Synthesis, Anticancer Activity, and Docking Studies of Novel Hydroquinone-Chalcone-Pyrazoline Hybrid Derivatives.

A novel series of antitumor hybrids was synthesized using 1,4-benzohydroquinone and chalcone, furane, or pyrazoline scaffolds. This were achieved through isosteric substitution of the aryl group of the chalcone ß-carbon with the furanyl moiety and structural modification of the α,ß-unsaturated carbonyl system. The potential antitumor activity of these hybrids was evaluated in vivo on MCF-7 breast adenocarcinoma and HT-29 colorectal carcinoma cells, demonstrating cytotoxic activity with IC50 values ranging from 28.8 to 124.6 µM. The incorporation of furan and pyrazoline groups significantly enhanced antiproliferative properties compared to their analogues and precursors (VII-X), which were inactive against both neoplastic cell lines. Compounds 4, 5, and 6 exhibited enhanced cytotoxicity against both cell lines, whereas compound 8 showed higher cytotoxic activity against HT-29 cells. Molecular docking studies revealed superior free-energy values (ΔGbin) for carcinogenic pathway-involved kinase proteins, with our in silico data suggesting that these derivatives could be promising chemotherapeutic agents targeting kinase pathways. Among all the synthesized PIBHQ compounds, derivatives 7 and 8 exhibited the best drug-likeness properties, with values of 0.53 and 0.83, respectively. ADME results collectively suggest that most of these compounds hold promise as potential candidates for preclinical assays.

Effect of Modified Forms of Sodium Humate PowHumus on the Balance of Arginine in Peritoneal Macrophages of Intact Mice.

Substances of silver nanoparticles dialyzed through a 13 kDa membrane, synthesized in a medium of humic ligands modified with hydroquinone and 2-hydroxynaphthoquinone from PowHumus brown coal, specifically enhance the M2 properties of peritoneal macrophages due to inhibition of NO synthase and significant activation of arginase, thus enhancing anti-inflammatory properties of cells. In small, but effective concentrations, they do not have cytotoxic properties and do not contain pyrogenic impurities. The studied humates are able to influence the mechanisms of immune response formation and are an effective means for correcting inflammation and regeneration.

Hyperpigmented Macules and Patches on the Face: Exogenous Ochronosis or Lichen Planus Pigmentosus?

We present a case of a patient with a 10-year history of blue-black macules and patches on the face and an associated history of skin-lightening cream usage. The skin lightening cream contained hydroquinone, which is often associated with exogenous ochronosis (EO). Interestingly, the biopsy did not show characteristic findings of ochronosis, confusing the final diagnosis, however discontinuing the skin-lightening creams halted the progression of the patient's skin lesions supporting a diagnosis of EO. EO presents as asymptomatic hyperpigmentation after using products containing hydroquinone. This condition is most common in Black populations, likely due to the increased use of skin care products and bleaching cream containing hydroquinone in these populations. Topical hydroquinone is FDA-approved to treat melasma, chloasma, freckles, senile lentigines, and hyperpigmentation and is available by prescription only in the US and Canada. However, with the increased use of skin-lightening creams in certain populations, it is important for dermatologists to accurately recognize the clinical features of exogenous ochronosis to differentiate it from similar dermatoses. An earlier diagnosis can prevent the progression to severe presentations with papules and nodules. We summarize the clinical presentations diagnostic features, and treatment pearls, concluding with a discussion of the differential diagnoses.  J Drugs Dermatol. 2024;23(7):567-568.     doi:10.36849/JDD.8248.

Oxidative Coupling of Hydroquinone Derivatives with Olefins to Dihydrobenzofurans.

Dihydrobenzofuran is an important skeleton for bioactive compounds and natural products. Hydroquinones can be easily modified into substituted hydroquinones, which effectively undergo oxidation to produce the corresponding benzoquinone derivatives. Benzoquinones are reactive electrophiles that are frequently utilized in coupling with olefins to dihydrobenzofurans. Herein, we report the one-pot oxidative coupling of hydroquinones bearing an electron-withdrawing group at the C2 position with olefins to dihydrobenzofurans in the presence of the Lewis acidic FeCl3 and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) oxidant. Furthermore, this method was applied to the oxidative coupling of N-electron-withdrawing group-substituted 4-aminophenol.

[Molecular modification of cyclodextrin glucosyltransferase and its application in the synthesis of α-arbutin].

α-arbutin has important applications in cosmetics and medicine. However, the extraction yield from plant tissues is relatively low, which restricts its application value. In this study, we investigated the synthesis of α-arbutin using maltodextrin as the donor and hydroquinone as the acceptor, using a cyclodextrin glucosyltransferase (CGTase) from Anaerobranca gottschalkii. We performed site-saturated and site-directed mutagenesis on AgCGTase. The activity of the variant AgCGTase-F235G-N166H was 3.48 times higher than that of the wild type. Moreover, we achieved a conversion rate of 63% by optimizing the reaction pH, temperature, and hydroquinone addition amount. Overall, this study successfully constructed a strain with improved conversion rate for the synthetic production of α-arbutin and hydroquinone. These findings have significant implications for reducing the industrial production cost of α-arbutin and enhancing the conversion rate of the product.

Role of the PARP1/NF-κB Pathway in DNA Damage and Apoptosis of TK6 Cells Induced by Hydroquinone.

Hydroquinone(HQ) is a widely used industrial raw material and is a topical lightening product found in over-the-counter products. However, inappropriate exposure to HQ can pose certain health hazards. This study aims to explore the mechanisms of DNA damage and cell apoptosis caused by HQ, with a focus on whether HQ activates the nuclear factor-κB (NF-κB) pathway to participate in this process and to investigate the correlation between the NF-κB pathway activation and poly(ADP-ribose) polymerase 1(PARP1). Through various experimental techniques, such as DNA damage detection, cell apoptosis assessment, cell survival rate analysis, immunofluorescence, and nuclear-cytoplasmic separation, the cytotoxic effects of HQ were verified, and the activation of the NF-κB pathway was observed. Simultaneously, the relationship between the NF-κB pathway and PARP1 was verified by shRNA interference experiments. The results showed that HQ could significantly activate the NF-κB pathway, leading to a decreased cell survival rate, increased DNA damage, and cell apoptosis. Inhibiting the NF-κB pathway could significantly reduce HQ-induced DNA damage and cell apoptosis and restore cell proliferation and survival rate. shRNA interference experiments further indicated that the activation of the NF-κB pathway was regulated by PARP1. This study confirmed the important role of the NF-κB pathway in HQ-induced DNA damage and cell apoptosis and revealed that the activation of the NF-κB pathway was mediated by PARP1. This research provides important clues for a deeper understanding of the toxic mechanism of HQ.

The effectiveness and safety of 3% tranexamic acid cream vs. 4% hydroquinone cream for mixed-type melasma in skin of color: a double-blind, split-face, randomized controlled trial.

INTRODUCTION: Melasma, a chronic acquired skin pigmentation disorder, is characterized by the presence of irregular-edged brown to gray-brown patches with a symmetrical distribution, primarily on sun-exposed areas such as the face. Topical hydroquinone (HQ) is the gold standard for melasma treatment but has numerous side effects. This study assesses the effectiveness of topical tranexamic acid (TA) as an alternative for melasma treatment. METHODS: In a double-blind, split-face, randomized controlled trial involving 20 subjects, the effectiveness of 3% TA versus 4% HQ cream was evaluated over 8 weeks. The modified melasma area and severity index (mMASI), melanin index, erythema index, and side effects were assessed. Subjective improvement was measured using the patient global assessment (PtGA). RESULTS: A significant decline in the mMASI score was observed at weeks 4 and 8 in both groups compared to baseline. There were no statistically significant differences in PtGA scores between the 3% TA group and the 4% HQ group. CONCLUSIONS: Topical 3% TA is as effective and safe as 4% HQ for treating melasma in the Indonesian population, with potential advantages in terms of side-effect profiles.

Nrf2 pathway activation promotes the expression of genes related to glutathione metabolism in alcohol-exposed astrocytes.

Introduction: Oxidative and antioxidant pathways play essential roles in the development of alcohol-induced brain injury. The Nrf2 pathway is an endogenous antioxidant response pathway, but there has been little research on the role of Nrf2 in alcohol-related diseases. Thus, we examined the effects of alcohol and an Nrf2 agonist (TBHQ) on astrocyte function, mRNA expression, and metabolite content to further explore the protective mechanisms of Nrf2 agonists in astrocytes following alcohol exposure. Methods: CTX TNA2 astrocytes were cultured with alcohol and TBHQ and then subjected to transcriptome sequencing, LC-MS/MS analysis, quantitative reverse transcription polymerase chain reaction (qRT-PCR), and malondialdehyde (MDA) and superoxide dismutase (SOD) activity assays. Results: Alcohol exposure significantly increased malondialdehyde (MDA) levels while decreasing superoxide dismutase (SOD) levels in astrocytes. Treatment with TBHQ effectively reversed these effects, demonstrating its protective role against oxidative stress induced by alcohol. Transcriptome sequencing and qRT-PCR analysis revealed that TBHQ specifically upregulates genes involved in glutathione metabolism, including a notable increase in the expression of the glutathione S-transferase A5 (GSTA5) gene, which was suppressed by alcohol exposure. Additionally, metabolomic analysis showed that TBHQ regulates key components of ether lipid metabolism in alcohol-exposed astrocytes, with significant reductions in the levels of lysophosphatidylcholine (18:0) (LysoPC (18:0)) and 2-acetyl-1-alkyl-sn-glycero-3-phosphocholine, both of which are critical markers in the ether lipid metabolic pathway. Discussion: The findings underscore the role of TBHQ as an Nrf2 agonist in mitigating alcohol-induced oxidative damage in astrocytes by modulating glutathione metabolism and ether lipid metabolism. The regulation of GSTA5 gene expression emerges as a key mechanism through which Nrf2 agonists confer neuroprotection against oxidative stress and lipid oxidation. These insights pave the way for potential therapeutic strategies targeting the Nrf2 pathway to protect astrocytes from alcohol-induced damage.

An update on the safety of hydroquinone.

Hydroquinone has been used for years for multiple conditions, including melasma, post-inflammatory hyperpigmentation, dyschromia from photoaging, and solar lentigines. It is known to be a very effective lightening agent, but several concerns have been raised about this widely used agent. The recent U.S. ban on over-the-counter skin lightening products containing hydroquinone has prompted further questioning of the safety of this widely used agent. While there have been prior informative, large-scale reviews on the safety of hydroquinone, new findings have since been reported. Here, we provide an updated review of studies published in the past 15 years on hydroquinone safety.

[Nuclear factor E2-related factor 2 attenuates endotoxin-induced acute lung injury by up-regulating cellular tight junction protein Claudin-18 expression].

OBJECTIVE: To investigate the effect of nuclear factor E2-related factor 2 (Nrf2) on the cellular tight junction protein Claudin-18 in endotoxin-induced acute lung injury (ALI). METHODS: Eighteen healthy male C57BL/6 mice were divided into control group, endotoxin-induced ALI model group (ALI group) and Nrf2 activator tert-butylhydroquinone (tBHQ) pretreatment group (tBHQ+ALI group) according to random number table method, with 6 mice in each group. Mice endotoxin-induced ALI model was reproduced by intraperitoneal injection of lipopolysaccharide (LPS, 15 mg/kg), and the mice in the control group was injected with an equal amount of phosphate buffer solution (PBS). The mice in the tBHQ+ALI group received three intraperitoneal injections of tBHQ (a total of 50 mg/kg) at an interval of 1 hour before molding. The last injection of tBHQ was accompanied by LPS of 15 mg/kg. The mice in the control group and model group were given equal amounts of PBS, and PBS or LPS was given at the last injection. The mice were sacrificed at 12 hours after LPS injection to take lung tissues. After the lung tissue was stained with hematoxylin-eosin (HE) staining, the pathological changes were observed under light microscopy, and the lung injury score was calculated. The lung wet/dry ratio (W/D) was determined. Nrf2 protein expression in the lung tissue was detected by Western blotting. Positive expression of Claudin-18 in the lung tissue was determined by immunohistochemistry. RESULTS: The lung tissue showed normal structure, without significant pathological change in the control group. Compared with the control group, the alveolar septum widened accompanied by inflammatory cell infiltration, capillary hyperemia and tissue edema in the ALI group, the lung injury score and lung W/D ratio were significantly increased (lung injury score: 6.50±1.05 vs. 1.83±0.75, lung W/D ratio: 3.79±0.22 vs. 3.20±0.14, both P < 0.01), and the Nrf2 protein expression and Claudin-18 positive expression in the lung tissue were significantly lowered [Nrf2 protein (Nrf2/ß-actin): 0.41±0.33 vs. 1.22±0.33, Claudin-18 (A value): 0.28±0.07 vs. 0.44±0.10, both P < 0.05]. After tBHQ pretreatment, the degree of lung histopathological injury was significantly reduced compared with the ALI group, the alveolar space slightly abnormal, inflammatory cell infiltration and tissue edema reduced, the lung injury score and lung W/D ratio were significantly decreased (lung injury score: 3.00±0.89 vs. 6.50±1.05, lung W/D ratio: 3.28±0.19 vs. 3.79±0.22, both P < 0.01), and Nrf2 protein expression and Claudin-18 positive expression in the lung tissue were significantly increased [Nrf2 protein (Nrf2/ß-actin): 1.26±0.09 vs. 0.41±0.33, Claudin-18 (A valure): 0.45±0.04 vs. 0.28±0.07, both P < 0.05]. CONCLUSIONS: Nrf2 alleviated pulmonary edema and improved endotoxin-induced ALI by up-regulating Claudin-18 expression.

An electrochemical sensor based on electrochemically activated carbon cloth and poly (o-aminothiophenol) cross-linked nanogold imprinted layer for the determination of tert-butylhydroquinone.

In this study, an electrochemical sensor based on MoS2 with enhanced electrochemical signals from electrochemically activated carbon cloth (EACC) electrodes and cross-linked o-aminothiophenol functionalized AuNPs (o-ATP@AuNPs) was developed for the detection of the unsaturated vegetable oil antioxidant tert-butylhydroquinone (TBHQ). In this approach, carbon cloth is activated through the implementation of electrochemical methods, thereby effectively increasing its specific surface area. The resulting EACC, serving as an electrode substrate, enables the growth of additional nanomaterials and enhances conductivity. The incorporation of MoS2 effectively augments the sensitivity of the electrochemical sensor. Subsequently, MIP/MoS2/EMCC is formed via electropolymerization, utilizing TBHQ as the template molecule and o-ATP@AuNPs as the functional monomer. The SS bond of o-ATP ensures a strong and stable connection between MoS2 and o-ATP@AuNPs, thereby facilitating the immobilization of MIP. In addition, the high conductivity possessed by o-ATP@AuNPs could effectively improve the sensitivity of the electrochemical sensor. Under the optimal conditions, MIP/MoS2/EMCC could determine TBHQ in the range of 1 × 10-3 µM to 120 µM by differential pulse voltammetry (DPV) with a detection line of 0.72 nM. The proposed MIP/MoS2/EMCC is expected to be applied in the future for the selective and sensitive detection of TBHQ in vegetable oils.

The antibacterial and antialgal enhancement of the hydroquinone acrylamide polyurethane coating based on microphase separation.

The undesirable and inevitable adhesion of marine organisms on submerged surfaces has seriously affect the environment, economy and society, so emerging and promising strategies for antifouling are required. Here, the novel and environmental strategy of the antibacterial and antialgal materials was proposed for the application of the antifouling coating without releasing harmful substances. The environment-friendly antifouling agent, the capsaicin derivative N-(2,5-dihydroxy-4-acrylamide meth-ylbenzyl)acrylamide (PHABA), was modified to the molecular chain of the polyurethane. The best tensile strength was up to 23.5 MPa of PUP-25% and the elongation at break was 415% of PUP-25%. The excellent wear resistance (300 wear cycles) and chemical solution resistance (H2SO4, NaOH, and NaCl solutions) revealed the applicability of the coating. PHABA would migrate to the surface of the polyurethane coating with time and enhanced the antibacterial and antialgal properties of the coating. PUP-25% prevented more than 90% of bacterial and algal adhesion, indicating the potential application of the antifouling coating.

Quantification of Arbutin and its degradation products, hydroquinone and p-Benzoquinone, in hyperpigmentation topical formulation: Effect of extraction procedure and interference assessment.

The utilization of Hydroquinone (HQ) in over-the-counter skincare items is subject to restrictions. Consequently, Arbutin (AR) serves as a reliable alternative for addressing hyperpigmentation in non-prescription topical formulations. Nevertheless, AR undergoes decomposition into HQ and p-Benzoquinone (BZ) when exposed to temperature stress, ultraviolet light, or dilution in an acidic environment, all of which can induce skin toxicity. The intention of this paper is to investigate the effect of extraction procedure on the conversion of AR to HQ and or BZ and to evaluate kinetics of AR hydrolysis to HQ. Meanwhile this study aims to evaluate AR and BZ interference with the United States Pharmacopoeia (USP) identification and assessment method for HQ Hydrolytic stress during extraction conditions underwent optimization through systematic screening tests. Subsequent assessment of the residual drug and its degradation products were achieved by HPLC method. The resulting data were meticulously fitted to various kinetic models. To analyze the potential interference of AR in HQ measurement using USP method, the standard concentrations of AR and HQ were analyzed through UV-VIS spectrophotometry. For enhanced certainty, a validated HPLC method analysis was also conducted. Notably, the acid hydrolysis of AR exhibited independence from its initial concentration. So, the hydrolytic degradation of AR exhibited a Zero-order kinetic profile. Furthermore, the proven interference of AR in the UV-VIS spectrophotometry method was identified within the context of the USP method. This study successfully utilized an adopted HPLC method for the concurrent quantification of AR, HQ, and BZ. The potential interference of AR in the UV-VIS spectrophotometric assay for HQ may lead to false results especially for regulatory purposes.

The role of chitosan in mitigating tert-butylhydroquinone induced cognitive impairment and neurotoxicity in a rat model.

OBJECTIVE: This study aimed to investigate the impact of tert-butylhydroquinone (TBHQ), chitosan, and their combination on memory and neurobiochemical parameters in a rat model. The primary objectives were to assess the cognitive effects of TBHQ, explore the cognitive-enhancing properties of chitosan, and evaluate the combined effects of these substances. MATERIALS AND METHODS: A rat model was employed for behavioral tests, biochemical analyses, and histological examinations. Rats were exposed to TBHQ, chitosan, or a combination of both, and cognitive function was assessed through behavioral tests. Biochemical analyses focused on neurobiochemical parameters associated with memory and oxidative stress. Histological examinations were conducted to observe any structural changes in the brain. RESULTS: TBHQ exposure was associated with memory impairments and increased oxidative stress, indicating potential neurotoxic effects. Chitosan supplementation demonstrated cognitive-enhancing effects and showed promise in mitigating the memory impairments and oxidative stress induced by TBHQ. The combination of chitosan and TBHQ presented a potential protective effect on neurological health. CONCLUSIONS: Chitosan supplementation alongside TBHQ may mitigate memory impairments and oxidative stress associated with TBHQ exposure in a rat model. The study provides valuable insights into the cognitive effects of TBHQ and the neuroprotective potential of chitosan, highlighting the need for further research to elucidate molecular pathways and clinical implications. These findings contribute to understanding chitosan's role in safeguarding neurological health in conditions where TBHQ exposure is a concern, warranting further investigations for translational applications in human health.

Comparative study of melasma in patients before and after treatment based on lipomics.

BACKGROUND: Skin barrier alterations play a crucial function in melasma development. Past researches have demonstrated variations in lipid content between the epidermis of melasma lesions and normal tissues, along with the varied expression of lipid-related genes in melasma. This study aimed to analyze the lipidome profiles of skin surface lipids (SSL) in patients with melasma before and after treatment to understand associated abnormalities. METHODS: Melasma was treated with tranexamic acid orally and hydroquinone cream topically. Disease was assessed using the Melasma Area and Severity Index (MASI), and the impact to life was evaluated with Melasma Quality of Life (MELASQoL) score. Epidermal melanin particles were observed using reflection confocal microscopy (RCM), whereas epidermal pigment and blood vessel morphology were observed using dermoscopy, and SSL samples were collected. Specific information regarding alterations in lipid composition was obtained through multivariate analysis of the liquid chromatography-mass spectrometry data. RESULTS: After treatment, patients with melasma exhibited decreased MASI and MELASQoL scores (P < 0.001); RCM revealed reduced melanin content in the lesions, and dermoscopy revealed fewer blood vessels. Fifteen lipid subclasses and 382 lipid molecules were identified using lipidomic assays. The expression levels of total lipids, phosphatidylcholine, and phosphatidylethanolamine in the melasma lesions decreased after treatment (P < 0.05). CONCLUSION: This study revealed alterations in the SSL composition after effective melasma treatment, suggesting a compensatory role for lipids in melasma barrier function. The mechanism involving SSL and the lipid barrier, which influences melasma's occurrence, needs further elucidation.

High-Resolution and Dynamic Visualization of Intracellular Redox Potential Using a Metal-Organic Framework-Functionalized Nanopotentiometer.

Redox potential plays a key role in regulating intracellular signaling pathways, with its quantitative analysis in individual cells benefiting our understanding of the underlying mechanism in the pathophysiological events. Here, a metal organic framework (MOF)-functionalized SERS nanopotentiometer has been developed for the dynamic monitoring of intracellular redox potential. The approach is based on the encapsulation of zirconium-based MOF (Uio-66-F4) on a surface of gold-silver nanorods (Au-Ag NRs) that is modified with the newly synthesized redox-sensitive probe ortho-mercaptohydroquinone (HQ). Thanks to size exclusion of MOF as the chemical protector, the nanopotentiometer can be adapted to long-term use and possess high anti-interference ability toward nonredox species. Combining the superior fingerprint identification of SERS with the electrochemical activity of the quinone/hydroquinone, the nanopotentiometer shows a reversible redox responsivity and can quantify redox potential with a relatively wide range of -250-100 mV. Furthermore, the nanopotentiometer allows for dynamic visualization of intracellular redox potential changes induced by drugs' stimulation in a high-resolution manner. The developed approach would be promising for offering new insights into the correlation between redox potential and tumor proliferation-involved processes such as oxidative stress and hypoxia.

Synergistic rosemary extract with TBHQ and citric acid improves oxidative stability and shelf life of peanut.

Lipid oxidation often accompanies the processing and storage of peanuts, which causes a serious waste of peanut resources. To solve the problem of being prone to oxidation in peanut processing, a ternary complex antioxidant based on rosemary extract (RE) was constructed to investigate its effect on the oxidative and thermal stability of peanuts, and the inhibition of peanut oxidation by compound antioxidants was revealed by dynamic Arrhenius formula and complexation theory. The results showed that there was a synergistic effect between RE and Tert-butyl hydroquinone (TBHQ), and the antioxidant effects of RE and TBHQ were 4.86 and 1.45 times higher when used in combination than when used alone, respectively. In addition, RE-TBHQ-CA (citric acid) effectively inhibited primary and secondary oxidation of peanuts with a shelf life 8.7 times longer than that of control peanuts. This study provides a novel antioxidant compounding idea, which has a positive effect on improving the quality of peanut and other nut products, prolonging the shelf life and reducing the waste of resources. PRACTICAL APPLICATION: Compounding a complex antioxidant that permits its use in peanuts. It was found that rosemary and TBHQ might have synergistic antioxidant effects. Meanwhile, this combination of RE-TBHQ-CA effectively inhibited the oxidation of peanut oils and prolonged the shelf life of peanuts. RE-TBHQ-CA is a highly efficient complex antioxidant that can reduce the amounts of antioxidants added while maintaining high antioxidant efficiency, which may be useful for the future preservation and storage of nut products as it positively affects the quality and shelf life of the product.

From Ground-State to Excited-State Activation Modes: Flavin-Dependent "Ene"-Reductases Catalyzed Non-natural Radical Reactions.

Enzymes are desired catalysts for chemical synthesis, because they can be engineered to provide unparalleled levels of efficiency and selectivity. Yet, despite the astonishing array of reactions catalyzed by natural enzymes, many reactivity patterns found in small molecule catalysts have no counterpart in the living world. With a detailed understanding of the mechanisms utilized by small molecule catalysts, we can identify existing enzymes with the potential to catalyze reactions that are currently unknown in nature. Over the past eight years, our group has demonstrated that flavin-dependent "ene"-reductases (EREDs) can catalyze various radical-mediated reactions with unparalleled levels of selectivity, solving long-standing challenges in asymmetric synthesis.This Account presents our development of EREDs as general catalysts for asymmetric radical reactions. While we have developed multiple mechanisms for generating radicals within protein active sites, this account will focus on examples where flavin mononucleotide hydroquinone (FMNhq) serves as an electron transfer radical initiator. While our initial mechanistic hypotheses were rooted in electron-transfer-based radical initiation mechanisms commonly used by synthetic organic chemists, we ultimately uncovered emergent mechanisms of radical initiation that are unique to the protein active site. We will begin by covering intramolecular reactions and discussing how the protein activates the substrate for reduction by altering the redox-potential of alkyl halides and templating the charge transfer complex between the substrate and flavin-cofactor. Protein engineering has been used to modify the fundamental photophysics of these reactions, highlighting the opportunity to tune these systems further by using directed evolution. This section highlights the range of coupling partners and radical termination mechanisms available to intramolecular reactions.The next section will focus on intermolecular reactions and the role of enzyme-templated ternary charge transfer complexes among the cofactor, alkyl halide, and coupling partner in gating electron transfer to ensure that it only occurs when both substrates are bound within the protein active site. We will highlight the synthetic applications available to this activation mode, including olefin hydroalkylation, carbohydroxylation, arene functionalization, and nitronate alkylation. This section also discusses how the protein can favor mechanistic steps that are elusive in solution for the asymmetric reductive coupling of alkyl halides and nitroalkanes. We are aware of several recent EREDs-catalyzed photoenzymatic transformations from other groups. We will discuss results from these papers in the context of understanding the nuances of radical initiation with various substrates.These biocatalytic asymmetric radical reactions often complement the state-of-the-art small-molecule-catalyzed reactions, making EREDs a valuable addition to a chemist's synthetic toolbox. Moreover, the underlying principles studied with these systems are potentially operative with other cofactor-dependent proteins, opening the door to different types of enzyme-catalyzed radical reactions. We anticipate that this Account will serve as a guide and inspire broad interest in repurposing existing enzymes to access new transformations.

A novel professional-use synergistic peel technology to reduce visible hyperpigmentation on face: Clinical evidence and mechanistic understanding by computational biology and optical biopsy.

Topicals and chemical peels are the standard of care for management of facial hyperpigmentation. However, traditional therapies have come under recent scrutiny, such as topical hydroquinone (HQ) has some regulatory restrictions, and high concentration trichloroacetic acid (TCA) peel pose a risk in patients with skin of colour. The objective of our research was to identify, investigate and elucidate the mechanism of action of a novel TCA- and HQ-free professional-use chemical peel to manage common types of facial hyperpigmentation. Using computational modelling and in vitro assays on tyrosinase, we identified proprietary multi-acid synergistic technology (MAST). After a single application on human skin explants, MAST peel was found to be more effective than a commercial HQ peel in inhibiting melanin (histochemical imaging and gene expression). All participants completed the case study (N = 9) without any adverse events. After administration of the MAST peel by a dermatologist, the scoring and VISIA photography reported improvements in hyperpigmentation, texture and erythema, which could be linked to underlying pathophysiological changes in skin after peeling, visualized by non-invasive optical biopsy of face. Using reflectance confocal microscopy (VivaScope®) and multiphoton tomography (MPTflex™), we observed reduction in melanin, increase in metabolic activity of keratinocytes, and no signs of inflammatory cells after peeling. Subsequent swabbing of the cheek skin found no microbiota dysbiosis resulting from the chemical peel. The strong efficacy with minimum downtime and no adverse events could be linked to the synergistic action of the ingredients in the novel HQ- and TCA-free professional peel technology.

Linc01588 deletion inhibits the malignant biological characteristics of hydroquinone-induced leukemic cells via miR-9-5p/SIRT1.

Leukemia caused by environmental chemical pollutants has attracted great attention, the malignant leukemic transformation model of TK6 cells induced by hydroquinone (HQ) has been previously found in our team. However, the type of leukemia corresponding to this malignant transformed cell line model needs further study and interpretation. Furthermore, the molecular mechanism of malignant proliferation of leukemic cells induced by HQ remains unclear. This study is the first to reveal the expression of aberrant genes in leukemic cells of HQ-induced malignant transformation, which may correspond to chronic lymphocytic leukemia (CLL). The expression of Linc01588, a long non-coding RNA (lncRNA), was significantly up-regulated in CLL patients and leukemic cell line model which previously described. After gain-of-function assays and loss-of-function assays, feeble cell viability, severe apoptotic phenotype and the increased secretion of TNF-α were easily observed in malignant leukemic TK6 cells with Linc01588 deletion after HQ intervention. The tumors derived from malignant TK6 cells with Linc01588 deletion inoculated subcutaneously in nude mice were smaller than controls. In CLL and its cell line model, the expression of Linc01588 and miR-9-5p, miR-9-5p and SIRT1 were negative correlation respectively in CLL and cell line model, while the expression of Linc01588 and SIRT1 were positive correlation. The dual-luciferase reporter assay showed that Linc01588 & miR-9-5p, miR-9-5p & SIRT1 could bind directly, respectively. Furthermore, knockdown of miR-9-5p successfully rescued the severe apoptotic phenotype and the increased secretion of TNF-α caused by the Linc01588 deletion, the deletion of Linc01588 in human CLL cell line MEC-2 could also inhibit malignant biological characteristics, and the phenotype caused by the deletion of Linc01588 could also be rescued after overexpression of SIRT1. Moreover, the regulation of SIRT1 expression in HQ19 cells by Linc01588 and miR-9-5 P may be related to the Akt/NF-κB pathway. In brief, Linc01588 deletion inhibits the malignant biological characteristics of HQ-induced leukemic cells via miR-9-5p/SIRT1, and it is a novel and hopeful clue for the clinical targeted therapy of CLL.