Ellagic acid inhibits CDK12 to increase osteoblast differentiation and alleviate osteoporosis in hindlimb-unloaded and ovariectomized mice.

BACKGROUND: Osteoporosis is a highly prevalent bone disease occurred commonly in astronauts and postmenopausal women due to mechanical unloading and estrogen deficiency, respectively. At present, there are some traditional Chinese medicine compounds for preventing and treating osteoporosis induced by simulated microgravity, but the detailed components of the traditional Chinese medicines still need to be confirmed and osteoporosis is still untreatable due to a lack of effective small-molecule natural medicine. PURPOSE: To explore the role of cyclin-dependent kinase 12 (CDK12) in osteoporosis induced by simulated microgravity and the therapeutic effect of CDK12-targeted Ellagic Acid (EA) on osteoporosis. METHODS: Our previous study has suggested that CDK12 as a potential target for treating and preventing osteoporosis. In this study, the role of CDK12 in osteoblasts and mice bone tissues was further studied under simulated microgravity. And by targeting CDK12, natural small-molecule product EA was screened out based on a large scale through the weighted set similarity (WES) method and the therapeutic effects of EA on osteoporosis was investigated in hindlimb-unloaded (HU) mouse model and ovariectomized (OVX) model. RESULTS: The results demonstrated that simulated microgravity inhibited bone formation and up-regulated the expression of CDK12. Furthermore, CDK12-siRNA or THZ531 (an inhibitor of CDK 12) promoted osteoblast differentiation, while the overexpression of CDK12 inhibited osteoblasts differentiation. And we further proved that CDK12-targeted EA showed a rescue effect on osteoblast differentiation inhibition caused by simulated microgravity. EA (50 mg·kg-1·day-1) daily intragastric administration alleviated the symptoms of osteoporosis and accompanied with the improvement of trabecular bone and cortical bone parameters with significantly overexpression of CDK12. CONCLUSION: EA efficiently improves osteoporosis by targeting CDK12, which is a suppresser of osteoblast differentiation and a novel therapeutic target for treating osteoporosis.

High and low dose of luzindole or 4-phenyl-2-propionamidotetralin (4-P-PDOT) reverse bovine granulosa cell response to melatonin.

Background: Communication between oocytes and granulosa cells ultimately dictate follicle development or atresia. Melatonin is also involved in follicle development. This study aimed to investigate the effects of melatonin and its receptor antagonists on hormone secretion, as well as gene expression related to hormone synthesis, TGF-ß superfamily, and follicle development in bovine granulosa cells, and assess the effects of melatonin in the presence of 4-P-PDOT and luzindole. Methods: Bovine ovaries were collected from a local abattoir and follicular fluid (follicle diameter 5-8 mm) was collected for granulosa cell isolation and culture. Granulosa cells and culture medium were collected 48 h after treatment with melatonin at high dose concentrations (10-5 M) and low dose concentrations (10-9 M) in the absence/presence of 4-P-PDOT and luzindole (10-5 M or 10-9 M). Furthermore, the expression level of genes related to hormonal synthesis (CYP11A1, CYP19A1, StAR, and RUNX2), TGF-ß superfamily (BMP6, INHA, INHBA, INHBB, and TGFBR3), and development (EGFR, DNMT1A, and FSHR) were detected in each experimental group by real-time quantitative PCR. In addition, the level of hormones in culture medium were detected using ELISA. Results: Both 10-5 M and 10-9 M melatonin doses promoted the secretion of inhibin A and progesterone without affecting the production of inhibin B and estradiol. In addition, both promoted the gene expression of INHA, StAR, RUNX2, TGFBR3, EGFR, and DNMT1A, and inhibited the expression of BMP6, INHBB, CYP11A1, CYP19A1, and FSHR. When combined with different doses of 4-P-PDOT and luzindole, they exhibited different effects on the secretion of inhibin B, estradiol, inhibin A, and progesterone, and the expression of CYP19A1, RUNX2, BMP6, INHBB, EGFR, and DNMT1A induced by melatonin. Conclusion: High and low dose melatonin receptor antagonists exhibited different effects in regulating hormone secretion and the expression of various genes in response to melatonin. Therefore, concentration effects must be considered when using luzindole or 4-P-PDOT.

Development of ligand modified erythrocyte coated polydopamine nanomedicine to codeliver chemotherapeutic agent and oxygen for chemo-photothermal synergistic cancer therapy.

The use of conventional chemotherapy often faces limitations such as severe side effects, weak tumor tissue specificity, and the development of multidrug resistance. To conquer these challenges, numerous novel drug carriers have been designed in recent years. However, due to the complex processes of tumor development, metastasis and recurrence, single chemotherapy cannot fulfill the goals of clinical diverse treatment. In this work, by utilizing the inherent characteristics of surface-modified erythrocyte and the outstanding photothermal conversion capability of polydopamine (PDA), we designed and constructed a biomimetic multifunctional nanomedicine DPPR NPs to codeliver chemotherapeutic agent doxorubicin (DOX) and oxygen. The results showed that DPPR NPs exhibited inspiring features including nanoscale droplet size, good physicochemical stability, and sustained, pH-, and NIR triggered drug release behavior. It can dramatically prolong the systematic circulation time and elevated the drug accumulated level in the tumor site. Moreover, DPPR NPs could be effectively internalized into tumor cells and destroyed the intracellular redox balance to mediate cell apoptosis. It exerted excellent in vivo tumor targeting effect, photothermal conversion efficiency, ultrasound imaging responses, antitumor efficacy, and good compatibility. In summary, DPPR NPs provide a biomimetic drug delivery platform to organically combine chemotherapy and photothermal therapy for precise cancer treatment.

An optimized CaO2-functionalized alginate bead for simultaneous and efficient removal of phosphorous and harmful cyanobacteria.

Simultaneous removal of phosphorus (P) and algae is important to mitigate eutrophication, however, it is rather challenging in remediation of harmful algal blooms (HABs)-contaminated water. In this study, a wet alginate bead functionalized by CaO2 particle formed layer by layer was prepared with an in-situ method and optimized to remove phosphorous and inhibit algae growth. The stable H2O2 release with a concentration level of 0.06 mM was observed for a period of 26 d. The content of peroxy groups (-O-O-) in the optimal bead was 0.44 mmol·g-1 through permanganate-based titration study. For solution with an initial phosphorous concentration of 10 mg·L-1, the removal was around 97% in pH 3.0-10.0. XRD, SEM, and XPS studies and kinetic modelings showed that removal of phosphorus was mainly due to formation of insoluble Ca-P compounds in the bead. The CaO2-functionalized bead inhibited algae growth with an effect lasting over 170 d, which was much better than liquid H2O2 and Ca(OH)2 bead; the phosphorous removal with an efficiency of about 70% was simultaneously obtained. Furthermore, the bead demonstrated to be effective in removing algae in the realistic water from a reservoir. In summary, this study shows that the CaO2-functionalized material is promising for simultaneous removal of phosphorous and management of HABs.

Cost-effective phosphorus removal from aqueous solution by a chitosan/lanthanum hydrogel bead: Material development, characterization of uptake process and investigation of mechanisms.

Excessive phosphorus is one of the main reasons leading to eutrophication that causes severe ecosystem imbalance and negative human health impacts. In this study, several chitosan (CS)/lanthanum (La) hydrogel beads were first synthesized and tested for phosphorus removal. The stable cross-linked CS/La hydrogel bead prepared with the optimized conditions of 10 wt% La/CS and 1.5 mL of 5% glutaraldehyde demonstrated exceptional performance in the removal. It removed phosphate effectively from an aqueous solution in the pH range from 2 to 7. The complete phosphate uptake was achieved at contact time of 6 h under the completely mixing batch condition. The experimental maximum adsorption capacity of 107.7 mg g-1 was observed at solution pH 4. The phosphate adsorption was well described by the Freundlich isotherm and the intraparticle surface diffusion model. Furthermore, the adsorbent was effectively regenerated and reused in a five-cycle adsorption-desorption operation. The removal of phosphate can be attributed to electrostatic attraction and ion exchange. Moreover, the bead was capable of removing heavy metals: copper, zinc and lead. This adsorbent may be served as a cost-effective material for the treatment of phosphorus-contaminated water so as to minimize the occurrence of eutrophication.

Bi2O2CO3/red phosphorus S-scheme heterojunction for H2 evolution and Cr(VI) reduction.

Red phosphorus (RP) has a suitable energy band structure and excellent photocatalytic properties. However, there are some problems, such as low quantum efficiency and serious photogenerated electron-hole recombination. The S-scheme heterostructure shows great potential in facilitating the separation and transfer of photogenerated carriers and obtaining strong photo-redox ability. Herein, hydrothermally treated red phosphorus (HRP) was combined with Bi2O2CO3 to construct Bi2O2CO3/HRP S-scheme heterojunction composite. The Bi2O2CO3 content was optimized, and the 5 %Bi2O2CO3/HRP composite obtained at 5 %Bi2O2CO3 mass fraction exhibited the strongest photoreduction ability. The Cr(VI) photoreduction and photolytic hydrogen production rates were as high as 0.22 min-1 and 157.2 µmol •h-1, which were 7.3 and 3.0 times higher than those of HRP, respectively. The promoted photocatalytic activity could be attributed to the formation of S-scheme heterojunctions, which accelerated the separation and transfer of useful photogenerated electron-hole pairs, while enhancing the recombination of relatively useless photogenerated electron-hole pairs, thereby resulting in the highest photocurrent density (17.3 µA/cm2) of the 5 %Bi2O2CO3/HRP composite, which was 1.6 and 4.3 times higher than pure Bi2O2CO3 (10.5 µA/cm2) and pure HRP (4.0 µA/cm2), respectively. This work would provide an advanced approach to enhance the photocatalytic activity of RP.

Photochemical Synthesis of Selenium Nanospheres of Tunable Size and Colloidal Stability with Simple Diketones.

Temporal and spatial segregations are two fundamental requirements for the successful synthesis of nanoparticles (NPs). To obtain colloidally stable selenium nanospheres (SeNSs), surfactants or polymers are generally needed as structure-directing agents or stabilizers in the reduction approaches for SeNP synthesis. The addition of such chemicals sacrifices the purity of the obtained SeNPs and, therefore, is detrimental to the applications. Here, for the first time, we report that low-molecular weight (less than six carbons) diketones are excellent photoreductants for green and tunable synthesis of SeNPs, owing to their merits in temporal and spatial control. With simple diketones as the photoreductants, the resultant SeNPs were pure and colloidally stable with nice photoelectronic properties. This finding not only provides a useful strategy for the synthesis of SeNPs but also might be a milestone in the development of ketone photochemistry.

Construction of Surface-Modified Polydopamine Nanoparticles for Sequential Drug Release and Combined Chemo-Photothermal Cancer Therapy.

Single chemotherapy often causes severe adverse effects and drug resistance to limit therapeutic efficacy. As a noninvasive approach, photothermal therapy (PTT) represents an attractive option for cancer therapy due to the benefits of remote control and precise treatment methods. Nanomedicines constructed with combined chemo-photothermal properties may exert synergistic effects and improved antitumor efficacy. In this study, we developed polydopamine (PDA)-coated nanoparticles grafted with folic acid (FA) and polyethylene glycol to transport doxorubicin (DOX) for targeted cancer therapy. The results showed that this delivery vehicle has a nanoscale particle size and narrow size distribution. No particle aggregation or significant drug leakage was observed during the stability test. This system presented excellent photothermal conversion capability under near-infrared light (NIR) laser irradiation due to the PDA layer covering. In vitro dissolution profiles demonstrated that sequential and triggered DOX release from nanoparticles was pH-, NIR irradiation-, and redox level-dependent and could be best fitted with the Ritger-Peppas equation. FA modification effectively promoted the intracellular uptake of nanoparticles by HepG2 cells and therefore significantly inhibited cell recovery and induced tumor cell apoptosis. Compared to the free DOX group, nanoparticles reduced the DOX concentration in the heart to avoid drug-related cardiotoxicity. More importantly, the in vivo antitumor efficacy results showed that compared with the single chemotherapy strategy, the nanoparticle group exerted combined and satisfactory tumor growth inhibition effects with good biocompatibility. In summary, this nanocarrier delivery system can organically combine chemotherapy and PTT to achieve effective and precise cancer treatment.

Folic Acid-Modified Erythrocyte Membrane Loading Dual Drug for Targeted and Chemo-Photothermal Synergistic Cancer Therapy.

To overcome the challenges of systemic toxicity and weak tumor selectivity caused by traditional antitumor drugs, numerous nanocarrier systems have been developed in recent decades, and their therapeutic effect has been improved to varying degrees. However, because of the drug resistance effect and metastasis involved in tumor recurrence, a single chemotherapy can no longer satisfy the diversified treatment needs. Recently, the application of chemotherapy in combination with thermotherapy as a synergistic approach has been proven to be more effective, and it provides a new strategy for cancer therapy. In this work, by utilizing the unique properties of erythrocytes, a surface-modified erythrocyte membrane was constructed as a novel nanocarrier system (DOX and ICG-PLGA@RBC nanoparticles, DIRNPs for short) for the simultaneous transportation of chemotherapeutic drugs (doxorubicin, DOX) and photothermal agents (indocyanine green, ICG) to achieve the effects of long-term circulation, active tumor targeting, and triggered drug release. The results indicated that DIRNPs have a nanoscale particle size of 158.4 nm with a narrow size distribution and a negative surface charge of -5.79 mV. No particle aggregation or remarkable drug leakage was observed during the 30 day storage test, and because of the excellent photothermal conversion ability of ICG, the local temperature of DIRNPs could dramatically increase from 33.7 to 49.8 °C in 10 min under near-infrared (NIR) laser irradiation. The in vitro drug dissolution data demonstrated that the DOX release from the DIRNPs was pH-dependent and NIR-triggered. Folic acid modifications of the erythrocyte membrane effectively facilitated the intracellular uptake of DIRNPs by HepG2 cells and, as a result, it significantly inhibited tumor cell growth, promoted reactive oxygen species levels, induced cell apoptosis, and restricted cell recovery and migration. In vivo pharmacokinetics and biodistribution studies indicated that the DIRNPs prolonged the half-life of DOX from 6.03 to 17.6 h and remarkably reduced the DOX level in the heart to avoid drug-related cardiotoxicity. More importantly, the DIRNPs exerted excellent in vivo antitumor efficacy against H22 tumors with superior safety. In conclusion, utilizing the advantageous properties of erythrocytes to construct a tumor-targeted biomimetic nanocarrier for codelivery of chemotherapeutics and photothermal agents to produce synergistic effects is considered an effective method for cancer therapy.

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We investigated the effects of tea plantation age on soil microbial community structure and diversity with surface and subsurface soil samples (0-20 and 20-40 cm) from tea plantation at different ages (0, 20, 25, 38 and 48 years). We analyzed soil bacterial and fungal communities by terminal restriction fragment length polymorphism (T-RFLP) and real-time quantitative PCR techniques. The results showed that soil physicochemical properties changed significantly after planting tea. The contents of soil organic carbon, available nitrogen, and available phosphorus increased at first, and gradually decreased with the increases of tea plantation age. The contents of organic carbon and total nitrogen in the topsoil were significantly higher than those in the subsoil. Moreover, soil bacterial community composition varied across tea plantation age. Bacterial diversity index decreased with increasing tea plantation age. The composition and diversity of soil fungal communities did not show a clear relationship with the tea plantation age. Overall, soil bacterial communities was more sensitive to the tea plantation age than fungal communities. With the increases of tea plantation age, the ratio of soil fungi to bacteria showed increasing trend. Soil microbial community in the tea plantation changed from a "bacterial type" with low fungi/bacteria ratio (F/B) to a "fungal type" with high F/B.