Krüppel-like factor 12 regulates aging ovarian granulosa cell apoptosis by repressing SPHK1 transcription and sphingosine-1-phosphate (S1P) production.

Oxidative stress triggered by aging, radiation, or inflammation impairs ovarian function by inducing granulosa cell (GC) apoptosis. However, the mechanism inducing GC apoptosis has not been characterized. Here, we found that ovarian GCs from aging patients showed increased oxidative stress, enhanced reactive oxygen species activity, and significantly decreased expression of the known antiapoptotic factor sphingosine-1-phosphate/sphingosine kinase 1 (SPHK1) in GCs. Interestingly, the expression of Krüppel-like factor 12 (KLF12) was significantly increased in the ovarian GCs of aging patients. Furthermore, we determined that KLF12 was significantly upregulated in hydrogen peroxide-treated GCs and a 3-nitropropionic acid-induced in vivo model of ovarian oxidative stress. This phenotype was further confirmed to result from inhibition of SPHK1 by KLF12. Interestingly, when endogenous KLF12 was knocked down, it rescued oxidative stress-induced apoptosis. Meanwhile, supplementation with SPHK1 partially reversed oxidative stress-induced apoptosis. However, this function was lost in SPHK1 with deletion of the binding region to the KLF12 promoter. SPHK1 reversed apoptosis caused by hydrogen peroxide-KLF12 overexpression, a result further confirmed in an in vitro ovarian culture model and an in vivo 3-nitropropionic acid-induced ovarian oxidative stress model. Overall, our study reveals that KLF12 is involved in regulating apoptosis induced by oxidative stress in aging ovarian GCs and that sphingosine-1-phosphate/SPHK1 can rescue GC apoptosis by interacting with KLF12 in negative feedback.

Vernalization promotes bolting in sugar beet by inhibiting the transcriptional repressors of BvGI.

Sugar beet (Beta vulgaris L.), a biennial sugar crop, contributes about 16% of the world's sugar production. The transition from vegetative growth, during which sugar accumulated in beet, to reproductive growth, during which sugar exhausted in beet, is determined by vernalization and photoperiod. GIGANTEA (GI) is a key photoperiodic flowering gene that is induced by vernalization in sugar beet. To identify the upstream regulatory factors of BvGI, candidate transcription factors (TF) that were co-expressed with BvGI and could bind to the BvGI promoter were screened based on weighted gene co-expression network analysis (WGCNA) and TF binding site prediction. Subsequently, their transcriptional regulatory role on the BvGI was validated through subcellular localization, dual-luciferase assays and yeast transformation tests. A total of 7,586 differentially expressed genes were identified after vernalization and divided into 18 co-expression modules by WGCNA, of which one (MEcyan) and two (MEdarkorange2 and MEmidnightblue) modules were positively and negatively correlated with the expression of BvGI, respectively. TF binding site predictions using PlantTFDB enabled the screening of BvLHY, BvTCP4 and BvCRF4 as candidate TFs that negatively regulated the expression of BvGI by affecting its transcription. Subcellular localization showed that BvLHY, BvTCP4 and BvCRF4 were localized to the nucleus. The results of dual-luciferase assays and yeast transformation tests showed that the relative luciferase activity and expression of HIS3 was reduced in the BvLHY, BvTCP4 and BvCRF4 transformants, which suggested that the three TFs inhibited the BvGI promoter. In addition, real-time quantitative reverse transcription PCR showed that BvLHY and BvTCP4 exhibited rhythmic expression characteristics similar to that of BvGI, while BvCRF4 did not. Our results revealed that vernalization crosstalked with the photoperiod pathway to initiate bolting in sugar beet by inhibiting the transcriptional repressors of BvGI.

New insights for gynecological cancer therapies: from molecular mechanisms and clinical evidence to future directions.

Advanced and recurrent gynecological cancers lack effective treatment and have poor prognosis. Besides, there is urgent need for conservative treatment for fertility protection of young patients. Therefore, continued efforts are needed to further define underlying therapeutic targets and explore novel targeted strategies. Considerable advancements have been made with new insights into molecular mechanisms on cancer progression and breakthroughs in novel treatment strategies. Herein, we review the research that holds unique novelty and potential translational power to alter the current landscape of gynecological cancers and improve effective treatments. We outline the advent of promising therapies with their targeted biomolecules, including hormone receptor-targeted agents, inhibitors targeting epigenetic regulators, antiangiogenic agents, inhibitors of abnormal signaling pathways, poly (ADP-ribose) polymerase (PARP) inhibitors, agents targeting immune-suppressive regulators, and repurposed existing drugs. We particularly highlight clinical evidence and trace the ongoing clinical trials to investigate the translational value. Taken together, we conduct a thorough review on emerging agents for gynecological cancer treatment and further discuss their potential challenges and future opportunities.

Self-Assembled Tetraphenylethene-Based Nanoaggregates with Tunable Electrochemiluminescence for the Ultrasensitive Detection of E. coli.

As an effective ECL emitter, tetraphenylethene (TPE)-based molecules have recently been reported with aggregation-induced electrochemiluminescence (AIECL) property, while it is still a big challenge to control its aggregation states and obtain uniform aggregates with intense ECL emission. In this study, we develop three TPE derivatives carrying a pyridinium group, an alkyl chain, and a quaternary ammonium group via the Menschutkin reaction. The resulting molecules exhibit significantly red-shifted FL and enhanced ECL emissions due to the tunable reduction of the energy gap between the highest occupied molecular orbitals (HOMOs) and the lowest unoccupied molecular orbitals (LUMOs). More importantly, the amphiphilicity of the as-developed molecules enables their spontaneous self-assembly into well-controlled spherical nanoaggregates, and the ECL intensity of nanoaggregates with 3 -CH2- (named as C3) is 17.0-fold higher compared to that of the original 4-(4-(1,2,2-triphenylvinyl)phenyl)pyridine (TPP) molecule. These cationic nanoaggregates demonstrate a high affinity toward bacteria, and an ECL sensor for the profiling of Escherichia coli (E. coli) was developed with a broad linear range and good selectivity in the presence of an E. coli-specific aptamer. This study provides an effective way to enhance the ECL emission of TPE molecules through their derivatization and a simple way to prepare well-controlled AIECL nanoaggregates for ECL application.

Developing patient-derived organoids to demonstrate JX24120 inhibits SAMe synthesis in endometrial cancer by targeting MAT2B.

Endometrial cancer (EC) is one of the most common gynecologic malignancies, which lacking effective drugs for intractable conditions or patients unsuitable for surgeries. Recently, the patient-derived organoids (PDOs) are found feasible for cancer research and drug discoveries. Here, we have successfully established a panel of PDOs from EC and conducted drug repurposing screening and mechanism analysis for cancer treatment. We confirmed that the regulatory ß subunit of methionine adenosyltransferase (MAT2B) is highly correlated with malignant progression in endometrial cancer. Through drug screening on PDOs, we identify JX24120, chlorpromazine derivative, as a specific inhibitor for MAT2B, which directly binds to MAT2B (Kd = 4.724 µM) and inhibits the viability of EC PDOs and canonical cell lines. Correspondingly, gene editing assessment demonstrates that JX24120 suppresses tumor growth depending on the presence of MAT2B in vivo and in vitro. Mechanistically, JX24120 induces inhibition of S-adenosylmethionine (SAMe) synthesis, leading to suppressed mTORC1 signaling, abnormal energy metabolism and protein synthesis, and eventually apoptosis. Taken together, our study offers a novel approach for drug discovery and efficacy assessment by using the PDOs models. These findings suggest that JX24120 may be a potent MAT2B inhibitor and will hopefully serve as a prospective compound for endometrial cancer therapy.

HPV prevalence and distribution characteristics in postmenopausal women from Nanjing, China.

BACKGROUND: Cervical cancer is strongly associated with human papillomavirus (HPV) infection. In this retrospective study, we analyzed the data of postmenopausal women who were tested for HPV in Nanjing First Hospital from 2019 to 2021. METHODS: We retrospectively analyzed the data of 14,608 postmenopausal women aged 45-90 years, who underwent HPV examination in Nanjing First Hospital between January 2019 and December 2021. All participants were tested for 23 HPV genotypes. We subsequently analyzed the infection rate and evaluated the distribution of HPV using the chi-square test. RESULTS: Our results showed that the HPV infection rate in postmenopausal women in Nanjing, China was 22.36%. In terms of age group, the infection rate was 19.54%, 24.30%, 26.58%, and 14.99% in those aged ≤ 50, 51-60, 61-70, and ≥ 71 years, respectively. The most common HPV subtypes were HPV52 (22.1 3%), HPV58 (15.86%), HPV53 (14.17%), HPV16 (12.61%), and HPV81 (11.66%), in that order. The single-HPV infection rate was 14.23%, and the multiple-genotype infection rate was 8.14% (1189/14,608). CONCLUSIONS: This study showed that in Nanjing, China, the different age groups of post-menopausal women could have different rates of HPV infection, and the most common types were HPV52, HPV58, HPV53, HPV16 and HPV81. These findings highlighted the importance of understanding the epidemiology of HPV infection in specific populations, such as postmenopausal women in Nanjing, China. The results could provide valuable information for healthcare professionals and policymakers to develop targeted prevention and screening strategies for reducing the burden of HPV-related diseases in this population.

High-dose VitC plus oncolytic adenoviruses enhance immunogenic tumor cell death and reprogram tumor immune microenvironment.

Preclinical and clinical studies have validated the antitumor effects of several oncolytic viruses (OVs). However, the efficacy of OVs is limited when they are administered as monotherapies. Combination therapy is a promising direction for oncolytic virotherapy in the future. A high dose of vitamin C (VitC) exerts anticancer effects by triggering the accretion of substantial amounts of reactive oxygen species (ROS). OVs can induce immunogenic tumor cell death and elicit an antitumor immune response. ROS play an important role in immunogenic cell death (ICD). This study aimed to explore whether high-dose VitC in combination with oncolytic adenoviruses (oAds) exhibited a synergistic antitumor effect. High-dose VitC synergized with oAds against tumor by enhancing immunogenic tumor cell death. Combination therapy with high-dose VitC and oAds significantly increased the number of T cells in the tumor microenvironment (TME) and promoted the activation of T cells. Furthermore, the antitumor effect of the combination therapy was CD8+ T cell dependent. In addition, combination therapy with high-dose VitC and oAds reprogramed the immunosuppressive TME. Our study provides a new strategy for combination therapy of OVs.

Spatial distribution of bacterial resistance towards antibiotics of rural sanitation system in China and its potential link with diseases incidence.

Chinese government is vigorously promoting toilet renovation in rural areas to reduce the risk of human feces exposure, which would cause infectious diseases, especially antibiotic resistance genes (ARGs) and pathogens. However, the distribution of ARGs in human feces from different regions of China remained ill-defined. It is not yet known how the survival of ARGs after toilet treatment is associated with the regional infection rates. Here, we investigated the prevalence of ARGs in human feces in rural areas of China and their potential relationship with infectious diseases for the first large-scale. The results showed that there were still high ARGs residues in human feces after rural toilet treatment, especially tetM-01 and ermB with average relative abundance as high as 1.21 × 10-1 (Eastern) and 1.56 × 10-1 (Northern), respectively. At a large regional scale, the significant differences in human feces resistomes were mainly shaped by the toilet types, TN, NH3-N, and the bacterial community. A critical finding was that toilets still cannot effectively decrease the pathogenicity risk in human feces. The significant positive relationship (P<0.05) between infectious diseases and ARGs can infer that ARGs in human feces exposure might be a critical path for enhancing the incidence of diseases, as these ARGs hinder the effectiveness of antibiotics.

The relationship between serum oestrogen levels and clinical outcomes of hormone replacement therapy-frozen embryo transfer: a retrospective clinical study.

BACKGROUND: This study aimed to explore the relationship between serum oestrogen (E2) levels before endometrial transformation and pregnancy outcomes of hormone replacement therapy-frozen embryo transfer (HRT-FET) cycles, which has been investigated for years without any consensus. METHODS: A retrospective cohort study of 10,209 cycles HRT-FET cycles was conducted at the Reproductive Medicine Center of Nanjing Drum Tower Hospital from March 2017 to December 2020. A smooth fitting curve was constructed to identify the relationship between serum E2 levels before endometrial transformation and the clinical pregnancy rate. Then, threshold and saturation effect analysis was employed to explore the cut-off value of serum E2 levels. In addition, patients were divided into 2 groups based on their levels of serum E2 measured before progesterone-induced endometrial transformation: Group 1, < 300 pg/mL (n = 6251) and Group 2, ≥ 300 pg/mL (n = 3958). The clinical pregnancy and miscarriage rates of all groups were compared. Further smooth fitting curve analysis was employed by different subgroups segmented according to different endometrial thicknesses. RESULTS: When the serum E2 level was greater than 300 pg/mL, the clinical pregnancy rate decreased significantly (62.9% vs. 59.8%, p < 0.01), but the miscarriage rates were similar (13.5% vs. 15.6%, p = 0.14). While serum E2 level reached or exceeded 1400 pg/mL, there was no significant correlation between the clinical pregnancy rate and E2 level. The clinical pregnancy rate reached its higher level at lower E2 levels, regardless of the different endometrail thicknesses. CONCLUSIONS: Patients with a lower pretransformation serum E2 level (less than 300 pg/mL) have a higher clinical pregnancy rate and there was no correlation between the clinical pregnancy rate and a higher serum E2 level (greater than 1400 pg/mL) in HRT-FET cycles.

What role does organic fertilizer actually play in the fate of antibiotic resistome and pathogenic bacteria in planting soil?

Organic fertilizer increase antibiotic resistance genes (ARGs) and bacterial pathogens have widely documented. However, how organic fertilizer is involved in changing soil ARGs and pathogenic bacteria after long-term (≥5 years) application remains unclear. Herein, the ARGs and pathogenic bacteria were compared in organic fertilized soils (AF) and non-fertilized soils (NF), and the contribution of input sources (organic fertilizer, irrigation water, air and background soil) on soil ARGs also was determined in this study. Results showed that the abundances of some ARGs, such as vanR and aac(6')-I in AF, were significantly higher than these of NF (p < 0.05). And a relatively higher abundance of potential pathogens, especially, Salmonella enterica and Stenotrophomonas maltophilia, in AF was observed. This indicated that organic fertilizer application can maintain a high level of some soil ARGs and pathogenic bacteria for at least 5 years. Traceability analysis unearthed that organic fertilizer application mainly increased its own contribution to soil ARGs from 1.16% to 9.05%, as well reduced the contribution of background soil, suggesting that the increase in soil ARGs may be partly attributable to organic fertilizer inputs. Notably, organic fertilizer application did not significantly alter the contribution ratio of input sources to microorganisms, but there was a clear change in the composition of soil microorganisms, which meant that the effect of the input source on the microorganism may emanate from other factors, rather than direct inputs. Subsequent structural equation demonstrated that organic fertilizer application significantly enhanced the effect of environmental factors on ARGs, and also indirectly increased the influence of communities on ARGs. Collectively, under the long-term fertilization, the role of organic fertilizers on soil ARGs not just stems from its own input, and also dominates the influence of environmental factors on ARGs. This study elucidates main causes for the difference in ARGs in AF vs. NF and enlightens actual role of organic fertilizer in them.

Systematically assess the advancing and limiting factors of using the multi-soil-layering system for treating rural sewage in China: From the economic, social, and environmental perspectives.

Solving the problem of rural sewage is considered an essential task in China's rural revitalization strategy. Based on the yearbook data of sewage treatment in rural areas between 2014 and 2019, although the rate of sewage treatment in rural areas of China showed an upward trend, it was still below 35%, mainly due to the lack of suitable sewage treatment technologies. Here, we discuss the multi-soil-layering (MSL) system, which is an emerging technology suitable for rural sewage treatment. It was deemed to overcome the shortcomings of current biological and ecological treatment technologies, such as complex operation, large area, and high operating costs. We used system dynamics to evaluate the advancing and limiting factors of MSL application for rural sewage treatment from the social, environmental, and economic dimensions. The results illustrated a complete causal loop diagram in which essential variables and relationships were concentrated in the technology, operation and maintenance, and satisfaction of farmers. The efficiency of MSL is the key variable affecting the final decision of the MSL application. Overall, using MSL to treat rural sewage could be an option to improve the rural environment in China. However, the scientific technological model for MSL should be further explored. This review provides guidance on how to promote MSL systems in rural areas.

Optimising mixed aerobic and anaerobic composting process parameters for reducing bacterial pathogenicity in compost-derived products.

Although composting techniques are continuously optimised and adjusted, the removal of bacterial pathogen based on the quality of composting products needs further to ensure safe of agricultural use. In this study, we combined aerobic composting and anaerobic process to determine the optimal combination (turning frequency of once a day, the proportion of swine manure to corn straw (3:1), and mixed 6-day anaerobic process) that benefits the reduction of bacterial pathogens, among which the maximum removal efficiency of up to 92.96% was observed for Clostridium_sensu_stricto_1 reached, thereby improving the quality of the compost products. The variation partition analysis and redundancy analysis indicated that physicochemical factors such as temperature, TOC, and pH significantly affected the removal of bacterial pathogens. Therefore, the additive effects of physicochemical factors on bacterial pathogen removal requires further process optimisation. These findings offer powerful technological support for improving agricultural waste recycling and enhancing the safety of fertiliser application.

Effect of different carriers on in vitro dissolution behavior and physicochemical characterization of glycyrrhetinic acid solid dispersions.

The effect of PEG 4000, PVP K30, poloxamer 407 and urea as carriers glycyrrhetinic acid solid dispersions (GA-SDs) on dissolution behavior and physicochemical properties were investigated. In vitro dissolution test results show that GA-SDs prepared with four different carriers have better dissolution properties compared with pure drug and corresponding physical mixtures. The enhancement effect of four carriers on dissolution rate and equilibrium solubility shows that PVP K30>PEG 4000>P 407>urea. In addition, the dissolution rate and solubility of the GA-SDs with a carrier-drug ratio of 8:1 were better than the samples of 4:1. The DSC and XRD patterns showed that crystallization of GA-SDs prepared by PVP K30 was significantly inhibited and both were transformed to amorphous. Based on FTIR detection, hydrogen-bond between carriers (PVP K30, PEG 4000 and P 407) and GA molecules were formed. SEM results showed that compared to GA-SDs prepared by the other three carriers, GA-PVP K30-SDs have a smoother surface and clearer boundary. In conclusion, the findings of this study demonstrated that the dissolution performance of the GA-SDs prepared by the solvent method is related to carrier type. The samples with PVP K30 as the carrier have the best dissolution performance.

Attenuated monoamine oxidase a impairs endometrial receptivity in women with adenomyosis via downregulation of FOXO1†.

The establishment of endometrial receptivity is a prerequisite for successful pregnancy. Women with adenomyosis possess a lower chance of clinical pregnancy after assisted reproductive technology, which is partially due to impaired endometrial receptivity. The establishment of endometrial receptivity requires the participation of multiple processes, and proper endometrial epithelial cell (EEC) proliferation is indispensable. Monoamine oxidase A (MAOA) is a key molecule that regulates neurotransmitter metabolism in the nervous system. In the present study, we demonstrated a novel role for MAOA in the establishment of endometrial receptivity in women with adenomyosis and in an adenomyotic mouse model. Attenuated MAOA impairs endometrial receptivity by promoting inappropriate proliferation of EECs via the downregulation of FOXO1 during the window of implantation. These results revealed that MAOA plays a vital role in endometrial receptivity in female reproduction.

Three-compartment septic tanks as sustainable on-site treatment facilities? Watch out for the potential dissemination of human-associated pathogens and antibiotic resistance.

Improved sanitation is critical important to reduce the spread of human deposited pathogens and antibiotic resistance genes (ARGs). In the China's rural "Toilet Revolution", three-compartment septic tanks (SPTs) are widely used as household domestic sewage treatment facilities. The effluents of SPTs are encouraged to be used as fertilizer in agriculture. However, whether SPT could eliminate fecal pathogens and ARGs is still unrevealed which is crucial in risk assessment of SPT effluent utilization. Herein, we employed metagenomic sequencing to investigate the pathogens and ARGs in rural household SPTs from Tianjin, China. We found that rural household SPT effluents conserved pathogens comparable to that of the influents. A total of 441 ARGs conferring resistance to 26 antibiotic classes were observed in rural household SPTs, with the relative abundance ranging from 709 to 1800 ppm. Results of metagenomic assembly indicated that some ARG-MGE-carrying contigs were carried by pathogens, which may pose risk to human and animal health after being introduced to the environment. This study raises the question of SPTs as sustainable on-site treatment facilities for rural domestic sewage and underscores the need for more attention to the propagation and dissemination of antibiotic-resistant pathogens from SPT to the environments, animals, and humans.

miR-21 reverses impaired decidualization through modulation of KLF12 and NR4A1 expression in human endometrial stromal cells†.

Impaired decidualization has been considered a major cause of infertility in adenomyosis. However, the mechanism remains poorly understood. Recent studies suggest that microRNAs (miRNA) play a crucial role in embryo implantation. The aim of the present study was to identify the role of miR-21 in human endometrial stromal cell (hESC) decidualization in vitro. To explore the roles of miR-21 in decidualization, we detected the expression of miR-21 in the endometrium of fertile control and adenomyosis patients, and analyzed the effects of miR-21 on the biological behaviors of hESC decidualization. The results demonstrated that miR-21 was downregulated in the endometrium of adenomyosis patients compared with the control endometrium. miR-21 effectively promoted the expression of the 8Br-cAMP plus medroxyprogesterone acetate (MPA)-induced hESC decidualization marker genes PRL and IGFBP-1 and morphological transformation through the modulation of KLF12 and NR4A1 expression; conversely, inhibition of miR-21 expression compromised hESC decidualization in vitro. In addition, Luciferase reporter, western blotting, and quantitative real-time PCR (qRT-PCR) assays confirmed that miR-21 interacted with the 3' untranslated region of the transcription factor KLF12 and downregulated KLF12 at the transcriptional and translational levels. KLF12 overexpression abolished miR-21-enhanced 8Br-cAMP plus MPA-induced decidualization. Taken together, these results illustrate that miR-21 promotes endometrial decidualization by inhibiting KLF12, and miR-21 overexpression reverses the poor decidual response of hESCs in patients with adenomyosis in vitro.

MicroRNA-181a promotes follicular granulosa cell apoptosis via sphingosine-1-phosphate receptor 1 expression downregulation†.

Oxidative stress induces granulosa cell (GC) apoptosis and subsequent follicular atresia. Since our previous studies indicate that microRNA-181a (miR-181a) expression is increased in GCs undergoing apoptosis, the present study was designed to define the relationship between exposure to oxidative stressors in GCs and changes in miR-181a expression and function. To achieve this, we employed an H2O2-induced in vitro model and a 3-nitropropionic acid-induced in vivo model of ovarian oxidative stress. We demonstrated that in vitro miR-181a overexpression promoted GC apoptosis in a dose-dependent manner; sphingosine-1-phosphate (S1P) significantly reversed both H2O2-induced and miR-181a-induced apoptosis in GCs. Moreover, we identified sphingosine-1-phosphate receptor 1 (S1PR1), a critical receptor of S1P, as a novel target of miR-181a in GCs. MicroRNA-181a induced GC apoptosis by repressing S1PR1 expression in vitro. Importantly, increased miR-181a expression and decreased S1PR1 expression were detected in the in vivo ovarian oxidative stress model by Western blot analysis and immunohistochemistry. Furthermore, we found similar expression patterns of miR-181a and S1PR1 in GCs from patients with premature ovarian insufficiency. In conclusion, our results suggest that miR-181a directly suppresses expression of S1PR1, which has critical roles in mediating oxidative stress-induced GC apoptosis both in vitro and in vivo.

Extracellular matrix protein DMP1 suppresses osteogenic differentiation of Mesenchymal Stem Cells.

Mesenchymal Stem Cells (MSCs) are self-renewing and multipotent stem cells which was investigated for diverse clinical applications. However, complex mechanism of MSCs fate determination is still not fully disclosed. Extracellular matrix (ECM) proteins contribute to maintain MSCs stemness by providing extracellular microenvironment. Increasing evidences show that ECM proteins could also regulate the fate of MSCs directly. Dentin matrix protein 1 (DMP1) is an ECM protein enrich in bone tissue and terminal cells, which well-known in promoting osteoblasts and osteocytes maturation, and facilitate mineralization. Recently, our experiment indicated that DMP1 was also expressed in MSCs of long bone. In present study, it is found that DMP1 expressed in Prx1 positive MSCs. And, DMP1 is down-regulated in early osteoblasts and up-regulated again in mature osteoblasts. DMP1 conditional knockout mice model under Prx1cre was generated to explore whether DMP1 regulates MSCs osteogenic differentiation. Specific ablation of DMP1 in Prx1 positive MSCs increased bone mass in vivo and promoted osteoblasts activity in vitro. This study provides a new understanding of DMP1's function in regulation of osteogenesis: not only an enhancer of bone formation, but also a negative regulator of MSCs differentiation in bone.

Lamellar-cubic transition of a dihydrazide derivative and its effect on the gel stability.

N,N'-Bis(4-n-alkyloxybenzoyl)hydrazine (4D16) was demonstrated to show three different aggregates, i.e. a crystalline cubic phase and two kinds of lamellar structure with layer spacings of 34.20 Å (termed the L1 structure) and 40.85 Å (L2 structure) depending on the type of solvents. Lamellar (L1)-crystalline cubic transition during heating was confirmed for 4D16 showing the L1 structure. 4D16 organogels in cyclohexane and benzene exhibited either a mixture of the L1 structure and the crystalline cubic phase or only one of the two structures. 4D16 gels prepared at a higher concentration or a lower incubation temperature consisted of more lamellar L1 structures compared to those obtained at a lower concentration or a higher incubation temperature. Annealing of the as-prepared 4D16 gels at certain temperatures for different time periods caused gradual lamellar L1-cubic transition, and thus increased the content of the cubic phase in the gels, which showed lower Tgel compared to those of the as-prepared ones. The existence of the cubic phase in 4D16 gels in cyclohexane and benzene destabilized the gels.

The effects of metformin on fibroblast growth factor 19, 21 and fibroblast growth factor receptor 1 in high-fat diet and streptozotocin induced diabetic rats.

To understand metformin's effects on fibroblast growth factors (FGFs) and fibroblast growth factor receptor 1 (FGFR1), we investigated circulating fibroblast growth factor-19 (FGF19), FGF21 levels, and FGFR1 in type 2 diabetes mellitus (T2DM). In addition, protein kinase B (Akt) signaling pathway was detected to explain the possible mechanisms. T2DM was induced by feeding rats with high-fat diet for 11 weeks, followed by a low dose of streptozotocin (STZ, 30-35 mg/kg, intraperitoneally). Control rats (Con) were fed on a normal chow; diabetic rats (DM) were fed on high-fat diet supplemented with or without metformin (METF) for 12 weeks (500 mg·kg-1·d-1). Biochemical parameters were detected at the end of 24th weeks. FGFR1 expression and protein kinase B (Akt) phosphorylation in the pancreas and visceral adipose tissues were detected using either Western blot (WB) or immunohistochemistry (IHC). Serum FGF19 and FGF21 were measured using enzyme-linked immune sorbent assay (ELISA). Metformin treated DM rats showed improved glucose, lipid and bile acid metabolism. Besides, significantly decreased FGF19 and increased FGF21 were observed in DM+METF rats. DM rats showed significantly increased FGFR1 both in the pancreas and visceral adipose tissues. While in DM+METF rats, FGFR1 was almost remained at a normal level in the pancreas and increased in the visceral adipose tissue compared to that in DM rats. Besides, metformin treatment restores Akt phosphorylation in both tissues. The altered glucose and lipid profiles by metformin treatment may be associated with the increased circulating FGF21 and tissue-specific expressions of FGFR1.