Progress of Bone Marrow Mesenchymal Stem Cell Mitochondrial Transfer in Organ Injury Repair.

There has been an upsurge of interest in the bone marrow mesenchymal stem cell (BMSC) mitochondrial transfer as a potential therapeutic innovation in organ injury repair. Previous research mainly focused on its transfer routes and therapeutic effects. However, its intrinsic mechanism has not been well deciphered. The current research status needs to be summarized for the clarification of future research direction. Therefore, we review the recent significant progress in the application of BMSC mitochondrial transfer in organ injury repair. The transfer routes and effects are summarized, and some suggestions on the future research direction are provided.

Dual-Site Chemosensor for Monitoring ·OH-Cysteine Redox in Cells and In Vivo.

The reaction between hydroxyl radical (·OH) and cysteine (Cys) plays an important role in the redox balance of living cells. A deeper insight into this intracellular reaction modulation and process is necessary and draws great interest. A highly effective technique consists of the real-time visualization of the two bioactive species and the perception of their respective changes by using a fluorescent probe. In this study, a dual-site chemosensor SPI based on phenothiazine-cyanine was developed, which realized quantitative detection and real-time imaging of ·OH and Cys at their own fluorescence channels (·OH: λex = 485 nm, λem = 608 nm; Cys: λex = 426 nm, λem = 538 nm) without spectral crosstalk. The fluorescent sensor showed excellent anti-interference and selectivity for common biological substances, apart from the successful imaging of exogenous and endogenous ·OH and Cys. We further visualized the redox dynamic reaction and explored the correlation of ·OH and Cys generated by different inhibitors (sulfasalazine and (1S, 3R)-RSL3). Notably, the chemosensor also possesses the capacity to clearly monitor ·OH and Cys in living mice and zebrafish. This study reports on the first chemosensor to investigate the process of intracellular redox modulation and control between ·OH and Cys, which show potential to further explore some metabolic and physiological mechanisms.

Connexin 43 Channels in Osteocytes Are Necessary for Bone Mass and Skeletal Muscle Function in Aged Male Mice.

Osteoporosis and sarcopenia (termed "Osteosarcopenia"), the twin-aging diseases, are major contributors to reduced bone mass and muscle weakness in the elderly population. Connexin 43 (Cx43) in osteocytes has been previously reported to play vital roles in bone homeostasis and muscle function in mature mice. The Cx43-formed gap junctions (GJs) and hemichannels (HCs) in osteocytes are important portals for the exchange of small molecules in cell-to-cell and cell-to-extracellular matrix, respectively. However, the roles of Cx43-based GJs and HCs in both bone and muscle aging are still unclear. Here, we used two transgenic mouse models with overexpression of the dominant negative Cx43 mutants primarily in osteocytes driven by the 10-kb Dmp1 promoter, R76W mice (inhibited gap junctions but enhanced hemichannels) and Δ130-136 mice (both gap junction and hemichannels are inhibited), to determine the actions of Cx43-based hemichannels (HCs) and gap junctions (GJs) in the regulation of bone and skeletal muscle from aged mice (18 months) as compared with those from adult mice (10 months). We demonstrated that enhancement of Cx43 HCs reduces bone mass due to increased osteoclast surfaces while the impairment of Cx43 HCs increases osteocyte apoptosis in aged mice caused by reduced PGE2 levels. Furthermore, altered mitochondrial homeostasis with reduced expression of Sirt-1, OPA-1, and Drp-1 resulted in excessive ROS level in muscle soleus (SL) of aged transgenic mice. In vitro, the impairment of Cx43 HCs in osteocytes from aged mice also promoted muscle collagen synthesis through activation of TGFß/smad2/3 signaling because of reduced PGE2 levels in the PO CM. These findings indicate that the enhancement of Cx43 HCs while GJs are inhibited reduces bone mass, and the impairment of Cx43 HCs inhibits PGE2 level in osteocytes and this reduction promotes muscle collagen synthesis in skeletal muscle through activation of TGFß/smad2/3 signaling, which together with increased ROS level contributes to reduced muscle force in aged mice.

Functional Heterogeneity of Bone Marrow Mesenchymal Stem Cell Subpopulations in Physiology and Pathology.

Bone marrow mesenchymal stem cells (BMSCs) are multi-potent cell populations and are capable of maintaining bone and body homeostasis. The stemness and potential therapeutic effect of BMSCs have been explored extensively in recent years. However, diverse cell surface antigens and complex gene expression of BMSCs have indicated that BMSCs represent heterogeneous populations, and the natural characteristics of BMSCs make it difficult to identify the specific subpopulations in pathological processes which are often obscured by bulk analysis of the total BMSCs. Meanwhile, the therapeutic effect of total BMSCs is often less effective partly due to their heterogeneity. Therefore, understanding the functional heterogeneity of the BMSC subpopulations under different physiological and pathological conditions could have major ramifications for global health. Here, we summarize the recent progress of functional heterogeneity of BMSC subpopulations in physiology and pathology. Targeting tissue-resident single BMSC subpopulation offers a potentially innovative therapeutic strategy and improves BMSC effectiveness in clinical application.

Update on the effects of energy metabolism in bone marrow mesenchymal stem cells differentiation.

BACKGROUND: As common progenitor cells of osteoblasts and adipocytes, bone marrow mesenchymal (stromal) stem cells (BMSCs) play key roles in bone homeostasis, tissue regeneration, and global energy homeostasis; however, the intrinsic mechanism of BMSC differentiation is not well understood. Plasticity in energy metabolism allows BMSCs to match the divergent demands of osteo-adipogenic differentiation. Targeting BMSC metabolic pathways may provide a novel therapeutic perspective for BMSC differentiation unbalance related diseases. SCOPE OF REVIEW: This review covers the recent studies of glucose, fatty acids, and amino acids metabolism fuel the BMSC differentiation. We also discuss recent findings about energy metabolism in BMSC differentiation. MAJOR CONCLUSIONS: Glucose, fatty acids, and amino acids metabolism provide energy to fuel BMSC differentiation. Moreover, some well-known regulators including environmental stress, hormone drugs, and biological and pathological factors may also influence BMSC differentiation by altering metabolism. This offers insight to the significance of metabolism on BMSC fate determination and provides the possibility of treating diseases related to BMSC differentiation, such as obesity and osteoporosis, from a metabolic perspective.

Colorimetric detection of alkaline phosphatase activity based on pyridoxal phosphate-induced chromatic switch of polydiacetylene nano-liposomes.

A colorimetric assay based on polydiacetylenes (PDA) nano-liposomes is reported for facile and sensitive detection of alkaline phosphatase (ALP) activity. The critical basis of this method is that the interaction of pyridoxal phosphate (PLP) with nitrogenous group functionalized PDA nano-liposomes induces distinct blue-to-red color changes of PDA nano-liposomes. In the presence of ALP, as a nature substrate, PLP is enzymatically hydrolyzed to form pyridoxal, which cannot interact with PDA nano-liposomes. As a result, the concentration of PLP is reduced and the color change of PDA nano-liposomes is retarded, which is associated with ALP level. Under optimal conditions, the proposed method showed good linear relationship with ALP activity in the range 10-200 U/L with a limit of detection of 2.8 U/L. The detection process could be vividly observed with the naked eye. Additional attempts by using the method for the evaluation of inhibitor efficiency were also achieved with satisfying results. The method was further challenged with real human serum samples, showing consistent results when compared with a commercial standard assay kit. Such simple and easy-to-use approach may provide a new alternative for clinical and biological detection of ALP.

Primary Osteocyte Supernatants Metabolomic Profiling of Two Transgenic Mice With Connexin43 Dominant Negative Mutants.

Osteocytes could release some small molecules (≤ 1 kDa) through gap junctions and hemichannels to extracellular environment, such as prostaglandin E2 (PGE2), nitric oxide (NO) and adenosine triphosphate (ATP), which play key roles in transferring signals between bone cells and other tissue cells. Connexin (Cx) 43 is the most abundant connexin in osteocytes. To further discover molecules released by osteocytes through Cx43 channels and better understand the regulatory function of Cx43 channels in osteocytes, we performed non-targeted global metabolomics analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) on conditioned medium collected from osteocytes isolated from two transgenic mouse models with Cx43 dominant negative mutants driven by a 10 kb-DMP1 promoter: R76W (gap junctions are blocked, whereas hemichannels are promoted) and Δ130-136 (both gap junctions and hemichannels are blocked). The results revealed that several new categories of molecules, such as "fatty acyls" and "carboxylic acids and derivatives", could be released through osteocytic Cx43 channels. In addition, alteration of Cx43 channel function affected the release of metabolites related to inflammatory reaction and oxidative stress. Pathway analysis further showed that citric acid cycle was the most differential metabolic pathway regulated by Cx43 channels. In sum, these results isolated new potential metabolites released by osteocytes through Cx43 channels, and offered a novel perspective to understand the regulatory mechanisms of osteocytes on themselves and other cells as well.

Polydiacetylene liposomes with phenylboronic acid tags: a fluorescence turn-on sensor for sialic acid detection and cell-surface glycan imaging.

Sialic acid (SA) located at the terminal end of glycans on cell membranes has been shown to play an important yet distinctive role in various biological and pathological processes. Effective methods for the facile, sensitive and in situ analysis of SA on living cell surfaces are of great significance in terms of clinical diagnostics and therapeutics. Here, a new polydiacetylene (PDA) liposome-based sensor system bearing phenylboronic acid (PBA) and 1,8-naphthalimide derived fluorophore moieties was developed as a fluorescence turn-on sensor for the detection of free SA in aqueous solution and the in situ imaging of SA-terminated glycans on living cell surfaces. In the sensor system, three diacetylene monomers, PCDA-pBA, PCDA-Nap and PCDA-EA, were designed and synthesized to construct the composite PDA liposome sensor. The monomer PCDA-pBA modified with PBA molecules was employed as a receptor for SA recognition, while the monomer PCDA-Nap containing a 1,8-naphthalimide derivative fluorophore was used for fluorescence signaling. When the composite PDA liposomes were formed, the energy transfer between the fluorophore and the conjugated backbone could directly quench the fluorescence of the fluorophore. In the presence of additional SA or SA abundant cells, the strong binding of SA with PBA moieties disturbed the pendent side chain conformation, resulting in the fluorescence restoration of the fluorophore. The proposed methods realized the fluorescence turn-on detection of free SA in aqueous solution and the in situ imaging of SA on living MCF-7 cell surfaces. This work provides a new potential tool for simple and selective analysis of SA on living cell membranes.

Fabrication of Polydiacetylene Liposome Chemosensor with Enhanced Fluorescent Self-Amplification and Its Application for Selective Detection of Cationic Surfactants.

Polydiacetylene (PDA) materials have been adopted as one of the powerful conjugated polymers for sensing applications due to their unique optical properties. In this paper, we present a new PDA liposome-based sensor system with enhanced fluorescent self-amplification by tuning a fluorophore fluorescence emission. In this system, a 1,8-naphthalimide derivative employed as a highly fluorescent fluorophore was incorporated into a PDA supermolecule. During the formation of blue PDA liposomes, the fluorescence emission of the fluorophore can be directly quenched, while thermal-induced phase transition of PDA liposomes from blue to red can readily restore this fluorescence emission. These phenomena could be ascribed to the tunable Förster energy transfer between the excited fluorophore and PDA conjugated framework. To demonstrate the sensing performance of this newly prepared PDA liposome-based sensor, the sensor with fluorescent self-amplification was successfully applied for the detection of cationic surfactants (CS). The results show that the PDA liposomes displayed a distinct color change and fluorescence restoration in the presence of cationic surfactant species, and allowed detection of cationic surfactants with high sensitivity and selectivity. The limit of detection for target CS, such as cetyltrimethylammonium bromide (CTAB), can reach as low as 184 nM. Compared to the traditional methods based on colorimetric PDA liposomes, this newly fabricated PDA sensor system was superior for sensitivity. Thus, our findings offer an avenue for the design and development of new types of PDA sensors with enhanced sensitivity.

Branched truxene and triindole compounds and their solid-state luminescent enhancement.

C3-symmetric truxene and triindole have been widely used to design the branched optoelectronic molecules. However, most of them exhibit high luminous efficiency in the solution and quenched luminescence in the solid state. Here, we respectively chose alkylated truxene and triindole as the central core, 2-methylphenyl as the peripheral functional groups to synthesize three branched compounds. Their photophysical properties have been explored combining with the theoretical calculation. The three compounds exhibit good solubility and high solid-state fluorescence quantum yields. The absorption and emission peaks of triindole compound exhibit apparent red-shift in comparison with those of truxene compounds, which indicates triindole more highly electron delocalization than truxene. The single-crystal structure shows that alkylation of the central core and branched steric bulkiness of these molecules effectively reduce the intermolecular π⋯π stacking and avoid the non-radiative transition of these molecules from excited state to ground state in the solid state.

Quantum dots modified with quaternized poly(dimethylaminoethyl methacrylate) for selective recognition and killing of bacteria over mammalian cells.

Copper-free click chemistry has been used to graft quaternized poly(dimethylaminoethyl methacrylate) (QPA) modified with azide to the quantum dots (QDs) derived with dibenzocyclooctynes (DBCO). The success of the quaternary ammonium polymer-modified QDs was confirmed by ultraviolet-visible spectrophotometry (UV-Vis), fluorescence spectroscopy, zeta (ζ) potential, size distribution, and transmission electron microscopy (TEM). The QPA-modified QDs exhibited properties of selective recognition and killing of bacteria. The novelty of this study lies in fact that the synthesis method of the antimicrobial QPA-modified QDs is simple. Moreover, from another standpoint, QPA-modified QDs simultaneously possess abilities of selective recognition and killing of bacteria over mammalian cells, which is very different from the currently designed multifunctional antimicrobial systems composed of complicated systematic compositions.

A TBET-based ratiometric probe for Au(3+) and its application in living cells.

In this paper, we designed and synthesized a novel TBET-based ratiometric fluorescent chemodosimeter, RH-Au, for Au(3+). It was found that the probe RH-Au displayed highly selective, sensitive and naked-eye detection upon the addition of Au(3+). The probe RH-Au can be used in the pH range 6.0-7.5 and the detection limit was determined to be as low as 2.91 nM (0.57 ppb). We also demonstrated a successful application of imaging Au(3+) in living cells using RH-Au.

Truxene-cored π-expanded triarylborane dyes as single- and two-photon fluorescent probes for fluoride.

Fluoride anion (F(-)) significantly affects chemical, biological, and environmental processes. Fluoride recognition and detection have received increasing attention. Convenient, effective, and sensitive fluorescent probes for F(-) should urgently be designed and synthesized. In this study, we describe a strategy for constructing two triarylborane-based fluoride fluorescent probes: 2,7,12-tri(2-(5-(dimesitylboryl)thiophen-2-yl)ethynyl)-5,5',10,10',15,15'-hexaethyltruxene (C3B3) with π-3A (acceptor) configuration and 2,7-di(N,N-diphenylamino)-12-(5-(dimesitylboryl)thiophen-2-yl)-5,5',10,10',15,15'-hexaethyltruxene (N2SB) with 2D (donor)-π-A configuration. The loss of color of the tetrahydrofuran solution of these probes from greenish yellow suggests that they can conveniently monitor F(-) at a low concentration (10 µM) free of apparatus. The different structural features of these probes varied their fluorescent responses to F(-). The single-photon fluorescence intensity of C3B3 declined to 90% upon the addition of 4.5 equivalents of F(-) to its tetrahydrofuran solution. However, the single-photon fluorescence intensity of N2SB was enhanced six-fold upon addition of 2.5 equivalents of the F(-). Under the experimental conditions, the detection limits of the two probes for F(-) can reach 12-13 µM (C3B3) and 3-5 µM (N2SB). The ability of the two probes in detecting F(-) in their toluene solutions in the two-photon mode was also investigated. The sensitive two-photon fluorescence responses of both probes make them excellent two-photon fluorescence probes.

Synthesis, characterization and activity evaluation of matrinic acid derivatives as potential antiproliferative agents.

A series of new matrinic acid derivatives 5a-e was synthesized. The chemical structures of the synthesized compounds were confirmed by ¹H-NMR, ¹³C-NMR, and electrospray ionization mass spectroscopy. The anti-tumor activities were also investigated in vitro by evaluating the effect of synthesized compounds on the proliferation of A375, A549, HeLa, and HepG2 cells. Compound 5e was found to be the most potent against A375 and HeLa cells, with IC50 values of 37 and 75.5 µg/mL, respectively. Compounds 5b, 5c, 5g, and 5h also exhibited antiproliferative activities against A549 cells, with IC50 values within the 36.2-47 µg/mL range. For HepG2 cells, 5e and 5i, with IC50 values of 78.9 and 61 µg/mL, respectively, showed higher antiproliferative activity than taxol.

Click synthesis of neutral, cationic, and zwitterionic poly(propargyl glycolide)-co-poly(ɛ-caprolactone)-based aliphatic polyesters as antifouling biomaterials.

With the development of polymer-based biomaterials, aliphatic polyesters have attracted considerable interest because of their non-toxicity, non-allergenic property, and good biocompatibility. However, the hydrophobic nature and the lack of side chain functionalities of aliphatic polyesters limit their biomedical applications. In this study, we prepared four new polyesters: poly(sulfobetaine methacrylate)-, poly(2-methacryloyloxyethyl phosphotidylcholine)-, poly(ethylene glycol)-, and quaternized poly[(2-dimethylamino)ethyl methacrylate]-grafted poly(propargyl glycolide)-co-poly(ɛ-caprolactone). Their synthesis was conducted through ring-opening polymerization of acetylene-functionalized lactones and subsequent graft of bioactive units using click chemistry. The chemical structures of the polyesters were characterized through nuclear magnetic resonance and Fourier-transform infrared spectroscopy, and their physical properties (including molecular weight, glass transition temperature, and melting point) were determined using gel permeation chromatography and differential scanning calorimetry. For studies on their hydrophilicity, stability, and anti-bioadhesive property, a series of polymeric surfaces of these polyesters was prepared by coating them onto glass substrates. The hydrophilicity and stability of these polyester surfaces were examined by contact angle measurements and attenuated total reflection Fourier-transform infrared spectroscopy. Their anti-bioadhesive property was investigated through protein adsorption, as well as cellular and bacterial adhesion assays. The prepared polyesters showed good hydrophilicity and long-lasting stability, as well as significant anti-fouling property. The newly prepared polyesters could be developed as promising anti-fouling materials with extensive biomedical applications.

Nitrogen-containing apigenin analogs: preparation and biological activity.

A series of nitrogen-containing apigenin analogs 4a-j was synthesized via Mannich reactions to develop anticancer, antibacterial, and antioxidant agents from plant-derived flavonoids. The chemical structures of these compounds were confirmed using (1)H-NMR, (13)C-NMR, and ESI-MS. The in vitro biological activities of the analogs were evaluated via assays of their antiproliferative, antibacterial, and antioxidant activities. The prepared apigenin analogs exhibited different antiproliferative activities against four human cancer cell lines, namely human cervical (HeLa), human hepatocellular liver (HepG2), human lung (A549), and human breast (MCF-7) cancer cells. Compound 4i showed the most favorable in vitro antiproliferative activity with IC50 values of 40, 40, 223, and 166 µg/mL against HeLa, HepG2, A549, and MCF-7, respectively. The 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging activity assay also showed that 4i had the most potent antioxidant activity, with the smallest IC(50) value (334.8 µg/mL). The antibacterial activities of the analogs were determined using a two-fold serial dilution technique against four pathogenic bacteria, namely Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa. All the prepared apigenin analogs exhibited more potent activities than the parent apigenin. Compounds 4h and 4j, in particular, exhibited the best inhibitory activities against the Gram-positive bacteria Staphylococcus aureus and Bacillus subtilis with MIC values of 3.91 and 1.95 µg/mL, respectively.