A Clinical Study Evaluating the Efficacy of Topical Bakuchiol (UP256) Cream on Facial Acne.

Acne vulgaris is a common skin disease that manifests clinically as comedones, papules, nodules, and cysts. In this single center, open-label pilot study (ISRCTN13992386), we aimed to evaluate the effectiveness of UP256 cream, a newly patented topical product containing 0.5% bakuchiol, on facial acne and acne-related post-inflammatory hyperpigmentation (PIH). A series of 13 subjects enriched for Fitzpatrick skin types III–VI with mild or moderate acne received treatment with UP256 twice daily for 12 weeks. Efficacy assessments included changes in inflammatory and non-inflammatory lesions as well as a reduction in Evaluator Global Severity Score (EGSS) assessments of acne severity and PIH. Safety, adverse events, and cutaneous tolerability were evaluated throughout the study. UP256 significantly reduced the number of inflammatory lesions and improved existing PIH. UP256 was also cosmetically acceptable and well tolerated by all study subjects. Overall, our results demonstrate that monotherapy with UP256 improves mild to moderate acne and may be particularly well suited for individuals with skin of color. J Drugs Dermatol. 2021;20(3):307-310. doi:10.36849/JDD.5655.

Osmogen-Mediated One-Step Technique of Fabricating Hollow Microparticles for Encapsulation and Delivery of Bioactive Molecules.

Microparticulate systems composed of biodegradable polymers, such as poly(d,l-lactic-co-glycolic acid) (PLGA), are widely used for controlled release of bioactive molecules. However, the acidic microenvironment within these microparticles, as they degrade, has been reported to perturb the configuration of most encapsulated proteins. In addition, these polymer particles are also reported to suffer from unrealistically slow and incomplete release of proteins. To address these drawbacks, hollow PLGA microparticles are fabricated through a novel one-step oil-in-water emulsion solvent evaporation technique, by capitalizing on the osmotic property of an osmogen. The effects of fabrication para-meters on particle size and morphology, i.e., volume space of hollow cavity and shell thickness, are also studied. These hollow microparticles are subsequently loaded with bovine insulin microcrystals. It is shown that insulin release profiles can be tuned by simply changing the amount of osmogen in the formulation. At the same time, these hollow microparticles are shown to be effective in maintaining the bioactivity of the encapsulated protein.

Delivery of doxorubicin and paclitaxel from double-layered microparticles: The effects of layer thickness and dual-drug vs. single-drug loading.

Double-layered microparticles composed of poly(d,l-lactic-co-glycolic acid, 50:50) (PLGA) and poly(l-lactic acid) (PLLA) were loaded with doxorubicin HCl (DOX) and paclitaxel (PCTX) through a solvent evaporation technique. DOX was localized in the PLGA shell, while PCTX was localized in the PLLA core. The aim of this study was to investigate how altering layer thickness of dual-drug, double-layered microparticles can influence drug release kinetics and their antitumor capabilities, and against single-drug microparticles. PCTX-loaded double-layered microparticles with denser shells retarded the initial release of PCTX, as compared with dual-drug-loaded microparticles. The DOX release from both DOX-loaded and dual-drug-loaded microparticles were observed to be similar with an initial burst. Through specific tailoring of layer thicknesses, a suppressed initial burst of DOX and a sustained co-delivery of two drugs can be achieved over 2months. Viability studies using spheroids of MCF-7 cells showed that controlled co-delivery of PCTX and DOX from dual-drug-loaded double-layered microparticles were better in reducing spheroid growth rate. This study provides mechanistic insights into how by tuning the layer thickness of double-layered microparticles the release kinetics of two drugs can be controlled, and how co-delivery can potentially achieve better anticancer effects. STATEMENT OF SIGNIFICANCE: While the release of multiple drugs has been reported to achieve successful apoptosis and minimize drug resistance, most conventional particulate systems can only deliver a single drug at a time. Recently, although a number of formulations (e.g. micellar nanoparticles, liposomes) have been successful in delivering two or more anticancer agents, sustained co-delivery of these agents remains inadequate due to the complex agent loading processes and rapid release of hydrophilic agents. Therefore, the present work reports the multilayered particulate system that simultaneously hosts different drugs, while being able to tune their individual release over months. We believe that our findings would be of interest to the readers of Acta Biomaterialia because the proposed system could open a new avenue on how two drugs can be released, through rate-controlling carriers, for combination chemotherapy.

Inhibition of 3-D tumor spheroids by timed-released hydrophilic and hydrophobic drugs from multilayered polymeric microparticles.

First-line cancer chemotherapy necessitates high parenteral dosage and repeated dosing of a combination of drugs over a prolonged period. Current commercially available chemotherapeutic agents, such as Doxil and Taxol, are only capable of delivering single drug in a bolus dose. The aim of this study is to develop dual-drug-loaded, multilayered microparticles and to investigate their antitumor efficacy compared with single-drug-loaded particles. Results show hydrophilic doxorubicin HCl (DOX) and hydrophobic paclitaxel (PTX) localized in the poly(dl-lactic-co-glycolic acid, 50:50) (PLGA) shell and in the poly(l-lactic acid) (PLLA) core, respectively. The introduction of poly[(1,6-bis-carboxyphenoxy) hexane] (PCPH) into PLGA/PLLA microparticles causes PTX to be localized in the PLLA and PCPH mid-layers, whereas DOX is found in both the PLGA shell and core. PLGA/PLLA/PCPH microparticles with denser shells allow better control of DOX release. A delayed release of PTX is observed with the addition of PCPH. Three-dimensional MCF-7 spheroid studies demonstrate that controlled co-delivery of DOX and PTX from multilayered microparticles produces a greater reduction in spheroid growth rate compared with single-drug-loaded particles. This study provides mechanistic insights into how distinctive structure of multilayered microparticles can be designed to modulate the release profiles of anticancer drugs, and how co-delivery can potentially provide better antitumor response.

Modulation of cytokine and nitric oxide production by keratinocytes, epithelial cells, and mononuclear phagocytes in a co-culture model of inflammatory acne.

INTRODUCTION: Ultraviolet B (UVB, 290 nm to 320 nm) has been reported to modulate the cytokine-mediated inflammatory process in various inflammatory skin conditions, including production of TNF-α, IL-1α, IL-6, IL-8, and IL-10. We constructed an in vitro model system involving co-culture of different cell types to study the effect of UVB on the inflammatory process using nitric oxide (NO) and tumor necrosis factor (TNF)-α as markers of inflammation. OBJECTIVE: This study was conducted to quantitatively assess the products secreted by human epithelial keratinocytes in the presence and absence of macrophages/monocytes. METHODS: Cells were exposed to UVB radiation (50 mJ to 200 mJ per cm2) or treated with bacterial lipopolysaccharide (LPS) as stimulator of inflammatory response. Nitric oxide (NO) was measured by modified Griess assay and TNF-α was measured by quantitative ELISA. For the co-culture system, SC monocytes were seeded in a 24-well Transwell tissue culture plate whereas irradiated keratinocytes were seeded in the individual baskets subsequently placed on top of the monocyte cultures, and samples of culture supernatants were collected at 1 to 6 days. RESULTS: When primary human epidermal keratinocytes (NHEK) were irradiated with UVB, a dose-dependent stimulation of TNF-α production was observed (33% to 200% increase). TNF-α production was not changed significantly in SC monocytes/NHEK co-culture. In contrast, when macrophages were irradiated with UVB, significant inhibition of NO production (40% suppression, P<0.001) was seen. CONCLUSION: This improved model of cutaneous inflammation could use multiple cells to study their interactions and to offer convenience, reproducibility, and a closer approximation of in vivo conditions.

Activation of P2X(7) receptors decreases glutamate uptake and glutamine synthetase activity in RBA-2 astrocytes via distinct mechanisms.

Glutamate clearance by astrocytes is critical for controlling excitatory neurotransmission and ATP is an important mediator for neuron-astrocyte interaction. However, the effect of ATP on glutamate clearance has never been examined. Here we report that treatment of RBA-2 cells, a type-2-like astrocyte cell line, with ATP and the P2X(7) receptor selective agonist 3'-O-(4-benzoylbenzoyl) adenosine 5'-triphosphate (BzATP) decreased the Na+-dependent [3H]glutamate uptake within minutes. Mechanistic studies revealed that the decreases were augmented by removal of extracellular Mg2+ or Ca2+, and was restored by P2X7 selective antagonist , periodate-oxidized 2',3'-dialdehyde ATP (oATP), indicating that the decreases were mediated through P2X(7) receptors. Furthermore, stimulation of P2X7 receptors for 2 h inhibited both activity and protein expression of glutamine synthetase (GS), and oATP abolished the inhibition. In addition, removal of extracellular Ca(2+) and inhibition of protein kinase C (PKC) restored the ATP-decreased GS expression but failed to restore the P2X(7)-decreased [3H]glutamate uptake. Therefore, P2X7-mediated intracellular signals play a role in the down-regulation of GS activity/expression. Activation of P2X7 receptors stimulated increases in intracellular Na+ concentration ([Na+](i)) suggesting that the P2X(7)-induced increases in [Na+](i) may affect the local Na+ gradient and decrease the Na+-dependent [3H]glutamate uptake. These findings demonstrate that the P2X7-mediated decreases in glutamate uptake and glutamine synthesis were mediated through distinct mechanisms in these cells.

Influence of alkalinity, hardness and dissolved solids on drinking water taste: A case study of consumer satisfaction.

Two surveys of consumer satisfaction with drinking water conducted by Taiwan Water Supply Corp. are presented in this study. The study results show that although a lot of money was invested to modify traditional treatment processes, over 60% of local residents still avoided drinking tap water. Over half of the respondents felt that sample TT (from the traditional treatment process) was not a good drinking water, whether in the first or second survey, whereas almost 60% of respondents felt that samples PA, PB, CCL and CT (from advanced treatment processes) were good to drink. For all drinking water samples, respondent satisfaction with a sample primarily depended on it having no unpleasant flavors. Taiwan Environmental Protection Administration plans to revise the drinking water quality standards for TH and TDS in the near future. The new standards require a lower TH concentration (from currently 400mg/L (as CaCO(3)) to 150mg/L (as CaCO(3))), and a lower TDS maximum admissible concentration from the current guideline of 600 to 250mg/L. Therefore, this study also evaluated the impacts on drinking water tastes caused by variations in TH and TDS concentrations, and assessed the need to issue more strict drinking water quality standards for TH and TDS. The research results showed that most respondents could not tell the difference in water taste among water samples with different TDS, TH and alkalinity. Furthermore, hardness was found to be inversely associated with cardiovascular diseases and cancers, and complying with more strict standards would lead most water facilities to invest billions of dollars to upgrade their treatment processes. Consequently, in terms of drinking water tastes alone, this study suggested that Taiwan Environmental Protection Administration should conduct more thorough reviews of the scientific literature that provides the rationale for setting standards and reconsider if it is necessary to revise drinking water quality standards for TH and TDS.

Anti-inflammatory properties of narrow-band blue light.

BACKGROUND: Narrow-band blue light (420 nm) has demonstrated safety and efficacy in the treatment of acne vulgaris. It works by exhibiting a phototoxic effect on the heme metabolism of Propionibacterium acnes. Previous studies using blue light showed more improvement in inflammatory lesions than in comedones, as well as some improvement on the untreated side. Cytokines have demonstrated a critical role in the development of inflammation. The expression of pro-inflammatory cytokines such as IL-1alpha have been shown to result in the expression of vascular and dermal adhesion molecules, the chemoattraction of inflammatory cells, and the stimulation of other inflammatory mediators. In addition, UVB radiation serves as a potent modulator of cell-mediated immune responses. PURPOSE: This study investigated the effect of narrow-band blue light on the inflammatory process in the presence and absence of cytokines and UVB using IL-1alpha and ICAM-1 as markers for inflammation. METHODS: Two immortalized keratinocyte cell lines were compared: HaCaT, produced by spontaneous immortalization of a genetically altered cell line, and hTERT, obtained by stable transfection of primary cell culture with human telomerase reverse transcriptase. Cells were treated with INF-y and TNF-alpha and exposed to UVB (312 nm at 50 mJ/cm2) and/or blue light (420 nm at 54 mJ/cm2 and 134 mJ/cm2). The expression of IL-1alpha and ICAM-1 was measured by quantitative ELISA. RESULTS: The results showed that blue light and low-dose UVB treatment of HaCaT and hTERT cells resulted in inhibition of cytokine-induced production of IL-1alpha. The level of IL-1alpha decreased by 82% in HaCaT and by 75% in hTERT cells when exposed to blue light. It decreased by 95% in HaCaT and by 91% in hTERT cells when blue light was used in combination with UVB. ICAM-1 expression was similarly reduced in HaCaT, but not in hTERT cells. CONCLUSIONS: This study showed that narrow-band blue light has anti-inflammatory effects on keratinocytes by decreasing the cytokine-induced production of IL-1alpha and ICAM-1. In addition, blue light demonstrated synergistic effects with low-dose UVB light. These results expand the properties of narrow-band blue light in modulating the inflammatory process and will facilitate testing of its phototherapeutic applications in different inflammatory skin conditions.