Polydopamine/IR820 nanoparticles as topical phototheranostics for inhibiting psoriasiform lesions through dual photothermal and photodynamic treatments.

Dual photothermal and photodynamic therapy (PTT and PDT) is an attractive approach that generates a synergistic effect for inhibiting keratinocyte hyperproliferation in the treatment of psoriasis. Here, we developed phototheranostic nanocarriers capable of producing hyperthermia and reactive oxygen species (ROS) in response to near-infrared (NIR) illumination. To this end, IR820 with photothermal and photodynamic features was embedded in nano-sized polydopamine (PDA) acting as a PTT agent. A comprehensive characterization of the PDA/IR820 nanosystem was performed according to its morphology, size, zeta potential, UV absorbance, and heat generation. Its therapeutic efficacy was assessed by a keratinocyte-based study and using an imiquimod (IMQ)-stimulated psoriasiform murine model. PDA/IR820 nanoparticles were facilely internalized into keratinocytes and mainly resided in lysosomes. Upon irradiation with NIR light, ROS were generated inside the keratinocytes to cause a photodynamic effect. The live/dead cell assay and cytotoxicity assay demonstrated that PDA and IR820 acted as effective photoabsorbers to induce keratinocyte death. The highest cytotoxic effect was detected in the group of NIR-irradiated PDA/IR820 nanoparticles, which killed 52% of keratinocytes. The nanosystem acted through the caspase and poly ADP-ribose polymerase (PARP) pathways to induce keratinocyte apoptosis. In vitro and in vivo skin permeation indicated the selective accumulation of the topically applied PDA/IR820 nanoparticles within psoriasiform skin, suggesting their skin-targeting capability. The combination of PDA/IR820 nanoparticles and NIR irradiation increased the skin temperature by 11.7 °C. PTT/PDT eliminated psoriasiform plaques in mice by decreasing hyperplasia, inhibiting cytokine overexpression, and recovering the barrier function. The epidermal thickness of the IMQ-treated skin was reduced from 134 to 34 µm by the nanocarriers plus NIR. The IR820 nanoparticles were largely deposited on the inflamed areas of psoriasiform lesions for monitoring the severity of inflammation. The image-guided phototheranostic nanoparticles showed their potential for applications in psoriasis management via noninvasive topical administration.

Nanoencapsulation of Tea Catechins for Enhancing Skin Absorption and Therapeutic Efficacy.

Tea catechins are a group of flavonoids that show many bioactivities. Catechins have been extensively reported as a potential treatment for skin disorders, including skin cancers, acne, photoaging, cutaneous wounds, scars, alopecia, psoriasis, atopic dermatitis, and microbial infection. In particular, there has been an increasing interest in the discovery of cosmetic applications using catechins as the active ingredient because of their antioxidant and anti-aging activities. However, active molecules with limited lipophilicity have difficulty penetrating the skin barrier, resulting in low bioavailability. Nevertheless, topical application is a convenient method for delivering catechins into the skin. Nanomedicine offers an opportunity to improve the delivery efficiency of tea catechins and related compounds. The advantages of catechin-loaded nanocarriers for topical application include high catechin loading efficiency, sustained or prolonged release, increased catechin stability, improved bioavailability, and enhanced accumulation or targeting to the nidus. Further, various types of nanoparticles, including liposomes, niosomes, micelles, lipid-based nanoparticles, polymeric nanoparticles, liquid crystalline nanoparticles, and nanocrystals, have been employed for topical catechin delivery. These nanoparticles can improve catechin permeation via close skin contact, increased skin hydration, skin structure disorganization, and follicular uptake. In this review, we describe the catechin skin delivery approaches based on nanomedicine for treating skin disorders. We also provide an in-depth description of how nanoparticles effectively improve the skin absorption of tea catechins and related compounds, such as caffeine. Furthermore, we summarize the possible future applications and the limitations of nanocarriers for topical delivery at the end of this review article.

Wild Bitter Melon Extract Abrogates Hypoxia-Induced Cell Death via the Regulation of Ferroptosis, ER Stress, and Apoptosis in Microglial BV2 Cells.

Microglial cells are well-known phagocytic cells that are resistant to the central nervous system (CNS) and play an important role in the maintenance of CNS homeostasis. Activated microglial cells induce neuroinflammation under hypoxia and typically cause neuronal damage in CNS diseases. In this study, we propose that wild bitter melon extract (WBM) has a protective effect on hypoxia-induced cell death via regulation of ferroptosis, ER stress, and apoptosis. The results demonstrated that hypoxia caused microglial BV-2 the accumulation of lipid ROS, ferroptosis, ER stress, and apoptosis. In this study, we investigated the pharmacological effects of WBM on BV-2 cells following hypoxia-induced cell death. The results indicated that WBM reversed hypoxia-downregulated antiferroptotic molecules Gpx4 and SLC7A11, as well as upregulated the ER stress markers CHOP and Bip. Moreover, WBM alleviated hypoxia-induced apoptosis via the regulation of cleaved-caspase 3, Bax, and Bcl-2. Our results suggest that WBM may be a good candidate for preventing CNS disorders in the future.

An Association Rule Analysis of the Acupressure Effect on Sleep Quality.

BACKGROUND: Sleep is recognized as an all-important physiological process, which also contributes to maintaining several bodily functions and systems. According to the Pittsburgh Sleep Quality Index (PSQI), also known as the most widely used tool in the field of subjective assessment of self-perceived sleep quality, a combination of acupoints could be more effective than single acupoint treatment in improving sleep quality. METHODS: The present study was based on the extracted eligible studies rooted in a previous meta-analysis that worked on the basis of association rule mining and examined the potential kernel acupoint combinations for improving sleep quality. RESULTS: Depending on the Apriori algorithm, we summarized 26 acupoints as binary data from the 32 eligible studies based on a previous meta-analysis and analyzed them. The top 10 most frequently selected acupoints were HT7, SP6, PC6, KI1, GV20, EM5, EX-HN3, EX-HN16, KI3, and MA-TF1. Furthermore, as deduced from 21 association rules, the primary relevant rules in the combination of acupoints are (EX-HN3, EX-HN16)=>(GV20) and (HT7, KI1)=>(PC6). CONCLUSIONS: In order to use acupuncture to improve sleep quality, integrating (EX-HN3, EX-HN16, GV20) with (HT7, KI1, PC6) acupoints could be deemed as the kernel acupoint combination.

Nephroprotective Role of Chrysophanol in Hypoxia/Reoxygenation-Induced Renal Cell Damage via Apoptosis, ER Stress, and Ferroptosis.

Acute kidney injury (AKI) is caused by hypoxia-reoxygenation (H/R), which is a kidney injury produced by a variety of causes, resulting in the remaining portion of the kidney function being unable to maintain the balance for performing the tasks of waste excretion metabolism, and electrolyte and acid-base balance. Many studies have reported the use of Chinese medicine to slow down the progression and alleviate the complications of chronic renal failure. Chrysophanol is a component of Rheum officinale Baill, a traditional Chinese medicine that has been clinically used to treat renal disease. We aimed to study the nephroprotective effect of chrysophanol on hypoxia/ reoxygenation (H/R)-induced cell damage. The results showed that chrysophanol prevented H/R-induced apoptosis via downregulation of cleaved Caspase-3, p-JNK, and Bax but upregulation of Bcl-2 expression. In contrast, chrysophanol attenuated H/R-induced endoplasmic reticulum (ER) stress via the downregulation of CHOP and p-IRE1α expression. Our data demonstrated that chrysophanol alleviated H/R-induced lipid ROS accumulation and ferroptosis. Therefore, we propose that chrysophanol may have a protective effect against AKI by regulating apoptosis, ER stress, and ferroptosis.

Poor tumor differentiation is an independent adverse prognostic variable in patients with locally advanced oral cavity cancer--Comparison with pathological risk factors according to the NCCN guidelines.

METHODS: We sought to compare the prognostic impact of tumor differentiation with respect to adverse risk factors (RFs) identified by the National Comprehensive Cancer Network (NCCN) guidelines--including extranodal extension (ENE), positive/close margins, perineural invasion, lymphatic invasion, and vascular invasion--in patients with locally advanced oral cavity squamous cell carcinoma (OCSCC). RESULTS: Between 1996 and 2018, 1179 consecutive patients with first primary pT3-4 OCSCC were included. A three-level grading system was adopted--in which the final classification was assigned according to the most prevalent tumor grade. We identified 382/669/128 patients with well/moderately/poorly differentiated tumors, respectively. Compared with well/moderately differentiated tumors, poorly differentiated OCSCC had a higher prevalence of the following variables: female sex (4%/6%/11%), ENE, (14%/36%/61%), positive margins (0.5%/2%/4%), close margins (10%/14%/22%), perineural invasion (22%/50%/63%), lymphatic invasion (2%/9%/17%), vascular invasion (1%/4%/10%), and adjuvant therapy (64%/80%/87%). The 5-year rates of patients with well/moderately/poorly differentiated OCSCC were as follows: local control (LC, 85%/82%/84%, p = 0.439), neck control (NC, 91%/83%/70%, p < 0.001), distant metastases (DM, 6%/18%/40%, p < 0.001), disease-free survival (DFS, 78%/63%/46%, p < 0.001), disease-specific survival (DSS, 85%/71%/49%, p < 0.001), and overall survival (OS, 68%/55%/39%, p < 0.001). Multivariable analysis identified the following variables as independent prognosticators for 5-year outcomes: ENE (LC/NC/DM/DFS/DSS/OS), poorly differentiated tumors (NC/DM/DFS/DSS/OS), positive margins (LC/DFS), lymphatic invasion (DFS/DSS/OS), perineural invasion (DM), and age ≥65 years (OS). CONCLUSIONS: In addition to ENE, poor tumor differentiation was identified as the second most relevant adverse RF for patients with pT3-4 OCSCC. We suggest that the NCCN guidelines should include poor tumor differentiation as an adverse RF to refine and tailor clinical management.

Precision Adjuvant Therapy Based on Detailed Pathologic Risk Factors for Resected Oral Cavity Squamous Cell Carcinoma: Long-Term Outcome Comparison of CGMH and NCCN Guidelines.

PURPOSE: The evidence for adjuvant therapy of oral cavity squamous cell carcinoma (OCSCC) in National Comprehensive Cancer Network (NCCN) guidelines is derived from patients with head and neck cancer. Here, we examined whether adjuvant therapy should be guided by a detailed analysis of pathologic risk factors in patients with pure OCSCC. METHODS AND MATERIALS: Between 2004 and 2016, we retrospectively reviewed 1200 consecutive patients with OCSCC who underwent radical surgery and neck dissection in the Chang-Gung Memorial Hospital (CGMH). Patients were divided into 3 prognostic groups. High-risk patients were those with extranodal extension (ENE) and/or positive margins (ENE/margins+, n = 267). Intermediate-risk patients were further divided into 3 subgroups: (1) patients in whom adjuvant therapy was indicated according to the CGMH but not the NCCN guidelines (NCCN[-]/CGMH[+], n = 14); (2) patients in whom adjuvant therapy was indicated by the NCCN but not the CGMH guidelines (NCCN[+]/CGMH[-], n = 160); and (3) patients in whom adjuvant therapy was indicated according to both guidelines (NCCN[+]/CGMH[+], n = 411). Low-risk patients were those for whom adjuvant therapy was not suggested in light of either guideline (NCCN[-]/CGMH[-], n = 348). RESULTS: According to NCCN guidelines, postoperative adjuvant therapy was indicated in 69.8% of the participants. However, only 57.7% of patients were in need of adjuvant therapy by CGMH guidelines. The following 5-year outcomes were observed in the NCCN(-)/CGMH(-), NCCN(-)/CGMH(+), NCCN(+)/CGMH(-), NCCN(+)/CGMH(+), and ENE/margins+ subgroups: locoregional control, 88%/70%/83%/79%/68%, P < .001 (NCCN[+]/CGMH[-] vs NCCN[+]/CGMH[+], P = .576); distant metastases, 2%/7%/2%/9%/36%, P < .001 (NCCN[+]/CGMH[-] vs NCCN[+]/CGMH[+], P = .003); disease-specific survival, 97%/86%/94%/84%/56%, P < .001 (NCCN[+]/CGMH[-] vs NCCN[+]/CGMH[+], P < .001); and overall survival, 92%/86%/87%/68%/42%, P < .001 (NCCN[+]/CGMH[-] vs NCCN[+]/CGMH[+], P < .001), respectively. CONCLUSIONS: Patients in the NCCN(+)/CGMH(-) subgroup, 28% (160/571[160 + 411]) of NCCN intermediate-risk patients, had more favorable 5-year disease-specific and overall survival (94% and 87%) than the NCCN(+)/CGMH(+) subgroup. The former are unlikely to derive clinical benefits from NCCN guidelines. The 70% adjuvant therapy rate required by NCCN guidelines after radical surgery might be too high, ultimately leaving room for improvement.

Murine models of psoriasis and their usefulness for drug discovery.

INTRODUCTION: Psoriasis is an autoimmune skin disease characterized by red plaques with silver or white multilayered scales with a thickened acanthotic epidermis. Using mouse models of cutaneous inflammation, IL-23/Th17 was identified to have a potential key role in psoriasis. New treatments to slow this inflammatory skin disorder are urgently needed. To aid their discovery, a psoriasis animal model mimicking human psoriasis is urgently needed for their early preclinical evaluation. Areas covered: The authors review animal models of psoriasis and analyze the features and molecular mechanisms involved in these mouse models. The application of various mouse models of psoriasis for drug discovery and development has also been reviewed and the possible molecular targets in psoriasis for future anti-psoriatic drug design is discussed. Expert opinion: So far, it has been difficult to create an animal model that exactly simulates a human disease or condition. The xenotransplantation model is regarded as the closest to incorporating the complete genetic, phenotypic, and immunopathogenic processes of psoriasis. However, the imiquimod (IMQ)-induced model is the most prevalent among psoriatic mouse models due to its ease of use, convenience, and low cost. Further efforts to develop psoriasis-like skin models in mice are needed for the study and treatment of this complex disease.

Relationship Between Expression of Proteins ERCC1, ERCC2, and XRCC1 and Clinical Outcomes in Patients with Rectal Cancer Treated with FOLFOX-Based Preoperative Chemoradiotherapy.

BACKGROUND: Platinum resistance enhances DNA damage repair through nucleotide excision repair mechanisms involving the excision repair cross-complementing group 1 (ERCC1), X-ray cross-complementing group 1 (XRCC1), and excision repair cross-complementing group 2 (ERCC2). We evaluated the correlation between the expression of these three DNA repair genes and clinical outcomes in patients with rectal cancer receiving FOLFOX-based preoperative chemoradiotherapy (CRT). METHODS: Using immunohistochemistry, we examined the expression of ERCC1, ERCC2, and XRCC1 in pre-CRT cancer tissues from 86 patients with rectal cancer who had undergone curative resection and preoperative CRT with FOLFOX-4 to identify potential predictors of clinical outcomes. RESULTS: Following CRT, 57 and 29 patients were classified as responders (pathological tumor regression grade TRG 0 and TRG 1) and poor responders (TRG 2 and TRG 3), respectively. The multivariate analysis revealed that ERCC1 overexpression was correlated with a poor CRT response [p < 0.0001; odds ratio (OR), 9.397; 95% confidence interval (CI) 2.721-32.457]. Furthermore, a poor response to CRT (pathological TRG of 2-3) (p = 0.18; OR 5.685; 95% CI 1.349-23.954) and abnormal pre-CRT serum carcinoembryonic antigen levels (>5 ng/mL) (p = 0.03; OR 6.288; 95% CI 1.198-33.006) were independent predictors of postoperative relapse. By contrast, ERCC2 and XRCC1 expression did not play predictive roles in the analyzed patients. CONCLUSIONS: ERCC1 overexpression is associated with a poor preoperative CRT response in patients with rectal cancer receiving FOLFOX-based preoperative CRT. ERCC1 is a potential biomarker for identifying patients who can benefit from customized treatment programs.

Clinical Outcomes of Taiwanese Patients with cT4 Oral Cavity Squamous Cell Carcinoma: Toward the Identification of the Optimal Initial Treatment Approach for cT4b Patients.

BACKGROUND: The National Comprehensive Cancer Network guidelines recommend that patients with oral cavity squamous cell carcinoma (OSCC) and cT4b disease should be either included in clinical trials or treated with a nonsurgical approach. However, surgery may be feasible in selected patients with adequate safety margins. Using the nationwide Taiwanese Cancer Registry Database, we examined the prognosis of cT4b OSCC patients in relation to their treatment approach. METHODS: Of the 18,910 patients with previously untreated first primary OSCC identified between 2004 and 2010, 492 (2.6 %) had cT4b tumors. Of them, 327 (66 %) received initial treatment with surgery, whereas 165 (34 %) were initially treated with a nonsurgical approach. Of the latter group, 78 patients subsequently underwent surgery. A 5-year disease-specific survival (DSS) ≥45 % was considered as a favorable outcome. RESULTS: Better 5-year DSS and overall survival (OS) rates were observed in cT4b patients initially treated with surgery (vs. nonsurgery; DSS, 51 vs. 38 %; OS, 43 vs. 27 %, respectively, p < 0.001). Of the participants initially treated with surgery, patients with cN0-2 disease had better 5-year survival rates (DSS: cN0, 59 %; cN1, 53 %; cN2, 46 %; OS: cN0, 49 %; cN1, 50 %; cN2, 37 %) than those with cN3 disease (DSS: 0 %; OS: 0 %). Among cT4b patients who initially received a nonsurgical treatment, subjects who subsequently underwent surgery showed better outcomes. CONCLUSIONS: Primary surgery is performed in approximately two-thirds of cT4b OSCC patients, with cN0-2 cases showing a good prognosis. Patients who initially received a nonsurgical approach can subsequently be treated with surgery and achieve favorable outcomes.

Decreased peritherapeutic VEGF expression could be a predictor of responsiveness to first-line FOLFIRI plus bevacizumab in mCRC patients.

OBJECTIVE: Bevacizumab is the only anti-angiogenic agent approved in first-line therapy for metastatic colorectal cancer (mCRC). Although chemotherapy plus bevacizumab has led to improve outcomes for mCRC patients and is a common choice for first-line treatment of mCRC, previous research has established no prominent biomarker that can help to select patients who may benefit from bevacizumab in order to improve cost-effectiveness and therapeutic outcomes. The aim of this study was to compare pre- and post-therapeutic VEGF immunohistochemical (IHC) expression in mCRC patients treated with FOLFIRI plus bevacizumab to identify its potential role as a predictive biomarker. METHODS: A total of 57 mCRC patients who underwent FOLFIRI combined with bevacizumab chemotherapy as a first-line neoadjuvant regimen were enrolled and clinical outcome data analyzed. RESULTS: Low post-therapeutic VEGF expression (P < 0.001) and decreased peri-therapeutic VEGF expression (P < 0.001) were significantly predictive factors of responders. Furthermore, the 6-month progression-free survival (PFS) rate in mCRC patients with decreased peri-therapeutic VEGF expression was significantly better than the rate for those patients with no peri-therapeutic VEGF expression alterations (P = 0.033). CONCLUSIONS: Decreased peri-therapeutic VEGF expression in mCRC patients could probably be used to predict responsiveness to bevacizumab and subsequent PFS in clinical practice.

Relationships between SMAD3 expression and preoperative fluoropyrimidine-based chemoradiotherapy response in locally advanced rectal cancer patients.

BACKGROUND: SMAD3, which is accumulated in the nucleus, transcriptionally regulates TGF-ß target genes, playing a significant role in mediating the activities of TGF-ß. In this study, we assessed the roles of TGF-ß1, SMAD3, and phosphorylated SMAD3 expressions in patients with locally advanced rectal cancer following preoperative fluoropyrimidine-based chemoradiotherapy. METHODS: Using immunohistochemistry, we examined TGF-ß1, SMAD3, and phosphorylated SMAD3 expressions in pre-chemoradiotherapy cancer tissues from 86 locally advanced rectal cancer patients. After chemoradiotherapy, 64 of 86 (74.4 %) locally advanced rectal cancer patients were classified as responders (pathological tumor regression grades of 2-4). RESULTS: A multivariate analysis showed that phosphorylated SMAD3 overexpression correlated to poor preoperative chemoradiotherapy responses (P = 0.015; OR 7.218; 95 % CI 1.479-35.229). Furthermore, a poor response (pathological tumor regression grades of 0-1) was an independent predictor of postoperative relapse (P = 0.021; OR 5.452; 95 % CI 1.286-23.113). Additionally, patients with phosphorylated SMAD3 overexpression were found to have a worse disease-free survival (P = 0.023). CONCLUSIONS: Our data suggested that analyzing pre-chemoradiotherapy tumors for phosphorylated SMAD3 overexpression would assist physicians in identifying locally advanced rectal cancer patients who may have a poor response risk to preoperative fluoropyrimidine-based chemoradiotherapy.

Predictive value of ERCC1, ERCC2, and XRCC1 overexpression for stage III colorectal cancer patients receiving FOLFOX-4 adjuvant chemotherapy.

OBJECTIVES: To determine the correlation between expression of three DNA repair genes and early failure/clinical outcome of stage III colorectal cancer (CRC) patients administrated with FOLFOX-4, including the excision repair cross-complementation group 1 (ERCC1), the excision repair cross-complementing 2 (ERCC2), and X-ray repair cross-complementing protein 1 (XRCC1). MATERIALS AND METHODS: We retrospectively analyzed clinicopathological features and ERCC1, ERCC2, XRCC1 expressions by immunohistochemical staining in 180 stage III CRC patients undergoing curative resection and treated with FOLFOX-4 chemotherapy to identify predictors of postoperative early failure. RESULTS: Among 180 CRC patients, 44 patients were classified into early failure group, and 136 patients were categorized into non-early failure group. A multivariate logistic regression analysis showed that ERCC1 overexpression (P = 0.005), and high postoperative carcinoembryonic antigen (CEA) levels (P = 0.001) were independent predictors of early failure. Additionally, ERCC1 overexpression was not only a predictor of early failure but also for disease-free survival (P < 0.001) and overall survival (P < 0.001). However, no predictive roles of ERCC2 and XRCC1 expression among these analyzed patients. CONCLUSIONS: ERCC1 overexpression is an important predictor of early failure in patients with stage III CRC administrating FOLFOX-4 adjuvant chemotherapy and this marker may help identify patients who would benefit from intensive follow-up and enhance therapeutic programs.

Camptothecin-Loaded Liposomes with α-Melanocyte-Stimulating Hormone Enhance Cytotoxicity Toward and Cellular Uptake by Melanomas: An Application of Nanomedicine on Natural Product.

In this study, we attempted to develop functional liposomes loaded with camptothecin and attached to α-melanocyte-stimulating hormone (α-MSH) to target melanoma cells. The liposomes were mainly composed of phosphatidylcholine, cholesterol, and stearylamine, and were characterized by the vesicle size, zeta potential, camptothecin encapsulation efficiency, and release behavior. Results revealed that α-MSH liposomes possessed an average size of approximately 250 nm with a surface charge of 60 mV. Camptothecin was successfully entrapped by the targeted liposomes with an encapsulation percentage of nearly 95%. The liposomes provided sustained and controlled camptothecin release. Non-targeted liposomes with the drug exerted superior cytotoxicity against melanomas compared to the free control. Cell viability was reduced from 48% to 32% compared to conventional liposomes. Peptide ligand conjugation further promoted cytotoxicity to 18% viability, which was a 2.7-fold decrease versus the free control. According to the images of fluorescence microscopy, α-MSH liposomes exhibited greater cell endocytosis than did non-targeted liposomes and the free control. α-MSH liposomes were predominantly internalized in the cytoplasm. These findings demonstrate that α-MSH liposomes could enhance the anti-melanoma activity of camptothecin owing to their targeting ability and controlled drug delivery.

In vitro and in vivo percutaneous absorption of seleno-L-methionine, an antioxidant agent, and other selenium species.

AIM: To investigate the in vitro and in vivo percutaneous absorption of seleno-L-methionine (Se-L-M), an ultraviolet (UV)-protecting agent, from aqueous solutions. METHODS: Aqueous solutions of Se-L-M were prepared in pH 4, 8, and 10.8 buffers. The pH 8 buffer contained 30% glycerol, propylene glycol (PG) and polyethylene glycol (PEG) 400. The in vitro skin permeation of Se-L-M via porcine skin and nude mouse skin was measured and compared using Franz diffusion cells. The in vivo skin tolerance study was performed, which examined transepidermal water loss (TEWL), skin pH and erythema. RESULTS: In the excised porcine skin, the flux was 0.1, 11.4 and 8.2 µg·cm(-2)·h(-1) for the pH 4, 8, and 10.8 buffers, respectively. A linear correlation between the flux and skin deposition was determined. According to permeation across skin with different treatments (stripping, delipidation, and ethanol treatments), it was determined that the intracellular route comprised the predominant pathway for Se-L-M permeation from pH 8 buffer. Aqueous solutions of seleno-DL-methionine (Se-DL-M), selenium sulfide and selenium-containing quantum dot nanoparticles were also used as donor systems. The DL form showed a lower flux (7.0 vs 11.4 µg·cm(-2)·h(-1)) and skin uptake (23.4 vs 47.3 µg/g) as compared to the L form, indicating stereoselective permeation of this compound. There was no or only negligible permeation of selenium sulfide and quantum dots into and across the skin. With in vivo topical application for 4 and 8 h, the skin deposition of Se-L-M was about 7 µg/g, and values were comparable to each other. The topical application of Se-L-M for up to 5 d did not caused apparent skin irritation. However, slight inflammation of the dermis was noted according to the histopathological examination. CONCLUSION: Se-L-M was readily absorbed by the skin in both the in vitro and in vivo experiments. The established profiles of Se-L-M skin absorption will be helpful in developing topical products of this compound.

Oligostilbenes from the roots of Vitis thunbergii.

Reinvestigating the constituents of the roots of Vitis thunbergii Sieb. & Zucc. led to the isolation of three new resveratrol derivatives, vitisinols E-G (1-3), together with 14 known compounds. The structures of compounds 1-3 were established by application of spectroscopic analyses (NMR, MS, UV, and IR).

A safe and effective way for reduction of temporomandibular joint dislocation.

Anterior dislocation of the temporomandibular joint (TMJ) is a common problem which demands immediate reduction to relieve the discomfort. The most popular technique is to put the operator's thumbs over the molar teeth of the patient and push the dislocated jaw downward and backward. This maneuver takes a lot of effort and usually needs sedation. Failure to reduction is not uncommon. Furthermore, the physician has to take the risk of being bitten and disease transmission. A novel method for reduction of the dislocated TMJ via extraoral route is presented, based on the observation that once the mandible is dislocated anteriorly, the coronoid process and anterior border of the ramus can be palpated easily over the cheek. By applying steady pressure over this prominent part, the anteriorly dislocated mandible can be reduced easily. From May 2000 to July 2005, there were 7 anterior mandible dislocations treated successfully by this method in Chang Gung Memorial Hospital. None of the patients need any adjuvant medication for sedation or relaxation. This technique is simple and effective, and the physicians are spared from the risk of bite trauma and unexpected disease transmission.

The similarities and diversities of signal pathways leading to consolidation of conditioning and consolidation of extinction of fear memory.

It is generally believed that consolidation of long-term memory requires activation of protein kinases, transcription of genes, and new protein synthesis. However, little is known about the signal cascades involved in the extinction of memory, which occurs when the conditioned stimulus is no longer followed by the unconditioned stimulus. Here, we show for the first time that an intra-amygdala injection of transcription inhibitor actinomycin D at the dose that blocked acquisition failed to affect extinction of a learned response. Conversely, protein synthesis inhibitor anisomycin blocked both acquisition and extinction. Extinction training-induced expression of calcineurin was blocked by anisomycin but not by actinomycin D. NMDA receptor antagonist, phosphatidylinositol 3-kinase (PI-3 kinase), and MAP kinase inhibitors that blocked the acquisition also blocked the extinction of conditioned fear. Likewise, PI-3 kinase inhibitor blocked fear training-induced cAMP response element-binding protein (CREB) phosphorylation as well as extinction training-induced decrease in CREB phosphorylation, the latter of which was associated with calcineurin expression and could be reversed by a specific calcineurin inhibitor. Thus, molecular processes that underlie long-term behavioral changes after acquisition and extinction share some common mechanisms and also display different characteristics.