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Background: Ovarian cancer (OC) is the most lethal malignant gynecological tumor type for which limited therapeutic targets and drugs are available. Enhanced mitochondrial oxidative phosphorylation (OXPHOS), which enables cell growth, migration, and cancer stem cell maintenance, is a critical driver of disease progression and a potential intervention target of OC. However, the current OXPHOS intervention strategy mainly suppresses the activity of the electron transport chain directly and cannot effectively distinguish normal tissues from cancer tissues, resulting in serious side effects and limited efficacy. Methods: We screened natural product libraries to investigate potential anti-OC drugs that target OXPHOS. Additionally, LC-MS, qRT-PCR, western-blot, clonogenic assay, Immunohistochemistry, wound scratch assay, and xenograft model was applied to evaluate the anti-tumor mechanism of small molecules obtained by screening in OC. Results: Gossypol acetic acid (GAA), a widely used gynecological medicine, was screened out from the drug library with the function of suppressing OXPHOS and OC progression by targeting the leucine-rich pentatricopeptide repeat containing (LRPPRC) protein. Mechanically, LRPPRC promotes the synthesis of OXPHOS subunits by binding to RNAs encoded by mitochondrial DNA. GAA binds to LRPPRC directly and induces LRPPRC rapid degradation in a ubiquitin-independent manner. LRPPRC was overexpressed in OC, which is highly correlated with the poor outcomes of OC and could promote the malignant phenotype of OC cells in vitro and in vivo. GAA management inhibits cell growth, clonal formation, and cancer stem cell maintenance in vitro, and suppresses subcutaneous graft tumor growth in vivo. Conclusions: Our study identified a therapeutic target and provided a corresponding inhibitor for OXPHOS-based OC therapy. GAA inhibits OC progression by suppressing OXPHOS complex synthesis via targeting LRPPRC protein, supporting its potential utility as a natural therapeutic agent for ovarian cancer. [ABSTRACT FROM AUTHOR]

• Lipid profiling for malignant mesothelioma plasma samples. • Thirty-four differential lipids were detected as potential biomarkers for MM. • PCs, PEs and ceramides exhibited outstanding diagnostic performance. • Plasma TG and Hex1Cer levels served as predictors for MM prognosis. Malignant mesothelioma (MM), being a rare and aggressive carcinoma, can barely be cured. Incidence of this cancer will keep climbing up in the next few decades since its major carcinogen, asbestos, is still in use in many countries. Unfortunately, prognosis of MM is unsatisfactory principally due to poor early diagnosis as a result of its long latency period and ambiguous symptoms. Lipids are known to contribute to cellular structure, signaling, and energy storage, and are widely reported to be related with tumorigenesis. Therefore, we aim to discover novel lipid biomarkers by plasma-based lipidomics that may improve MM diagnosis. Plasma samples from 25 MM patients and 32 healthy controls (HCs) were collected and analysed using a high-throughput liquid chromatography-mass spectrometry (LC-MS). Univariate and multivariate analyses were subsequently performed to visualize the separation trend between two groups and to screen for differential feature ions. Ions were annotated using LipidSearch 4.2 and their enriched pathways were detected on LIPEA. Receiver operating characteristic (ROC) curves were used for analysing each annotated lipid's diagnostic value. Survival analyses were performed to investigate each lipid's prognostic value. In supervised partial least squares discriminant analysis (PLS-DA), clear separation between MM and HC groups was observed. A total of 34 differential lipids were annotated, among which 5 upregulated and 29 downregulated. Levels of plasma triacylglycerols (TGs) were higher in smoking versus non-smoking patients, and lower in female versus male patients. The top six lipids possessing highest diagnostic value included two phosphatidylethanolamines (PEs), two phosphatidylcholines (PCs) and two ceramides. Moreover, elevated circulating TG levels were associated with poorer survival, whereas increased monohexosylceramide (Hex1Cer) might be beneficial. Our study revealed differentially expressed lipid patterns in MM compared to HC. PC, PE, and ceramides showed outstanding diagnostic performance, while TG and Hex1Cer exhibited significant prognostic values. Nevertheless, more studies should verify these trends as well as further investigating on underlying mechanisms. [ABSTRACT FROM AUTHOR]

Background: Malignant pleural mesothelioma (MPM) is a rare and aggressive carcinoma located in pleural cavity. Due to lack of effective diagnostic biomarkers and therapeutic targets in MPM, the prognosis is extremely poor. Because of difficulties in sample extraction, and the high rate of misdiagnosis, MPM is rarely studied. Therefore, novel modeling methodology is crucially needed to facilitate MPM research.Methods: A novel patient-derived xenograft (PDX) modeling strategy was designed, which included preliminary screening of patients with pleural thickening using computerized tomography (CT) scan, further reviewing history of disease and imaging by a senior sonographer as well as histopathological analysis by a senior pathologist, and PDX model construction using ultrasound-guided pleural biopsy from MPM patients. Gas chromatography-mass spectrometry-based metabolomics was further utilized for investigating circulating metabolic features of the PDX models. Univariate and multivariate analysis, and pathway analysis were performed to explore the differential metabolites, enriched metabolism pathways and potential metabolic targets.Results: After screening using our strategy, 5 out of 116 patients were confirmed to be MPM, and their specimens were used for modeling. Two PDX models were established successfully. Metabolomics analysis revealed significant metabolic shifts in PDX models, such as dysregulations in amino acid metabolism, TCA cycle and glycolysis, and nucleotide metabolism.Conclusions: To sum up, we suggested a novel modeling strategy that may facilitate specimen availability for MM research, and by applying metabolomics in this model, several metabolic features were identified, whereas future studies with large sample size are needed. [ABSTRACT FROM AUTHOR]

Summary: Endophytes may participate in the conversion of metabolites within medicinal plants, influencing the efficacy of host. However, the distribution of endophytes within medicinal plants P. notoginseng and how it contributes to the conversion of saponins are not well understood. Here, we determined the distribution of saponins and endophytes within P. notoginseng compartments and further confirm the saponin conversion by endophytes. We found metabolites showed compartment specificity within P. notoginseng. Potential saponin biomarkers, such as Rb1, Rg1, Re, Rc and Rd, were obtained. Endophytic diversity, composition and co‐occurrence networks also showed compartment specificity, and bacterial alpha diversity values were highest in root compartment, consistently decreased in the stem and leaf compartments, whereas those of fungi showed the opposite trend. Potential bacterial biomarkers, such as Rhizobium, Bacillus, Pseudomonas, Enterobacter, Klebsiella, Pantoea and fungal biomarkers Phoma, Epicoccum, Xylariales, were also obtained. Endophytes related to saponin contents were found by Spearman correlation analysis, and further verification experiments showed that Enterobacter chengduensis could convert ginsenoside Rg1 to F1 at a rate of 13.24%; Trichoderma koningii could convert ginsenoside Rb1 to Rd at a rate of 40.00% and to Rg3 at a rate of 32.31%; Penicillium chermesinum could convert ginsenoside Rb1 to Rd at a rate of 74.24%. [ABSTRACT FROM AUTHOR]

Lung cancer patients with malignant pleural effusions (MPE) have a particular poor prognosis. It is crucial to distinguish MPE from benign pleural effusion (BPE). The present study aims to develop a rapid, convenient and economical diagnostic method based on FTIR near-infrared spectroscopy (NIRS) combined with machine learning strategy for clinical pleural effusion classification. NIRS spectra were recorded for 47 MPE samples and 35 BPE samples. The sample data were randomly divided into train set (n = 62) and test set (n = 20). Partial least squares, random forest, support vector machine (SVM), and gradient boosting machine models were trained, and subsequent predictive performance were predicted on the test set. Besides the whole spectra used in modeling, selected features using SVM recursive feature elimination algorithm were also investigated in modeling. Among those models, NIRS combined with SVM showed the best predictive performance (accuracy: 1.0, kappa: 1.0, and AUCROC: 1.0). SVM with the top 50 feature wavenumbers also displayed a high predictive performance (accuracy: 0.95, kappa: 0.89, AUCROC: 0.99). Our study revealed that the combination of NIRS and machine learning is an innovative, rapid, and convenient method for clinical pleural effusion classification, and worth further evaluation. [ABSTRACT FROM AUTHOR]

Background: Panax notoginseng is a highly valuable medicinal plant. Reduced P. notoginseng yield is a common and serious problem that arises in a continuous cropping system. Variation in the composition and function of soil microbial community is considered the primary cause of yield reduction. Methods: This study used shotgun metagenomic sequencing approaches to describe the taxonomic and functional features of P. notoginseng rhizosphere microbiome and screen microbial taxa and functional traits related to yields. Results: At the family and genus level, a total of 43 families and 45 genera (relative abundance > 0.1%) were obtained, and the correlation with the yield of P. notoginseng was further analyzed. Nitrosomonadaceae, Xanthomonadaceae, Mycobacterium and Arthrobacter that were enriched in soils with higher yields were positively correlated with P. notoginseng yields, thereby suggesting that they might increase yields. Negative correlation coefficients indicated that Xanthobacteraceae, Caulobacteraceae, Oxalobacteraceae, Chitinophagaceae, Sphingomonas, Hyphomicrobium, Variovorax and Phenylobacterium might be detrimental to P. notoginseng growth. A total of 85 functional traits were significantly (P < 0.05) correlated with P. notoginseng yields. Functional traits, likely steroid biosynthesis and MAPK signaling pathway were positively correlated with P. notoginseng yields. In contrast, functional traits, such as bacterial secretion system, ABC transporters, metabolism of xenobiotics by cytochrome P450 and drug metabolism–cytochrome P450, were negatively associated with yields. Conclusions: This study describes an overview of the rhizosphere microbiome of P. notoginseng with discrepant yields and identifies the taxa and functional traits related to yields. Our results provide valuable information to guide the isolation and culture of potentially beneficial microorganisms and to utilize the power of the microbiome to increase plant yields in a continuous cropping system. [ABSTRACT FROM AUTHOR]

• Long-acting MNs are the future of microneedle technique. • Biodegradable and swellable polymers are applicable to prolong drug release. • Separable design enables implantable tips for sustained release in skin. • Bioinspired needles enhance skin adhesion. • Backing layer based reservoir is advantageous in drug loading. Microneedles (MNs) are a self-administrable and painless alternative to hypodermic needles for bolus drug delivery. Sustained drug release is the preferable drug delivery method because it reduces the chemical burden in patients and can deliver therapeutics that require long-term exposure. Here, we review recent advances in long-acting MNs, summarizing polymers used to fabricate long-acting MNs and mechanisms controlling drug release. We also introduce novel designs of separable needles to achieve implantable tips and bioinspired needles for enhanced skin adhesion, as well as strategies using the back layer as a drug reservoir. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract Synchronized release, defined as simultaneous release of multiple components while keeping the inter-component ratios steady, is crucial to the design and development of sustained- or controlled-release delivery systems of herbal medicines. A theory of infinite dose dividing is proposed to interpret the rationale behind synchronized release. The key point of the mechanisms is to curb diffusion so as to offset the release divergence caused by differences in physicochemical properties of multiple components. In practice, pH-dependent gradient-release, erosion-controlled and osmotic pump delivery systems have been adapted to attain synchronized release of model herbal medicines. Nevertheless, synchronized release is still in the proof-of-concept stages and should be corroborated by more evidence with more model herbal medicines. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract The aim of this work was to develop biocompatible ionic liquids (ILs) for enhancement of dermal delivery of hydrophilic macromolecules. The ILs were prepared from malic acid and choline, which are commonly used as food additives and generally regarded as safe. The choline malate IL (CM-IL) was formed via ionic interactions, which has been validated by Fourier transform infrared spectroscopy and nuclear magnetic resonance. Analysis by differential scanning calorimetry confirmed a melting point of −65.2 °C for CM-IL. In skin penetration study, CM-IL was proved to be able to deliver a model hydrophilic macromolecule dextran into deep skin. The amount of dextran delivered to epidermis and dermis by CM-IL is approximately two folds that of by dextran solution. Enhanced in vivo skin penetration by CM-IL was proved as well. The fluorescence of FITC-dextran could be observed permeating pervasively throughout the skin from 4 h to 24 h, while in the control groups it was mainly concentrated in stratum cornea (SC) and hair follicles. In addition, CM-IL did not shown any irritation to mice skin within 7 days of successive treatment and any toxicity to human epidermal cells (HEK-A) within 24 h. In conclusion, CM-IL could be potentially used as enhancers or vehicles for dermal delivery of hydrophilic macromolecules. [ABSTRACT FROM AUTHOR]

Transcutaneous immunization (TCI) is a promising alternative to vaccine delivery via the subcutaneous and intramuscular routes because of the unique immunological characteristics of the skin. However, the stratum corneum (SC) prevents entry of most therapeutic compounds into the body. Several physical devices have been developed to overcome the SC barrier, but still damage the skin. However, by targeting antigens to the abundant perifollicular antigen-presenting cells (APCs), the transfollicular route might be a promising approach for TCI without compromising the skin barrier. [ABSTRACT FROM AUTHOR]

Treatment of aggressive prostate cancer remains a great challenge due to inadequate drug distribution into the cancerous lesions after administration. This study aimed to develop aptamer-anchored nanoparticles (apt-NPs) for systemic delivery of docetaxel (DTX) and to evaluate the tumoricidal activity against the prostate cancer in vitro and in vivo . DTX-loaded apt-NPs (DTX-apt-NPs) were prepared by a solvent diffusion technique using functional PLGA- b -PEG and sodium oleate. DTX-apt-NPs were characterized by in vitro release, antitumor activity, cellular uptake and cytotoxic mechanisms. Pharmacokinetics and tissue distribution studies were performed in rats to investigate the biofate of DTX-apt-NPs. Finally, the in vivo antitumor efficacy was examined on the LNCaP cells xenograft tumor model. The resulting DTX-apt-NPs were 93.6 nm in particle size with narrow distribution and possessed a high entrapment efficiency (97.62%) and acceptable drug loading (8.91%). DTX-apt-NPs demonstrated an enhanced in vitro antitumor effect and marked cellular uptake compared with the solution formulation or conventional nanoparticles. The intracellular trafficking of DTX-apt-NPs was shown to be an active transport process involving the clathrin-dependent endocytosis. Anti-PSMA aptamer-mediated delivery was assumed mainly responsible for the enhanced antitumor efficacy. DTX-apt-NPs that can target to PSMA-overexpressed prostate cancer provide a feasible approach for systemic delivery of DTX to the cancerous prostate to achieve a fine prognosis. [ABSTRACT FROM AUTHOR]

[Display omitted] • EPS matrix composes the major hurdle for antibiofilm treatment. • Nanoparticles are potent in biofilm penetration and elimination. • Size and surface properties are crucial for biofilm penetration. • EPS destruction and stimuli-responsive release enhance biofilm eradication. • QS inhibition shall be integrated into antibiofilm nanoparticles. Biofilms are colonies of microorganisms that are embedded in autocrine extracellular polymeric substances (EPS), imparting antibiotic resistance and recalcitrant bacterial infection. Nanoparticles (NPs) can enhance the biofilm inhibition and eradication of delivered antibiotics. This is mainly because of enhanced EPS penetration and a high local drug concentration. As we discuss here, novel strategies are being developed to further enhance the antibiofilm capacity of NPs, including size optimization, surface modification, stimuli-triggered release, and combined strategies. Thus, NPs represent an effective and promising approach to combat biofilms. [ABSTRACT FROM AUTHOR]

Objectives This study was designed to explore the pathogenesis of psoriasis and to identify potential bio-targets. Genome array technology was used to analyze the gene expression profiles of lesional and non-lesional psoriatic skin samples and normal skin samples. Methods Gene expression profile GSE14905 was downloaded from the Gene Expression Omnibus ( GEO) database. This included skin biopsy samples from normal healthy donors ( n = 21), lesional skin biopsy samples from psoriasis patients ( n = 33), and non-lesional skin biopsy samples from psoriasis patients ( n = 28). Differentially expressed genes ( DEGs) were identified using the Limma package in R language. Functions of specific DEGs were predicted by Gene Ontology ( GO) enrichment analysis. A protein-protein interaction network was constructed to display the interactions among common DEGs. Finally, DAVID and WebGestalt were used to achieve a functional analysis of common DEGs. Results Totals of 1020, 562, and 643 genes, respectively, were identified as being differentially expressed in normal versus lesional, normal versus non-lesional, and lesional versus non-lesional samples. The specific DEGs in the three groups were enriched for several GO terms, including mitotic cell cycle, immune response, and response to organic matter. The 40 common DEGs in the three groups may be involved in the defense response pathway in the development of psoriasis. Furthermore, three genes ( RGS1, SOCS3, and NAMPT) may play key roles in distinguishing lesional and non-lesional tissues from normal tissues, and 10 genes ( PTRRC, ALDH1A3, SAMSA1, C15orf48, ZC3H12A, SOD2, IL8, LTF, RHCG, and IL7R) may play key roles in distinguishing non-lesional from normal and lesional samples. Conclusions These genes may be considered as potential diagnostic markers and targets of therapeutics in psoriasis. [ABSTRACT FROM AUTHOR]

L-type lectin receptor-like kinases (L-LecRKs) act as sensors of extracellular signals and as initiators for plant immune responses; however, the function of LecRK-S.4 in plant immunity has not yet been extensively investigated. In the present study we found that MdLecRK-S.4.3 in apple (Malus domestica), a homologous gene of LecRK-S.4 , was differentially expressed during infection by Valsa mali and Valsa pyri. Overexpression of MdLecRK-S.4.3 facilitated the induction of immune responses and enhanced the resistance to Valsa canker of fruits of apple and pear (Pyrus betulifolia), and of suspension cells of pear 'Duli-G03'. The expression of PbePUB36 , a RLCK XI sub-family member, was significantly repressed in the MdLecRK-S.4.3 -overexpressing cell lines. Overexpression of PbePUB36 interfered with the resistance to Valsa canker and the immune response caused by up-regulation of MdLecRK-S.4.3. In addition, we found that MdLecRK-S.4.3 interacted with BAK1 and/or PbePUB36 in vivo. Thus, whilst MdLecRK-S.4.3 activated various immune responses and positively regulated Valsa canker resistance, this could be largely compromised by PbePUB36. MdLecRK-S.4.3 interacted with PbePUB36 and/or MdBAK1 to mediate the immune responses. Our finding provides a basis for further examination of the molecular mechanisms underlying resistance to Valsa canker, and can contribute to resistance breeding. [ABSTRACT FROM AUTHOR]

Abstract: Flos Chrysanthemi (the flower of Chrysanthemum morifolium Ramat.) is widely used in China as a food and traditional Chinese medicine for many diseases. Luteolin and apigenin are two main bioactive components in Flos Chrysanthemi, and chrysoeriol and diosmetin are two methylated metabolites of luteolin in vivo by cathechol-O-methyltransferase (COMT). However, there was lack of pharmacokinetic information of chrysoeriol and diosmetin after oral administration of Flos Chrysanthemi extract (FCE). The present study aimed to develop an HPLC-UV method for simultaneous determination of rat plasma concentration of luteolin, apigenin, chrysoeriol and diosmetin and utilize it in pharmacokinetic study of the four compounds after orally giving FCE to rats. The method was successfully validated and applied to the pharmacokinetic study when oral administration of FCE to rats with or without co-giving a COMT inhibitor, entacapone. Chrysoeriol and diosmetin were detected in rat plasma after oral administration of FCE and their concentrations were significantly decreased after co-giving entacapone. Furthermore, AUC of luteolin was significantly increased by entacapone, while that of chrysoeriol was decreased by entacapone, which revealed COMT might play an important role in the disposition of luteolin in rats after dosing of FCE. In conclusion, a sensitive, accurate and reproducible HPLC-UV method for simultaneous determination of luteolin, apigenin, chrysoeriol and diosmetin in rat plasma were developed, pharmacokinetics of chrysoeriol and diosmetin combined with luteolin and apigenin were characterized after oral administration of FCE to rats, which gave us more information on pharmacokinetics and potential pharmacological effects of FCE in vivo. [Copyright &y& Elsevier]

abstract 1. Tetrahydropalmatine (THP), with one chiral centre, is one of the major constituents of Rhizoma corydalis. THP is considered to possess analgesic, sedative, hypnotic actions and cardiac protection. The aim of this study was to elucidate the stereoselective interaction between THP and ABC transporters. 2. The present study investigated three most important ABC transporters, including P-glycoprotein (P-gp), multidrug resistance protein 1 (MRP1) and breast cancer resistance protein (BCRP). The intracellular accumulation and bidirectional transport suggested THP enantiomers were inhibitors of P-gp, but not of MRP1 or BCRP. The IC50 values of (-)-THP and (+)-THP on rhodamine 123 (P-gp substrate) efflux were 48.6 and 20.0 µM, respectively, which showed obvious stereoselective difference. In the bidirectional transport, THP enantiomers showed high passive permeability and the contribution of P-gp could not be testified. The western blot and real-time RT-PCR assays showed that THP enantiomers reduced the protein expression of P-gp, but did not affect its mRNA expression. In in vitro cytotoxicity test, THP enantiomers showed the potential of increasing the cytotoxicity of doxorubicin in P-gp-mediated multidrug resistant tumour cells. 3. The present study showed the stereoselective interaction between THP enantiomers and P-gp, which should be considered in clinical practice. [ABSTRACT FROM AUTHOR]

It was to study the oral bioavailability of the all-trans-retinoic acid (ATRA)/2-hydroxypropyl cyclodextrin (HPCD) inclusion complex pellets. The ATRA/HPCD inclusion complex pellets was prepared with fluid-bed coating technique and characterized in vitro by SEM and dissolution. The oral bioavailability of the ATRA/HPCD inclusion complex pellets was compared with ATRA suspension in beagle dogs at a dose of 10 mg/kg. The resulting pellets were spherical and intact in shape. SEM analysis revealed a surface with crevices and a tightly coated inclusion complex layer. In vitro dissolution of ATRA from the inclusion complex pellets was significantly enhanced as compared with ATRA suspension. Calculated by AUC0-t, the relative bioavailability of the ATRA/HPCD inclusion complex pellets increased by approximately 20 times. The ATRA/HPCD inclusion complex pellets showed a considerable potential to enhance the oral bioavailability of ATRA. [ABSTRACT FROM AUTHOR]

α1-Adrenergic receptors are one of the three subfamilies of G protein coupled receptors activated by epinephrine and norepinephrine to control important functions in many target organs. Three human subtypes (α1A, α1B, α1D) are derived from separate genes and are highly homologous in their transmembrane domains but not in their amino or carboxyl termini. Recent advances in our understanding of these “non-identical triplets” include development of knockout mice lacking single or multiple subtypes, new insights into subcellular localization and trafficking, identification of allosteric modulators, and increasing evidence for an important role in brain function. Although all three subtypes activate the same Gq/11 signaling pathway, they also appear to interact with different protein binding partners. Recent evidence suggests they may also form dimers, and may initiate independent signals through pathways yet to be clearly elucidated. Thus, this subfamily represents a common phenomenon of a group of similar but non-identical receptor subtypes activated by the same neurotransmitter, whose individual functional roles remain to be clearly established. [Copyright &y& Elsevier]

[Display omitted] • AD manifests as an imbalance of the epithelial immune environment, reflected in epidermal barrier and immune dysfunction. • The lipid-microbiome loop involves abnormal epithelial lipids and microbial dysregulation, weakening the skin barrier. • Adaptive immunity regulates the lipid-microbiome feedback loop which plays a destructive role and drives AD. • The association between altered epithelial lipids, microbial imbalance, and adaptive immunity's role in AD is explored. • Targeting the epithelial immune environment to boost the epidermal barrier and immune responses may attenuate AD. The promotion of epidermal barrier dysfunction is attributed to abnormalities in the lipid-microbiome positive feedback loop which significantly influences the imbalance of the epithelial immune microenvironment (EIME) in atopic dermatitis (AD). This imbalance encompasses impaired lamellar membrane integrity, heightened exposure to epidermal pathogens, and the regulation of innate and adaptive immunity. The lipid-microbiome loop is substantially influenced by intense adaptive immunity which is triggered by abnormal loop activity and affects the loop's integrity through the induction of atypical lipid composition and responses to dysregulated epidermal microbes. Immune responses participate in lipid abnormalities within the EIME by downregulating barrier gene expression and are further cascade-amplified by microbial dysregulation which is instigated by barrier impairment. This review examines the relationship between abnormal lipid composition, microbiome disturbances, and immune responses in AD while progressively substantiating the crosstalk mechanism among these factors. Based on this analysis, the "lipid-microbiome" positive feedback loop, regulated by immune responses, is proposed. The review delves into the impact of adaptive immune responses that regulate the EIME, driving AD, and investigates potential mechanisms by which lipid supplementation and probiotics may alleviate AD through the up-regulation of the epidermal barrier and modulation of immune signaling. This exploration offers support for targeting the EIME to attenuate AD. [ABSTRACT FROM AUTHOR]

[Display omitted] • The latest immunotherapeutic strategies for skin cancer are highlighted, with a special focus on tumour-associated macrophages(TAMs). • Interactions between TAMs and immune cells are discussed, underlining the key role of TAMs in shaping the immunosuppressive microenvironment. • The paper comprehensively analyzes the origin, classification, and functions of TAMs, shedding light on their crucial role in skin cancer. • Targeting TAMs as a novel immunotherapy strategy sheds new light on the treatment of skin cancer. • Immunotherapy strategies centred on TAMs could complement existing treatments for skin cancer and show excellent prospects. The incidence of skin cancer is currently increasing, and conventional treatment options inadequately address the demands of disease management. Fortunately, the recent rapid advancement of immunotherapy, particularly immune checkpoint inhibitors (ICIs), has ushered in a new era for numerous cancer patients. However, the efficacy of immunotherapy remains suboptimal due to the impact of the tumor microenvironment (TME). Tumor-associated macrophages (TAMs), a major component of the TME, play crucial roles in tumor invasion, metastasis, angiogenesis, and immune evasion, significantly impacting tumor development. Consequently, TAMs have gained considerable attention in recent years, and their roles have been extensively studied in various tumors. However, the specific roles of TAMs and their regulatory mechanisms in skin cancer remain unclear. This paper aims to elucidate the origin and classification of TAMs, investigate the interactions between TAMs and various immune cells, comprehensively understand the precise mechanisms by which TAMs contribute to the pathogenesis of different types of skin cancer, and finally discuss current strategies for targeting TAMs in the treatment of skin cancer. With a specific emphasis on the interrelationship between TAMs and skin cancer, this paper posits that therapeutic modalities centered on TAMs hold promise in augmenting and harmonizing with prevailing clinical interventions for skin cancer, thereby charting a novel trajectory for advancing the landscape of immunotherapeutic approaches for skin cancer. [ABSTRACT FROM AUTHOR]

Intraperitoneal (i.p.) administered nanomedicine has been widely applied in the clinical treatment of intra-abdominal diseases and preclinical pharmacological investigations. However, current understandings about the in vivo fate of i.p.-administered drug remains controversial owing to lack of reliable investigation tools. This work presents a nanoparticle-labeling strategy based on aggregation-caused quenching (ACQ) probes in the second near-infrared (NIR-II) window, which can eliminate the interference of unbound probes and allow for non-invasive tracking of nanoparticles in deep tissues. Our results strongly evidence a size-dependent absorption and biodistribution of the i.p.-administered polymeric nanocarriers (PNs) with particle sizes ranging from 30 to 1000 nm both in vivo and ex vivo , and moreover provide a clear visualization of lymphatic transportation and lymph node retention of integral PNs. Importantly, our findings suggest that small particles (≤30 nm) are favorable in systemic therapies due to their rapid absorption and high concentration (>19 %ID mL−1) in circulation, while large particles (over 1000 nm) are meant for localized treatment of abdominal diseases. Besides, the high retention of 200 nm nanoparticles within lymph nodes indicates their promising role in cancer vaccines and lymphatic diseases including lymph node metastasis. [Display omitted] [ABSTRACT FROM AUTHOR]

• Combination of metabolomics and machine learning algorithms. • ESCC displays a disturbed amino acid metabolism. • Prognostic significance of tissue metabolites. • Amino acid transporters (SLC7A5, SLC1A5, and SLC16A10) are up-regulated in ESCC. Prognosis for esophageal squamous cell carcinoma (ESCC) is poor, so it is essential to develop a more complete understanding of the disease. The purpose of this study was to explore metabolic biomarkers and potential therapeutic targets for ESCC. An ultra-high-performance liquid chromatography coupled with high resolution mass (UPLC/MS)-based metabolomic analysis was performed in 141 ESCC cancerous tissue samples and 70 non-cancerous counterparts. The results showed that 41 differential metabolites were annotated in the training set, and 37 were validated in the test set. Single-metabolite-based receiver operating characteristic (ROC) curves as well as metabolite-based machine learning models, including Partial Least Squares (PLS), Support Vector Machine (SVM), and Random Forest (RF), were investigated for cancerous and non-cancerous tissue classification. Six most prevalent diagnostic metabolites—adenylsuccinic acid, UDP-GalNAc, maleylacetoacetic acid, hydroxyphenylacetylglycine, galactose, and kynurenine—showed testing predictive accuracies of 0.89, 0.95, 0.97, 0.89, 0.84, and 0.84, respectively. Moreover, the metabolite-based models (PLS, SVM, and RF) had testing predictive accuracies of 0.95, 0.95, and 1.00, respectively. Kaplan–Meier survival analysis and Cox proportional hazards regression analysis demonstrated that 2-hydroxymyristoylcarnitine (HR: 0.55, 95 % CI: 0.32 to 0.92), 3-hydroxyhexadecanoylcarnitine (HR: 0.49, 95 % CI: 0.29 to 0.83), and 2,3-Dinor-TXB1 (HR: 0.56, 95 % CI: 0.33 to 0.95) to be significantly associated with OS. Based on the observation of accumulation in amino acids, immunohistochemistry (IHC) staining revealed that the amino acid transporters SLC7A5/LAT1, SLC1A5/ASCT2, and SLC16A10/MCT10 were up-regulated in ESCC cancerous tissues when compared to non-cancerous equivalents. Consistently, the same panel of amino acids were downregulated in cells with SLC1A5 knockdown. Herein, it is concluded that this study not only identified several metabolites with diagnostic and/or prognostic value, but also provided accurate metabolite-based prediction models for ESCC tissue classification. Furthermore, the three up-regulated amino acid transporters were identified as potential therapeutic targets for ESCC, especially SLC1A5. [ABSTRACT FROM AUTHOR]

Osterix (or Sp7) is an important transcription factor that promotes osteoblast differentiation by modulating the expression of a range of target genes. Although many studies have focused on Osterix/Sp7 regulatory mechanisms, the detailed functions have not been fully elucidated. Toward this end, in this study, we used CRISPR/Cas9 technology to knock out the zebrafish sp7 gene, and then analyzed its phenotype and biological function. Two knockout sp7 mutant lines were successfully obtained. The bone mineralization level was significantly reduced in the zebrafish sp7−/− homozygote, resulting in abnormal tooth development in the larvae. Quantitative real-time polymerase chain reaction showed that loss of sp7 led to down-regulated expression of the dlx2b and bglap genes related to tooth development and bone mineralization, respectively. Moreover, cell transfection experiments demonstrated that Sp7 directly regulates the expression of dlx2b and bglap through Sp7-binding sites on the promoter regions of these two genes. Overall, this study provides new insight into the role of Sp7 in bone mineralization and tooth development. [ABSTRACT FROM AUTHOR]

Ionic liquids (ILs) have been widely used in biomedical and pharmaceutical fields as solvents or permeation enhancers. Recently, more and more researchers focused on optimizing the physicochemical properties of active pharmaceutical ingredient (API) by ILs technology. Converting APIs into ILs (API-ILs) has shown great potential for drug delivery by eliminating polymorphism, tailoring solubility, improving thermal stability, increasing dissolution, controlling drug release, modulating the surfactant properties, enhancing permeability of APIs and modulating cytotoxicity on tumor cells. In addition, API-ILs are also used in various formulations as active ingredients, such as solutions, emulsions, even tablets or nanoparticles. This paper aims to review current status of API-ILs, including the rational and design, preparation and characterization, the improvement on the physicochemical characteristics of APIs, the compatibility of API-ILs with various formulations, and the future prospects of API-ILs in biomedical and pharmaceutical fields. [Display omitted] [ABSTRACT FROM AUTHOR]

Accurate fluorescence imaging of nanocarriers in vivo remains a challenge owing to interference derived mainly from biological tissues and free probes. To address both issues, the current study explored fluorophores in the near-infrared (NIR)-II window with aggregation-caused quenching (ACQ) properties to improve imaging accuracy. Candidate fluorophores with NIR-II emission, ACQ984 (λem = 984 nm) and IR-1060 (λem = 1060 nm), from the aza-BODIPY and cyanine families, respectively, were compared with the commercial fluorophore ICG with NIR-II tail emission and the NIR-I fluorophore P2 from the aza-BODIPY family. ACQ984 demonstrates high water sensitivity with complete fluorescence quenching at a water fraction greater than 50%. Physically embedding the fluorophores illuminates various nanocarriers, while free fluorophores cause negligible interference owing to the ACQ effect. Imaging based on ACQ984 revealed fine structures in the vascular system at high resolution. Moreover, good in vivo and ex vivo correlations in the monitoring of blood nanocarriers can be established, enabling real-time noninvasive in situ investigation of blood pharmacokinetics and dynamic distribution in various tissues. IR-1060 also has a good ACQ effect, but the lack of sufficient photostability and steady post-labeling fluorescence undermines its potential for nanocarrier bioimaging. P2 has an excellent ACQ effect, but its NIR-I emission only provides nondiscriminative ambiguous images. The failure of the non-ACQ probe ICG to display the biodistribution details serves as counterevidence for the improved imaging accuracy by NIR-II ACQ probes. Taken together, it is concluded that fluorescence imaging of nanocarriers based on NIR-II ACQ probes enables accurate in vivo bioimaging and real-time in situ pharmacokinetic analysis. [ABSTRACT FROM AUTHOR]

[Display omitted] • This article focuses on immunotherapy, a new treatment for tumors with low side effects, and suggests the direction of improvement. • Programmed cell death (apoptosis, necroptosis, ferroptosis, pyroptosis and autophagy) induced by nanomedicine was reviewed in this paper. • This paper focuses on the role of nanomedicine-induced programmed cell death in cancer therapy. • This article reviews the improvement of the limitations of immunotherapy with nanomedicine-induced PCD. • In this paper, the development prospect of tumor therapy and immunotherapy of PCD mediated by nanomedical drugs is prospected. There has been widespread concern about the high cancer mortality rate and the shortcomings of conventional cancer treatments. Immunotherapy is a novel oncology therapy with high efficiency and low side effects, which is a revolutionary direction for clinical oncology treatment. However, its clinical effectiveness is uneven. Based on the redefinition and reclassification of programmed cell death (PCD) (divided into necroptosis, ferroptosis, pyroptosis, and autophagy), the role of nanomedicine-induced PCD in cancer therapy has also received significant attention. Clinical and preclinical studies have begun to combine PCD with immunotherapy. In this article, we present recent research in tumor immunotherapy, provide an overview of how nanomedicine-induced PCD is involved in tumor therapy, and review how nanomedicine-induced PCD can improve the limitations of immunotherapy to enhance tumor immunotherapy. The future development of nanomedicine-mediated PCD tumor therapy and tumor immunotherapy is also proposed Key scientific concepts of overview Nanomedicine-induced PCD is a prospective method of tumor immunotherapy. Nanomedicines increase tumor site penetration and targeting ability, and nanomedicine-mediated PCD activation can stimulate powerful anti-tumor immune effects, which has a good contribution to immunotherapy of tumors. [ABSTRACT FROM AUTHOR]

Wall‐associated kinases (WAKs) have been determined to recognize pathogenic signals and initiate plant immune responses. However, the roles of the family members in host resistance against Valsa canker, a serious fungal disease of apples and pears, are largely unknown. Here, we identified MbWAK1 in Malus baccata, a resistant germplasm differentially expressed during infection by Valsa mali (Vm). Over‐expression of MbWAK1 enhanced the Valsa canker resistance of apple and pear fruits and 'Duli‐G03' (Pyrus betulifolia) suspension cells. A large number of phloem, cell wall, and lipid metabolic process‐related genes were differentially expressed in overexpressed suspension cell lines in response to Valsa pyri (Vp) signals. Among these, the expression of xyloglucan endotransglucosylase/hydrolase (XTH) gene PbeXTH1 and sieve element occlusion B‐like (SEOB) gene PbeSEOB1 were significantly inhibited. Transient expression of PbeXTH1 or PbeSEOB1 compromised the expressional induction of MbWAK1 and the resistance contributed by MbWAK1. In addition, PbeXTH1 and PbeSEOB1 suppressed the immune response induced by MbWAK1. Our results enriched the molecular mechanisms for MbWAK1 against Valsa canker and resistant breeding. [ABSTRACT FROM AUTHOR]

Adoptive cellular immunotherapy using immune cells expressing chimeric antigen receptors (CARs) is a highly specific anti-tumor immunotherapy that has shown promise in the treatment of hematological malignancies. However, there has been a slow progress toward the treatment of solid tumors owing to the complex tumor microenvironment that affects the localization and killing ability of the CAR cells. Solid tumors with a strong immunosuppressive microenvironment and complex vascular system are unaffected by CAR cell infiltration and attack. To improve their efficacy toward solid tumors, CAR cells have been modified and upgraded by "decorating" and "pruning". This review focuses on the structure and function of CARs, the immune cells that can be engineered by CARs and the transformation strategies to overcome solid tumors, with a view to broadening ideas for the better application of CAR cell therapy for the treatment of solid tumors. [Display omitted] [ABSTRACT FROM AUTHOR]

The chemical composition of black tea during tea processing is in a state of flux. However, the dynamic changes of this sophisticated metabolic process are far from clear. GC–MS-based metabolomic analyses were performed to examine changes in volatile and non-volatile compounds throughout the five stages of tea processing. The results showed that the most striking differences were observed at the withering and rolling stages, during which 62 non-volatile and 47 volatile compounds were significantly changed. The levels of most monosaccharides decreased at the withering stage and increased in subsequent stages while di-saccharides decreased as the process progressed. Free amino acids increased sharply at the withering stage, and most kept increasing or remained stable afterwards. However, levels of catechin, epicatechin, epigallocatechin, and epigallocatechin gallate decreased after withering and remained at low levels afterwards. Among the 47 volatile compounds with altered levels, phenylpropanoids/benzenoids and carotenoid-derived volatiles, which contribute to the honey-like and rose-like fragrances and quality of Danxia2 tea, kept increasing during the processing, among them eight were newly produced. Furthermore, 19 volatiles with a grassy odor decreased during processing. This study provides a comprehensive profile of metabolic changes during black tea processing, which is potentially important for both quality control and improvement of the flavor of black teas. Unlabelled Image • GC–MS-based metabolic profiling of Camellia sinensis during black tea processing. • Stage-specific dynamic changes of non-volatile/volatile compounds were revealed. • Sixty-two non-volatiles were changed significantly during the processing. • Eight volatiles were newly produced, and 19 were decreased during the processing. • Changes in various metabolites may contribute to black tea unique sensory quality. [ABSTRACT FROM AUTHOR]

Psoriasis is an inflammatory skin disease mediated by the immune system and characterized by an inflammatory ring, also known as an epithelial immune microenvironment (EIME). The interaction between the epithelial tissue of the skin and the immune system has a crucial role in the immune cycle of psoriasis. Although the formation of new blood vessels in skin lesions provides energy support for the proliferation of epidermal keratinocytes, the role of angiogenesis in psoriasis has not been extensively studied. Vascular endothelial growth factor A (VEGFA) is a key regulator of angiogenesis that has an important role in the development of psoriasis. VEGFA promotes angiogenesis and directly stimulates epidermal keratinocytes and infiltrating immune cells, thus contributing to the progression of psoriasis. Measuring VEGFA levels to identify angiogenic characteristics in psoriasis patients may be a predictive biomarker for disease severity and response to anti-angiogenic therapy. Clinical data have shown that anti-angiogenic therapy can improve skin lesions in psoriasis patients. Therefore, this study aimed to uncover the underestimated role of blood vessels in psoriasis, explore the relationship between VEGFA and keratinocytes in the EIME, and inspire innovative drug therapies for the treatment of psoriasis. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic inflammatory skin disease characterised by the abnormal proliferation of keratinocytes and dysregulation of immune cells. The upregulation of fibroblast growth factor-inducible molecule 14 (Fn14) in psoriatic lesions has been linked to the development of psoriasis. Transdermal delivery of siRNAs for Fn14 inhibition is challenging. In this study, we developed a composite ionic liquid (CIL) for the transdermal delivery of Fn14 siRNA (siFn14) into keratinocytes, with the aim of modulating the inflammatory response associated with psoriasis. The results showed that CIL-siFn14 effectively suppressed Fn14 expression, resulting in a reduction in both the Psoriasis Area and Severity Index (PASI) score and skin thickness. Furthermore, CIL-siFn14 effectively inhibited the abnormal proliferation of keratinocytes, decreased the production of inflammatory factors associated with psoriasis, prevented the over-activation of CD4+ and CD8+ T cells, and restored the balance of Type 1 T helper (Th1), Th2, Th17 and Treg cells. In conclusion, our findings unveiled the critical role of Fn14 in the pathogenesis of psoriasis and demonstrated the potential of CIL-siFn14 as a novel and effective topical treatment for its management. [Display omitted] • Composite Ionic Liquid (CIL) offers a highly safe and permeable delivery system for siRNA. • CIL effectively enhances the transdermal penetration of siFn14 by temporarily suppressing the epidermal barrier function. • CIL-siFn14 exhibits anti-inflammatory properties and inhibits the proliferation of keratinocytes. • CIL-siFn14 plays a crucial role in modulating the immune microenvironment in the epidermis of psoriasis patients. [ABSTRACT FROM AUTHOR]

Abstract Chidamide is a new subtype-selective histone deacetylase inhibitor (HDACi), which has been approved for the treatment of recurrent or refractory peripheral T-cell lymphoma (PTCL) in China. However, there are few studies about the application of chidamide in PTCL with central nervous system (CNS) involvement. It is essential to investigate the penetration of chidamide in the blood brain barrier (BBB). LC-MS methods were established firstly to determine the concentration of chidamide in rat plasma and CSF. Then five rats were anaesthetized and the plasma and CSF samples were collected at the time of 5, 15, 30, 60, 120, 180, 240, 360 and 480 min after being administered 1 mg/kg chidamide by intravenous injection, respectively. All samples were analyzed with the established LC-MS method by using the precursor/product transitions (m / z) of 391.1/265.1 for chidamide and 441.1/138.2 for internal standard (IS). The PK parameters were calculated after both of the concentrations of chidamide in plasma and CSF were determined. The penetration ratio of chidamide in BBB ranged from 0.19% to 0.67%. Result indicated chidamide could pass through the BBB, enter into the CNS and have the potential to be utilized in PTCL with CNS involvement. Highlights • First report about the LC-MS method determining chidamide in rat cerebrospinal fluid. • Studied the penetration ratio of chidamide in blood brain barrier (BBB). • Application of multiple CSF sampling method on rat. [ABSTRACT FROM AUTHOR]

Smoothened (Smo), the main transducer of the Hedgehog (Hh) signaling pathway, is a promising target for anticancer therapy. Although vismodegib and sonidegib have demonstrated effectiveness for the treatment of basal cell carcinoma (BCC), their clinical use has been associated with mutation-related drug resistance. In this review, we outline the resistance mechanisms of Smo inhibitors and point the way for future endeavors. We focus in particular on the development of second-generation Smo inhibitors based on co-crystal structures, inhibition of downstream components, and the regulation of other interacting pathways or mediators that could compensate for the inhibitory activity of upstream inhibitors. [ABSTRACT FROM AUTHOR]

Gout is a common inflammatory arthritis caused by persistently elevated uric acid levels. With the improvement of people's living standards, the consumption of processed food and the widespread use of drugs that induce elevated uric acid, gout rates are increasing, seriously affecting the human quality of life, and becoming a burden to health systems worldwide. Since the pathological mechanism of gout has been elucidated, there are relatively effective drug treatments in clinical practice. However, due to (bio)pharmaceutical shortcomings of these drugs, such as poor chemical stability and limited ability to target the pathophysiological pathways, traditional drug treatment strategies show low efficacy and safety. In this scenario, drug delivery systems (DDS) design that overcome these drawbacks is urgently called for. In this review, we initially describe the pathological features, the therapeutic targets, and the drugs currently in clinical use and under investigation to treat gout. We also comprehensively summarize recent research efforts utilizing lipid, polymeric and inorganic carriers to develop advanced DDS for improved gout management and therapy. New drug delivery systems have shown tremendous potential in treating complicated diseases. Gout may benefit from these approaches to increase efficacy and attenuate toxicity of the different therapeutics. [Display omitted] • This review introduces the pathological characteristics, therapeutic targets and drugs to treat gout. • Drug delivery systems (DDS) (especially nano-DDS) for the disease is outlined. DDS is promising to break through the dilemma of gout treatment. • This creview will serve clinicians and researchers alike to chart a new roadmap for treating gout. [ABSTRACT FROM AUTHOR]

Widespread human exposure and associated adverse health effects led to regulations on the usage of bisphenol A (BPA). Several bisphenol analogues (BPs) have been introduced as BPA alternatives in various applications. However, these BPs have been shown to exhibit similar or even stronger endocrine-disrupting activities compared with that of BPA. Currently, information on the human exposure to BPA alternatives remains limited. In this study, nine BPs were quantified in 81 pairs of plasma and red blood cell (RBC) samples from Chinese participants. In human plasma, the predominant BPs was BPA, bisphenol S (BPS), and bisphenol AF (BPAF), with the mean concentrations of 0.40, 0.15, and 0.073 ng/mL, respectively. BPA (accounting for 63% of total BPs) and BPS (18%) were the major BPs in the RBC fraction. Mass fractions in plasma (Fr) were found to be highest for BPS (mean, 0.78), followed by BPAF (0.71) and BPA (0.67), indicating strong partitioning to the plasma fraction. However, bisphenol AP was more frequently detected in the RBC fraction. Estimated total daily intake (EDI) of BPA was in the range of 0.0048-0.75 /ig/kg bw/day for the participants, and adults aged >50 years had comparatively lower EDI. To our knowledge, this is the first study to assess the occurrence and partitioning of BPA alternatives in paired human plasma and RBCs from the Chinese general population. [ABSTRACT FROM AUTHOR]

Skin diseases are among the most prevalent non-fatal conditions worldwide. The transdermal drug delivery system (TDDS) has emerged as a promising approach for treating skin diseases, owing to its numerous advantages such as high bioavailability, low systemic toxicity, and improved patient compliance. However, the effectiveness of the TDDS is hindered by several factors, including the barrier properties of the stratum corneum, the nature of the drug and carrier, and delivery conditions. In this paper, we provide an overview of the development of the TDDS from first-generation to fourth-generation systems, highlighting the characteristics of each carrier in terms of mechanism composition, penetration method, mechanism of action, and recent preclinical studies. We further investigated the significant challenges encountered in the development of the TDDS and the crucial significance of clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: This study examines prognostic value of preoperative serum bilirubin, including unconjugated bilirubin (UCB), conjugated bilirubin (CB), and total bilirubin (TB), in esophageal squamous cell carcinoma (ESCC) patients who underwent curative resection. Methods: Between May 2010 and December 2012, a total of 351 ESCC patients were retrospectively reviewed. All the patients underwent curative resection as their primary treatment. Clinicopathological features and overall survival (OS) rate were investigated. Kaplan-Meier curves were used to calculate the OS rate, and the prognostic factors were identified by Cox regression model. Besides, the potential inhibition effect of UCB on ESCC was investigated with both in vitro and in vivo models. Results: The higher-level groups of UCB, CB, and TB demonstrated longer OS than their low counterparts, with hazard ratio (HR) values of 0.567 (95% CI: 0.424–0.759), 0.698 (95% CI: 0.522–0.933), and 0.602 (95% CI: 0.449–0.807), respectively. All three forms of bilirubin were identified as independent prognostic factors for patients with ESCC, and they were found to effectively stratify the survival risk of patients at TNM stage III. In vivo and in vitro models further confirmed the inhibitory effect of unconjugated bilirubin (UCB) on the proliferation of ESCC. Conclusion: The findings of our study have shed new light on the prognostic value and biological functions of bilirubin in relation to ESCC. These results may contribute to a better understanding of the underlying mechanisms involved in ESCC tumorigenesis and provide potential therapeutic pathways for treating ESCC. [ABSTRACT FROM AUTHOR]

Nanocrystals (NCs) have the potential to enhance the oral bioavailability of Class IV drugs in the Biopharmaceutical Classification System (BCS) due to the absorption of the intact crystals. The performance is compromised by the dissolution of NCs. Drug NCs have recently been adopted as solid emulsifiers to prepare nanocrystal self-stabilized Pickering emulsions (NCSSPEs). They are advantageous in high drug loading and low side effects due to the specific drug loading mode and the absence of chemical surfactants. More importantly, NCSSPEs may further enhance the oral bioavailability of drug NCs by impeding their dissolution. This is especially true for BCS IV drugs. In this study, curcumin (CUR), a typical BCS IV drug, was adopted to prepare CUR-NCs stabilized Pickering emulsions using either indigestible (isopropyl palmitate, IPP) or digestible (soybean oil, SO) oils, i.e., IPP-PEs and SO-PEs. The optimized formulations were spheric with CUR-NCs adsorbed on the water/oil interface. The CUR concentration in the formulation reached 20 mg/mL, which was far beyond the solubility of CUR in IPP (158.06 ± 3.44 μg/g) or SO (124.19 ± 2.40 μg/g). Moreover, the Pickering emulsions enhanced the oral bioavailability of CUR-NCs, being 172.85% for IPP-PEs and 152.07% for SO-PEs. The digestibility of the oil phase affected the amounts of CUR-NCs that remained intact in lipolysis and, thus, the oral bioavailability. In conclusion, converting NCs into Pickering emulsions provides a novel strategy to enhance the oral bioavailability of CUR and BCS IV drugs. [ABSTRACT FROM AUTHOR]

Ionic liquids (ILs) loading ketoconazole (KCZ) have shown better efficacy on rats with tinea pedis than the marketed Daktarin® but clinical studies are still lacking. In this study, we described the clinical translation of ILs containing KCZ (KCZ‐ILs) from the lab into the clinic and evaluated the efficacy and safety of KCZ‐ILs in patients with tinea pedis. Thirty‐six enrolled participants were randomized to receive either KCZ‐ILs (KCZ, 4.72 mg/g) or Daktarin® (control group; KCZ, 20 mg/g) topically twice daily, making the lesion be covered with a thin layer of medication. The randomized controlled trial lasted for 8 weeks including 4 weeks of intervention and 4 weeks of follow‐up. Primary efficacy outcome was the proportion of treatment success responders, defined as patients achieving negative mycological result and ≥60% relative reduction in total clinical symptom score (TSS) from baseline at week 4. Secondary outcomes mainly for evaluating the relapse of disease included the proportion of treatment success individuals at week 8 and fungal recurrence rate at weeks 2, 3, 4, and 8. After 4 weeks of medication, 47.06% of the KCZ‐ILs subjects were treatment successes compared with only 25.00% of those using Daktarin®. Throughout the trial period, KCZ‐ILs induced a significantly lower recurrence rate (52.94%) than that of control patients (68.75%). Furthermore, KCZ‐ILs were found to be safe and well‐tolerated. In conclusion, ILs loading only 1/4 KCZ dose of Daktarin® showed a better efficacy and safety profile in the management of tinea pedis, creating a new opportunity for the treatment of skin diseases caused by fungal infection and is worthy of clinical application. [ABSTRACT FROM AUTHOR]

Background: Topical anticancer drugs offer a potential therapeutic modality with high compliance for treating cutaneous squamous cell carcinoma (cSCC). However, the existing topical treatments for cSCC are associated with limited penetrating ability to achieve the desired outcome. Therefore, there remains an urgent requirement to develop drugs with efficient anticancer activity suitable for treating cSCC and to overcome the skin physiological barrier to improve the efficiency of drug delivery to the tumor. Results: We introduced lycorine (LR) into the topical treatment for cSCC and developed a cell-penetrating peptide (CPP)-modified cationic transfersome gel loaded with lycorine-oleic acid ionic complex (LR-OA) (LR@DTFs-CPP Gel) and investigated its topical therapeutic effects on cSCC. The anti-cSCC effects of LR and skin penetration of LR-OA transfersomes were confirmed. Simultaneously, cationic lipids and modification of R5H3 peptide of the transfersomes further enhanced the permeability of the skin and tumor as well as the effective delivery of LR to tumor cells. Conclusions: Topical treatment of cSCC-xenografted nude mice with LR@DTFs-CPP Gel showed effective anticancer properties with high safety. This novel formulation provides novel insights into the treatment and pathogenesis of cSCC. [ABSTRACT FROM AUTHOR]

Ovarian cancer (OC), the second leading cause of death among gynecological cancers, is often diagnosed at an advanced stage due to its asymptomatic nature at early stages. This study aimed to explore the diagnostic potential of plasma-based lipidomics combined with machine learning (ML) in OC. Non-targeted lipidomics analysis was conducted on plasma samples from participants with epithelial ovarian cancer (EOC), benign ovarian tumor (BOT), and healthy control (HC). The samples were randomly divided into a train set and a test set. Differential lipids between groups were selected using two-tailed Student's t-test and partial least squares discriminant analysis (PLS-DA). Both single lipid-based receiver operating characteristic (ROC) model, and multiple lipid-based ML model, were constructed to investigate the diagnostic value of the differential lipids. The results showed several lipids with significant diagnostic potential. ST 27:2;O achieved the highest prediction accuracy of 0.92 in distinguishing EOC from HC. DG 42:2 had the highest prediction accuracy of 0.96 in diagnosing BOT from HC. Cer d18:1/18:0 had the highest prediction accuracy of 0.65 in differentiating EOC from BOT. Furthermore, multiple lipid-based ML models illustrated better diagnostic performance. K-nearest neighbors (k-NN), partial least squares (PLS), and random forest (RF) models achieved the highest prediction accuracy of 0.96 in discriminating EOC from HC. The support vector machine (SVM) model reached the highest prediction accuracy both in distinguishing BOT from HC, and in differentiating EOC from BOT, with accuracies of 1.00 and 0.74, respectively. In conclusion, this study revealed that the combination of plasma-based lipidomics and ML algorithms is an effective method for diagnosing OC. • Plasma lipidomics with machine learning offer promising ovarian cancer diagnosis. • Comparison of diagnostic capabilities between single lipid and multiple lipids. • Multiple lipid-based machine learning models show potential as a diagnostic tool. [ABSTRACT FROM AUTHOR]

Ovarian cancer is the third most common gynecological malignancy worldwide and the fifth leading cause of cancer-related death among women. This may be attributed to difficulties in diagnosing early-stage ovarian cancer, as it is typically asymptomatic until metastases, and due to the ineffective management of patients with late-stage ovarian cancer. The aim of the present study was to investigate potential therapeutic targets for the treatment of ovarian cancer. Bioinformatics techniques were used to analyze the expression levels of tryptophan (Trp) metabolism-related genes in tissue samples from patients with ovarian cancer. Additionally, western blots, clonogenic assays, immunohistochemical staining, chromatin immunoprecipitation-quantitative PCR, cell co-culture assays, a xenograft model and high-performance liquid chromatography-tandem mass spectrometry were performed to evaluate the antitumor effects of genes identified from the bioinformatics analysis. Increased expression levels of the amino acid transporter, solute carrier family 7 member 5 (SLC7A5), in tissue samples from patients with ovarian cancer was demonstrated. Inhibition of SLC7A5 reduced ovarian cancer cell proliferation through G2/M cell cycle arrest and blocked intracellular aryl hydrocarbon receptor nucleus entry, which downregulated PD-L1 expression levels. Dysregulation of Trp metabolism in ovarian cancer tissue samples, as well as the upregulation of kynurenine expression levels in the plasma of patients with ovarian cancer, were demonstrated to be unfavorable prognostic factors for the progression-free survival of patients with ovarian cancer. The present study demonstrated that the dysregulation of Trp metabolism could potentially be used as a diagnostic biomarker for ovarian cancer, as well as the potential of targeting SLC7A5 for immunotherapeutic management of patients with ovarian cancer in the future. [ABSTRACT FROM AUTHOR]

[Display omitted] Ionic liquids (ILs) show promises as chemical penetration enhancers (CPEs) for transdermal delivery of macromolecular drugs. However, their high viscosity and strong drug-IL affinity may limit drug diffusion and release from the drug-loaded IL (one-step strategy). Herein, a two-step strategy was used by applying choline-based ILs as pretreatment agents followed by insulin solution to improve penetration. Insulin remained stable in the ILs and are released slowly from the IL matrices. In vitro and in vivo studies showed that two-step treatment enhanced insulin penetration compared to one-step treatment, with choline citrate ([Ch][Ci]) and choline geranate ([Ch][Ge]) performing the best. In a diabetic rat model, two-step treatment with [Ch][Ge] reduced blood glucose levels to below 80% within 8 h, while one-step treatment only maintained for 12 h. Trans-epidermal water loss and molecular dynamics simulations suggested that variations in release rates and skin condition accounted for the differences between the two strategies. Physical characterization confirmed that ILs enhanced transdermal delivery of insulin by permeabilizing stratum corneum and opening tight junctions. Preliminary safety assessment indicated mild irritation by [Ch][Ge], whereas [Ch][Ci] showed good biocompatibility. It is concluded that ILs hold potential in enhancing transdermal delivery of insulin. [ABSTRACT FROM AUTHOR]

[Display omitted] Triple-negative breast cancer (TNBC) is a highly heterogeneous and aggressive disease that is prone to metastasis and recurrence. It accounts for 15–20% of all breast cancer cases. Surgical resection is effective in removing most of the malignant tissues for non-metastasized tumors; however, some residual tumor tissues would be left, leading to a poor prognosis. Thus, real-time monitoring of surgical resection would be beneficial for the surgical resection of tumors. Although NIR-II fluorescent probe-guided surgical resection has been widely used for other types of diseases, it is not currently used for TNBC in clinical practice. Here, we describe the design and synthesis of a novel NIR-II fluorescent probe, FD-1050@NPs-cRGD , that targets TNBC. We found that it has a high fluorescence quantum efficiency, good stability, and low cytotoxicity. In vivo imaging in mice demonstrated a high tumor signal/normal tissue signal ratio, indicating that FD-1050@NPs-cRGD has great potential to be applied in tumor imaging of TNBC. [ABSTRACT FROM AUTHOR]

The oral route is the most desirable drug administration path. The oral bioavailability is always compromised from the poor physicochemical and/or biopharmaceutical properties of the active pharmaceutical ingredients. Food protein nanoparticles show promise for oral drug delivery, with improved biosafety and cost-effectiveness compared to polymeric nanoparticles. More importantly, diverse food proteins provide "choice and variety" to meet the challenges faced by different drugs in oral delivery resulting from low solubility, poor permeability, and gastrointestinal stability. The abundance of hydroxyl, amino, and carboxyl groups in food proteins allows easy surface modification of the nanoparticles to impart unique functions. Albeit being in its infancy, food protein nanoparticles exhibit high capability to enhance oral bioavailability of a wide range of drugs from small molecules to biomacromolecules. Considering the rapid growth of the field, the achievements and mechanisms of food protein nanoparticles in enhancing oral bioavailability are reviewed. Factors affecting the performance of food protein nanoparticles are discussed with the purpose to inspire the development of food protein nanoparticle-based oral drug delivery systems. [Display omitted] • Food proteins are safe and cost-effective in developing oral nanoparticles. • Enhanced bioavailability is due to improved solubility, permeability, and stability. • Digestibility and types of food proteins affect stability, adhesion, and transport. • Surface properties, size and morphology affect performance of nanoparticles. [ABSTRACT FROM AUTHOR]

Over the past decade, the dose of nanoparticles given to solid tumors has remained at a median of 0.7% of the injected dose. Most nanoparticles are trapped in a mononuclear phagocyte system (MPS), of which 85% are Kupffer cells. In our study, threshold doses of bovine serum albumin (BSA) nanoparticles were investigated for the uptake of Kupffer cells in vitro and in vivo. The antitumor effect and safety of albumin-bound paclitaxel (ABP) were improved by using threshold doses of BSA nanoparticles. We found a threshold dose of 20,000 nanoparticles per macrophage uptake in vitro and a saturation dose of 0.3 trillion nanoparticles in tumor-bearing mice. In vivo efficacy and safety evaluations demonstrated that the threshold doses of blank BSA nanoparticles could significantly improve the efficacy and safety of ABP against tumors compared with ABP alone. In this study, the delivery efficiency of ABP was improved by using blank nanoparticles to saturate Kupffer cells, which provided a new approach to studying the Kupffer cell saturation threshold and thus a new scheme for improving the curative effect of ABP. [ABSTRACT FROM AUTHOR]