the ALP and BMP2 were confirmed to be the direct target genes of MYC. Furthermore, interferon-γ (IFN-γ), which showed high expression in AS ligaments, was found to promote the expression of MYC in fibroblasts in the process of ossification in vitro. CONCLUSIONS: This study demonstrates the role of MYC in ectopic ossification. MYC may act as the critical bridge that links inflammation with ossification in AS, thus providing new insights into the molecular mechanisms of ectopic ossification in AS.

Identification of Transcriptional Heterogeneity and Construction of a Prognostic Model for Melanoma Based on Single-Cell and Bulk Transcriptome Analysis.

Melanoma is one of the most aggressive and heterogeneous life-threatening cancers. However, the heterogeneity of melanoma and its impact on clinical outcomes are largely unknown. In the present study, intra-tumoral heterogeneity of melanoma cell subpopulations was explored using public single-cell RNA sequencing data. Marker genes, transcription factor regulatory networks, and gene set enrichment analysis were further analyzed. Marker genes of each malignant cluster were screened to create a prognostic risk score, and a nomogram tool was further generated to predict the prognosis of melanoma patients. It was found that malignant cells were divided into six clusters by different marker genes and biological characteristics in which the cell cycling subset was significantly correlated with unfavorable clinical outcomes, and the Wnt signaling pathway-enriched subset may be correlated with the resistance to immunotherapy. Based on the malignant marker genes, melanoma patients in TCGA datasets were divided into three groups which had different survival rates and immune infiltration states. Five malignant cell markers (PSME2, ARID5A, SERPINE2, GPC3, and S100A11) were selected to generate a prognostic risk score. The risk score was associated with overall survival independent of routine clinicopathologic characteristics. The nomogram tool showed good performance with an area under the curve value of 0.802.

A new peptide originated from amphibian skin alleviates the ultraviolet B-induced skin photodamage.

Although amphibian-derived bioactive peptides have attracted increasing attention for their potential use in the treatment of photodamage, research is still in its infancy. In this study, we obtained a new antioxidant peptide, named OA-GI13 (GIWAPWPPRAGLC), from the skin of the odorous frog Odorrana andersonii and determined its effects on ultraviolet B (UVB)-induced skin photodamage as well as its possible molecular mechanisms. Results showed that OA-GI13 directly scavenged free radicals, maintained the viability of hydrogen peroxide-challenged keratinocytes, promoted the release of superoxide dismutase, catalase, and glutathione, and reduced the level of lactate dehydrogenase. Furthermore, topical application of OA-GI13 in mice alleviated dorsal skin erythema and edema and protected the skin against UVB irradiation by increasing antioxidant levels and decreasing peroxide, malondialdehyde, and 8-hydroxydeoxyguanosine levels. OA-GI13 also alleviated oxidative stress injury in vivo and in vitro, possibly by inhibiting p38 protein phosphorylation. Our study confirmed the anti-photodamage effects of this novel amphibian-derived peptide, thus providing a new molecule for the development of drugs and topical agents for the treatment of skin photodamage.

Characterization of a lactate metabolism-related signature for evaluation of immune features and prediction prognosis in glioma.

Background: Glioma is one of the most typical tumors in the central nervous system with a poor prognosis, and the optimal management strategy remains controversial. Lactate in the tumor microenvironment is known to promote cancer progression, but its impact on clinical outcomes of glioma is largely unknown. Methods: Glioma RNA-seq data were obtained from TCGA and GCGA databases. Lactate metabolism genes (LMGs) were then evaluated to construct an LMG model in glioma using Cox and LASSO regression. Immune cell infiltration, immune checkpoint gene expression, enriched pathways, genetic alteration, and drug sensitivity were compared within the risk subgroups. Based on the risk score and clinicopathological features, a nomogram was developed to predict prognosis in patients with glioma. Results: Five genes (LDHA, LDHB, MRS2, SL16A1, and SL25A12) showed a good prognostic value and were used to construct an LMG-based risk score. This risk score was shown as an independent prognostic factor with good predictive power in both training and validation cohorts (p < 0.001). The LMG signature was found to be correlated with the expression of immune checkpoint genes and immune infiltration and could shape the tumor microenvironment. Genetic alteration, dysregulated metabolism, and tumorigenesis pathways could be the underlying contributing factors that affect LMG risk stratification. The patients with glioma in the LMG high-risk group showed high sensitivity to EGFR inhibitors. In addition, our nomogram model could effectively predict overall survival with an area under the curve value of 0.894. Conclusion: We explored the characteristics of LMGs in glioma and proposed an LMG-based signature. This prognostic model could predict the survival of patients with glioma and help clinical oncologists plan more individualized and effective therapeutic regimens.

Excessive CD11c+Tbet+ B cells promote aberrant TFH differentiation and affinity-based germinal center selection in lupus.

Excessive self-reactive and inadequate affinity-matured antigen-specific antibody responses have been reported to coexist in lupus, with elusive cellular and molecular mechanisms. Here, we report that the antigen-specific germinal center (GC) response-a process critical for antibody affinity maturation-is compromised in murine lupus models. Importantly, this defect can be triggered by excessive autoimmunity-relevant CD11c+Tbet+ age-associated B cells (ABCs). In B cell-intrinsic Ship-deficient (ShipΔB) lupus mice, excessive CD11c+Tbet+ ABCs induce deregulated follicular T-helper (TFH) cell differentiation through their potent antigen-presenting function and consequently compromise affinity-based GC selection. Excessive CD11c+Tbet+ ABCs and deregulated TFH cell are also present in other lupus models and patients. Further, over-activated Toll-like receptor signaling in Ship-deficient B cells is critical for CD11c+Tbet+ ABC differentiation, and blocking CD11c+Tbet+ ABC differentiation in ShipΔB mice by ablating MyD88 normalizes TFH cell differentiation and rescues antigen-specific GC responses, as well as prevents autoantibody production. Our study suggests that excessive CD11c+Tbet+ ABCs not only contribute significantly to autoantibody production but also compromise antigen-specific GC B-cell responses and antibody-affinity maturation, providing a cellular link between the coexisting autoantibodies and inadequate affinity-matured antigen-specific antibodies in lupus models and a potential target for treating lupus.

Hyperprolactinemia is associated with a high prevalence of serum autoantibodies, high levels of inflammatory cytokines and an abnormal distribution of peripheral B-cell subsets.

PURPOSE: Hyperprolactinemia (HPRL) has been reported in many autoimmune diseases. However, the serum autoantibody profile and peripheral B-cell subset distribution in women with HPRL are largely unknown. The current study aimed to investigate the autoantibody prevalence and cytokine levels as well as to further explore the B-cell subset distribution in women with HPRL. METHODS: Sera from 202 women with HPRL and 97 healthy women were included in this study. All sera were examined for prolactin (PRL), anti-nuclear antibody (ANA), rheumatoid factor, anticardiolipin (ACL), immunoglobulin G, immunoglobulin M, complement 3, complement 4, interleukin 4 (IL-4) and interleukin 6 (IL-6). Peripheral blood was collected from 22 women with HPRL and 19 healthy women, and B-cell subsets were measured by flow cytometry. RESULTS: At least one autoantibody was found in 47 out of 202 women with HPRL compared with 9 of 97 healthy women (p < 0.001). The levels of IL-4 (p < 0.0001) and IL-6 (p < 0.0001) were significantly higher in women with HPRL than in healthy women. The percentages of naive IgD+IgM- B cells (BND cells, p < 0.0001), antibody-secreting cells (p = 0.007) and unswitched memory B cells (p = 0.004) among the total B cells from HPRL women were significantly higher than those from healthy women. CONCLUSIONS: Women with HPRL had a higher prevalence of autoantibodies, higher serum levels of IL-4 and IL-6, and more BND cells, antibody-secreting B cells and unswitched memory B cells than healthy women. These data imply that a high level of PRL is associated with autoimmune diseases.