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.

Metal-Catalyst-Free One-Pot Aqueous Synthesis of trans-1,2-Diols from Electron-Deficient α,ß-Unsaturated Amides via Epoxidation Using Oxone as a Dual Role Reagent.

In organic synthesis, incorporating two functional groups into the carbon-carbon double bond of α,ß-unsaturated amides is challenging due to the electron-deficient nature of the olefin moiety. Although a few examples of dihydroxylation of α,ß-unsaturated amides have been demonstrated, producing cis-1,2-diols using either highly toxic OsO4 or other specialized metal reagents in organic solvents, they are limited to several specific amides. We describe herein a general and one-pot direct synthesis of trans-1,2-diols from electron-deficient α,ß-unsaturated amides through dihydroxylation using oxone as a dual-role reagent in water. This reaction does not require any metal catalyst and produces non-hazardous and nontoxic K2 SO4 as the sole byproduct. Moreover, epoxidation products could also be selectively formed by adjusting the reaction conditions. By the strategy, the intermediates of Mcl-1 inhibitor and antiallergic bioactive molecule can be synthesized in one pot. The gram-scale synthesis of trans-1,2-diol which is isolated and purified by recrystallization further shows the potential applications of this new reaction in organic synthesis.

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.

Clinical benefit and tolerance profile of a keratolytic and hydrating shampoo in subjects with mild to moderate psoriasis. Results from a double-blind, randomized, vehicle-controlled study.

INTRODUCTION: Scalp psoriasis frequently goes with other disease location and may lead to a significant burden and impairment of quality of life (QoL). Adherence to local treatments is a frequent problem. A keratolytic and hydrating shampoo containing 2% salicylic acid, 5% urea, and 1% glycerin (active shampoo) has been developed for psoriasis-prone scalp. OBJECTIVE: To assess the efficacy and tolerability of an active shampoo in subjects with mild to moderate scalp psoriasis. MATERIALS AND METHODS: A single-center, randomized, double-blind, vehicle-controlled study was conducted on 67 adults with mild to moderate psoriasis. The active shampoo or its vehicle were applied daily for 14 days and 3 times/week for another 14 days. Assessments included the Psoriasis Scalp Severity Index (PSSI), Investigator Global Assessment (IGA), calculated total surface affected hair, scalp greasiness, irritation, and assessed scalp dermatitis-specific quality-of-life issues using SCALPDEX and product acceptability. RESULTS: The active shampoo significantly (p < 0.05) reduced the PSSI by 39.0%, 37.2%, 63.0%, and 69.0% immediately after washing compared to a 22.8%, 5.5%, 19.6%, and 13.0% with the vehicle at Days 1, 8, 15, and 30, respectively. SCALPDEX items, IGA, and irritation significantly (p < 0.05) reduced with the active shampoo. Hair and scalp greasiness improved continuously with both products until Day 21. Subject-reported symptom scores paralleled the positive evolution of clinical signs. The active shampoo was well tolerated, subjects were highly satisfied and had an improved QoL. CONCLUSION: The active shampoo significantly improved clinical signs, symptoms, and QoL of mild-to-moderate scalp psoriasis compared to the vehicle. It was very well tolerated and highly appreciated by the subjects.

[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.

Response to comment on "Sexual selection promotes giraffoid head-neck evolution and ecological adaptation".

Hou et al. challenged the giraffoid affinity of Discokeryx and its ecology and behavior. In our response we reiterate that Discokeryx is a giraffoid that, along with Giraffa, shows extreme evolution of head-neck morphologies that were presumably shaped by selective pressure from sexual competition and marginal environments.

[Distribution of Biodegradable Dissolved Organic Matter and Its Affecting Factors in a Typical Peri-urban Watershed in Yangtze River Delta].

Dissolved organic matter (DOM) plays key roles in the carbon biogeochemical cycle, and biodegradable dissolved organic matter (BDOM) is one of the key fractions of DOM. Rapid urbanization and intensive human activities substantially influence the distribution of DOM at the watershed scale. Identifying the spatial and temporal variability in BDOM has become an important and urgent issue of water quality control in rapid urbanization areas. However, limited studies have been conducted to explore the role of human activities on the occurrence and distribution of BDOM in peri-urban watersheds. In this study, the spatial and temporal distribution of BDOM and related affecting factors were investigated in a typical peri-urban watershed (Zhangxi watershed) located at Ningbo City in Yangtze River Delta. Water samples were collected in wet and dry seasons in 2019 based on topographic features, land use, and intensity of human activities. The BDOM were characterized by fluorescence excitation-emission matrix and parallel factor analysis (EEM-PARAFAC), and land use patterns were analyzed using the Source-Sink Landscape Model. The results of this study showed that the BDOM concentrations ranged from 0.57 to 6.80 mg·L-1. Obvious spatial and temporal heterogeneities of BDOM were found at the watershed scale, and significantly higher concentrations of BDOM were observed in the wet season than those in the dry season. Furthermore, relatively high concentrations of BDOM were found in areas with relatively higher intensive human activities. Two fluorescent components (a terrestrial humic-like substance and protein-like substance) were observed using the PARAFAC model. The results of spatial analysis showed that terrestrial humic-like fluorescent components were closely positively correlated with anthropogenic parameters (percentages of agricultural and urban land and ratio of source and sink landscapes). The results showed that the occurrence and distribution of BDOM were strongly influenced by human activities, which could provide scientific guidance for water quality control and related land management in peri-urban aquatic ecosystems.

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.

Sexual selection promotes giraffoid head-neck evolution and ecological adaptation.

The long neck of the giraffe has been held as a classic example of adaptive evolution since Darwin's time. Here we report on an unusual fossil giraffoid, Discokeryx xiezhi, from the early Miocene, which has an unusual disk-shaped headgear and the most complicated head-neck joints in known mammals. The distinctive morphology and our finite element analyses indicate an adaptation for fierce head-butting behavior. Tooth enamel isotope data suggest that D. xiezhi occupied a niche different from that of other herbivores, comparable to the characteristic high-level browsing niche of modern giraffes. The study shows that giraffoids exhibit a higher headgear diversity than other ruminants and that living in specific ecological niches may have fostered various intraspecific combat behaviors that resulted in extreme head-neck morphologies in different giraffoid lineages.

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.

Large-scale isolation of functional dermal papilla cells using novel surface marker LEPTIN Receptor.

Dermal papilla (DP) cells regulate hair follicle epithelial cells and melanocytes by secreting functional factors, playing a key role in hair follicle morphogenesis and hair growth. DP cells can reconstitute new hair follicles and induce hair regeneration, providing a potential therapeutic strategy for treating hair loss. However, current methods for isolating DP cells are either inefficient (physical microdissection) or only applied to genetically labeled mice. We systematically screened for the surface proteins specifically expressed in skin DP using mRNA expression databases. We identified two antibodies against receptors LEPTIN Receptor (LEPR ) and Scavenger Receptor Class A Member 5 (SCARA5) which could specifically label and isolate DP cells by flow cytometry from mice back skin at the growth phase. The sorted LEPR+ cells maintained the DP characteristics after culturing in vitro, expressing DP marker alkaline phosphatase and functional factors including RSPO1/2 and EDN3, the three major DP secretory factors that regulate hair follicle epithelial cells and melanocytes. Furthermore, the low-passage LEPR+ DP cells could reconstitute hair follicles on nude mice using chamber graft assay when combined with epithelial stem cells. The method of isolating functional DP cells we established here lays a solid foundation for developing DP cell-based therapy.

Types of Descemet Membrane Detachment After Ocular Surface Burns: The Factor Long Been Ignored.

PURPOSE: The aim of this study was to explore types of Descemet membrane detachment (DMD) after ocular surface burns by anterior segment optical coherence tomography. METHODS: This is a pilot, case series, observational study. Patients with DMD after ocular surface burns were enrolled. Ophthalmologic examinations were performed in all patients including slit-lamp photography and anterior segment optical coherence tomography. RESULTS: Three types of DMDs in 9 eyes of 9 patients with ocular surface burns were identified depending on the detachment components involved with the pre-Descemet layer (PDL). Type A was referred as a taut chord that the PDL and Descemet membrane (DM) detached simultaneously but were remained attached to each other, while type B was identified as a wavy line separated from the stroma by a dark slit that demonstrated the detachment of DM from the PDL and stroma. Type C was defined as the DM detached with or without PDL but they were separated from each other. We found that DM and PDL were detached simultaneously in most condition, with type A in 4 cases, type C in 5 cases, and type B in only 1 case. CONCLUSIONS: Our study demonstrated 3 types of DMDs after ocular surface burns and revealed that the limbal involvement and retrocorneal exudations may give clues to DMD in the corresponding areas. DMDs may be neglected for long in patients with extensive limbal involvement in early stages and also play an important role in unstable ocular surface condition until the late stages of conjunctivalization after ocular surface burns.

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.

Protein Kinase C Alpha Cellular Distribution, Activity, and Proximity with Lamin A/C in Striated Muscle Laminopathies.

Striated muscle laminopathies are cardiac and skeletal muscle conditions caused by mutations in the lamin A/C gene (LMNA). LMNA codes for the A-type lamins, which are nuclear intermediate filaments that maintain the nuclear structure and nuclear processes such as gene expression. Protein kinase C alpha (PKC-α) interacts with lamin A/C and with several lamin A/C partners involved in striated muscle laminopathies. To determine PKC-α's involvement in muscular laminopathies, PKC-α's localization, activation, and interactions with the A-type lamins were examined in various cell types expressing pathogenic lamin A/C mutations. The results showed aberrant nuclear PKC-α cellular distribution in mutant cells compared to WT. PKC-α activation (phos-PKC-α) was decreased or unchanged in the studied cells expressing LMNA mutations, and the activation of its downstream targets, ERK 1/2, paralleled PKC-α activation alteration. Furthermore, the phos-PKC-α-lamin A/C proximity was altered. Overall, the data showed that PKC-α localization, activation, and proximity with lamin A/C were affected by certain pathogenic LMNA mutations, suggesting PKC-α involvement in striated muscle laminopathies.

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.

Design, synthesis, and biological activity evaluation of BACE1 inhibitors with antioxidant activity.

The proteolytic enzyme ß-secretase (BACE1) plays a central role in the synthesis of the pathogenic ß-amyloid peptides (Aß) in Alzheimer's disease (AD), antioxidants could attenuate the AD syndrome and prevent the disease progression. In this study, BACE1 inhibitors (D1-D18) with free radical-scavenging activities were synthesized by molecular hybridization of 2-aminopyridine with natural antioxidants. The biological activity evaluation showed that D1 had obvious inhibitory activity against BACE1, and strong antioxidant activity in 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azinobis-(3-ethylbenzthiazoline-6-sulphonate) (ABTS+• ) assay, which could be used as a lead compound for further study.

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.

Sodium Tanshinone IIA Silate Alleviates High Glucose Induced Barrier Impairment of Human Retinal Pigment Epithelium through the Reduction of NF-κB Activation via the AMPK/p300 Pathway.

Purpose: The disruption of retinal pigment epithelium (RPE) barrier may perform a crucial role in the pathogenesis of diabetic retinopathy (DR). AMPK exerts several salutary effects on photoreceptors and the RPE function and improves retina abnormalities. The current study aimed to determine whether sodium tanshinone IIA silate (STS) has an inhibitory effect on ARPE-19 cell monolayer permeability under high glucose conditions, and establish the underlying mechanism.Methods: We used a model of high glucose (25 mmol glucose, HG) condition mimicking diabetes in ARPE-19 cells, to assess the protective effects of STS. The barrier function of RPE cells were measured by Transepithelial Electrical Resistance (TEER) and fluorescein isothiocyanate (FITC)-dextran permeability. The interaction of NF-κB p65 and p300 were tested using immunoblotting and immunoprecipitation and immunofluorescence assay. Protein levels were assayed using Western blot.Results: We found STS promoted the phosphorylation of AMP-activated protein kinase (AMPK) at T172 in RPE cells, and STS treatment thus inhibited ARPE-19 cell monolayer permeability under HG condition, similar to the permeability under normal glucose (5.5 mmol glucose, NG). Moreover, we found that STS obviously prevented the colocalization of NF-κB and p300, and significantly inhibited their binding, subsequent decreased ARPE-19 cell monolayer permeability. Notably, Compound C (CC), a specific inhibitor of AMPK, blocked STS-mediated inhibition of ARPE-19 cell monolayer permeability.Conclusions: STS inhibited HG-induced RPE permeability possibly through the reduction of NF-κB activation via the AMPK/p300 pathway. The protective effects of STS were attained through the suppression of p300-mediated NF-κB acetylation and STS might be utilized for treatment of DR, in terms of preventing inflammation.