Effect of minoxidil combined with triamcinolone acetonide on alopecia areata by microneedle injection.

OBJECTIVE: Alopecia areata (AA) is often characterized by sudden onset of patchy hair loss. Topical corticosteroid injection is the most common treatment. This study retrospectively observed the clinical efficacy of microneedle minoxidil combined with triamcinolone acetonide in the treatment of AA. METHODS: A total of 230 patients with AA were selected. The experimental group (n = 120) received physician training and home microneedle treatment with minoxidil combined with triamcinolone acetonide once a week. Topical minoxidil and triamcinolone acetonide were used twice daily at other times. The control group (n = 110) was treated with minoxidil combined with triamcinolone acetonide, twice a day. Cure rate, response rate, SALT, dermatological Quality of Life Index (DLQI), visual analogue (VAS), and cost were assessed at weeks 4 and 12. RESULTS: Treated group SALT score(Severity of Alopecia Tool) remarkable lower than control group after treated 4 and 12 weeks. After 12 weeks treatment, DLQI score of the treated group (1.8 ± 1.67) were significantly lower than those of the control group (2.45 ± 1.88) (p < 0.05). VAS score and adverse reaction between two group showed no significant different (p = 0.823, p = 0.484 respectively). The total cost was 53.93 ± 15.85 in the treatment group and 53.26 ± 11.51 in the control group. There was no significant difference between the two groups (p = 0.72). In the treated group, the complete response rate (CR: 78.33%) and total effective rate (CR+PR: 95%) were significantly higher than those in the control group (CR: 40.91% and CR+PR: 51.82%), with statistically significant differences (p < 0.001). CONCLUSION: Microneedle introduction of minoxidil and triamcinolone acetonide in the treatment of AA is a safe, effective, economical, and convenient method, with few adverse reactions, and has a good application prospect.

DNA Gate-Based CRISPR-Cas Exponential Amplification System for Ultrasensitive Small Extracellular Vesicle Detection to Enhance Breast Cancer Diagnosis.

Tumor-derived small extracellular vesicles (tEVs) as potential biomarkers possess abundant surface proteins closely related to parent cells, which are crucial for noninvasive cancer diagnosis. However, tEVs exhibit phenotype heterogeneity and low abundance, posing a significant challenge for multiplex detection with a high sensitivity. Herein, we developed a DNA gate-based exponential amplification CRISPR-Cas (DGEAC) system for accurate and ultrasensitive detection of tEVs, which can greatly improve the accuracy of breast cancer (BC) diagnosis. Based on the coexpression of CD63 and vascular endothelial growth factor (VEGF) on BC-derived tEVs, we developed a dual-aptamer-based AND gate fluorescent probe by proximity hybridization. By integrating the target recognition and trans-cleavage activity of Cas12a, an autocatalysis-driven exponential amplification circuit was developed for ultrasensitive detection of CD63 and VEGF proteins on tEVs, which could avoid false negative signals from single protein or other interfering proteins. We achieved highly sensitive detection of tEVs over a linear range from 1.75 × 103 to 3.5 × 108 particles/mL with a detection limit as low as 1.02 × 103 particles/mL. Furthermore, the DGEAC system can distinguish tEVs from tEVs derived from different BC cell lines, including MDA-MB-231, MCF-7, SKBR3, and MCF-10A. Compared to linear amplification (AUC 90.0%), the DGEAC system effectively differentiates BC in different stages (AUC 98.3%).

Application of cantharidin, retinoic acid cream and salicylic acidy in multiple palmoplantar warts.

OBJECTIVE: Multiple palmoplantar warts, caused by human papillomavirus (HPV) infection, were investigated for clinical efficacy using cantharidin, retinoic acid cream, and salicylic acid cream. METHODS: A total of 110 patients with multiple palmoplantar warts were enrolled. The experimental group (54 cases) received a 1:1:1 combination (CRS) of 0.25% cantharidin, 0.1% retinoic acid cream, and 5% salicylic acid, applied with pressurized encapsulation for 8 h every night, three times per week. The control group (56 cases) underwent conventional liquid nitrogen freezing. Monthly follow-ups assessed cure rate, effective rate, dermatological life quality index (DLQI), visual analog scale (VAS), and cost, with evaluations conducted after 3 months. RESULTS: The treatment group exhibited a cure rate of 85.19% and a total effective rate of 96.30%, surpassing the control group with rates of 39.29% and 51.79%, respectively (p < 0.05). The treatment group's DLQI score (1.84 ± 1.06) was significantly lower than the control group's score (6.04 ± 1.78) (p = 0.0005). Additionally, the treatment group's VAS score (1.84 ± 1.06) was notably lower than the control group's score (8.56 ± 1.07) (p < 0.0001). The treatment group's total cost (43.20 ± 2.85) was markedly lower than the control group's cost (206.38 ± 90.81), with a statistically significant difference (p < 0.0001). CONCLUSION: The combination of cantharidin, retinoic acid cream, and salicylic acid with local encapsulation is a safe, effective, economical, and convenient treatment method for multiple palmoplantar warts, exhibiting few side effects and showing promise.

The probiotic fermented milk of Lacticaseibacillus paracasei JY062 and Lactobacillus gasseri JM1 alleviates constipation via improving gastrointestinal motility and gut microbiota.

Constipation is directly related to the intestinal microenvironment, in which the promotion of gastrointestinal (GI) motility and improvement of gut microbiota distribution are important for alleviating symptoms. Herein, after the intervention of probiotic fermented milk (FMMIX) containing Lacticaseibacillus paracasei JY062 and Lactobacillus gasseri JM1 for 14 d in Kunming mice with loperamide-induced constipation, the results indicated that FMMIX significantly increased the secretion of serum motilin, gastrin and 5-hydroxytryptamine, as well as decreased the secretion of peptide YY, vasoactive intestinal peptide, and nitric oxide in mice. As determined by immunohistochemical analysis, FMMIX promoted an augmentation in the quantity of Cajal interstitial cells. In addition, the mRNA and protein expression of c-kit and stem cell factor (SCF) were upregulated to facilitate intestinal motility. High-throughput sequencing and gas chromatography techniques revealed that FMMIX led to an increase in the relative abundance of beneficial bacteria (Lactobacillus, Oscillospira, Ruminococcus, Coprococcus, and Akkermansia), reduced the presence of harmful bacteria (Prevotella), and resulted in elevated levels of short-chain fatty acids (SCFA) with a superior improvement compared with unfermented milk. Untargeted metabolomics revealed significant upregulation of functional metabolites such as l-pipecolinic acid, dl-phenylalanine, and naringenin in FMMIX, presumably playing a potential role in constipation relief. Overall, our results showed that FMMIX had the potential to alleviate constipation symptoms in mice by improving the secretion of serum GI regulatory peptides and neurotransmitters, increasing the expression of c-kit and SCF proteins, and modulating the gut microbiota structure and SCFA levels, and may be associated with an increase in these functional metabolites. This suggested that FMMIX could be a promising adjunctive strategy for managing constipation symptoms and could contribute to the development of functional foods aimed at improving gut health.

An erythrocyte membrane-camouflaged fluorescent covalent organic framework for starving/nitric oxide/immunotherapy of triple-negative breast cancer.

It is a great challenge to effectively treat triple-negative breast cancer (TNBC) due to lack of therapeutic targets and drug resistance of systemic chemotherapy. Rational design of nanomedicine with good hemocompatibility is urgently desirable for combination therapy of TNBC. Herein, an erythrocyte membrane-camouflaged fluorescent covalent organic framework (COF) loaded with an NO donor (hydroxyurea, Hu), glucose oxidase (GOx) and cytosine-phosphate-guanine oligonucleotides (CPG) (COF@HGC) was developed for imaging-guided starving/nitric oxide (NO)/immunization synergistic treatment of TNBC. The substances of HGC are easily co-loaded onto the COF due to the ordered pore structure and large surface area. And a folic acid-modified erythrocyte membrane (FEM) is coated on the surface of COF@HGC to improve targeted therapy and haemocompatibility. When COF@HGC@FEM is internalized into tumor cells, hemoglobin (Hb) on FEM and GOx loaded on the COF can trigger cascade reactions to kill tumor cells due to the simultaneous production of NO and exhaustion of glucose. Meanwhile, the COF with excellent fluorescence properties can be used as a self-reporter for bioimaging. Furthermore, the CPG can reprogram tumor-associated macrophages from tumor-supportive phenotype to anti-tumor phenotype and enhance immunotherapy. Through the "three-in-one" strategy, the biomimetic nanoplatform can effectively inhibit tumor growth and reprogram the tumor immunosuppression microenvironment in the TNBC mouse model.

ZjWRKY23 and ZjWRKY40 Promote Fruit Size Enlargement by Targeting and Downregulating Cytokinin Oxidase/Dehydrogenase 5 Expression in Chinese Jujube.

Fruit size is crucial for fruit trees, as it contributes to both quality and yield. However, the underlying mechanism of fruit size regulation remains largely unknown. Taking advantage of using a fruit double-sized bud mutant of Chinese jujube, "Jinkuiwang" and its wild type, "Jinsixiaozao", we carried out a comprehensive study on the mechanism of fruit size development in jujube. Using weighted gene coexpression network analyses, a number of candidate regulators for fruit size including those involved in hormonal signaling pathways, transcription factors, and heat shock proteins were identified. A hub gene named cytokinin oxidase/dehydrogenase 5 (ZjCKX5), responsible for cytokinin degradation, was found to play a negative role in regulating fruit size development, and overexpressing ZjCKX5 in tomato and Arabidopsis resulted in much smaller fruits and dwarf plants. Furthermore, another two hub genes, ZjWRKY23 and ZjWRKY40 transcription factors, were found to participate in fruit size regulation by targeting and downregulating the ZjCKX5 expression. Overexpressing ZjWRKY23 or ZjWRKY40 in tomato led to much larger fruits and promoted plant architecture. Based on these results, a molecular framework for jujube fruit size regulation, namely, ZjWRKY-ZjCKX5 module, was proposed. This study provides a new insight into the molecular networks underlying fruit size regulation.

Recent advances on natural colorants-based intelligent colorimetric food freshness indicators: fabrication, multifunctional applications and optimization strategies.

With the increasing concerns of food safety and public health, tremendous efforts have been concentrated on the development of effective, reliable, nondestructive methods to evaluate the freshness level of different kinds of food. Natural colorants-based intelligent colorimetric indicators which are typically constructed with natural colorants and polymer matrices has been regarded as an innovative approach to notify the customers and retailers of the food quality during the storage and transportation procedure in real-time. This review briefly elucidates the mechanism of natural colorants used for intelligent colorimetric indicators and fabrication methodologies of natural colorants-based food freshness indicators. Subsequently, their multifunctional applications in intelligent food packaging systems like antioxidant packaging, antimicrobial packaging, biodegradable packaging, UV-blocking packaging and inkless packaging are well introduced. This paper also summarizes several optimizing strategies for the practical application of this advanced technology from different perspectives. Strategies like adopting a hydrophobic matrix, constructing double-layer film and encapsulation have been developed to improve the stability of the indicators. Co-pigmentation, metal ion complexation, pigment-mixing and using substrates with high surface area are proved to be effective to enhance the sensitivity of the indicators. Approaches include multi-index evaluation, machine learning and smartphone-assisted evaluation have been proven to improve the accuracy of the intelligent food freshness indicators. Finally, future research opportunities and challenges are proposed. Based on the fundamental understanding of natural colorants-based intelligent colorimetric food freshness indicators, and the latest research and findings from literature, this review article will help to develop better, lower cost and more reliable food freshness evaluation technique for modern food industry.

Pickering emulsion stabilized by Haematococcus pluvialis protein particles and its application in dumpling stuffing.

In this study, the oil-in-water Pickering emulsions were prepared using Haematococcus Pluvialis protein (HPP) particles as an emulsifier by a simple one-step emulsification method. The internal oil phase was as high as 70 % due to the excellent emulsifying properties of HPP, and the average size of oil droplets in the emulsion was around 20 µm. The emulsion prepared by 2.5 % HPP with the oil phase ratio of 70 % showed the best stability after 14 days of storage, and the emulsion could maintain stability at acidic condition, high ionic strength, low and high temperatures. However, all emulsion samples exhibited shear thinning phenomenon, and the higher HPP concentration and oil phase ratio led to greater G' and G″ modulus. NMR relaxation results showed that high concentration HPP could limit the mobility of free water in the emulsion and improve the emulsion stability. The HPP-stabilized emulsion could inhibit the oxidation of oil phase during storage due to the DPPH and ABTS radical scavenging activity of astaxanthin (AST) in HPP. Finally, the nutritional microspheres based on HPP-stabilized emulsion showed good stability in traditional dumplings and could reduce the loss of AST and DHA in algae oil during the boiling of dumplings.

Polymerase-Driven Logic Signal Amplification for the Detection of Small Extracellular Vesicle Surface Proteins and the Identification of Breast Cancer.

Small extracellular vesicles (sEVs) derived from tumors contain a vast amount of cellular information and are regarded as a potential diagnostic biomarker for noninvasive cancer diagnosis. Nevertheless, it remains challenging to accurately measure sEVs from clinical samples due to the low abundance of these vesicles as well as their phenotypic heterogeneity. Herein, a polymerase-driven logic signal amplification system (PLSAS) was developed for the high-sensitivity detection of sEV surface proteins and breast cancer (BC) identification. Aptamers were introduced to serve as sensing modules to specifically recognize target proteins. By changing the input DNA sequences, two polymerase-driven primer exchange reaction systems were rationally designed for DNA logic computing. This allows for autonomous targeting of a limited number of targets using "OR" and "AND" logic, leading to a significant increase in fluorescence signals and enabling the specific and ultrasensitive detection of sEV surface proteins. In this work, we investigated surface proteins of mucin 1 (MUC1) and the epithelial cell adhesion molecule (EpCAM) as model proteins. When MUC1 or EpCAM proteins were used as single signal input in the "OR" DNA logic system, the detection limit of sEVs was 24 or 58 particles/µL, respectively. And MUC1 and EpCAM proteins of sEVs can be simultaneously detected in the AND logic method, which can significantly reduce the effect of phenotypic heterogeneity of sEVs to distinguish the source of sEVs derived from various mammary cell lines, such as MCF-7, MDA MB 231, SKBR3, and MCF-10A. The approach has achieved high discrimination in serologically tested positive BC samples (AUC 98.1%) and holds significant potential in advancing the early diagnosis and prognostic assessments of BC.

The Probiotic Combination of Lacticaseibacillus paracasei JY062 and Lactobacillus gasseri JM1 Alleviates Gastrointestinal Motility Disorder via Improving Gut Microbiota.

Probiotics have received wide attention as a potential way to alleviate gastrointestinal (GI) motility disorders. Herein, we investigated the effects of Lacticaseibacillus paracasei JY062, Lactobacillus gasseri JM1, and the probiotic combination at 5 × 109 CFU/mL on mice induced by loperamide and explored the possible underlying mechanisms in GI motility disorder. After two weeks of probiotic intervention, the results indicated that the probiotic combination alleviated GI motility disorder better. It increased the secretion of excitatory GI regulators motilin, gastrin, and 5-hydroxytryptamine (5-HT) and decreased the secretion of the inhibitory GI regulators peptide YY and nitric oxide (NO), except vasoactive intestinal peptide. 5-HT and NO were related to the mRNA expression of 5-HT4 receptor and nitric oxide synthase, respectively. The intervention of probiotic combination also increased the number of interstitial cells of Cajal and the expression of SCF/c-kit protein. In addition, it also increased the abundance of beneficial bacteria (Lactobacillus, Rikenellaceae, and Clostridiaceae_Clostridium) and improved the contents of short-chain fatty acids in cecum contents of mice. In conclusion, the probiotic combination of L. paracasei JY062 and L. gasseri JM1 has the potential to alleviate GI motility disorders by balancing intestinal homeostasis.

Multi-emitter metal-organic frameworks as ratiometric luminescent sensors for food contamination and spoilage detection.

Food contamination and spoilage is a worldwide concern considering its adverse effect on public health and food security. Real time monitoring food quality can reduce the risk of foodborne disease to consumers. Particularly, the emergence of multi-emitter luminescent metal-organic frameworks (LMOFs) as ratiometric sensory materials has provided the possibility for food quality and safety detection with high sensitivity and selectivity taking advantage of specific host-guest interactions, pre-concentrating and molecule-sieving effects of MOFs. Furthermore, the excellent sensing performance of multi-emitter MOF-based ratiometric sensors including self-calibration, multi-dimensional recognition and visual signal readout is able to meet the increasing rigor requirement of food safety evaluation. Multi-emitter MOF-based ratiometric sensors have become the focus of food safety detection. This review focuses on design strategies for different multiple emission sources assembly to construct multi-emitter MOFs materials based on at least two emitting centers. The design strategies for creating multi-emitter MOFs can be mainly classified into three categories: (1) multiple emission building blocks assembly in a single MOF phase; (2) single non-luminescent MOF or LMOF phase as a matrix for chromophore guest(s); (3) heterostructured hybrids of LMOF with other luminescent materials. In addition, the sensing signal output modes of multi-emitter MOF-based ratiometric sensors have critically discussed. Next, we highlight the recent progress for the development of multi-emitter MOF as ratiometric sensors in food contamination and spoilage detection. Their future improvement and advancing direction potential for their practical application is finally discussed.

A comparison of study on intestinal barrier protection of polysaccharides from Hericium erinaceus before and after fermentation.

The intestinal barrier protects the host from harmful substances. This paper investigated two polysaccharides extracted from the Hericium erinaceus before and after fermentation (HEP and FHEP). The effects of two polysaccharides on the intestinal barrier were investigated in cell and mice models. The results showed that polysaccharides had a protective effect against acrylamide-induced injury in IEC-6 cell. Compared with HEP, FHEP significantly increased TEER and paracellular permeability (P < 0.05). Both polysaccharides the expression of alter tight junction (TJ) and mucin (MUC) as observed in cell Western Bolt (WB). Polysaccharides also enhance the intestinal barrier function in mice by improving cyclophosphamide induced cytokines level, TJ and MUC expression, and gut microbiota. The results showed that FHEP significantly increased IgA, IgG, and IgM levels while decreasing TNF-, IL-1, and IL-6 levels (P < 0.05). The immunohistochemical results showed that both polysaccharides significantly increased the expression of occludin, ZO-1, ZO-2, claudin-3, claudin-4, MUC2 and decreased claudin-2. In parallel, polysaccharides could alter the composition of the gut microbiota, indicating that increased in Bacteriodetes, Firmicutes and decreased in Klebsiella and Shigella. This work provides important views on the protective effect of fermented polysaccharides on the intestinal barrier, and provides a potential mechanism for the beneficial health properties of these biomacromolecules.

Nucleic acid and nanomaterial-assisted signal-amplified strategies in fluorescent analysis of circulating tumor cells and small extracellular vesicles.

As two main types of liquid biopsy markers, both circulating tumor cells (CTCs) and small extracellular vesicles (sEVs) play important roles in the diagnosis and prognosis of cancers. CTCs are malignant cells that detach from the original tumor tissue and enter the circulation of body fluids. sEVs are nanoscale vesicles secreted by normal cells or pathological cells. However, CTCs and sEVs in body fluids are scarce, leading to great difficulties in the accurate analysis of related diseases. For the sensitive detection of CTCs and sEVs in body fluids, various types of nucleic acid and nanomaterial-assisted signal amplification strategies have been developed. In this review, we summarize the recent advances in fluorescent detection of CTCs and sEVs in liquid biopsy based on nucleic acid and nanomaterial-assisted signal amplification strategies. We also discuss their advantages, challenges, and future prospects.

Dual-Channel Fluorescent Probe for the Detection of Peroxynitrite and Glutathione in Mitochondria: Accurate Discrimination of Inflammatory and Progressing Tumor Cells.

Distinguishing between normal, inflammatory, and progressing tumor cells plays a vital role in early diagnoses and clinical studies. The simultaneous quantification of multiple biomarkers in cells can reveal cellular heterogeneity, which contributes to the discrimination of different types of cells. Herein, a dual-channel fluorescent probe has been developed for monitoring peroxynitrite (ONOO-) and glutathione (GSH) to accurately discriminate normal cells, inflammatory cells, and progressing cancer cells. The probe can monitor exogenous and endogenous mitochondrial GSH and ONOO- in living cells and zebrafish by green (530 nm, G530) and red (630 nm, R630) emission based on its good selectivity and low biotoxicity. GSH and ONOO- are visualized via fluorescence imaging, and the corresponding output signals can be employed to differentiate nontumorigenic, malignant, and metastatic breast cells in cocultured cells. Furthermore, the accurate discrimination among normal, inflammatory, and cancerous cells is achieved through the changes in the dual-channel fluorescence signal, which shows great potential for the diagnosis of inflammation and cancer diseases.

Discovery of a tetrahydroisoquinoline-based CDK9-cyclin T1 protein-protein interaction inhibitor as an anti-proliferative and anti-migration agent against triple-negative breast cancer cells.

Triple-negative breast cancer (TNBC) is a highly aggressive and metastasizing cancer that has the worst prognosis out of all breast cancer subtypes. The epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) have been proposed as important mechanisms underlying TNBC metastasis. CDK9 is highly expressed in breast cancer, including TNBC, where it promotes EMT and induces cancer cell stemness. In this study, we have identified a tetrahydroisoquinoline derivative (compound 1) as a potent and selective CDK9-cyclin T1 inhibitor via virtual screening. Interestingly, by targeting the ATP binding site, compound 1 not only inhibited CDK9 activity but also disrupted the CDK9-cyclin T1 protein-protein interaction (PPI). Mechanistically, compound 1 reversed EMT and reduced the ratio of CSCs by blocking the CDK9-cyclin T1 interaction, leading to reduced TNBC cell proliferation and migration. To date, compound 1 is the first reported tetrahydroisoquinoline-based CDK9-cyclin T1 ATP-competitive inhibitor that also interferes with the interaction between CDK9 and cyclin T1. Compound 1 may serve as a promising scaffold for developing more selective and potent anti-TNBC agents. Our work also provides insight into the role of the CDK9-cyclin T1 PPI on EMT and CSCs and highlights the feasibility and significance of targeting CDK9 for the treatment of TNBC.

Ganoderma spp. polysaccharides are potential prebiotics: a review.

The gut microbiota (GM) is a complex ecosystem that is closely linked to host health. Ganoderma spp. polysaccharides (GPs), a major bioactive component of the fungal genus Ganoderma, can modulate the GM, exhibiting various health effects and prebiotic potential. This review comprehensively concluded the structural features and extraction method of GPs. The mechanism of GPs for anti-obesity, anti-diabetes, anti-inflammatory, and anti-cancer were further evaluated. The simulated gastrointestinal digestion of GPs and the utilization mechanism of host microorganisms were discussed. It was found that the physicochemical properties and biological activities of GPs depend on their structural characteristics (molecular weight, monosaccharide composition, glycosidic bonds, etc.). Their extraction method also affects the structure and bioactivities of polysaccharides. GPs supplementation could increase the relative abundance of beneficial bacteria (e.g. Bacteroides, Parabacteroides, Akkermansia, and Bifidobacterium), while reducing that of pathogenic bacteria (e.g. Aerococcus, Ruminococcus), thus promoting health. Moreover, GPs are resistant to digestion in the stomach and small intestine but are digested in the large intestine. Therefore, GPs can be considered as potential prebiotics. However, further studies should investigate how GPs as prebiotics regulate GM and improve host health.

Ratiometrically pH-Insensitive Upconversion Nanoprobe: Toward Simultaneously Quantifying Organellar Calcium and Chloride and Understanding the Interaction of the Two Ions in Lysosome Function.

Calcium and chloride levels are closely related to lysosome dysfunction. However, the simultaneous measurement of calcium (Ca2+) and chloride (Cl-) in acidic subcellular organelles, which is conducive to a deep understanding of lysosome-related biological events, remains a challenge. In this study, we developed a pH-insensitive, ratiometric NIR nanoprobe for the simultaneous detection of Ca2+ and Cl- in acidic lysosomes and determined the roles of the two ions in lysosome function. The upconversion nanoprobe with blue, green, and red emissions was modified with a Ca2+-sensitive dye (Rhod-5N) and Cl--responsive fluorophore (10,10'-bis[3-carboxypropyl]-9,9'-biacridinium dinitrate, BAC). As a result of a dual-luminescence resonance energy transfer between upconversion nanoparticles (UCNPs) and Rhod-5N/BAC, the blue and green upconversion luminescence (UCL) of UCNPs were quenched and the red UCL was used as the reference signal. The ratiometric upconversion nanoprobe possesses a specific ability for the concurrent recognition of Ca2+ and Cl- ions independent of the influence of the environmental pH. To locate the probe in the lysosome, dextran was further modified with upconversion nanoparticles. Then, the nanoprobe with a high spatial resolution was constructed for the simultaneous monitoring of Ca2+ and Cl- in acidic lysosomes. Moreover, it was found that the reduction of lysosomal Cl- affects the release of lysosomal Ca2+, which further blocks the activities of specific lysosomal enzymes. The ratiometric NIR nanoprobe has great potential for decoding and evaluating lysosomal diseases.

Inhibition of the CDK9-cyclin T1 protein-protein interaction as a new approach against triple-negative breast cancer.

Cyclin-dependent kinase 9 (CDK9) activity is correlated with worse outcomes of triple-negative breast cancer (TNBC) patients. The heterodimer between CDK9 with cyclin T1 is essential for maintaining the active state of the kinase and targeting this protein-protein interaction (PPI) may offer promising avenues for selective CDK9 inhibition. Herein, we designed and generated a library of metal complexes bearing the 7-chloro-2-phenylquinoline CˆN ligand and tested their activity against the CDK9-cyclin T1 PPI. Complex 1 bound to CDK9 via an enthalpically-driven binding mode, leading to disruption of the CDK9-cyclin T1 interaction in vitro and in cellulo. Importantly, complex 1 showed promising anti-metastatic activity against TNBC allografts in mice and was comparably active compared to cisplatin. To our knowledge, 1 is the first CDK9-cyclin T1 PPI inhibitor with anti-metastatic activity against TNBC. Complex 1 could serve as a new platform for the future design of more efficacious kinase inhibitors against cancer, including TNBC.