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.

Role of irisin in physiology and pathology.

Irisin, out-membrane part of fibronectin type III domain-containing 5 protein (FNDC5), was activated by Peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) during physical exercise in skeletal muscle tissues. Most studies have reported that the concentration of irisin is highly associated with health status. For instance, the level of irisin is significantly lower in patients with obesity, osteoporosis/fractures, muscle atrophy, Alzheimer's disease, and cardiovascular diseases (CVDs) but higher in patients with cancer. Irisin can bind to its receptor integrin αV/ß5 to induce browning of white fat, maintain glucose stability, keep bone homeostasis, and alleviate cardiac injury. However, it is unclear whether it works by directly binding to its receptors to regulate muscle regeneration, promote neurogenesis, keep liver glucose homeostasis, and inhibit cancer development. Supplementation of recombinant irisin or exercise-activated irisin might be a successful strategy to fight obesity, osteoporosis, muscle atrophy, liver injury, and CVDs in one go. Here, we summarize the publications of FNDC5/irisin from PubMed/Medline, Scopus, and Web of Science until March 2022, and we review the role of FNDC5/irisin in physiology and pathology.

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.

Effects of Immobilization and Swimming on the Progression of Osteoarthritis in Mice.

Osteoarthritis (OA) is a chronic joint disease characterized by the degeneration of articular cartilage and thickening and sclerosis of the subchondral bone. Mechanical factors play significant roles in the development and progression of OA, but it is still controversial whether exercise or rest is a more effective treatment for OA patients. In this study, we compared the effects of swimming and immobilization at different stages of OA in mice. Four weeks (the middle stage of OA) or eight weeks (the late stage of OA) after DMM (destabilization of the medial meniscus) surgery, the mice were subjected to four-week immobilization or swimming. Ink blot analysis and a beam walking test were performed to measure the gait and balance ability. Histological analysis was performed to determine the trabecular bone area, the thickness of subchondral bone, the thickness of the cartilage, the OARSI score, and the expression of MMP13 (matrix metalloproteinases) and IL-6 (interleukin). The results showed that at the middle stage of OA, both immobilization and swimming slowed down the progression of OA. Immobilization relieved OA to a certain extent by decreasing the production of regulatory factors to attenuate the degeneration of cartilage, which partly relieved the effects of DMM on gait, mainly in the hindlimb. Swimming mainly attenuated the thickening and rescued the area of subchondral bone.

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.

Muscle-bone crosstalk and potential therapies for sarco-osteoporosis.

The nature of muscle-bone crosstalk has been historically considered to be only mechanical, where the muscle is the load applier while bone provides the attachment sites. However, this dogma has been challenged with the emerging notion that bone and muscle act as secretory endocrine organs affect the function of each other. Biochemical crosstalk occurs through myokines such as myostatin, irisin, interleukin (IL)-6, IL-7, IL-15, insulin-like growth factor-1, fibroblast growth factor (FGF)-2, and ß-aminoisobutyric acid and through bone-derived factors including FGF23, prostaglandin E2 , transforming growth factor ß, osteocalcin, and sclerostin. Aside from the biochemical and mechanical interaction, additional factors including aging, circadian rhythm, nervous system network, nutrition intake, and exosomes also have effects on bone-muscle crosstalk. Here, we summarize the current research progress in the area, which may be conductive to identify potential novel therapies for the osteoporosis and sarcopenia, especially when they develop in parallel.

Osteocytic connexin 43 channels affect fracture healing.

The cross-talk between cells is very critical for moving forward fracture healing in an orderly manner. Connexin (Cx) 43-formed gap junctions and hemichannels mediate the communication between adjacent cells and cells and extracellular environment. Loss of Cx43 in osteoblasts/osteocytes results in delayed fracture healing. For investigating the role of two channels in osteocytes in bone repair, two transgenic mouse models with Cx43 dominant negative mutants driven by a 10 kb-DMP1 promoter were generated: R76W (gap junctions are blocked, whereas hemichannels are promoted) and Δ130-136 (both gap junctions and hemichannels are blocked). R76W mice (promotion of hemichannels) showed a significant increase of new bone formation, whereas delayed osteoclastogenesis and healing was observed in Δ130-136 (impairment of gap junctions), but not in R76W mice (hemichannel promotion may recover the delay). These results suggest that gap junctions and hemichannels play some similar and cooperative roles in bone repair.

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.

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.

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.

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.

Simple preparation of aminothiourea-modified chitosan as corrosion inhibitor and heavy metal ion adsorbent.

By a simple and convenient method of using formaldehyde as linkages, two new chitosan (CS) derivatives modified respectively with thiosemicarbazide (TSFCS) and thiocarbohydrazide (TCFCS) were synthesized. The new compounds were characterized and studied by Fourier transform infrared spectroscopy, elemental analysis, thermal gravity analysis and differential scanning calorimetry, and their surface morphologies were determined via scanning electron microscopy. These CS derivatives could form pH dependent gels. The behavior of 304 steel in 2% acetic acid containing different inhibitors or different concentrations of inhibitor had been studied by potentiodynamic polarization test. The preliminary results show that the new compound TCFCS can act as a mixed-type metal anticorrosion inhibitor in some extent; its inhibition efficiency is 92% when the concentration was 60 mg/L. The adsorption studies on a metal ion mixture aqueous solution show that two samples TSFCS and TCFCS can absorb As (V), Ni (II), Cu (II), Cd (II) and Pb (II) efficiently at pH 9 and 4.

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.