Characteristics of Ocular Inflammatory Side Effects Associated with Immune Checkpoint Inhibitors in a Northern California Population.

PURPOSE: To characterize the ocular inflammatory side effects associated with immune checkpoint inhibitor (CPI) treatment in a Northern California population. DESIGN: Retrospective case series. PARTICIPANTS: Patients receiving CPI within an integrated healthcare delivery system. METHODS: All patients within Kaiser Permanente Northern California receiving CPI between January 1, 2012 and November 1, 2018 were identified. Medical records of those seen in the ophthalmology clinic at least once were retrospectively reviewed. MAIN OUTCOME MEASURES: Type and duration of ocular inflammation, indication for and exposure to CPI, time from exposure to diagnosis of ocular inflammation. RESULTS: 31 cases of ocular inflammation were identified in 5061 patients (0.61%) receiving CPI. Mean ± SD age was 67 ± 11.9 (range 38-89). Mean time from exposure to diagnosis was 6.8 ± 5.5 months (range 0.5-17). 87% of cases were bilateral, and 43% of cases were chronic. Average ophthalmology follow-up was 16 ± 18 months (range 0-71). 16/31 (52%) had anterior uveitis, 7/31 (23%) had serous retinal detachment or panuveitis resembling Vogt-Koyanagi-Harada syndrome, 4/31 (13%) had papillitis, and 6/31 (19%) had diplopia or ocular motility defect. There was one case each (3.2%) of melanoma associated retinopathy, corneal edema, granulomatous lacrimal gland enlargement, and choroidal neovascularization. CONCLUSIONS: Ocular inflammation is a rare immune associated side effect of CPI treatment, the most common manifestation of which is anterior uveitis.

Topical Chinese herbal medicine in treating atopic dermatitis (eczema): A systematic review and meta-analysis with core herbs exploration.

ETHNOPHARMACOLOGICAL RELEVANCE: Topical Chinese herbal medicine (CHM) is commonly used to relieve atopic dermatitis (AD); however, the up-to-date evidence concerning the effectiveness of topical CHM on treating AD is lacking. Moreover, the CHM prescriptions are often too complicated to realize the overall mechanisms of CHM, especially when compared to western medicines (WM). AIM OF THE STUDY: To evaluate the effectiveness of topical CHM for treating AD by conducting a meta-analysis on randomized clinical trials (RCTs). METHODS: Twenty RCTs comparing topical CHM to active control/placebo were included in the final analysis. The primary outcome was the symptom scores changed from baseline and the effectiveness rate was the secondary outcome. Subgroup analysis on different initial symptom severity and the different interventions in control groups was performed. System pharmacology analysis was performed to explore core CHM and possible pharmacological mechanisms of CHM for AD. RESULTS: Compared with active/blank placebo, topical CHM seemed more effective (SMD: -0.35, 95 %CI: -0.59 to -0.10, p-value = 0.005, I2 = 60%). The effectiveness rate was higher (RR: 1.29, 95 %CI 1.15-1.44, p-value <0.00001, I2 = 71%). In subgroup analysis, mild and moderate AD patients with topical CHM were more effective than placebo (SMD: -0.28, 95 %CI -0.56 to -0.01, p-value = 0.04, I2 = 5%; -0.34, 95%CI -0.64 to -0.03, p-value = 0.03, I2 = 0%, separately). Topical CHM has 1.25 times more effective than the topical glucocorticoid (95 %CI 1.09-1.43, p-value = 0.001, I2 = 64%). Core CHMs, such as Phellodendron chinense C.K. Schneid., Sophora flavescens Ait., Cnidium monnieri (L.) Cusson, and Dictamnus dasycarpus Turcz., had effects on the pathways on immune and metabolism systems different from WM. CONCLUSION: Our results exploit the potential role of CHM on treating AD, especially for mild and moderate AD.

Characterization of New Egyptian Linseed Varieties and the Effects of Roasting on Their Pigments, Tocochromanols, Phytosterols, Omega-3 Fatty Acids, and Stability.

The purpose of this study was to explore the effects of roasting linseeds on the pigment, lipid profile, bioactive components, and oxidative stability of the extracted oils. The linseed varieties Giza 11, Giza 12, Sakha 3, and Sakha 6 were roasted at 180 °C for 10 min, and the oils were extracted by cold pressing. The results showed that, after roasting, there was an increase in oil percentage and peroxide value, as well as small increases in p-anisidine and acid values. Roasting also caused an increase in chlorophyll content, while lutein and ß-carotene tend to slightly decrease, except in the Giza 11 variety. The total phenolics content was markedly enhanced after roasting. Omega-3 fatty acids were not affected by the roasting process. The total amounts of tocochromanol were found to decrease in the Giza 12 and Sakha 6 varieties after roasting. Plastochromanol-8 increased in all varieties after roasting. The phytosterol composition was minimally affected by roasting. Roasting enhanced the stability of the extracted oils, increasing the induction period and decreasing EC50 values. These results may thus help to discriminate between the different linseed varieties and serve to recommend the use of roasting to enhance the oxidative stability of extracted oil.

On the Core Prescriptions and Their Mechanisms of Traditional Chinese Medicine in Hepatitis B, Liver Cirrhosis, and Liver Cancer Treatment.

Background: As a frequent cause of death in cancer patients, liver cancer usually occurs in hepatitis B and cirrhosis. In China, Chinese people have been using traditional Chinese medicine (TCM) in treating various chronic liver diseases, which could effectively improve the symptoms and slow down the progression of liver diseases. However, due to the complexity rules of TCM prescription, their action mechanisms are still not clearly understood, which may affect the popularization of effective prescriptions. This study aims to identify the core TCM herbs in the treatment of hepatitis B, liver cirrhosis, and liver cancer so as to clarify the mechanism of action of the core herb networks. Methods: There were 1,673 prescriptions for chronic liver diseases collected in this study, of which 854 were hepatic B prescriptions, 530 were for liver cirrhosis, and 289 were for liver cancer. The basic characteristics of herbal medicine were firstly explained via descriptive analysis, then the core prescriptions of herbal medicine were analyzed through association rule, and finally, the mechanism of core prescriptions was explored with the help of systematic network pharmacology and by applying such databases as TCMIP, HERB, OMIM, GeneCards, KEGG, and software like RStudio and Cytoscape. Results: The rule of the core prescriptions in these cases was characterized by the application of herbs with both cold and warm properties, in which bitter herbs with cold property took priority. Tonifying deficiency, clearing heat, and activating blood circulations to remove stasis were common treatment principles for the three liver diseases. Turmeric Root Tuber (YuJin), White Peony Root (BaiShao), Bupleurum (ChaiHu), Salvia miltiorrhiza (DanShen), and Astragali Radix (HuangQi) were prescribed the most in hepatitis B treatment to invigorate the spleen and soothe the liver. Astragali Radix (HuangQi), Tuckahoe (FuLing), Atractylodis Macrocephalae Rhizoma (BaiZhu), Fructus Polygoni Orientalis (ShuiHongHuaZi), and Curcumae Rhizome (EZhu) were most frequently applied in liver cirrhosis treatment to replenish qi and activate blood. Oldenlandia (BaiHuaSheSheCao), Bearded Scutellaria (BanZhiLian), Curcumae Rhizome (EZhu), and Cardamom (DouKou) were most frequently prescribed to eliminate cancer toxin, invigorate the spleen, and activate blood. These core herbs mainly act through signal transduction and immune system pathways, in which the PI3K-Akt pathway plays a key role. The core prescription for liver cirrhosis regulated more endocrine system pathways than the hepatitis B prescription, and liver cancer prescription regulated more nervous system-related pathways. Conclusion: Three core prescriptions for hepatitis B, liver cirrhosis, and liver cancer treatment were identified, which acted mainly through signal transduction and immune system pathways to regulate immunity and cell growth and participate in inflammation inhibition, in which liver cancer prescription regulated more pathways, especially more nervous system-related pathways than the other two.

Purity of Olive Oil Commercially Available in Poland.

The aim of this study was to examine olive oils purchased in Poland for their compliance with label declarations and EEC criteria. Statistical analysis was used to compare the olive oils in terms of their content and composition of essential constituents and color parameters. Fifty olive oils (extra virgin, bioextra virgin, cold-pressed, refined, and pomace) from different countries (Spain, Italy, Greece, Portugal, Germany, France, Israel, and the European Union), were purchased commercially in Poland. The contents of triacylglycerols, sterols, and tocopherols, the fatty acid composition, and the color parameters were determined using chromatographic and spectrophotometric methods. Statistical methods were used to divide the olive oils into clusters. Our results show that the composition and color parameters of olive oils available commercially in Poland, excluding pomace olive oils, are similar. It can thus be concluded that, irrespective of the type of olive oil stated on the label, their quality is the same or very similar.

Profiling of the lipophilic components of seed oils recovered from twelve Japanese quince (Chaenomeles japonica) genotypes.

The seeds and oil yield and profile/levels of fatty acids, tocopherols and phytosterols in seed oils of twelve Japanese quince (Chaenomeles japonica) genotypes were studied. The seeds and oil yield ranged from 3.8 to 5.7% w/w fresh fruit, and 10.9 to 14.6% w/w dry weight seeds, respectively. The range of three predominated fatty acids C16:0, C18:1 and C18:2 in the seed oil of twelve Japanese quince genotypes were 8.1-9.8, 37.5-48.1, and 40.1-50.3%, respectively. α-Tocopherol and ß-sitosterol were the main minor lipophilic compounds detected in all investigated genotypes. The percentage of predomination of α-tocopherol and ß-sitosterol in each investigated genotype was very similar and amounted to 97-99% of total tocopherols and 76-80% of total phytosterols, respectively. The range of total content tocopherols and phytosterols in 12 genotypes of Japanese quince were 91.9-129.3 and 7830-14166 mg/100 g oil, respectively.

Curcumol inhibits malignant biological behaviors and TMZ-resistance in glioma cells by inhibiting long noncoding RNA FOXD2-As1-promoted EZH2 activation.

Currently, conventional treatment is not sufficient to improve the survival of glioma patients. Hence, adopting novel personalized treatment programs is imperative. Curcumol, a Chinese herbal medicine extract from the roots of Rhizoma Curcumae, has attracted significant interest due to its beneficial pharmacological activities. The current study revealed that curcumol inhibited the proliferation, metastasis, self-renewal ability, and TMZ resistance in glioma cells in vitro and in vivo. Next, the potential molecular mechanisms of curcumol in inhibiting glioma were investigated. We found that the long non-coding RNA (lncRNA) FOXD2-As1 might contribute to the effects of curcumol on glioma cells. Enforced expression of FOXD2-As1 attenuated the curcumol-induced reduction in glioma cell proliferation, metastasis, self-renewal ability, and TMZ resistance. Moreover, the forced expression of FOXD2-As1 reversed the inhibitory effect of curcumol on the binding ability of EZH2 and H3K27me3 modification in the promoter regions of anti-oncogenes. Our results showed for the first time that curcumol is effective in inhibiting malignant biological behaviors and TMZ-resistance of glioma cells by suppressing FOXD2-As1-mediated EZH2 activation. Our study offers the possibility of exploiting curcumol as a promising therapeutic agent for glioma treatment and may provide an option for the clinical application of this natural herbal medicine.

Silica-Based Nanoframeworks Involved Hepatocellular Carcinoma Theranostic.

Silica-based nanoframeworks have been extensively studied for diagnosing and treating hepatocellular carcinoma (HCC). Several reviews have summarized the advantages and disadvantages of these nanoframeworks and their use as drug-delivery carriers. Encouragingly, these nanoframeworks, especially those with metal elements or small molecular drugs doping into the skeleton structure or modifying onto the surface of nanoparticles, could be multifunctional components participating in HCC diagnosis and treatment rather than functioning only as drug-delivery carriers. Therefore, in this work, we described the research progress of silica-based nanoframeworks involved in HCC diagnosis (plasma biomarker detection, magnetic resonance imaging, positron emission tomography, photoacoustic imaging, fluorescent imaging, ultrasonography, etc.) and treatment (chemotherapy, ferroptotic therapy, radiotherapy, phototherapy, sonodynamic therapy, immunotherapy, etc.) to clarify their roles in HCC theranostics. Further, the future expectations and challenges associated with silica-based nanoframeworks were highlighted. We believe that this review will provide a comprehensive understanding for researchers to design novel, functional silica-based nanoframeworks that can effectively overcome HCC.

Complex analysis of the personalized pharmacotherapy in the management of COVID-19 patients and suggestions for applications of predictive, preventive, and personalized medicine attitude.

AIMS: Coronavirus disease 2019 (COVID-19) is rapidly spreading worldwide. Drug therapy is one of the major treatments, but contradictory results of clinical trials have been reported among different individuals. Furthermore, comprehensive analysis of personalized pharmacotherapy is still lacking. In this study, analyses were performed on 47 well-characterized COVID-19 drugs used in the personalized treatment of COVID-19. METHODS: Clinical trials with published results of drugs use for COVID-19 treatment were collected to evaluate drug efficacy. Drug-to-Drug Interactions (DDIs) were summarized and classified. Functional variations in actionable pharmacogenes were collected and systematically analysed. "Gene Score" and "Drug Score" were defined and calculated to systematically analyse ethnicity-based genetic differences, which are important for the safer use of COVID-19 drugs. RESULTS: Our results indicated that four antiviral agents (ritonavir, darunavir, daclatasvir and sofosbuvir) and three immune regulators (budesonide, colchicine and prednisone) as well as heparin and enalapril could generate the highest number of DDIs with common concomitantly utilized drugs. Eight drugs (ritonavir, daclatasvir, sofosbuvir, ribavirin, interferon alpha-2b, chloroquine, hydroxychloroquine (HCQ) and ceftriaxone had actionable pharmacogenomics (PGx) biomarkers among all ethnic groups. Fourteen drugs (ritonavir, daclatasvir, prednisone, dexamethasone, ribavirin, HCQ, ceftriaxone, zinc, interferon beta-1a, remdesivir, levofloxacin, lopinavir, human immunoglobulin G and losartan) showed significantly different pharmacogenomic characteristics in relation to the ethnic origin of the patient. CONCLUSION: We recommend that particularly for patients with comorbidities to avoid serious DDIs, the predictive, preventive, and personalized medicine (PPPM, 3 PM) strategies have to be applied for COVID-19 treatment, and genetic tests should be performed for drugs with actionable pharmacogenes, especially in some ethnic groups with a higher frequency of functional variations, as our analysis showed. We also suggest that drugs associated with higher ethnic genetic differences should be given priority in future pharmacogenetic studies for COVID-19 management. To facilitate translation of our results into clinical practice, an approach conform with PPPM/3 PM principles was suggested. In summary, the proposed PPPM/3 PM attitude should be obligatory considered for the overall COVID-19 management. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13167-021-00247-0.

Isothiocyanate From Moringa oleifera Seeds Inhibits the Growth and Migration of Renal Cancer Cells by Regulating the PTP1B-dependent Src/Ras/Raf/ERK Signaling Pathway.

Moringa oleifera Lam. is a tropical and subtropical plant that has been used for centuries as both food and traditional medicine. 4-[(α-L-Rhamnosyloxy) benzyl] isothiocyanate (MIC-1) is an active substance in M. oleifera, with anti-cancer activity. However, whether MIC-1 exerts anti-renal cancer effects is unknown. Therefore, the aim of the present study was to evaluate the effects of MIC-1 on the growth and migration of renal cell carcinoma (RCC) cells and to identify the putative underlying mechanism. We found that, among 30 types of cancer cells, MIC-1 exerted the strongest growth inhibitory effects against 786-O RCC cells. In addition, MIC-1 (10 µM) significantly inhibited the growth of five RCC cell lines, including 786-O, OSRC-2, 769-P, SK-NEP-1, and ACHN cells, but was not toxic to normal renal (HK2) cells. Also, MIC-1 suppressed 786-O and 769-P cell migration and invasion abilities, and reduced the expression of matrix metalloproteinase (MMP)-2 and MMP-9. Furthermore, MIC-1 induced apoptosis and cell cycle arrest, increased Bax/Bcl-2 ratio, and decreased cell cycle-related protein expression in 786-O cells and 769-P cells. Molecular docking and small-molecule interaction analyses with PTP1B both showed that MIC-1 inhibited PTP1B activity by binding to its active site through hydrogen bonding and hydrophobic interactions. Additionally, MIC-1 could suppress the growth and migration of 786-O cells by inhibiting PTP1B-mediated activation of the Src/Ras/Raf/ERK signaling pathway. In vivo experiments further showed that MIC-1 markedly inhibited the growth of xenograft tumors in mice, and greatly increased Bax/Bcl-2 ratio in tumor tissues. In addition, MIC-1 had no effect on the PTP1B-dependent Src/Ras/Raf/ERK signaling pathway in HCT-116 cells, Hep-G2 cells, and A431 cells. Overall, our data showed that MIC-1 could be a promising, non-toxic, natural dietary supplement for the prevention and treatment of renal cancer.

Gut Microbiota and Epilepsy: A Systematic Review on Their Relationship and Possible Therapeutics.

Dysbiosis of gut microbiota may lead to a range of diseases including neurological disorders. Thus, it is hypothesized that regulation of the intestinal microbiota may prevent or treat epilepsy. The purpose of this systematic review is to evaluate the evidence investigating the relationship between gut microbiota and epilepsy and possible interventions. A systematic review of the literature was done on four databases (PubMed, Scopus, EMBASE, and Web of Science). Study selection was restricted to original research articles while following the PRISMA guidelines. Six studies were selected. These studies cohesively support the interaction between gut microbiota and epileptic seizures. Gut microbiota analysis identified increases in Firmicutes, Proteobacteria, Verrucomicrobia, and Fusobacteria with decreases in Bacteroidetes and Actinobacteria in epileptic patients. Ketogenic diet, probiotics, and fecal microbiota transplantation (FMT) improved the dysbiosis of the gut microbiota and seizure activity. However, the studies either had a small sample size, lack of subject variability, or short study or follow-up period, which may question their reliability. Nevertheless, these limited studies conclusively suggest that gut microbiota diversity and dysbiosis may be involved in the pathology of epilepsy. Future studies providing more reliable and in depth insight into the gut microbial community will spark promising alternative therapies to current epilepsy treatment.

Determination of Triacylglycerols by HTGC-FID as a Sensitive Tool for the Identification of Rapeseed and Olive Oil Adulteration.

Triacylglycerols (TGs) are the most common compounds in food lipids, accounting for 95% of the weight of edible oils. The aim of this study was to scrutinize a procedure for quantitatively assessing possible adulteration of olive and rapeseed oil through GC-FID analysis of TGs. The recovery of TG standards ranged from 21% to 148%, and the relative response factor (RRF) ranged from 0.42 to 2.28. The limits of detection were in the range of 0.001 to 0.330 µg/mL, and the limits of quantitation from 0.001 to 1.000 µg/mL. The validated method was used to determine the TGs in olive oil (OO), refined rapeseed oil (RRO), and their blends. Eight TGs were detected in refined rapeseed oil, and 10 in olive oil. The addition of 1% of olive oil to rapeseed oil or vice versa can be detected using this method. Three triacylglycerols were pinpointed as indicators of adulteration of rapeseed oil with olive oil (PPO, PPL, PSO). The method described here can be used for controlling the quality of these oils.

Feature-Based Molecular Networking Analysis of the Metabolites Produced by In Vitro Solid-State Fermentation Reveals Pathways for the Bioconversion of Epigallocatechin Gallate.

Dark teas are prepared by a microbial fermentation process. Flavan-3-ol B-ring fission analogues (FBRFAs) are some of the key bioactive constituents that characterize dark teas. The precursors and the synthetic mechanism involved in the formation of FBRFAs are not known. Using a unique solid-state fermentation system with ß-cyclodextrin inclusion complexation as well as targeted chromatographic isolation, spectroscopic identification, and Feature-based Molecular Networking on the Global Natural Products Social Molecular Networking web platform, we reveal that dihydromyricetin and the FBRFAs, including teadenol A and fuzhuanin A, are derived from epigallocatechin gallate upon exposure to fungal strains isolated from Fuzhuan brick tea. In particular, the strains from subphylum Pezizomycotina were key drivers for these B-/C-ring oxidation transformations. These are the same transformations seen during the fermentation process of dark teas. These discoveries set the stage to enrich dark teas and other food products for these health-promoting constituents.

The investigation of unique water-soluble heptamethine cyanine dye for use as NIR photosensitizer in photodynamic therapy of cancer cells.

In this paper, a unique water-soluble heptamethine cyanine dye as NIR photosensitizer was synthesized to explore its properties associated with potential applications in photodynamic therapy (PDT). In the strategy of designing this photosensitizer, a sulfonic acid was used as a water soluble functional group and linked to the fluorophore through alkyl chains. 4-amino-2,2,6,6-tetramethylpiperidine-N-oxyl(Tempo) moiety was used as the a nitroxide spin label in obtaining biochemical reaction information in vivo due to it could greatly increase the inter-system crossing (ISC) process for triplet-state photosensitizers and low toxicity. As expected, the photosensitizers performed well in vitro photodynamic therapy. There were a remarkable absorbance band located at 692 nm and emission peaks falls at 762 nm, the quantum yield (Φf) was calculated to be 12.12% in pure aqueous solution using ICG as standards. The photosensitizer also has high singlet oxygen quantum yield (Φ△) for 16.96% with NIR LED irradiation. This photosensitizer can rapidly produce singlet oxygen and exhibit high phototoxicity under NIR light irradiation. It has excellent cellular uptake ability and better cell compatibility. It was also successfully applied in Near-infrared fluorescence imaging and AO/EB staining. In a whole, the organic dye based on Heptamethine cyanine used as photosensitizer has great potential in vivo cancer treatment.

Exploring the protective effect of ShengMai-Yin and Ganmaidazao decoction combination against type 2 diabetes mellitus with nonalcoholic fatty liver disease by network pharmacology and validation in KKAy mice.

ETHNOPHARMACOLOGICAL RELEVANCE: ShengMai-Yin and Ganmaidazao decoction are classic formulas in traditional Chinese medicine. Individually, Shengmai-Yin is used to treat cardiovascular diseases, and Ganmaidazao decoction for therapy of mental disorders. The combination of Shengmai-Yin and Ganmaidazao decoction (SGD) is normally used as adjuvant therapy for type 2 diabetes mellitus (T2DM). AIM OF THE STUDY: The central aim is to elucidate the pharmacological efficacy of SGD and its mechanism in the treatment of T2DM with non-alcoholic fatty liver disease (NAFLD). MATERIALS AND METHODS: Active ingredients in SGD and their drug targets were identified using network analysis followed by experimental validation. First, existing databases were mined for information relevant to SGD, including pharmacological actions, chemical components, physicochemical characteristics, potential targets, and implicated diseases. Candidate patterns obtained with the network analysis were then tested in a KKAy mouse model of T2DM with NAFLD. Various doses of SGD were administered, followed by measurements of fasting blood glucose, oral glucose tolerance tests, insulin tolerance tests, markers of lipid metabolism - including free fatty acids (FFA), triglycerides (TG), and total cholesterol (TC) - liver histology, and expression levels of implicated molecules including PI3K/AKT and PPARα. RESULTS: Over 300 potential active compounds with their physicochemical characteristics and 562 candidate targets were collected, and then the network of them was constructed. Follow-up pathway and functional enrichment analyses indicated that SGD influences metabolism-related signaling pathways including PI3K-Akt, AMPK, and PPAR. In validation experiments, treatment of KKAy mice with SGD reduced serum levels of glucose, TC, TG, and FFA, decreased numbers of crown-like structures in visceral adipose tissue, reduced adipocyte size, and lowered liver lipid deposits. Further, SGD improved liver metabolism by increasing the expressions of PPARα, HSL, and PI3K/Akt, and decreasing expressions of SREBP-1 and FASN, inhibiting lipid biosynthesis, and increasing insulin sensitivity. CONCLUSION: Experimental validation of network analysis revealed anti-diabetic effects of the plant product SGD, manifested most notably by improved serum profiles and diminished insulin resistance. These experimental results may have clinical implications.

The complete chloroplast genome sequence of plumed cockscomb (Celosia argentea, Amaranthaceae).

The complete chloroplast genome of Celosia argentea, an important horticultural and medicinal herb, was identified and sequenced in this study. The genome size is 153,474 bp, the GC content is 36.7%. A total of 123 genes were identified, including 84 protein-coding genes, 8 rRNA genes, and 33 tRNA genes. Twenty-nine plastome accessions from Caryophyllales were selected to assess the phylogenetic placement of genus and the result showed that C. argentea is most closely related to Amaranthus hypochondriacus.

A selenamorpholine-based redox-responsive fluorescent probe for targeting lysosome and visualizing exogenous/endogenous hydrogen peroxide in living cells and zebrafish.

A simple selenamorpholine-based fluorescent probe has been designed and synthesized using a combination of selenamorpholine and a BODIPY fluorophore. BODIPY-Se has a low pKa value of 4.78 because of the selenamorpholine unit, which is beneficial for the probe to detect the lysosome. BODIPY-Se can turn on partial fluorescence only in lysosomes, due to a PET-inhibited process of protonation of selenamorpholine. In addition, the selenamorpholine unit of BODIPY-Se could selectively react with H2O2 through a redox reaction, leading to the alteration of the valence state of selenium from Se(ii) to Se(iv) and an additional PET-inhibited process. When BODIPY-Se tracked H2O2 in lysosomes, the two PET-inhibited processes would obviously amplify the fluorescence signal in living cells and in vivo. The probe could also detect the redox cycles between H2O2 and GSH continuously. Using confocal fluorescence imaging, the fluorescence localization of lysosomes demonstrated that BODIPY-Se could successfully target lysosomes. The probe could not only detect exogenous/endogenous H2O2 in living cells, but could also realize real-time monitoring of H2O2 in cancer cells and zebrafish. The results proved that BODIPY-Se is a promising fluorescent probe in biological applications.

Efficacy and safety of combined high-dose interferon and red light therapy for the treatment of human papillomavirus and associated vaginitis and cervicitis: A prospective and randomized clinical study.

BACKGROUND: We evaluated the efficacy and safety of combined high-dose interferon (IFN) and red light therapy for the treatment of subclinical and latent human papillomavirus (HPV) infections. METHODS: Ninety women diagnosed with subclinical or latent HPV infection were randomized to receive topical application of low-dose recombinant IFNα-2b (1 million IU), high-dose IFNα-2b (9 million IU), or a combination of high-dose IFNα-2b and red light therapy on the cervix and vagina. All patients received treatment once daily for 4 weeks. HPV titer was measured immediately and 4, 8, and 12 weeks after treatment to determine the rates of viral clearance and infection cure. Treatment of HPV-associated vaginitis and cervicitis was also evaluated. RESULTS: Results showed that immediately and 4, 8, and 12 weeks after treatment, the HPV clearance rates and infection cure rates were higher in the high-dose IFN and combination groups compared to the low-dose IFN group. High-dose IFN and combination therapies were significantly effective against both low-risk and high-risk HPV infections. Although the cure rates for vaginitis and cervicitis were significantly higher in the high- compared to the low-dose IFN group, rates were even higher in the combination group compared to the high-dose IFN group. Mild adverse effects were reported by a very small subset of patients (3/30) in the combination group. CONCLUSIONS: This study suggests that combination of high-dose IFN and red light therapy is safe and effective against subclinical and latent HPV infections.

Shenmai injection enhances the cytotoxicity of chemotherapeutic drugs against colorectal cancers via improving their subcellular distribution.

Shenmai injection (SMI) is a Chinese patent-protected injection, which was mainly made of Red Ginseng and Radix Ophiopogonis and widely used for treating coronary heart disease and tumors by boosting Qi and nourishing Yin. In this study we examined whether SMI could produce direct synergetic effects on the cytoxicity of adriamycin (ADR) and paclitaxel (PTX) in colorectal cancers in vivo and in vitro, and explored the underlying pharmacokinetic mechanisms. BALB/c nude mice with LoVo colon cancer xenografts were intraperitoneally injected with ADR (2 mg·kg-1·3d-1) or PTX (7.5 mg·kg-1·3d-1) with or without SMI (0.01 mL·g-1·d-1) for 13 d. Co-administration of SMI significantly enhanced the chemotherapeutic efficacy of ADR and PTX, whereas administration of SMI alone at the given dosage did not produce visible anti-cancer effects, The chemosensitizing action of SMI was associated with increased concentrations of ADR and PTX in the plasma and tumors. In Caco-2 and LoVo cells in vitro, co-treatment with SMI (2 µL/mL) significantly enhanced the cytotoxicity of ADR and PTX, and resulted in some favorable pharmacokinetic changes in the subcellular distribution of ADR and PTX. In addition, SMI-induced intracellular accumulation of ADR was closely correlated with the increased expression levels of P-glycoprotein in 4 colon cancer cell lines (r2=+0.8558). SMI enhances the anti-cancer effects of ADR and PTX in colon cancers in vivo and in vitro by improving the subcellular distributions of ADR and PTX.

γ-Carboxyethyl hydroxychroman, a metabolite of γ-tocopherol, preserves nitric oxide bioavailability in endothelial cells challenged with high glucose.

Endothelial dysfunction occurs when there are imbalances between factors that regulate the synthesis and degradation of nitric oxide (NO•), and has been reported in patients with hyperglycemia and insulin resistance. We reported that supplementation with γ-tocopherol (γ-T) in humans limits impairments in endothelial function otherwise induced by postprandial hyperglycemia. Given the rapid metabolism of γ-T into γ-carboxyethyl hydroxychroman (γ-CEHC), we hypothesized that the vasoprotective activities of γ-T could be attributed to its metabolite γ-CEHC. To test this, human aortic endothelial cells (HAECs) treated with 0 (vehicle control) or 3 µM γ-CEHC for 24 h prior to incubation with normal (5 mM) or high (25 mM) glucose for 48 h. High-glucose increased levels of uncoupled endothelial nitric oxide synthase (eNOS) as evidenced by reduced ( p < 0.05) eNOS dimer:monomer. High glucose also prevented insulin-stimulated increases in p-AktSer473: total Akt, p-eNOSSer1177: total eNOS, and NO• production. These adverse changes were accompanied by increased ( p < 0.05) reactive oxygen species and mRNA expression of inflammatory mediators (VCAM-1, E-selectin, IL-8). However, each deleterious response evoked by high glucose was prevented when HAECs were incubated with γ-CEHC prior to the high glucose challenge. Taken together, our data support the hypothesis that vascular protection provided by γ-T in vivo may be elicited through the bioactivity of its metabolite, γ-CEHC. Furthermore, it is possible that the antioxidant and anti-inflammatory activities of γ-CEHC may mediate this protective activity.