A bidirectional Mendelian randomization study of sarcopenia-related traits and inflammatory bowel diseases.

Background: There is increasing evidence pointing to a close relationship between sarcopenia and inflammatory bowel disease. However, it remains unclear whether or in which direction causal relationships exist, because these associations could be confounded. Methods: We conducted a two-sample bidirectional mendelian randomization analysis using data from European genome-wide association studies of the appendicular lean mass(n = 450,243), walking pace(n = 459,915), grip strength (left hand, n = 461,026; right hand, n = 461,089), inflammatory bowel disease (25,042 patients and 34,915 controls), ulcerative colitis (12,366 patients and 33,609 controls), and Crohn's disease (12,194 patients and 28,072 controls) to investigate the causal relationship between sarcopenia-related traits and inflammatory bowel disease and its subtypes on each other. The inverse-variance weighted method was used as the primary analysis method to assess the causality, and a comprehensive sensitivity test was conducted. Results: Genetically predicted appendicular lean mass was significantly associated with inflammatory bowel disease (OR = 0.916, 95%CI: 0.853-0.984, P = 0.017), ulcerative colitis (OR =0.888, 95%CI: 0.813-0.971, P = 0.009), and Crohn's disease (OR = 0.905, 95%CI: 0.820-0.999, P = 0.049). Similar results also revealed that the usual walking pace was causally associated with Crohn's disease (OR = 0.467, 95%CI: 0.239-0.914, P = 0.026). Reverse mendelian randomization analysis results found that genetic susceptibility to inflammatory bowel disease, and Crohn's disease were associated with lower appendicular lean mass. A series of sensitivity analyses ensured the reliability of the present research results. Conclusion: The mendelian randomization study supports a bidirectional causality between inflammatory bowel disease, Crohn's disease and appendicular lean mass, but no such bidirectional causal relationship was found in ulcerative colitis. In addition, genetically predicted usual walking pace may reduce the risk of Crohn's disease. These findings have clinical implications for sarcopenia and inflammatory bowel disease management.

Network pharmacology and bioinformatics analysis identifies potential therapeutic targets of Naringenin against COVID-19/LUSC.

Background: Coronavirus disease 2019 (COVID-19) is a highly contagious respiratory disease that has posed a serious threat to people's daily lives and caused an unprecedented challenge to public health and people's health worldwide. Lung squamous cell carcinoma (LUSC) is a common type of lung malignancy with a highly aggressive nature and poor prognosis. Patients with LUSC could be at risk for COVID-19, We conducted this study to examine the potential for naringenin to develop into an ideal medicine and investigate the underlying action mechanisms of naringenin in COVID-19 and LUSC due to the anti-viral, anti-tumor, and anti-inflammatory activities of naringenin. Methods: LUSC related genes were obtained from TCGA, PharmGKB, TTD,GeneCards and NCBI, and then the transcriptome data for COVID-19 was downloaded from GEO, DisGeNET, CTD, DrugBank, PubChem, TTD, NCBI Gene, OMIM. The drug targets of Naringenin were revealed through CTD, BATMAN, TCMIP, SymMap, Chemical Association Networks, SwissTargetPrediction, PharmMapper, ECTM, and DGIdb. The genes related to susceptibility to COVID-19 in LUSC patients were obtained through differential analysis. The interaction of COVID-19/LUSC related genes was evaluated and demonstrated using STRING to develop a a COX risk regression model to screen and evaluate the association of genes with clinical characteristics. To investigate the related functional and pathway analysis of the common targets of COVID-19/LUSC and Naringenin, KEGG and GO enrichment analysis were employed to perform the functional analysis of the target genes. Finally, The Hub Gene was screened and visualized using Cytoscape, and molecular docking between the drug and the target was performed using Autodock. Results: We discovered numerous COVID-19/LUSC target genes and examined their prognostic value in LUSC patients utilizing a variety of bioinformatics and network pharmacology methods. Furthermore, a risk score model with strong predictive performance was developed based on these target genes to assess the prognosis of LUSC patients with COVID-19. We intersected the therapeutic target genes of naringenin with the LUSC, COVID-19-related targets, and identified 354 common targets, which could be used as potential target genes for naringenin to treat COVID-19/LUSC. The treatment of COVID-19/LUSC with naringenin may involve oxidative stress, anti-inflammatory, antiviral, antiviral, apoptosis, immunological, and multiple pathways containing PI3K-Akt, HIF-1, and VEGF, according to the results of the GO and KEGG enrichment analysis of these 354 common targets. By constructing a PPI network, we ascertained AKT1, TP53, SRC, MAPK1, MAPK3, and HSP90AA1 as possible hub targets of naringenin for the treatment of COVID-19/LUSC. Last but not least, molecular docking investigations showed that naringenin has strong binding activity in COVID-19/LUSC. Conclusion: We revealed for the first time the pharmacological targets and potential molecular processes of naringenin for the treatment of COVID-19/LUSC. However, these results need to be confirmed by additional research and validation in real LUSC patients with COVID-19.

Family functioning and nicotine dependence among smoking fathers: a cross-sectional study.

BACKGROUND: Nicotine dependence is a significant public health issue, and understanding the factors associated with nicotine dependence in this population is crucial for developing effective interventions. This study examined the association between family functioning and nicotine dependence levels of smoking fathers based on the McMaster model of family functioning (MMFF), providing evidence for future interventions. METHODS: In this study, we selected fathers of first- to fifth-grade students from 10 pilot elementary schools in Qingdao whose families smoked. We used the Fagerstrom test to assess nicotine dependence and the Family Assessment Device to evaluate family functioning. We performed univariate analysis to compare differences among those with different levels of nicotine dependence, and we used an ordinal logistic regression analysis to investigate the influences related to nicotine dependence. RESULTS: This study included 874 smokers, with 78.5% having mild nicotine dependence, 11.7% having moderate dependence, and 9.84% having severe dependence. Univariate analysis showed that smokers with severe dependence had lower education levels, higher prevalence of chronic diseases, more frequent alcohol consumption, and poorer family functioning compared to those with mild to moderate dependence. Ordinal logistic regression analysis showed that poorer general functioning scores (OR = 1.087, 95% CI: 1.008-1.173, P = 0.030), poorer behavioral control (OR = 1.124, 95% CI: 1.026-1.232, P = 0.012), more quit attempts, frequent alcohol consumption, and longer smoking duration may be associated with a higher likelihood of developing severe nicotine dependence. The older age of starting smoking and higher education level may be associated with a lower likelihood of developing severe nicotine dependence. However, it is important to note that the cross-sectional nature of this study precludes the determination of causal relationships. CONCLUSIONS: This study finds that heavy nicotine dependence in smoking fathers is associated with risky behaviors and demographics such as longer smoking duration and frequent alcohol consumption. Targeted smoking cessation interventions are crucial for this group, taking these specific factors into consideration. Family functioning, particularly general functioning and behavioral control, may also be linked to nicotine dependence, indicating the need for further research in this area.

[Miao medicinal crossbow acupuncture therapy as adjuvant treatment for lung cancer pain: a randomized controlled trial].

OBJECTIVE: To observe the clinical efficacy of Miao medicinal crossbow acupuncture therapy as adjuvant treatment for lung cancer pain based on oxycodone hydrochloride extended-release tablet. METHODS: A total of 60 patients with lung cancer pain were randomized into an observation group (30 cases, 1 case dropped off) and a control group (30 cases). In the control group, oxycodone hydrochloride extended-release tablet was given orally, 10 mg a time, once every 12 hours. On the basis of the treatment in the control group, Miao medicinal crossbow acupuncture therapy was applied once every other day in the observation group. The treatment of 14 days was required in the two groups. Before and after treatment, the numerical rating scale (NRS) score, number of break-out pain and Karnofsky performance status (KPS) score were observed in the two groups. The equivalent oxycodone consumption and rate of adverse reactions were recorded, the analgesic effect was evaluated in the two groups. RESULTS: Compared before treatment, the NRS scores and number of break-out pain were decreased while the KPS scores were increased after treatment in the two groups (P<0.01). After treatment, the NRS score and number of break-out pain in the observation group were lower than the control group (P<0.01), the KPS score in the observation group was higher than the control group (P<0.05). The equivalent oxycodone consumption of whole course and the rate of adverse reactions i.e. constipation, drowsiness, nausea and vomiting in the observation group were lower than the control group (P<0.05). The analgesic effect rate was 93.1% (27/29) in the observation group, which was superior to 63.3% (19/30) in the control group (P<0.05). CONCLUSION: On the basis of oxycodone hydrochloride extended-release tablet, Miao medicinal crossbow acupuncture therapy as adjuvant treatment can effectively relieve the pain degree, reduce the number of break-out pain and improve the health status and quality of life in patients with lung cancer pain, enhance the efficacy of medication and reduce its adverse reactions.

A Study on the Structure and Biomedical Application Characteristics of Phosphate Coatings on ZKX500 Magnesium Alloys.

Magnesium-matrix implants can be detected by X-ray, making post-operative monitoring easier. Since the density and mechanical properties of Mg alloys are similar to those of human bones, the stress-shielding effect can be avoided, accelerating the recovery and regeneration of bone tissues. Additionally, Mg biodegradability shields patients from the infection risk and medical financial burden of needing another surgery. However, the major challenge for magnesium-matrix implants is the rapid degradation rate, which necessitates surface treatment. In this study, the ZKX500 Mg alloy was used, and a non-toxic and eco-friendly anodic oxidation method was adopted to improve corrosion resistance. The results indicate that the anodic coating mainly consisted of magnesium phosphate. After anodic oxidation, the specimen surface developed a coating and an ion-exchanged layer that could slow down the degradation and help maintain the mechanical properties. The results of the tensile and impact tests reveal that after being immersed in SBF for 28 days, the anodic oxidation-treated specimens maintained good strength, ductility, and toughness. Anodic coating provides an excellent surface for cell attachment and growth. In the animal experiment, the anodic oxidation-treated magnesium bone screw used had no adverse effect and could support the injured part for at least 3 months.

Clinical efficacy of microwave in the treatment of axillary osmidrosis and primary hyperhidrosis.

Axillary osmidrosis (AO) and primary hyperhidrosis (PH) are common diseases, but there are still difficulties in treatment. Microwave therapy may become a new method. In order to evaluate long-time efficacy of patients with AO or PH treated by microwave and to discuss possible mechanism of microwave therapy by combining results of clinical and pathological, the study was carried out. Ten AO or PH patients with moderate or severe level were selected as subjects, and each subject received microwave treatment of bilateral armpits. The follow-up period lasted 2 years, and the changes of perspiration and odor were evaluated in subjective and objective ways. Each subject took skin biopsy in the treatment area before and after treatment or each follow-up. Hematoxylin-eosin and immunohistochemical staining were performed. Both subjective and objective index reflected the significant improvement of AO and PH after treatment (p < 0.05). Dermatology life quality index score decreased by 10.4 ± 4.6 (p < 0.05). The number of apocrine glands decreased significantly after treatment, and most of them changed from secretory phase to quiescent phase. In conclusion, microwave therapy can destroy apocrine sweat glands, reduce number of functional glands, so as to improve symptoms of AO and PH and elevate quality of life, which is safe, effective, and stable.

An efficient strategy for digging protein-protein interactions for rational drug design - A case study with HIF-1α/VHL.

The ubiquitination of the hypoxia-inducible factor-1α (HIF-1α) is mediated by interacting with the von Hippel-Lindau protein (VHL), and is associated with cancer, chronic anemia, and ischemia. VHL, an E3 ligase, has been reported to degrade HIF-1 for decades, however, there are few successful inhibitors currently. Poor understanding of the binding pocket and a lack of in-depth exploration of the interactions between two proteins are the main reasons. Hence, we developed an effective strategy to identify and design new inhibitors for protein-protein interaction targets. The hydroxyproline (Hyp564) of HIF-1α contributed the key interaction between HIF-1α and VHL. In this study, detailed information of the binding pocket were explored by alanine scanning, site-directed mutagenesis and molecular dynamics simulations. Interestingly, we found the interaction(s) between Y565 and H110 played a key role in the binding of VHL/HIF-1α. Based on the interactions, 8 derivates of VH032, 16a-h, were synthesized by introducing various groups bounded to H110. Further assay on protein and cellular level exhibited that 16a-h accessed higher binding affinity to VHL and markable or modest improvement in stabilization of HIF-1α or HIF-1α-OH in HeLa cells. Our work provides a new orientation for the modification or design of VHL/HIF-1α protein-protein interaction inhibitors.

Safety and tolerability of 68Ga-NT-20.3, a radiopharmaceutical for targeting neurotensin receptors, in patients with pancreatic ductal adenocarcinoma: the first in-human use.

INTRODUCTION: Over the last decades, multiple peptide receptors were recognized as potential diagnostic and therapeutic targets in nuclear medicine. 68Ga-NT-20.3 radiopharmaceutical has been developed for diagnosis of neurotensin receptors. High neurotensin receptor expression has been observed in pancreatic ductal adenocarcinoma as well as various malignancies. Until now, 68Ga-labelled NT ligand was successfully applied in in vitro as well as in animal model. Our study is the first in-human study on safety and tolerability of 68Ga-NT-20.3. METHODS: Subjects were intravenously injected with 2.5 MBq of 68Ga-DOTA-NT-20.3 per kilogramme of body weight, and series of PET images were acquired at 5-25 min, 25-45 min, 45-65 min, and 65-85 min after 68Ga-NT-20.3 injection. Vital parameters are as follows: systolic and diastolic blood pressure (mmHg), heart rate (heart beat/min), respiratory rate (number of breaths/min), ECG, and body temperature (°C) were checked before, immediately after, and 3 h after 68Ga-NT-20.3 injection. The organ-absorbed doses were calculated for the self-dose and cross-dose from each organ region using the OLINDA/EXM version 2.1 software. RESULTS AND CONCLUSION: The results from this small trial demonstrate that PET radiopharmaceutical 68Ga-NT-20.3 is safe and well tolerated.

Total synthesis, chemical modification and structure-activity relationship of bufadienolides.

Bufadienolides are a type of natural cardiac steroids and originally isolated from the Traditional Chinese Medicine Chan'Su, they have been used for the treatment of heart disease in traditional remedies as well as in modern medicinal therapy with potent anti-tumor activities. Due to their unique molecular structures with unsaturated six-membered lactones attached to the steroid core, bufadienolides have received great attention in the synthetic organic community. This review presents total synthetic efforts to some representative bufadienolides, chemical modification of bufadienolides will also be given to discuss their structure-activity relationship in anti-tumor.

Increased expression of TLR7 and TLR9 in alopecia areata.

Alopecia areata (AA) is thought to be an autoimmune process. In other autoimmune diseases, the innate immune system and Toll-like receptors (TLRs) can play a significant role. Expression of TLR7, TLR9 and associated inducible genes was evaluated by quantitative PCR in peripheral blood mononuclear cells (PBMCs) from 10 healthy individuals and 19 AA patients, categorized according to disease duration, activity and hair loss extent. Microdissected scalp biopsies from five patients and four controls were also assessed by quantitative PCR and immunohistology. TLR9 was significantly upregulated 2.37 fold in AA PBMCs. Notably, TLR9 was most significantly upregulated in patients with active AA, as shown by a positive hair pull test, compared to stable AA patients. In hair follicle bulbs from AA patients, IFNG and TLR7 exhibited statistically significant 3.85 and 2.70 fold increases in mRNA, respectively. Immunohistology revealed TLR7 present in lesional follicles, while TLR9 positive cells were primarily observed peri-bulbar to AA affected hair follicles. The increased expression of TLR7 and TLR9 suggest components of the innate immune system may be active in AA pathogenesis.

Superinfective Hepatitis E Virus Infection Aggravates Hepatocytes Injury in Chronic Hepatitis B.

Hepatitis E virus (HEV) infection is a major cause of morbidity in endemic areas. Its consequences among chronic hepatitis B (CHB) patients have been under-reported. The aim of this study was to assess the impact of superinfective HEV infection (acute and past) on virological and clinical features of patients with CHB infection. Clinical, biochemical, virological and immunological data of 153 CHB patients including 98 with hepatitis B virus (HBV) monoinfection and 55 with HBV-HEV superinfection with both HEV and HBV infection was retrospectively investigated and analyzed in this study conducted in Wuhan, China. An overall anti-HEV IgG seroprevalence was found to be 35.9% in CHB patients. HBV-HEV superinfection patients showed significantly higher rate of complications (ascites, hepato-renal syndrome & encephalopathy) (all with P=0.04), cirrhosis (P<0.001) and acute-on-chronic liver failure (P<0.001) than HBV monoinfection patients. They also displayed elevated ALTs (P<0.001) and total serum bilirubin (P<0.001) with diminished albumin (P<0.001) and HBV viral load (P<0.001). Cytokines assay revealed increased expression of IL-6 (P=0.02), IL-10 (P=0.009) and TNF-α (P=0.003) in HBV-HEV superinfection patients compared to HBV monoinfection patients. Our study demonstrated that HEV superinfection in CHB patients was associated with progressive clinical manifestation, which is likely due to the enhanced expression of cytokines related with hepatocytes necrosis. HEV was also associated with repressed HBV replication, but the underlying mechanism requires further investigation.

Acute kidney injury in acute-on-chronic liver failure is different from in decompensated cirrhosis.

AIM: To evaluate the differences in acute kidney injury (AKI) between acute-on-chronic liver failure (ACLF) and decompensated cirrhosis (DC) patients. METHODS: During the period from December 2015 to July 2017, 280 patients with hepatitis B virus (HBV)-related ACLF (HBV-ACLF) and 132 patients with HBV-related DC (HBV-DC) who were admitted to our center were recruited consecutively into an observational study. Urine specimens were collected from all subjects and the levels of five urinary tubular injury biomarkers were detected,including neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), liver-type fatty acid binding protein (L-FABP), cystatin C (CysC), and kidney injury molecule-1 (KIM-1). Simultaneously, the patient demographics, occurrence and progression of AKI, and response to terlipressin therapy were recorded. All patients were followed up for 3 mo or until death after enrollment. RESULTS: AKI occurred in 71 and 28 of HBV-ACLF and HBV-DC patients, respectively (25.4% vs 21.2%, P = 0.358). Among all patients, the levels of four urinary biomarkers (NGAL, CysC, L-FABP, IL-18) were significantly elevated in patients with HBV-ACLF and AKI (ACLF-AKI), compared with that in patients with HBV-DC and AKI (DC-AKI) or those without AKI. There was a higher proportion of patients with AKI progression in ACLF-AKI patients than in DC-AKI patients (49.3% vs 17.9%, P = 0.013). Forty-three patients with ACLF-AKI and 19 patients with DC-AKI were treated with terlipressin. The response rate of ACLF-AKI patients was significantly lower than that of patients with DC-AKI (32.6% vs 57.9%, P = 0.018). Furthermore, patients with ACLF-AKI had the lowest 90 d survival rates among all groups (P < 0.001). CONCLUSION: AKI in ACLF patients is more likely associated with structural kidney injury, and is more progressive, with a poorer response to terlipressin treatment and a worse prognosis than that in DC patients.

Modified Technique of Cultured Epithelial Cells Transplantation on Facial Segmental Vitiligo.

BACKGROUND: Cultured epithelial cells transplantation is a known surgical technique for vitiligo. OBJECTIVE: To evaluate the factors influencing efficacy and safety of cultured epithelial cells transplantation in 9-month follow-up. METHODS: Demographic, clinical, and repigmentation outcomes were reviewed for patients with facial segmental vitiligo who had undergone cultured epithelial cells transplantation from November 2013 to July 2015 at the clinic of the Department of Dermatology, Huashan Hospital, China. RESULTS: Twenty-eight patients who had undergone cultured epithelial cells transplantation were included. A satisfactory result (>50% repigmentation) was achieved in 79% patients with facial segmental vitiligo in 9 months. The treatment effect was significantly different in 6th month (P = 0.032), 9th month (P = 0.006) compared with 3rd month. Disease stability did significantly affect repigmentation outcome in 9th month (Z = 2.113, P = 0.035). No significant difference was observed between single segmental type versus mixed type (Z = 1.081, P = 0.280). Adverse effects were nearly absent. CONCLUSION: Cultured epithelial cells transplantation is a relatively safe and effective therapy for facial segmental stable vitiligo patients.

Design, Synthesis, and Biological Evaluation of Scutellarein Derivatives Based on Scutellarin Metabolic Mechanism In Vivo.

Three series of scutellarein derivatives have been designed and synthesized based on metabolic mechanism of scutellarin (1) in vivo. Their thrombin inhibition activities were tested through the analyzation of prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), and fibrinogen (FIB). The antioxidant activities of these target products were assessed by 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) assay and the ability to protect PC12 cells against H2 O2 -induced cytotoxicity, and their solubilities were evaluated by ultraviolet (UV) spectrophotometer. The results showed that the two isopropyl groups substituted derivative (18c) demonstrated stronger anticoagulant activity, better water solubility, and good antioxidant activity compared with scutellarein (2), which warrants further development of 18c as a promising agent for ischemic cerebrovascular disease treatment.

Synthesis and biological evaluation of methylated scutellarein analogs based on metabolic mechanism of scutellarin in vivo.

Scutellarin (1) could be hydrolyzed into scutellarein (2) in vivo and then converted into methylated, sulfated and glucuronidated forms. In order to investigate the biological activities of these methylated metabolites, eight methylated analogs of scutellarein (2) were synthesized via semi-synthetic methods. The antithrombotic activities of these compounds were evaluated through the analyzation of prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and fibrinogen (FIB). Their antioxidant activities were assessed by measuring their scavenging capacities toward 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and the ability to protect PC12 cells against H2O2-induced cytotoxicity. Furthermore, the physicochemical properties of these compounds including aqueous solubility and lipophilicity were also investigated. The results showed that 6-O-methylscutellarein (5) demonstrated potent antithrombotic activity, stronger antioxidant activity and balanced solubility and permeability compared with scutellarin (1), which warrants further development of 5 as a promising lead for the treatment of ischemic cerebrovascular disease.

Synthesis of scutellarein derivatives to increase biological activity and water solubility.

In order to improve the biological activity and water solubility of scutellarin (1), some derivatives of its main metabolite (scutellarein) were designed and synthesized. All the compounds were tested for their thrombin inhibition activity through the analyzation of thrombin time (TT), activated partial thromboplastin time (APTT), prothrombin time (PT) and fibrinogen (FIB). Their antioxidant activities were assessed by measuring their scavenging capacities toward 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) and the ability to protect PC12 cells against H2O2-induced cytotoxicity, their water solubility were also assessed by ultraviolet (UV) spectrophotometer. The results showed that compound 8b demonstrated stronger anticoagulant and antioxidant activity, better water solubility compared with scutellarein (2), which warrants it as a promising agent for the treatment of ischemic cerebrovascular disease.

Vitamin C protects against UV irradiation-induced apoptosis through reactivating silenced tumor suppressor genes p21 and p16 in a Tet-dependent DNA demethylation manner in human skin cancer cells.

AIM: DNA methylation plays important roles in various kinds of carcinogenesis. Vitamin C could induce Tet-dependent DNA demethylation in embryonic stem cells. Therefore, the antagonizing activity of vitamin C on ultraviolet (UV)-induced apoptosis was investigated in this study. METHODS: Apoptosis of human epidermoid carcinoma A431 cells and p16-knockout (KO) or p21-KO fibroblasts was assessed by a fluorescence-activated cell sorter. Real-time PCR and western blot were used to determine the relative expression levels of p12, p21, and Tet1/2/3 genes. The global DNA methylation levels were determined using MethylFlash Methylated DNA Quantification Kit in A431 cells with or without vitamin C treatment. To examine the DNA demethylation activity of vitamin C, DNA immunoprecipitation (DIP)-qPCR was performed to determine the relative levels of 5-methylcytosine (5mC) or 5-hydroxymethylcytosine (5hmC) in p16 and p21 promoter regions containing cytosine-phosphorothiolated guanine (CpG) islands. RESULTS: The increasing apoptosis of A431 cells under prolonged UV irradiation was remarkably decreased by the combination of vitamin C treatment, suggesting that vitamin C protects against UV-induced apoptosis. Concurrently, vitamin C induced a significant reduction of global DNA methylation in a time- and dose-dependent manner in A431 cells. Vitamin C also reactivated the expression of p16 and p21 at mRNA and protein levels. Mechanistically, about 27% 5hmC-positive cells were observed in vitamin C-treated A431 cells, and the 5hmC enrichment at p16 and p21 promoter regions was also largely increased by vitamin C. Moreover, the expression of p16 and p21 was decreased in Tet1/2 double-knockdown cells, in which the inhibitory effect of vitamin C on UV-induced apoptosis was dismissed. Furthermore, the inhibition of UV-induced apoptosis on vitamin C treatment nearly disappeared in p16- or p21-knockout primary cultured fibroblasts. CONCLUSION: These results demonstrate that vitamin C effectively antagonizes UV-induced apoptosis through regulation of Tet activity, DNA demethylation, and subsequent tumor suppressor gene activation in skin cancer cells.

Increased expression of S100A8 and S100A9 in patients with diffuse cutaneous systemic sclerosis. A correlation with organ involvement and immunological abnormalities.

S100A8 and S100A9 play important roles in immune and inflammatory disorders. The role of the two proteins in systemic sclerosis (SSc) remains unknown. Fifty-seven diffuse cutaneous SSc (dcSSc) patients, 31 limited cutaneous SSc (lcSSc) patients were recruited in the present study. The expression of S100A8 and S100A9 in plasma was measured using an enzyme-linked immunosorbent assay and the mRNA levels in peripheral blood were assessed using reverse transcriptase quantitative PCR. The expression and distribution of S100A8, S100A9, and receptor for advanced glycation end products (RAGE), in skin tissues was analyzed by immunohistochemistry. The plasma concentrations of S100A8 and S100A9 were significantly higher in dcSSc patients than in normal controls and lcSSc patients. Both S100A8 and S100A9 levels were significantly increased in dcSSc patients with lung or kidney involvement. Increased plasma levels of S100A8 and S100A9 in dcSSc patients were associated with several autoantibodies. Transcription levels of S100A8 and S100A9 in peripheral blood were found elevated in both dcSSc and lcSSc patients than normal controls. Immunohistochemistry demonstrated higher S100A8 and S100A9 expression in sclerotic skin than in normal skin. The number of S100A8, S100A9, or RAGE positive fibroblasts was also significantly increased. Highly elevated expression of both S100A8 and S100A9 was found in dcSSc patients. There was close correlation with disease severity and serological abnormalities, suggesting that the two proteins may play important roles in the development of systemic sclerosis.

Sodium tanshinone IIA silate inhibits oxygen-glucose deprivation/recovery-induced cardiomyocyte apoptosis via suppression of the NF-κB/TNF-α pathway.

BACKGROUND AND PURPOSE: Inhibition of apoptosis may attenuate the irreversible injury associated with reperfusion. In the current study, we focused on the cytoprotective effects and the underlying mechanism of sodium tanshinone IIA silate (STS) against damage induced by oxygen-glucose deprivation/recovery (OGD/R). in H9c2 cardiomyocytes and the underlying mechanisms. EXPERIMENTAL APPROACH: We used a model of cardiac ischaemia/reperfusion, OGD/R in H9c2 cardiomyocytes, to assess the cardioprotective effects of STS. Apoptosis of cells was measured with Hoechst 33342-based fluorescence microscopy, and annexin V-FITC-based flow cytometry. Caspase-3 and caspase-8 activities and mitochondrial membrane potential were also measured using commercial kits. TNF-α in the cell culture supernatant fractions were measured with sandwich elisa, and protein levels assayed using Western blot. KEY RESULTS: STS inhibited OGD/R-induced apoptosis by suppressing JNK-mediated activation of NF-κB, TNF-α expression, activation of caspase-3 and caspase-8 and the Bax/Bcl-2 ratio. Additionally, positive feedback between NF-κB and TNF-α and amplification of TNF-α were inhibited, suggesting that STS plays a protective role against apoptosis in cardiomyocytes, even upon activation of pro-inflammatory cytokines. Interestingly, the cytoprotective effects of STS on OGD/R-induced apoptosis and promotion of cell survival were attenuated after inhibition of PI3K. CONCLUSION AND IMPLICATIONS: The inhibitory effects of STS on TNF-α and positive feedback signalling of the NF-κB/TNF-α pathways may play important roles in myocardial protection against ischaemia/reperfusion. These protective effects of STS are mediated by suppressing JNK activity through activation of the PI3K-Akt pathway.

In vivo reflectance confocal microscopy of Basal cell carcinoma: feasibility of preoperative mapping of cancer margins.

BACKGROUND: Reflectance confocal microscopy (RCM) images skin at cellular resolution and has shown utility for the diagnosis of nonmelanoma skin cancer in vivo. It has the potential to define lesion margins before surgical therapy. OBJECTIVES: To investigate the feasibility of RCM in defining the margins of basal cell carcinoma before surgery. METHODS: The margins of 10 lesions were evaluated using RCM. Biopsies of the margins were used to confirm the results. A protocol was constructed to define margins. RCM was used to delineate preoperative surgical margins in 13 patients. Intraoperative frozen biopsy was used to confirm the margins. RESULTS: In seven of 10 (70.0%) cases, the margins of the cancer were identified suing RCM. The tumor island was the critical feature in identifying the margins. In 12 of 13 (92.3%) cases, frozen biopsy corroborated that the surgical margins delineated by RCM were clear. CONCLUSION: RCM imaging of the margins is feasible and demonstrates the possibility of preoperative mapping of cancer margins.