A piezoelectric-driven microneedle platform for skin disease therapy.

With over a million cases detected each year, skin disease is a global public health problem that diminishes the quality of life due to its difficulty to eradicate, propensity for recurrence, and potential for post-treatment scarring. Photodynamic therapy (PDT) is a treatment with minimal invasiveness or scarring and few side effects, making it well tolerated by patients. However, this treatment requires further research and development to improve its effective clinical use. Here, a piezoelectric-driven microneedle (PDMN) platform that achieves high efficiency, safety, and non-invasiveness for enhanced PDT is proposed. This platform induces deep tissue cavitation, increasing the level of protoporphyrin IX and significantly enhancing drug penetration. A clinical trial involving 25 patients with skin disease was conducted to investigate the timeliness and efficacy of PDMN-assisted PDT (PDMN-PDT). Our findings suggested that PDMN-PDT boosted treatment effectiveness and reduced the required incubation time and drug concentration by 25% and 50%, respectively, without any anesthesia compared to traditional PDT. These findings suggest that PDMN-PDT is a safe and minimally invasive approach for skin disease treatment, which may improve the therapeutic efficacy of topical medications and enable translation for future clinical applications.

Macrophage-derived mir-100-5p orchestrates synovial proliferation and inflammation in rheumatoid arthritis through mTOR signaling.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by synovial inflammation, causing substantial disability and reducing life quality. While macrophages are widely appreciated as a master regulator in the inflammatory response of RA, the precise mechanisms underlying the regulation of proliferation and inflammation in RA-derived fibroblast-like synoviocytes (RA-FLS) remain elusive. Here, we provide extensive evidence to demonstrate that macrophage contributes to RA microenvironment remodeling by extracellular vesicles (sEVs) and downstream miR-100-5p/ mammalian target of rapamycin (mTOR) axis. RESULTS: We showed that bone marrow derived macrophage (BMDM) derived-sEVs (BMDM-sEVs) from collagen-induced arthritis (CIA) mice (cBMDM-sEVs) exhibited a notable increase in abundance compared with BMDM-sEVs from normal mice (nBMDM-sEVs). cBMDM-sEVs induced significant RA-FLS proliferation and potent inflammatory responses. Mechanistically, decreased levels of miR-100-5p were detected in cBMDM-sEVs compared with nBMDM-sEVs. miR-100-5p overexpression ameliorated RA-FLS proliferation and inflammation by targeting the mTOR pathway. Partial attenuation of the inflammatory effects induced by cBMDM-sEVs on RA-FLS was achieved through the introduction of an overexpression of miR-100-5p. CONCLUSIONS: Our work reveals the critical role of macrophages in exacerbating RA by facilitating the transfer of miR-100-5p-deficient sEVs to RA-FLS, and sheds light on novel disease mechanisms and provides potential therapeutic targets for RA interventions.

Repurposed drug agomelatine is therapeutic against collagen-induced arthritis via iNOS targeting.

BACKGROUND: The most promising biologics tumor necrosis factor α (TNFα) inhibitors are effective in treating rheumatoid arthritis (RA) in only 50-70 % of the cases; thus, new drugs targeting TNFα-mediated inflammation are required. METHODS: Firstly, the drugs that could inhibit FLS proliferation and TNFα induced inflammatory cytokine production were screened. Secondly, treatment effects of the identified drugs were screened in collagen-induced arthritis (CIA) mouse model. Thirdly, the inhibitory effect of the identified drug, agomelatine (AOM), on TNFα induced inflammatory cytokine production and NF-κB activity were confirmed. Fourthly, bioinformatics was applied to predict the binding target of AOM and the binding was confirmed, and the already known inhibitor of target was used to test the treatment effect for CIA mouse model. Finally, the effect of AOM on signaling pathway was tested and on TNFα induced inflammatory cytokine production was observed after inhibiting the target. RESULTS: AOM effectively inhibited TNFα-induced NF-κB activation, NF-κB p65 translocation, and inflammatory cytokines production in vitro and was therapeutic against CIA. The mechanistic study indicated inducible nitric oxide synthase (iNOS) as the binding target of AOM. 1400 W, a known inhibitor of iNOS, could effectively treat CIA by decreasing iNOS activity and the levels of inflammatory cytokines. The inhibitory effect of AOM on TNFα-induced inflammation was further elucidated by 1400 W, or NF-κB p65 inhibitor JSH-23, indicating that AOM is therapeutic against CIA via iNOS/ERK/p65 signaling pathway after binding with iNOS. CONCLUSIONS: AOM is therapeutic against CIA via inhibition of the iNOS/ERK/p65 signaling pathway after binding with iNOS.

Interleukin-18 Gene Polymorphisms and Rheumatoid Arthritis Susceptibility: An Umbrella Review of Meta-Analyses.

This study systematically analyzes the association between interleukin-18 (IL-18) gene polymorphisms and rheumatoid arthritis (RA) susceptibility. The electronic databases Ovid MEDLINE, Ovid Excerpta Medica Database, and Cochrane Library were searched to identify meta-analyses that included case-control studies reporting IL-18 gene polymorphisms and RA susceptibility. Data were reanalyzed using Review Manager Software 5.1, and Mantel-Haenszel random effects were applied for the five genetic models: allelic, recessive, dominant, homozygote, and heterozygote. The effect size of odds ratios (ORs) and their corresponding 95% confidence interval (CI) were calculated. A total of seven meta-analyses with poor quality were included. The IL-18 polymorphisms -607 A/C, -137 C/G, -920 T/C, and -105 C/A have been reported. With weak evidence, IL-18 -607 A/C polymorphisms were associated with a reduced risk of RA susceptibility using the allele model (OR = 0.76, 95% CI: 0.61 - 0.93, p=0.01), dominant model (OR = 0.67, 95% CI: 0.50 - 0.90, p=0.008), homozygote model (OR = 0.57, 95% CI: 0.35 - 0.91, p=0.02), and heterozygote model (OR = 0.71, 95% CI: 0.54 - 0.93, p=0.01) in the overall population. IL-18 gene polymorphisms and RA susceptibility are affected by ethnicity: With weak evidence, IL-18 -137 C/G polymorphisms were related to reduce RA susceptibility in the Asian population (allele model: OR = 0.59, 95% CI: 0.40 - 0.88, p=0.01; dominant model: OR = 0.57, 95% CI: 0.37 - 0.89, p=0.01; heterozygote model: OR = 0.60, 95% CI: 0.38 - 0.94, p=0.03). IL-18 -607 A/C gene polymorphisms are a protective factor for RA susceptibility in the overall population, and IL-18 -137 C/G gene polymorphisms are a protective factor for RA susceptibility in the Asian population. Further studies are needed to confirm these results owing to the limitations of the included studies.

[Corrigendum] Downregulation of CD147 induces malignant melanoma cell apoptosis via the regulation of IGFBP2 expression.

Subsequently to the publication of the above article, an interested reader drew to the authors' attention that the ß­actin bands shown for the western blots portrayed in Fig. 4A and E on p. 2403 appeared to be strikingly similar, albeit that the bands were inverted with respect to their orientation and the dimensions of the bands differed slightly. After re­examining their original data, the authors have realized that these data in Fig. 4 had inadvertently been assembled incorrectly. The revised version of Fig. 4, showing the correct data for all the experiments in Fig. 4E, is shown on on the next page. The authors are grateful to the Editor of International Journal of Oncology for allowing them this opportunity to publish a Corrigendum, and all the authors agree to its publication. Furthermore, the authors apologize to the readership for any inconvenience caused. [International Journal of Oncology 53: 2397­2408, 2018; DOI: 10.3892/ijo.2018.4579].

Biomineral-binding liposomes with dual antibacterial effects for preventing and treating dental caries.

Dental caries is a chronic oral disease that results from the demineralization of dental hard tissues caused by the long-term interaction of various pathogenic factors in the human oral cavity. Although magnolol (Mag) and fluconazole (FLC) have shown promising antibacterial activity against Candida albicans (C. albicans) and Streptococcus mutans (S. mutans), their clinical application is limited due to hydrophobicity. In this study, we constructed biomineral-binding liposomes co-loaded with Mag and FLC (PPi-Mag/FLC-LPs) to overcome the hydrophobicity and achieve a dual antibacterial activity in the acidic microenvironment of caries. PPi-Mag/FLC-LPs were characterized by laser particle size analysis, transmission electron microscopy, and high-performance liquid chromatography (HPLC). The ability of PPi-Mag/FLC-LPs to bind hydroxyapatite was assessed in vitro using fluorescence microscopy and HPLC, while the antibacterial activity was examined by measuring drug effects on the acidogenicity, acid resistance, biofilm formation and survival of C. albicans and S. mutans. The pharmacodynamics of PPi-Mag/FLC-LPs was also evaluated in vivo in a rat model of dental caries. Mag and FLC were released rapidly from PPi-Mag/FLC-LPs in a pH-sensitive manner, and they bound effectively to hydroxyapatite, leading to a better antibacterial effect on C. albicans and S. mutans compared to free drugs or liposomes loaded with a single drug. PPi-Mag/FLC-LPs improved the medicinal properties of Mag and FLC and provided a rapid, pH-sensitive release of both drugs in vitro. PPi-Mag/FLC-LPs displayed good antibacterial activity in vivo, showing promise as a dual-drug delivery system for the prevention and treatment of caries.

Superficial shaving combined with photodynamic therapy for treating verrucous epidermal nevi: A case report.

Verrucous epidermal nevi is a refractory skin disease. Photodynamic therapy is considered a third-line treatment for verrucous epidermal nevi due to its unstable efficacy and high recurrence rate, mainly because of its limited depth of penetration. In this case, we conducted a successful treatment using superficial shaving combined with photodynamic therapy to treat verrucous epidermal nevi and gained a satisfactory efficacy. Before photodynamic therapy treatment, the epidermis in situ of each lesion in the tissue is removed with superficial shaving. Removal of the epidermal layer by intentional in situ injury improves the diffusion and absorption of topically applied photosensitizers and enhances the efficacy of photodynamic therapy. Our results show that photodynamic therapy combined with superficial shaving maybe is a safe and effective treatment for verrucous epidermal nevi.

Systematic review and meta-analysis of the current literature on tocilizumab in patients with refractory Takayasu arteritis.

Objective: To present the pooled quantitative evidence of baseline characteristics and clinical outcomes of tocilizumab (TCZ) in patients with refractory Takayasu arteritis (TAK). Methods: A comprehensive systematic review and meta-analysis was performed on all available studies retrieved from the MEDLINE, Embase, and Cochrane databases, using TCZ in patients with refractory TAK. We applied the commands metan and metaprop_one in Stata Software to pool overall estimates of continuous data and binomial data, respectively. A random-effects model was recruited for analysis. Results: Nineteen studies with 466 patients were included in this meta-analysis. The mean age at implementation of TCZ was 34.32 years. Female sex and Numano Type V were the most prominent baseline characteristics. During the 12-month follow-up when receiving TCZ treatment, pooled CRP was 1.17 mg/L (95% confidence interval [CI] -0.18-2.52), pooled ESR was 3.54 mm/h (95% CI 0.51-6.58), and pooled glucocorticoid dose was 6.26 mg/d (95% CI 4.24-8.27). Approximately 76% (95% CI 58-87%) of patients achieved a decrease in glucocorticoid dosage. Meanwhile, patients with TAK had a remission rate of 79% (95% CI 69-86%), a relapse rate of 17% (95% CI 5-45%), an imaging progress rate of 16% (95% CI 9-27%), and a retention rate of 68% (95% CI 50-82%). Adverse events occurred in 16% (95% CI 5-39%) of patients, and infection was the most common adverse event, with a rate of 12% (95% CI 5-28%). Conclusion: TCZ treatment can provide favorable outcomes in terms of inflammatory markers, steroid-sparing effects, clinical response, drug retention and minimizing adverse effects for patients with refractory TAK.

Fexofenadine protects against lipopolysaccharide-induced acute lung injury by targeting cytosolic phospholipase A2.

OBJECTIVE: Acute lung injury (ALI) causes acute respiratory distress syndrome, with a high mortality rate of 40%, with currently available pharmacological treatments. Cytosolic phospholipase A2 (cPLA2) plays a critical role in the lipopolysaccharide (LPS)-induced pathology of ALI. This study assessed the therapeutic effects of fexofenadine (FFD), an on-market small-molecule drug that can target cPLA2 in LPS-induced ALI. METHODS: Primary macrophages obtained from the bone marrow of wild-type and cPLA2 knockout mice and the alveolar macrophage cell line, MHS were used to test the inhibitory effect of FFD on the cPLA2/ERK/p65 signaling pathway, NF-κB p65 translocation, and cytokine and chemokine production. An LPS-induced ALI mouse model was used to assess the treatment effects of FFD. Flow cytometry detected subsets of macrophages and neutrophils. cPLA2 activity and downstream hydrolysates were detected. Treatment with a cPLA2 inhibitor or NF-κB p65 inhibitor confirmed that FFD functioned through the cPLA2/ERK/p65 signaling pathway by targeting cPLA2. RESULTS: FFD reduced the infiltration of macrophages and neutrophils, decreased the protein secretion in bronchoalveolar lavage fluid, and reduced the production of TNFα, IL-1ß, IL-6, MCP-1, and IL-8 in the lung, bronchoalveolar lavage fluid, and sera of LPS-induced ALI mice. FFD inhibited cPLA2 activity, suppressed the cPLA2/ERK/p65 signaling pathway, inhibited translocation of p65, and decreased the production of cytokines, chemokines, and downstream hydrolysates of cPLA2, arachidonic acid, and leukotriene B4. CONCLUSION: FFD inhibits the cPLA2/ERK/p65 signaling pathway by targeting cPLA2. Therefore, FFD is promising as a therapeutic against cPLA2-involved diseases, particularly ALI.

Neoplasm Risk in Patients With Rheumatoid Arthritis Treated With Fostamatinib: A Systematic Review and Meta-analysis.

Objective: This study aimed to assess neoplasm risk in patients with rheumatoid arthritis (RA) treated with fostamatinib. Methods: Studies were collected from electronic databases of OVID Medline, OVID EMBASE, Cochrane Central Register of Controlled Trials, and Web of Science. We included studies that reported neoplasms in patients with RA treated with fostamatinib. Study selection was repeated by two reviewers based on the study selection criteria. Data were collected and methodological quality assessment was performed. Data were pooled using the Peto odds ratio (OR) with a 95% confidence interval (CI). Subgroup analyses of the fostamatinib dose, trial duration, neoplasm nature, and neoplasm-originating systems were conducted. A funnel plot was used to estimate publication bias, and sensitivity analysis was performed to test the robustness of the results. Results: Seven trials involving 4,971 participants showing low to moderate risk of bias were included. Compared with the placebo, fostamatinib use was not associated with the risks of overall neoplasms (Peto OR = 2.62, 95%CI 0.97-7.10), malignant neoplasms (Peto OR = 3.08, 95%CI 0.96-9.91), or benign neoplasms (Peto OR = 1.71, 95%CI 0.26-11.36). Nevertheless, compared with the placebo, a longer duration of fostamatinib use had a higher risk of malignant neoplasms (Peto OR = 4.49, 95%CI 1.03-19.60) at 52 weeks. As for malignant neoplasms in the digestive system, lower doses of fostamatinib reduced the neoplasm risk (100 mg bid vs 150 mg qd: Peto OR = 0.06, 95%CI 0.01-0.59). Sensitivity analysis showed no significant differences in the effective trends, and no publication bias was found. Conclusion: Fostamatinib is not associated with the risks of overall neoplasms as compared to placebo. Nevertheless, a longer duration of fostamatinib use may be associated with a risk of malignant neoplasms and higher doses of fostamatinib may increase malignant neoplasms in the digestive system. Further well-planned cohort studies with a larger study population are needed to elucidate these outcomes. Systematic Review Registration: PROSPERO (CRD42020202121).

A novel dual-prodrug carried by cyclodextrin inclusion complex for the targeting treatment of colon cancer.

BACKGROUND: There is an obvious correlation between ulcerative colitis and colorectal cancer, and the risk of colorectal cancer in patients with ulcerative colitis is increasing. Therefore, the combination therapy of anti-inflammatory and anti-tumor drugs may show promising to inhibit colon cancer. 5-aminosalicylic acid (5-ASA) with anti-inflammatory function is effective for maintaining remission in patients with ulcerative colitis and may also reduce colorectal cancer risk. Histone deacetylase (HDAC) plays an essential role in the progression of colon cancer. Butyric acid (BA) is a kind of HDAC inhibitor and thus shows tumor suppression to colon cancer. However, the volatile and corrosive nature of BA presents challenges in practical application. In addition, its clinical application is limited due to its non-targeting ability and low bioavailability. We aimed to synthesize a novel dual-prodrug of 5-ASA and BA, referred as BBA, to synergistically inhibit colon cancer. Further, based on the fact that folate receptor (FR) is over-expressed in most solid tumors and it has been identified to be a cancer stem cell surface marker in colon cancer, we took folate as the targeting ligand and used carboxymethyl-ß-cyclodextrin (CM-ß-CD) to carry BBA and thus prepared a novel inclusion complex of BBA/FA-PEG-CM-ß-CD. RESULTS: It was found that BBA/FA-PEG-CM-ß-CD showed significant inhibition in cell proliferation against colon cancer cells SW620. It showed a pro-longed in vivo circulation and mainly accumulated in tumor tissue. More importantly, BBA/FA-PEG-CM-ß-CD gave great tumor suppression effect against nude mice bearing SW620 xenografts. CONCLUSIONS: Therefore, BBA/FA-PEG-CM-ß-CD may have clinical potential in colon cancer therapy.

Preparation and Formulation Optimization of Methotrexate-loaded Human Serum Albumin Nanoparticles Modified by Mannose.

BACKGROUND: Methotrexate (MTX) is the representative drug among the disease- modifying anti-rheumatic drugs. However, the conventional treatment with MTX showed many limitations and side effects. OBJECTIVE: To strengthen the targeting ability and circulation time of MTX in the treatment of rheumatoid arthritis, the present study focused on developing a novel drug delivery system of methotrexate-loaded human serum albumin nanoparticles (MTX-NPs) modified by mannose, which are referred to as MTX-M-NPs. METHODS: Firstly, mannose-derived carboxylic acid was synthesized and further modified on the surface of MTX-NPs to prepare MTX-M-NPs. The formulation of nanoparticles was optimized by the method of central composite design (CCD), with the drug lipid ratio, oil-aqueous ratio, and cholesterol or lecithin weight as the independent variables. The average particle size and encapsulation efficiency were the response variables. The response of different formulations was calculated, and the response surface diagram, contour diagram, and mathematical equation were used to relate the dependent and independent variables to predict the optimal formula ratio. The uptake of MTX-M-NPs by neutrophils was studied through confocal laser detection. Further, MTX-M-NPs were subjected to assessment of the pharmacokinetics profile after intravenous injection with Sprague-Dawley rats. RESULTS: This targeting drug delivery system was successfully developed. Results from Nuclear Magnetic Resonance and Fourier Transform Infrared Spectroscopy analysis can verify the successful preparation of this drug delivery system. Based on the optimized formula, MTX-M-NPs were prepared with a particle size of 188.17 ± 1.71 nm and an encapsulation rate of 95.55 ± 0.33%. MTX-M-NPs displayed significantly higher cellular uptake than MTX-NPs. The pharmacokinetic results showed that MTX-M-NPs could prolong the in vivo circulation time of MTX. CONCLUSION: This targeting drug delivery system laid a promising foundation for the treatment of RA.

Farnesal-loaded pH-sensitive polymeric micelles provided effective prevention and treatment on dental caries.

BACKGROUND: Farnesol is a sesquiterpene from propolis and citrus fruit that shows promising anti-bacterial activity for caries treatment and prevention, but its hydrophobicity limits the clinical application. We aimed to develop the novel polymeric micelles (PMs) containing a kind of derivative of farnesol and a ligand of pyrophosphate (PPi) that mediated PMs to adhere tightly with the tooth enamel. RESULTS: Farnesal (Far) was derived from farnesol and successfully linked to PEG via an acid-labile hydrazone bond to form PEG-hyd-Far, which was then conjugated to PPi and loaded into PMs to form the aimed novel drug delivery system, PPi-Far-PMs. The in vitro test about the binding of PPi-Far-PMs to hydroxyapatite showed that PPi-Far-PMs could bind rapidly to hydroxyapatite and quickly release Far under the acidic conditions. Results from the mechanical testing and the micro-computed tomography indicated that PPi-Far-PMs could restore the microarchitecture of teeth with caries. Moreover, PPi-Far-PMs diminished the incidence and severity of smooth and sulcal surface caries in rats that were infected with Streptococcus mutans while being fed with a high-sucrose diet. The anti-caries efficacy of free Far can be improved significantly by PPi-Far-PMs through the effective binding of it with tooth enamel via PPi. CONCLUSIONS: This novel drug-delivery system may be useful for the treatment and prevention of dental caries as well as the targeting therapy of anti-bacterial drugs in the oral disease.

The Application of Deep Learning in the Risk Grading of Skin Tumors for Patients Using Clinical Images.

According to diagnostic criteria, skin tumors can be divided into three categories: benign, low degree and high degree malignancy. For high degree malignant skin tumors, if not detected in time, they can do serious harm to patients' health. However, in clinical practice, identifying malignant degree requires biopsy and pathological examination which is time costly. Furthermore, in many areas, due to the severe shortage of dermatologists, it's inconvenient for patients to go to hospital for examination. Therefore, an easy to access screening method of malignant skin tumors is needed urgently. Firstly, we spend 5 years to build a dataset which includes 4,500 images of 10 kinds of skin tumors. All instances are verified pathologically thus trustworthy; Secondly, we label each instance to be either low-risk, high-risk or dangerous in which Junctional nevus, Intradermal nevus, Dermatofibroma, Lipoma and Seborrheic keratosis are low-risk, Basal cell carcinoma, Bowen's disease and Actinic keratosis are high-risk, Squamous cell carcinoma and Malignant melanoma are dangerous; Thirdly, we apply the Xception architecture to build the risk degree classifier. The area under the curve (AUC) for three risk degrees reach 0.959, 0.919 and 0.947 respectively. To further evaluate the validity of the proposed risk degree classifier, we conduct a competition with 20 professional dermatologists. The results showed the proposed classifier outperforms dermatologists. Our system is helpful to patients in preliminary screening. It can identify the patients who are at risk and alert them to go to hospital for further examination.

The Prevalence of Atopic Dermatitis and Chronic Spontaneous Urticaria are Associated with Parental Socioeconomic Status in Adolescents in China.

The association of atopic dermatitis and chronic spontaneous urticaria with socioeconomic status has been little studied. The aim of this study was to investigate the prevalence of skin diseases and their association with socioeconomic status in adolescents in China. A cross-sectional study was conducted at Central South University, Changsha, China. All newly enrolled students underwent dermatological examination and completed a survey. Socioeconomic status was measured in terms of parental education level and income. Two-level logistic regression models were used. A total of 8,226 students consented to participate. On dermatological examination, moderate to severe acne (10.2%) had the highest prevalence, followed by chronic spontaneous urticaria (2.7%), atopic dermatitis (2.5%), and tinea (1.7%). Socioeconomic status was positively associated with the prevalence of chronic spontaneous urticaria (ptrend = 0.001) and atopic dermatitis (ptrend = 0.0094). Tinea was inversely associated with socioeconomic status (ptrend = 0.025). Higher parental socioeconomic status was associated with higher risk of atopic dermatitis and chronic spontaneous urticaria, but lower risk of tinea.

Downregulation of CD147 induces malignant melanoma cell apoptosis via the regulation of IGFBP2 expression.

Cluster of differentiation (CD)147, as a transmembrane glycoprotein, is highly expressed in a variety of tumors. Accumulating evidence has demonstrated that CD147 serves critical roles in tumor cell death and survival; however, the underlying mechanism requires further investigation. In the present study, it was revealed that CD147 knockdown significantly increased melanoma cell apoptosis. In addition, downregulation of CD147 reversed the malignant phenotype of melanoma, as demonstrated by the induction of tumor cell apoptosis in a xenograft mouse model. In addition, a human apoptosis antibody array was performed and 9 differentially expressed apoptosis-related proteins associated with CD147 were identified, including insulin-like growth factor-binding protein 2 (IGFBP2). Additionally, CD147 knockdown was observed to significantly decreased IGFBP2 expression at the mRNA and protein levels in melanoma cells. Providing that IGFBP2 is a downstream molecule in the phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway, the effects of CD147 on this particular pathway were investigated. Interestingly, the expression of phosphorylated (p)-AKT and p­mechanistic target of rapamycin was attenuated, whereas PTEN was markedly upregulated in CD147-underexpressing melanoma cells. Furthermore, application of a PI3K­specific inhibitor also decreased IGFBP2 expression. Importantly, IGFBP2 was highly expressed in clinical tissues of melanoma compared with the control group, and its expression exhibited a positive association with CD147. The present study revealed that CD147 served a critical role in mediating the apoptosis of melanoma cells via IGFBP2 and the PTEN/PI3K/AKT signaling pathway. IGFBP2 and CD147 were observed to be overexpressed in clinical melanoma tissues; IGFBP2 was shown to be positively associated with CD147 expression, suggesting that CD147 may be considered as a potential therapeutic target for chemotherapy or prevention for in melanoma.

Propranolol enhanced the anti-tumor effect of sunitinib by inhibiting proliferation and inducing G0/G1/S phase arrest in malignant melanoma.

Both sunitinib, a multi-target tyrosine kinase inhibitor (TKI) and propranolol, a non-selective ß-blocker, have proven therapeutic effects on malignant melanoma (MM). This study reports a synergistic effect of propranolol and sunitinib upon A375, P8 MM cell lines and mice xenografts. Cell viability assays detected a significant decrease of sunitinib IC50 in combination with propranolol, which was confirmed by a colony formation assay. Western blot showed that propranolol and sunitinib combination significantly down-regulated phospho-Rb, phospho-ERK, Cyclin D1, and Cyclin E, but had no effect on Bax, Bcl-2, or cleaved PARP expression. The average tumor size of propranolol and low-dose sunitinib (Sun L) combination treated mice was reduced and similar to high-dose sunitinib treated A375 xenografts. The Ki67 index was significantly reduced in propranolol and Sun L combination treated group compared with single Sun L treated group. This synergistic effect between propranolol and sunitinib to inhibit MM proliferation was through suppressing ERK/Cyclin D1/Rb/Cyclin E pathways and inducing G0/G1/S phase arrest, rather than by inducing tumor cell apoptosis.