New Awareness of the Interplay Between the Gut Microbiota and Circadian Rhythms.

Circadian rhythms influence various aspects of the biology and physiology of the host, such as food intake and sleep/wake cycles. In recent years, an increasing amount of genetic and epidemiological data has shown that the light/dark cycle is the main cue that regulates circadian rhythms. Other factors, including sleep/wake cycles and food intake, have necessary effects on the composition and rhythms of the gut microbiota. Interestingly, the gut microbiota can affect the circadian rhythm of hosts in turn through contact-dependent and contact-independent mechanisms. Furthermore, the gut microbiota has been shown to regulate the sleep/wake cycles through gut-brain-microbiota interaction. In addition to diabetes, the gut microbiota can also intervene in the progression of neuro- degenerative diseases through the gut-brain-microbiota interaction, and also in other diseases such as hypertension and rheumatoid arthritis, where it is thought to have a spare therapeutic potential. Even though fecal microbiota transplantation has good potential for treating many diseases, the risk of spreading intestinal pathogens should not be ignored.

Actin polymerization and depolymerization in developing vertebrates.

Development is a complex process that occurs throughout the life cycle. F-actin, a major component of the cytoskeleton, is essential for the morphogenesis of tissues and organs during development. F-actin is formed by the polymerization of G-actin, and the dynamic balance of polymerization and depolymerization ensures proper cellular function. Disruption of this balance results in various abnormalities and defects or even embryonic lethality. Here, we reviewed recent findings on the structure of G-actin and F-actin and the polymerization of G-actin to F-actin. We also focused on the functions of actin isoforms and the underlying mechanisms of actin polymerization/depolymerization in cellular and organic morphogenesis during development. This information will extend our understanding of the role of actin polymerization in the physiologic or pathologic processes during development and may open new avenues for developing therapeutics for embryonic developmental abnormalities or tissue regeneration.

The role of fibromodulin in inflammatory responses and diseases associated with inflammation.

Inflammation is an immune response that the host organism eliminates threats from foreign objects or endogenous signals. It plays a key role in the progression, prognosis as well as therapy of diseases. Chronic inflammatory diseases have been regarded as the main cause of death worldwide at present, which greatly affect a vast number of individuals, producing economic and social burdens. Thus, developing drugs targeting inflammation has become necessary and attractive in the world. Currently, accumulating evidence suggests that small leucine-rich proteoglycans (SLRPs) exhibit essential roles in various inflammatory responses by acting as an anti-inflammatory or pro-inflammatory role in different scenarios of diseases. Of particular interest was a well-studied member, termed fibromodulin (FMOD), which has been largely explored in the role of inflammatory responses in inflammatory-related diseases. In this review, particular focus is given to the role of FMOD in inflammatory response including the relationship of FMOD with the complement system and immune cells, as well as the role of FMOD in the diseases associated with inflammation, such as skin wounding healing, osteoarthritis (OA), tendinopathy, atherosclerosis, and heart failure (HF). By conducting this review, we intend to gain insight into the role of FMOD in inflammation, which may open the way for the development of new anti-inflammation drugs in the scenarios of different inflammatory-related diseases.

Runx2 activates hepatic stellate cells to promote liver fibrosis via transcriptionally regulating Itgav expression.

BACKGROUNDS AND AIMS: As a central event during liver fibrosis, hepatic stellate cells (HSC) have been thought to be a potential therapeutic target for liver fibrosis. Previous studies have shown that runt-related transcription factor 2 (Runx2) is associated with the development of non-alcoholic fatty liver disease, while its specific role in HSC activation and hepatic fibrosis remains elusive. APPROACH AND RESULTS: In this study, we found that Runx2 expression was significantly upregulated in human liver fibrosis with different aetiologies. Runx2 expression was also gradually elevated in mouse liver during fibrosis, and Runx2 was mainly expressed in the activated HSC. Knockdown of Runx2 in HSC markedly alleviated CCl4 -induced, 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced or methionine-choline deficient (MCD)-induced liver fibrosis, while hepatic overexpression of Runx2 via HBAAV-Runx2 or VA-Lip-Runx2 injection exacerbated CCl4 -induced liver fibrosis. In vitro analysis demonstrated that Runx2 promoted HSC activation and proliferation, whereas Runx2 knockdown in HSC suppressed these effects. RNA-seq and Runx2 ChIP-seq analysis demonstrated that Runx2 could promote integrin alpha-V (Itgav) expression by binding to its promoter. Blockade of Itgav attenuated Runx2-induced HSC activation and liver fibrosis. Additionally, we found that cytokines (TGF-ß1, PDGF, EGF) promote the expression and nuclear translocation of Runx2 through protein kinase A (PKA) in HSC. CONCLUSIONS: Runx2 is critical for HSC activation via transcriptionally regulating Itgav expression during liver fibrosis, and may be a promising therapeutic target for liver fibrosis.

A Facile and Eco-Friendly Hydrothermal Synthesis of High Tetragonal Barium Titanate with Uniform and Controllable Particle Size.

The preparation of tetragonal barium titanate (BT) powders with uniform and suitable particle sizes is a significant prerequisite for ultra-thin and highly integrated multilayer ceramic capacitors (MLCCs). However, the balance of high tetragonality and controllable particle size remains a challenge, which limits the practical application of BT powders. Herein, the effects of different proportions of hydrothermal medium composition on the hydroxylation process are explored to obtain high tetragonality. The high tetragonality of BT powders under the optimal solvent condition of water:ethanol:ammonia solution of 2:2:1 is around 1.009 and increases with the particle size. Meanwhile, the good uniformity and dispersion of BT powders with particle sizes of 160, 190, 220, and 250 nm benefit from the inhibition of ethanol on the interfacial activity of BT particles (BTPs). The core-shell structure of BTPs is revealed by different lattice fringe spacings of the core and edge and the crystal structure by reconstructed atomic arrangement, which reasonably explains the trend between tetragonality and average particle size. These findings are instructive for the related research on the hydrothermal process of BT powders.

Focused ultrasound-mediated small-molecule delivery to potentiate immune checkpoint blockade in solid tumors.

In the last decade, immune checkpoint blockade (ICB) has revolutionized the standard of treatment for solid tumors. Despite success in several immunogenic tumor types evidenced by improved survival, ICB remains largely unresponsive, especially in "cold tumors" with poor lymphocyte infiltration. In addition, side effects such as immune-related adverse events (irAEs) are also obstacles for the clinical translation of ICB. Recent studies have shown that focused ultrasound (FUS), a non-invasive technology proven to be effective and safe for tumor treatment in clinical settings, could boost the therapeutic effect of ICB while alleviating the potential side effects. Most importantly, the application of FUS to ultrasound-sensitive small particles, such as microbubbles (MBs) or nanoparticles (NPs), allows for precise delivery and release of genetic materials, catalysts and chemotherapeutic agents to tumor sites, thus enhancing the anti-tumor effects of ICB while minimizing toxicity. In this review, we provide an updated overview of the progress made in recent years concerning ICB therapy assisted by FUS-controlled small-molecule delivery systems. We highlight the value of different FUS-augmented small-molecules delivery systems to ICB and describe the synergetic effects and underlying mechanisms of these combination strategies. Furthermore, we discuss the limitations of the current strategies and the possible ways that FUS-mediated small-molecule delivery systems could boost novel personalized ICB treatments for solid tumors.

Spatial analysis of stromal signatures identifies invasive front carcinoma-associated fibroblasts as suppressors of anti-tumor immune response in esophageal cancer.

BACKGROUND: Increasing evidence indicates that the tumor microenvironment (TME) is a crucial determinant of cancer progression. However, the clinical and pathobiological significance of stromal signatures in the TME, as a complex dynamic entity, is still unclear in esophageal squamous cell carcinoma (ESCC). METHODS: Herein, we used single-cell transcriptome sequencing data, imaging mass cytometry (IMC) and multiplex immunofluorescence staining to characterize the stromal signatures in ESCC and evaluate their prognostic values in this aggressive disease. An automated quantitative pathology imaging system determined the locations of the lamina propria, stroma, and invasive front. Subsequently, IMC spatial analyses further uncovered spatial interaction and distribution. Additionally, bioinformatics analysis was performed to explore the TME remodeling mechanism in ESCC. To define a new molecular prognostic model, we calculated the risk score of each patient based on their TME signatures and pTNM stages. RESULTS: We demonstrate that the presence of fibroblasts at the tumor invasive front was associated with the invasive depth and poor prognosis. Furthermore, the amount of α-smooth muscle actin (α-SMA)+ fibroblasts at the tumor invasive front positively correlated with the number of macrophages (MØs), but negatively correlated with that of tumor-infiltrating granzyme B+ immune cells, and CD4+ and CD8+ T cells. Spatial analyses uncovered a significant spatial interaction between α-SMA+ fibroblasts and CD163+ MØs in the TME, which resulted in spatially exclusive interactions to anti-tumor immune cells. We further validated the laminin and collagen signaling network contributions to TME remodeling. Moreover, compared with pTNM staging, a molecular prognostic model, based on expression of α-SMA+ fibroblasts at the invasive front, and CD163+ MØs, showed higher accuracy in predicting survival or recurrence in ESCC patients. Regression analysis confirmed this model is an independent predictor for survival, which also identifies a high-risk group of ESCC patients that can benefit from adjuvant therapy. CONCLUSIONS: Our newly defined biomarker signature may serve as a complement for current clinical risk stratification approaches and provide potential therapeutic targets for reversing the fibroblast-mediated immunosuppressive microenvironment.

MiR-199a-5P promotes osteogenic differentiation of human stem cells from apical papilla via targeting IFIT2 in apical periodontitis.

Introduction: Periapical alveolar bone loss is the common consequence of apical periodontitis (AP) caused by persistent local inflammation around the apical area. Human stem cells from apical papilla (hSCAPs) play a crucial role in the restoration of bone lesions during AP. Studies have recently identified the critical role of microRNAs (miRNAs) involved in AP pathogenesis, but little is known about their function and potential molecular mechanism, especially in the osteogenesis of hSCAPs during AP. Here, we investigated the role of clinical sample-based specific miRNAs in the osteogenesis of hSCAPs. Methods: Differential expression of miRNAs were detected in the periapical tissues of normal and patients with AP via transcriptomic analysis, and the expression of miR-199a-5p was confirmed by qRT-PCR. Treatment of hSCAPs with miR-199a-5p mimics while loaded onto beta-tricalcium phosphate (ß-TCP) ceramic particle scaffold to explore its effect on osteogenesis in vivo. RNA binding protein immunoprecipitation (RIP) and Luciferase reporter assay were conducted to identify the target gene of miR-199a-5p. Results: The expression of miR-199a-5p was decreased in the periapical tissues of AP patients, and miR-199a-5p mimics markedly enhanced cell proliferation and osteogenic differentiation of hSCAPs, while miR-199a-5p antagomir dramatically attenuated hSCAPs osteogenesis. Moreover, we identified and confirmed Interferon Induced Protein with Tetratricopeptide Repeats 2 (IFIT2) as a specific target of miR-199a-5p, and silencing endogenous IFIT2 expression alleviated the inhibitory effect of miR-199a-5p antagomir on the osteogenic differentiation of hSCAPs. Furthermore, miR-199a-5p mimics transfected hSCAPs loaded onto beta-tricalcium phosphate (ß-TCP) scaffolds induced robust subcutaneous ectopic bone formation in vivo. Discussion: These results strengthen our understanding of predictors and facilitators of the key AP miRNAs (miR-199a-5p) in bone lesion repair under periapical inflammatory conditions. And the regulatory networks will be instrumental in exploring the underlying mechanisms of AP and lay the foundation for future regenerative medicine based on dental mesenchymal stem cells.

The nano-windmill exerts superior anti-inflammatory effects via reducing choline uptake to inhibit macrophage activation.

Macrophages' activation plays a central role during the development and progression of inflammation, while the regulation of metabolic reprogramming of macrophages has been recently identified as a novel strategy for anti-inflammatory therapies. Our previous studies have found that tetrahedral framework nucleic acid (tFNA) plays a mild anti-inflammatory effect by inhibiting macrophage activation, but the specific mechanism remains unclear. Here, by metabolomics and RNA sequencing, choline uptake is identified to be significantly repressed by decreased slc44a1 expression in tFNA-treated activated macrophages. Inspired by this result, combined with the excellent delivery capacities of tFNA, siR-slc44a1 is loaded into the tFNA to develop a new tFNA-based small interfering RNA (siRNA) delivery system named 'nano-windmill,' which exhibits a synergetic role by targeting slc44a1, finally blowing up the anti-inflammatory effects of tFNA to inhibit macrophages activation via reducing choline uptake. By confirming its anti-inflammatory effects in chronic (periodontitis) and acute (sepsis) inflammatory disease, the tFNA-based nanomedicine developed for inflammatory diseases may provide broad prospects for tFNA upgrading and various biological applications such as anti-inflammatory.

Sox9CreER-mediated deletion of ß-catenin in palatal mesenchyme results in delayed palatal elevation accompanied with repressed canonical Wnt signaling and reduced actin polymerization.

Cleft palate is a good model to pushing us toward a deeper understanding of the molecular mechanisms of spatiotemporal patterns in tissues and organisms because of the multiple-step processes such as elevation and fusion. Previous studies have shown that the epithelial ß-catenin is crucial for palatal fusion, however, the function of the mesenchymal ß-catenin remains elusive. We investigate the role of mesenchymal ß-catenin in palatal development by generating a ß-catenin conditional knockout mouse (CKO) (Sox9CreER; Ctnnb1F/F ). We found that the CKO mice exhibited delayed palatal elevation, leading to cleft palate in both in vivo and ex vivo. Abnormal cell proliferation and repressed mesenchymal canonical Wnt signaling were found in the CKO palate. Interestingly, Filamentous actin (F-actin) polymerization was significantly reduced in the palatal mesenchyme of mutant embryos. Furthermore, overexpression of adenovirus-mediated transfection with Acta1 in the mutant could help to elevate the palatal shelves but could not prevent cleft palate in ex vivo. Our results suggest that conditionally knock out ß-catenin in the palatal mesenchyme by Sox9CreER leading to delayed palatal elevation, which results in repressed mesenchymal canonical Wnt signaling, decreased cell proliferation, and reduced actin polymerization, finally causes cleft palate.

Promotion of rs3746804 (p. L267P) polymorphism to intracellular SLC52A3a trafficking and riboflavin transportation in esophageal cancer cells.

Riboflavin is an essential micronutrient for normal cellular growth and function. Lack of dietary riboflavin is associated with an increased risk for esophageal squamous cell carcinoma (ESCC). Previous studies have identified that the human riboflavin transporter SLC52A3a isoform (encoded by SLC52A3) plays a prominent role in esophageal cancer cell riboflavin transportation. Furthermore, SLC52A3 gene single nucleotide polymorphisms rs3746804 (T>C, L267P) and rs3746803 (C >T, T278M) are associated with ESCC risk. However, whether SLC52A3a (p.L267P) and (p.T278M) act in riboflavin transportation in esophageal cancer cell remains inconclusive. Here, we constructed the full-length SLC52A3a protein fused to green fluorescent protein (GFP-SLC52A3a-WT and mutants L267P, T278M, and L267P/T278M). It was confirmed by immunofluorescence-based confocal microscopy that SLC52A3a-WT, L267P, T278M, and L267P/T278M expressed in cell membrane, as well as in a variety of intracellular punctate structures. The live cell confocal imaging showed that SLC52A3a-L267P and L267P/T278M increased the intracellular trafficking of SLC52A3a in ESCC cells. Fluorescence recovery after photobleaching of GFP-tagged SLC52A3a meant that intracellular trafficking of SLC52A3a-L267P and L267P/T278M was rapid dynamics process, leading to its stronger ability to transport riboflavin. Taken together, the above results indicated that the rs3746804 (p.L267P) polymorphism promoted intracellular trafficking of SLC52A3a and riboflavin transportation in ESCC cells.

The cGAS-STING Pathway in Bacterial Infection and Bacterial Immunity.

Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS), along with the adaptor stimulator of interferon genes (STING), are crucial components of the innate immune system, and their study has become a research hotspot in recent years. Many biochemical and structural studies that have collectively elucidated the mechanism of activation of the cGAS-STING pathway with atomic resolution have provided insights into the roles of the cGAS-STING pathway in innate immunity and clues to the origin and evolution of the modern cGAS-STING signaling pathway. The cGAS-STING pathway has been identified to protect the host against viral infection. After detecting viral dsDNA, cGAS synthesizes a second messenger to activate STING, eliciting antiviral immune responses by promoting the expression of interferons (IFNs) and hundreds of IFN-stimulated genes (ISGs). Recently, the cGAS-STING pathway has also been found to be involved in response to bacterial infections, including bacterial pneumonia, melioidosis, tuberculosis, and sepsis. However, compared with its functions in viral infection, the cGAS-STING signaling pathway in bacterial infection is more complex and diverse since the protective and detrimental effects of type I IFN (IFN-I) on the host depend on the bacterial species and infection mode. Besides, STING activation can also affect infection prognosis through other mechanisms in different bacterial infections, independent of the IFN-I response. Interestingly, the core protein components of the mammalian cGAS-STING signaling pathway have been found in the bacterial defense system, suggesting that this widespread signaling pathway may have originated in bacteria. Here, we review recent findings related to the structures of major molecules involved in the cGAS-STING pathway and the effects of the cGAS-STING pathway in various bacterial infections and bacterial immunity, which may pave the way for the development of new antibacterial drugs that specifically kill bacteria without harmful effects on the host.

Lithium-induced overexpression of ß-catenin delays murine palatal shelf elevation by Cdc-42 mediated F-actin remodeling in mesenchymal cells.

BACKGROUND: Lithium chloride (LiCl) is widely used for the treatment of manic and other psychotic disorders, but the administration of lithium can result in several congenital defects in the fetus, including cleft palate (Meng, Wang, Torensma, Jw & Bian, 2015) (Szabo, 1970). However, the mechanism of Lithium's action as a developmental toxicant in palatogenesis is not well known. METHODS: In this study, hematoxylin-eosin and immunofluorescence staining were employed to evaluate the phenotypes and the expression of related markers in the LiCl-treated mice model. The palatal mesenchymal cells were cultured in vitro, and stimulated with LiCl or SKL2000, and co-treated with CASIN. ß-catenin protein and other cytoskeleton associated markers were evaluated by Western blotting. RESULTS: We found that Lithium disrupted palate elevation by increasing the expression of ß-catenin in C57BL/6J mice with the high incidence of cleft palate (62.5%). LiCl disturbed the F-actin responsible for cytoskeletal remodeling in mesenchymal cells, which proved to be essential in generating the elevating force during palatal elevation. Additionally, our Western blotting analysis revealed that the overexpression of ß-catenin resulted in up-regulation of Cdc42, which mediated the downstream F-actin synthesis. CONCLUSIONS: We concluded the LiCl-induced ß-catenin overexpression delayed murine palatal shelf elevation by disturbing Cdc42 mediated F-actin cytoskeleton synthesis in the palatal mesenchyme.

A novel colorimetric and "turn-off" fluorescent probe based on catalyzed hydrolysis reaction for detection of Cu2+ in real water and in living cells.

A novel and highly selective fluorescent 1,8-naphthalimide-based probe, 3, was designed and synthesized for rapid Cu2+ detection in a CH3CN-H2O (3:1, v/v, pH = 7.4) solution by means of a distinct hydrolysis mechanism via its Cu2+-promoting feature. Upon treatment with Cu2+, the fluorescence response of probe 3 at 550 nm abruptly decreased, which was visible to the naked eye, and this response was accompanied by a clear change of the color of the solution; the color changed from the original yellow color to colorless. This color change occurred due to the Cu2+-promoted hydrolysis of 3, which yielded a fluorescence-quenched product. It is inspiring that probe 3 exhibited excellent sensitivity, a short response time and strong anti-interference recognition. Compared with the allowable amount of Cu2+ (∼20 µM) in drinking water, the detection limit of 3 for Cu2+ is calculated to be 9.15 nM, which is much lower than the amount defined by standards. The probe can be successfully applied for the determination of Cu2+ in real aqueous samples. Furthermore, probe 3 can be used as a fluorescent sensor to detect Cu2+ in biological environments, demonstrating its low toxicity to organisms and good cell permeability in live cell imaging.

Dietary riboflavin deficiency promotes N-nitrosomethylbenzylamine-induced esophageal tumorigenesis in rats by inducing chronic inflammation.

Epidemiological studies in high-incidence areas of esophageal cancer in China suggest that environmental carcinogen N-nitrosomethylbenzylamine (NMBA) and riboflavin (RBF) deficiency may be the main risk factors for esophageal cancer. However, it is not clear that the combination induces cancer. Here, experiment (Exp) 1 evaluated the effects of NMBA and RBF deficiency individually or in combination on esophageal tumorigenesis. Male F344 rats were randomly assigned to 4 groups into a 2 (no NMBA vs. NMBA) × 2 (normal RBF vs. RBF-deficient) factorial design, including normal RBF (6 mg/kg, R6), RBF-deficient (0 mg/kg, R0), normal RBF combined with NMBA (R6N), and RBF-deficient combined with NMBA (R0N) groups. The Exp 2 explored the effects of RBF deficiency at different doses combined with NMBA (0.6 mg/kg, R0.6N; 0.06 mg/kg, R0.06N) on esophageal tumorigenesis. Results showed that R0N enhanced the incidence of esophageal intraepithelial neoplasia (EIN, 53.3%, P = 0.06), including carcinoma in situ, whereas R6N mainly induced the occurrence of esophageal benign hyperplasia (38.9%) and EIN (16.7%). RBF deficiency promotes EIN in a dose-dependent manner, and R0.06N significantly increases the incidence of EIN (57.9%, P < 0.05). Gene expression profiling demonstrated that inflammatory cytokines were highly expressed in R0N EIN tissues, whereas R6N EIN tissues had a proliferation and differentiation gene signature (fold-change > 1.5). Furthermore, RBF deficiency aggravated oxidative DNA damage (8-OHdG) and double-strand breaks (γH2AX) (P < 0.05). Our results suggest that RBF deficiency causes chronic inflammation-associated genomic instability contributes to NMBA-induced esophageal tumorigenesis.

Di-(2-ethylhexyl)-phthalate interferes with T-follicular helper cell differentiation and cytokine secretion through signaling lymphocytic activation molecule family member-1.

Exposure to the widely-used phthalate plasticizer di-(2-ethylhexyl)-phthalate (DEHP) has been shown to be closely related to an increased prevalence of allergic diseases in infants and juveniles. Earlier work in our laboratory found that DEHP-related anaphylactic responses could be ascribed to T-follicular helper (Tfh) cell hyperfunction directly. The Tfh cell, a newly identified CD4+ TH cell subset, until recently has been considered as a key player in humoral immunity. Tfh cells can respond to stimulation through various receptors. Signaling lymphocytic activation molecule family member-1 (SLAMF1, CD150) is a surface co-stimulatory receptor that can bind to an intracytoplasmic adaptor signaling lymphocytic activation molecule-associated protein (SAP) to initiate downstream signaling cascades, regulating some events of immune response. The present study explored the role of SLAMF1 in Tfh cell differentiation and cytokine secretion under the condition of DEHP exposure. Using a weanling mice model of DEHP gavage with ovalbumin (OVA) sensitization, it was found that DEHP acted as an immunoadjuvant to elevate SLAMF1 and SAP expression in host Tfh cells. Ex vivo studies of effects from DEHP exposure on Tfh cells from OVA-sensitized hosts showed that DEHP acted in an adjuvant-like manner to promote the expression of adaptor protein SAP, transcription factors Bcl-6 and c-MAF, and cytokines interleukin (IL)-21 and IL-4 in Tfh cells. Transfection of these Tfh cells with Slamf1 small interfering RNA prior to exposure to the DEHP attenuated the over-expression of these molecules that was caused by the DEHP. In conclusion, this study demonstrated that DEHP, via a SLAMF1-mediated pathway, can impact on Tfh cell differentiation and their ability to form select cytokines.

A New Fluorescent Chemosensor for Cobalt(II) Ions in Living Cells Based on 1,8-Naphthalimide.

In this work, a highly selective fluorescent chemosensor N-(2-(2-butyl-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-6-yl)hydrazine-1-carbonothioyl)benzamide (L) was prepared and characterized. An assay to detect the presence of cobalt(II) ions was developed by utilizing turn-on fluorescence enhancement with visual colorimetric response. Upon treatment with Co2+, a remarkable fluorescence enhancement located at 450 nm was visible to naked eyes accompanied with a distinct color change (from pink to colorless) in a CH3CN/HEPES (4/1, v/v, pH = 7.4) solution due to the formation of a 1:1 complex at room temperature. In addition, the linear concentration range for Co2+ was 0-25 µM with the limit of detection down to 0.26 µM. Thus, a highly sensitive fluorescent method based on chelation-assisted fluorescence enhancement was developed for the trace-level detection of Co2+. The sensor was found to be highly selective toward Co2+ ions with a large number of coexisting ions. Furthermore, the L probe can serve as a fluorescent sensor for Co2+ detecting in biological environments, demonstrating its low toxic properties to organisms and good cell permeability in live cell imaging.

CDKN2B upregulation prevents teratoma formation in multipotent fibromodulin-reprogrammed cells.

Tumorigenicity is a well-documented risk to overcome for pluripotent or multipotent cell applications in regenerative medicine. To address the emerging demand for safe cell sources in tissue regeneration, we established a novel, protein-based reprogramming method that does not require genome integration or oncogene activation to yield multipotent fibromodulin (FMOD)-reprogrammed (FReP) cells from dermal fibroblasts. When compared with induced pluripotent stem cells (iPSCs), FReP cells exhibited a superior capability for bone and skeletal muscle regeneration with markedly less tumorigenic risk. Moreover, we showed that the decreased tumorigenicity of FReP cells was directly related to an upregulation of cyclin-dependent kinase inhibitor 2B (CDKN2B) expression during the FMOD reprogramming process. Indeed, sustained suppression of CDKN2B resulted in tumorigenic, pluripotent FReP cells that formed teratomas in vivo that were indistinguishable from iPSC-derived teratomas. These results highlight the pivotal role of CDKN2B in cell fate determination and tumorigenic regulation and reveal an alternative pluripotent/multipotent cell reprogramming strategy that solely uses FMOD protein.

A novel dithiourea-appended naphthalimide "on-off" fluorescent probe for detecting Hg2+ and Ag+ and its application in cell imaging.

An effective dithiourea-appended 1,8-naphthalimide fluorescent probe was designed and synthesized. This probe could recognize Hg2+ and Ag+ sensitively and selectively in neutral and alkaline conditions. Moreover, the probe detected Hg2+ alone at pH between 2 and 6. The sensing ability of the probe was explored by UV-vis, fluorescence, FTIR and 1H NMR spectroscopy. The probe was quenched by Hg2+ and Ag+ with 1:1 binding ratios in MeCN/H2O (4/1, v/v) mixed solution with binding constants of 3.76 × 104 L mol-1 and 2.47 × 104 L mol-1, respectively. The linear concentration ranges for Hg2+ and Ag+ were 0-17 µmol L-1 and 0-24 µmol L-1 with detection limits of 0.83 µmol L-1 and 1.20 µmol L-1, respectively, which allowed for the quantitative determination of Hg2+ and Ag+. The new probe, 3a, was successfully applied to the fluorescence imaging of Hg2+ and Ag+ in HepG2 cells, demonstrating its potential application in biological science. Moreover, 3a was used to measure Hg2+ and Ag+ in tap water, drinking water and ultrapure water samples. The recoveries of Hg2+ and Ag+ in water samples were 96-99% and 98-103%, respectively. Therefore, the proposed method showed promising perspectives for its application, aimed at detecting Hg2+ and Ag+ in fluorescence imaging and real water samples.

Small Leucine-Rich Proteoglycans in Skin Wound Healing.

Healing of cutaneous wounds is a complex and well-coordinated process requiring cooperation among multiple cells from different lineages and delicately orchestrated signaling transduction of a diversity of growth factors, cytokines, and extracellular matrix (ECM) at the wound site. Most skin wound healing in adults is imperfect, characterized by scar formation which results in significant functional and psychological sequelae. Thus, the reconstruction of the damaged skin to its original state is of concern to doctors and scientists. Beyond the traditional treatments such as corticosteroid injection and radiation therapy, several growth factors or cytokines-based anti-scarring products are being or have been tested in clinical trials to optimize skin wound healing. Unfortunately, all have been unsatisfactory to date. Currently, accumulating evidence suggests that the ECM not only functions as the structural component of the tissue but also actively modulates signal transduction and regulates cellular behaviors, and thus, ECM should be considered as an alternative target for wound management pharmacotherapy. Of particular interest are small leucine-rich proteoglycans (SLRPs), a group of the ECM, which exist in a wide range of connecting tissues, including the skin. This manuscript summarizes the most current knowledge of SLRPs regarding their spatial-temporal expression in the skin, as well as lessons learned from the genetically modified animal models simulating human skin pathologies. In this review, particular focus is given on the diverse roles of SLRP in skin wound healing, such as anti-inflammation, pro-angiogenesis, pro-migration, pro-contraction, and orchestrate transforming growth factor (TGF)ß signal transduction, since cumulative investigations have indicated their therapeutic potential on reducing scar formation in cutaneous wounds. By conducting this review, we intend to gain insight into the potential application of SLRPs in cutaneous wound healing management which may pave the way for the development of a new generation of pharmaceuticals to benefit the patients suffering from skin wounds and their sequelae.