Capsaicin attenuates Porphyromonas gingivalis-suppressed osteogenesis of periodontal ligament stem cells via regulating mitochondrial function and activating PI3K/AKT/mTOR pathway.

BACKGROUND AND OBJECTIVE: Prevention of periodontal bone resorption triggered by Porphyromonas gingivalis (P. gingivalis) is crucial for dental stability. Capsaicin, known as the pungent ingredient of chili peppers, can activate key signaling molecules involved in osteogenic process. However, the effect of capsaicin on osteogenesis of periodontal ligament stem cells (PDLSCs) under inflammation remains elusive. METHODS: P. gingivalis culture suspension was added to mimic the inflammatory status after capsaicin pretreatment. The effects of capsaicin on the osteogenesis of PDLSCs, as well as mitochondrial morphology, Ca2+ level, reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and osteogenesis-regulated protein expression levels were analyzed. Furthermore, a mouse experimental periodontitis model was established to evaluate the effect of capsaicin on alveolar bone resorption and the expression of osteogenesis-related proteins. RESULTS: Under P. gingivalis stimulation, capsaicin increased osteogenesis of PDLSCs. Not surprisingly, capsaicin rescued the damage to mitochondrial morphology, decreased the concentration of intracellular Ca2+ and ROS, enhanced MMP and activated phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway. The in vivo results showed that capsaicin significantly attenuated alveolar bone loss and augmented the expression of bone associated proteins. CONCLUSION: Capsaicin increases osteogenesis of PDLSCs under inflammation and reduces alveolar bone resorption in mouse experimental periodontitis.

ED-71 Improves Bone Mass in Ovariectomized Rats by Inhibiting Osteoclastogenesis Through EphrinB2-EphB4-RANKL/OPG Axis.

Purpose: Estrogen deficiency is the main reason of postmenopausal osteoporosis. Eldecalcitol (ED-71) is a new active vitamin D analogue clinically used in the treatment of postmenopausal osteoporosis. We aimed to investigate whether EphrinB2-EphB4 and RANKL/RANK/OPG signaling cooperate in mediating the process of osteoporosis by ED-71. Methods: In vivo, the ovariectomized (OVX) rats were administered orally with 30 ng/kg ED-71 once a day for 8 weeks. HE staining, Masson staining and Immunofluorescence staining were used to evaluate bone mass, bone formation, osteoclastogenesis associated factors and the expression of EphrinB2, EphB4, RANKL and OPG. In vitro, H2O2 stimulation was used to simulate the cell environment in osteoporosis. Immunofluorescence, quantitative real time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA) and Western Blot were applied to detect the expression of EphrinB2, EphB4, RANKL and OPG. In osteoblasts, EphB4 was knocked down by EphB4 small-interfering RNA (siRNA) transfection. LY294002 (PI3K inhibitor) or ARQ092 (AKT inhibitor) was used to block PI3K/AKT pathway. An indirect co-culture system of osteoblasts and osteoclasts was established. The mRNA and protein expression of osteoclastogenes is associated factors were tested by qRT-PCR and Western Blot. Results: ED-71 increased bone mass and decreased the number of osteoclasts in OVX rats. Moreover, ED-71 promoted the expression of EphrinB2, EphB4, and decreased the RANKL/OPG ratio in osteoblasts. Osteoclastogenesis was restrained when osteoclasts were indirectly co-cultured with ED-71-treated osteoblasts. After silencing of EphB4 expression in osteoblasts, ED-71 inhibited the expression of P-PI3K and P-AKT and increased the ratio of RANKL/OPG. This reversed the inhibitory effect of ED-71 on osteoclastogenes. Therefore, in ED-71-inhibited osteoclastogenes, EphB4 is a key factor affecting the secretion of RANKL and OPG by osteoblasts. EphB4 suppressed the RANKL/OPG ratio through activating PI3K/AKT signaling in osteoblasts. Conclusion: ED-71 inhibits osteoclastogenesis through EphrinB2-EphB4-RANKL/OPG axis, improving bone mass in ovariectomized rats. PI3K/AKT pathway is involved this process.

Perceived Social Mobility and Smartphone Dependence in University Students: The Roles of Hope and Family Socioeconomic Status.

Purpose: Drawing upon the cognitive-behavioral model of pathological Internet use (PIU) and tunnel effect, this study aimed to construct a moderated mediation model from the perspective of social ecology. Specifically, the model investigated the relationship between perceived social mobility and smartphone dependence, with a focus on the mediating role of hope and the moderating effect of family socioeconomic status (SES) underlying this relationship. Methods: A cross-sectional study was conducted with 718 Chinese university students (Mage = 19.19, 70.2% female) from Beijing, Henan, and Tianjin, who anonymously filled out the Perceptions of Socioeconomic Mobility Scale, Mobile Phone Addiction Index Scale, Openness to the Future Scale, and family socioeconomic status questionnaire. Preliminary data analysis was executed using SPSS 22.0, and the moderated mediation effect was tested using the latent moderated structural equations approach in Mplus 8.3. Results: The results showed that (a) less perceived social mobility was linked with greater smartphone dependence; (b) hope mediated the aforementioned relationship; and (c) family SES moderated the first-stage path of the indirect effect through hope. For university students with low (rather than high) family SES, their level of hope increased with the improvement of perceived social mobility, and in turn, that of smartphone dependence decreased. Conclusion: These findings suggest that positive perceptions of upward social class mobility and hopeful attitudes toward future opportunities and personal development among disadvantaged university students may alleviate their reliance on smartphones. Researchers and policymakers should pay attention to the role of individuals' perceptions of the macro environment in motivating specific risky behaviors among university students. Future interventions are essential to mitigate pessimistic environmental perceptions and foster a sense of hope among university students.

A coumarin-furoxan hybrid as novel nitric oxide donor induced cell apoptosis and ferroptosis in NSCLC by promoting S-nitrosylation of STAT3 and negative regulation of JAK2-STAT3 pathway.

Non-small cell lung cancer (NSCLC) still lacks effective treatment because of its extensive mutation diversity and frequent drug resistance. Therefore, it is urgent to develop new therapeutic strategies for NSCLC. In this study, we evaluated the inhibitory effect of a new coumarin-furoxan hybrid compound 9, a nitric oxide (NO) donor drug, on NSCLC proliferation and its mechanism. Our results show that compound 9 can inhibit the growth of four NSCLC cell lines and H1975 xenograft model in a dose-dependent manner. Compound 9 effectively releases high concentrations of NO within the mitochondria, leading to cellular oxidative stress, mitochondrial dysfunction, and apoptosis. Moreover, compound 9 inhibits JAK2/STAT3 protein phosphorylation and induces S-nitrosylation modification of STAT3, ultimately resulting in endogenous apoptosis in NSCLC. Additionally, compound 9 significantly induces NSCLC ferroptosis by depleting intracellular GSH, elevating MDA levels, inhibiting SLC7A11/GSH protein expression, and negatively regulating the JAK2/STAT3 pathway. In summary, this study elucidates the inhibitory effects of compound 9 on NSCLC proliferation and provides insights into the underlying mechanisms, offering new possibilities for NSCLC treatment strategies.

ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97.

The t(X,17) chromosomal translocation, generating the ASPSCR1::TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCCs), frustrating efforts to identify therapeutic targets for these rare cancers. Here, proteomic analysis identifies VCP/p97, an AAA+ ATPase with known segregase function, as strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1::TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1::TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributes with ASPSCR1::TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrate the oncogenic transcriptional signature of ASPSCR1::TFE3, by facilitating assembly of higher-order chromatin conformation structures demonstrated by HiChIP. Finally, ASPSCR1::TFE3 and VCP demonstrate co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCP's potential as a novel therapeutic target.

Global economic structure transition boosts PM2.5-related human health impact in Belt and Road Initiative.

The Belt and Road Initiative (BRI) is an open platform for international cooperation proposed by China to promote common global development and prosperity. The BRI can promote the optimal allocation of resources and promote in-depth cooperation in international trade. Meanwhile, it can establish a green supply chain cooperation network to help BRI countries achieve green transformation. BRI has made a notable contribution to the rapid growth of cross-border trade. However, it has also brought environmental impacts. Given that little attention has been paid to the trade-embodied particulate matter 2.5 related human health impacts (PM2.5-HHI) throughout the BRI, this study accounts for and traces the embodied PM2.5-HHI flows between the BRI countries and non-Belt and Road Initiative (non-BRI) countries. Moreover, this study also uncovers the critical socioeconomic drivers of PM2.5-HHI changes in BRI countries during 1990-2015, based on the multi-regional input-output based structural decomposition analysis (MRIO-SDA). Results show that, firstly, BRI countries had significantly increased their economic added value by exporting products to the non-BRI countries. They also have brought PM2.5-HHI to themselves. Secondly, the final demand of BRI countries was the largest potential driving force of PM2.5-HHI of BRI countries. Thirdly, the emission intensity change of BRI is the key socioeconomic factor for reducing PM2.5-HHI. While per capita final demand level change of BRI and production structure change of non-BRI are the key socioeconomic factors for increasing PM2.5-HHI. The study's findings on the one hand can help reduce the PM2.5-HHI and impacts of environmental pollution of BRI countries from a global perspective by providing scientific support. On the other hand, they can help provide relevant policy recommendations for the green transformation of BRI and the construction of green BRI.

Peroxiredoxin 1 regulates crosstalk between pyroptosis and autophagy in oral squamous cell carcinoma leading to a potential pro-survival.

Peroxiredoxin 1 (Prdx1), a vital antioxidant enzyme, has been proven to play an important role in the occurrence and development of cancers, but its effects on oral squamous cell carcinoma (OSCC) remain unclear. Here, we performed bioinformatics analysis and immunohistochemical (IHC) staining to confirm that Prdx1 was higher in OSCC tissues than in normal tissues. Consistently, RT-PCR and Western blot showed elevated Prdx1 expression in OSCC cell lines compared to human oral keratinocytes (HOK), which could be knockdown by small interfering RNA (siRNA) and Lentiviral vector delivery of short hairpin RNA (shRNA). Prdx1 silencing significantly blocked OSCC cell proliferation and metastasis, as evidenced by the CCK8, colony formation, in vivo tumorigenesis experiment, wound healing, transwell assays, and changes in migration-related factors. siPrdx1 transfection increased intracellular reactive oxygen species (ROS) levels and provoked pyroptosis, proved by the upregulation of pyroptotic factors and LDH release. Prdx1 silencing ROS-independently blocked autophagy. Mature autophagosome failed to form in the siPrdx1 group. Up-regulated autophagy limited pyroptosis triggered by Prdx1 deficiency, and down-regulated pyroptosis partly reversed siPrdx1-induced autophagy defect. Collectively, Prdx1 regulated pyroptosis in a ROS-dependent way and modulated autophagy in a ROS-independent way, involving the crosstalk between pyroptosis and autophagy.

ASPSCR1-TFE3 reprograms transcription by organizing enhancer loops around hexameric VCP/p97.

The t(X,17) chromosomal translocation, generating the ASPSCR1-TFE3 fusion oncoprotein, is the singular genetic driver of alveolar soft part sarcoma (ASPS) and some Xp11-rearranged renal cell carcinomas (RCC), frustrating efforts to identify therapeutic targets for these rare cancers. Proteomic analysis showed that VCP/p97, an AAA+ ATPase with known segregase function, was strongly enriched in co-immunoprecipitated nuclear complexes with ASPSCR1-TFE3. We demonstrate that VCP is a likely obligate co-factor of ASPSCR1-TFE3, one of the only such fusion oncoprotein co-factors identified in cancer biology. Specifically, VCP co-distributed with ASPSCR1-TFE3 across chromatin in association with enhancers genome-wide. VCP presence, its hexameric assembly, and its enzymatic function orchestrated the oncogenic transcriptional signature of ASPSCR1-TFE3, by facilitating assembly of higher-order chromatin conformation structures as demonstrated by HiChIP. Finally, ASPSCR1-TFE3 and VCP demonstrated co-dependence for cancer cell proliferation and tumorigenesis in vitro and in ASPS and RCC mouse models, underscoring VCP's potential as a novel therapeutic target.

Sex difference in the morbidity and pain response with stage 0 of medication-related osteonecrosis of the jaws.

OBJECTIVE: Medication-related osteonecrosis of the jaws (MRONJ) is a potentially severe complication associated with antiresorptive or antiangiogenic therapies. Prior studies, including our own clinical data, have indicated a higher incidence of MRONJ among women compare to men. However, robust evidence establishing a relationship between sex and the prevalence of MRONJ is lacking. METHODS: We conducted a meta-analysis and utilized murine models to investigate potential sex-based differences in the morbidity associated with MRONJ. RESULTS: Our results revealed no significant difference in the incidence of MRONJ between the sexes when using exposed necrotic bone as a diagnostic criterion. However, a histological examination of the murine models identified the presence of stage 0 MRONJ. Notably, pain assessments across all groups revealed that male mice with stage 0 MRONJ displayed less severe pain symptoms than their female counterparts. CONCLUSIONS: Our findings suggested that sex does not contribute to the risk of developing MRONJ. However, considering that approximately 50% of stage 0 MRONJ cases progress to more advanced stages, the less pronounced pain in male patients might delay medical consultation and potentially lead to disease progression. Clinicians should be particularly vigilant about the subdued pain response in male patients with stage 0 MRONJ to prevent disease advancement.

Prediction of Drug-Drug Interactions with Ensartinib as a Time-Dependent CYP3A Inhibitor Using Physiologically Based Pharmacokinetic Model.

Ensartinib (X-396) is a second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) indicated for the treatment of ALK-positive patients with locally advanced or metastatic non-small cell lung cancer. Although in vitro experiments and molecular docking suggested its potential as a cytochrome P450 inhibitor, no further investigation or clinical trials have been conducted to assess its drug-drug interaction (DDI) risk. In this study, we conducted a series of in vitro experiments to elucidate the inhibition mechanism of ensartinib. Furthermore, a physiologically-based pharmacokinetic (PBPK) model was developed based on in vitro, in silico, and in vivo parameters, verified using clinical data, and applied to predict the clinical DDI mediated by ensartinib. The in vitro incubation experiments suggested that ensartinib exhibited strong time-dependent inhibition. Simulation results from the PBPK model indicated a significant increase in the exposure of CYP3A substrates in the presence of ensartinib, with the maximal plasma concentration and area under the plasma concentration-time curve increasing up to 12-fold and 29-fold for sensitive substrates. Based on these findings, it is evident that co-administration of ensartinib and CYP3A substrates requires careful regulatory consideration. SIGNIFICANCE STATEMENT: Ensartinib was found to be a strong time-dependent inhibitor of CYP3A for the first time based on in vitro experiments, but there was no research conducted to estimate the risk of drug-drug interaction (DDI) of ensartinib in clinic. Therefore, the first ensartinib physiologically based pharmacokinetic model was developed and applied to predict various untested scenarios. The simulation result indicated that the exposure of CYP3A substrate increased significantly and urged the further clinical DDI study.

Brain Status Transferring Generative Adversarial Network for Decoding Individualized Atrophy in Alzheimer's Disease.

Deep learning has been widely investigated in brain image computational analysis for diagnosing brain diseases such as Alzheimer's disease (AD). Most of the existing methods built end-to-end models to learn discriminative features by group-wise analysis. However, these methods cannot detect pathological changes in each subject, which is essential for the individualized interpretation of disease variances and precision medicine. In this article, we propose a brain status transferring generative adversarial network (BrainStatTrans-GAN) to generate corresponding healthy images of patients, which are further used to decode individualized brain atrophy. The BrainStatTrans-GAN consists of generator, discriminator, and status discriminator. First, a normative GAN is built to generate healthy brain images from normal controls. However, it cannot generate healthy images from diseased ones due to the lack of paired healthy and diseased images. To address this problem, a status discriminator with adversarial learning is designed in the training process to produce healthy brain images for patients. Then, the residual between the generated and input images can be computed to quantify pathological brain changes. Finally, a residual-based multi-level fusion network (RMFN) is built for more accurate disease diagnosis. Compared to the existing methods, our method can model individualized brain atrophy for facilitating disease diagnosis and interpretation. Experimental results on T1-weighted magnetic resonance imaging (MRI) data of 1,739 subjects from three datasets demonstrate the effectiveness of our method.

Simvastatin inhibits proliferation and promotes apoptosis of oral squamous cell carcinoma through KLF2 signal.

OBJECTIVES: This study aimed to explore the role and specific mechanism of the cholesterol-lowering drug simvastatin in inhibiting oral squamous cell carcinoma (OSCC). METHODS: The proliferation, apoptosis, and migration levels of OSCC cells were detected by CCK8, quantitative real-time polymerase chain reaction, Western blot, colony formation, TdT-mediated dUTP Nick-End Labeling assay, and wound healing assay. The inhibitory effect of simvastatin in vivo was detected by a mouse xenograft tumor model. Immunohistochemistry and immunofluorescence staining were used to assess the KLF2 and ß-catenin expressions in cells and tissues. RESULTS: KLF2 expression in OSCC cells and tissues was downregulated. The addition of KLF2 inducer, GGTI298, inhibited the proliferation and migration of OSCC cells. Simvastatin played a role in inhibiting the proliferation and promoting the apoptosis of OSCC cells. Moreover, it inhibited ß-catenin expression and promoted KLF2 expression in OSCC cells. KLF2 siRNA reversed the effect of simvastatin on the proliferation and apoptosis of OSCC cells. CONCLUSIONS: KLF2, as a tumor suppressor gene, may be an important marker for diagnosing and treating OSCC. Simvastatin inhibits the progression of OSCC by regulating the KLF2 signal.

The histone acetyltransferase Mof regulates Runx2 and Osterix for osteoblast differentiation.

Osteoblast differentiation is regulated by various transcription factors, signaling molecules, and posttranslational modifiers. The histone acetyltransferase Mof (Kat8) is involved in distinct physiological processes. However, the exact role of Mof in osteoblast differentiation and growth remains unknown. Herein, we demonstrated that Mof expression with histone H4K16 acetylation increased during osteoblast differentiation. Inhibition of Mof by siRNA knockdown or small molecule inhibitor, MG149 which is a potent histone acetyltransferase inhibitor, reduced the expression level and transactivation potential of osteogenic key markers, Runx2 and Osterix, thus inhibiting osteoblast differentiation. Besides, Mof overexpression also enhanced the protein levels of Runx2 and Osterix. Mof could directly bind the promoter region of Runx2/Osterix to potentiate their mRNA levels, possibly through Mof-mediated H4K16ac to facilitate the activation of transcriptional programs. Importantly, Mof physically interacts with Runx2/Osterix for the stimulation of osteoblast differentiation. Yet, Mof knockdown showed indistinguishable effect on cell proliferation or apoptosis in MSCs and preosteoblast cells. Taken together, our results uncover Mof functioning as a novel regulator of osteoblast differentiation via the promotional effects on Runx2/Osterix and rationalize Mof as a potential therapeutic target, like possible application of inhibitor MG149 for the treatment of osteosarcoma or developing specific Mof activator to ameliorate osteoporosis.

Transcriptional patterns of sexual dimorphism and in host developmental programs in the model parasitic nematode Heligmosomoides bakeri.

BACKGROUND: Heligmosomoides bakeri (often mistaken for Heligmosomoides polygyrus) is a promising model for parasitic nematodes with the key advantage of being amenable to study and manipulation within a controlled laboratory environment. While draft genome sequences are available for this worm, which allow for comparative genomic analyses between nematodes, there is a notable lack of information on its gene expression. METHODS: We generated biologically replicated RNA-seq datasets from samples taken throughout the parasitic life of H. bakeri. RNA from tissue-dwelling and lumen-dwelling worms, collected under a dissection microscope, was sequenced on an Illumina platform. RESULTS: We find extensive transcriptional sexual dimorphism throughout the fourth larval and adult stages of this parasite and identify alternative splicing, glycosylation, and ubiquitination as particularly important processes for establishing and/or maintaining sex-specific gene expression in this species. We find sex-linked differences in transcription related to aging and oxidative and osmotic stress responses. We observe a starvation-like signature among transcripts whose expression is consistently upregulated in males, which may reflect a higher energy expenditure by male worms. We detect evidence of increased importance for anaerobic respiration among the adult worms, which coincides with the parasite's migration into the physiologically hypoxic environment of the intestinal lumen. Furthermore, we hypothesize that oxygen concentration may be an important driver of the worms encysting in the intestinal mucosa as larvae, which not only fully exposes the worms to their host's immune system but also shapes many of the interactions between the host and parasite. We find stage- and sex-specific variation in the expression of immunomodulatory genes and in anthelmintic targets. CONCLUSIONS: We examine how different the male and female worms are at the molecular level and describe major developmental events that occur in the worm, which extend our understanding of the interactions between this parasite and its host. In addition to generating new hypotheses for follow-up experiments into the worm's behavior, physiology, and metabolism, our datasets enable future more in-depth comparisons between nematodes to better define the utility of H. bakeri as a model for parasitic nematodes in general.

Brain-derived neurotrophic factor promotes orthodontic tooth movement by alleviating periodontal ligament stem cell senescence.

Orthodontic treatment in older adults is more difficult than in younger adults, partially due to delayed osteogenesis caused by senescence of human periodontal ligament stem cells (hPDLSCs). The production of brain-derived neurotrophic factor (BDNF) which regulates the differentiation and survival of stem cells decreases with age. We aimed to investigate the relationship between BDNF and hPDLSC senescence and its effects on orthodontic tooth movement (OTM). We constructed mouse OTM models using orthodontic nickel­titanium springs and compared the responses of wild-type (WT) and BDNF+/- mice with or without addition of exogenous BDNF. In vitro, hPDLSCs subjected to the mechanical stretch were used to simulate the cell stretch environment during OTM. We extracted periodontal ligament cells from WT and BDNF+/- mice to evaluate their senescence-related indicators. The application of orthodontic force increased BDNF expression in the periodontium of WT mice, while the mechanical stretch increased BDNF expression in hPDLSCs. Osteogenesis-related indicators, including RUNX2 and ALP decreased and cellular senescence-related indicators such as p16, p53 and ß-galactosidase increased in BDNF+/- mice periodontium. Furthermore, periodontal ligament cells extracted from BDNF+/- mice exhibited more senescent compared with cells from WT mice. Application of exogenous BDNF decreased the expression of senescence-related indicators in hPDLSCs by inhibiting Notch3, thereby promoting osteogenic differentiation. Periodontal injection of BDNF decreased the expression of senescence-related indicators in periodontium of aged WT mice. In conclusion, our study showed that BDNF promotes osteogenesis during OTM by alleviating hPDLSCs senescence, paving a new path for future research and clinical applications.

Identification and evaluation of potential probiotics against skin-ulceration disease in the Chinese tongue sole (Cynoglossus semilaevis).

In this study, three highly pathogenic bacterial strains (Vibrio harveyi TB6, Vibrio alginolyticus TN1, and Vibrio parahaemolyticus TN3) were isolated from skin ulcers and intestines of diseased Chinese tongue sole (Cynoglossus semilaevis). The bacteria were investigated using hemolytic activity tests, in vitro co-culture with intestinal epithelial cells, and artificial infection of C. semilaevis. A further 126 strains were isolated from the intestines of healthy C. semilaevis. The three pathogens were used as indicator bacteria, and the antagonistic strains were identified from the 126 strains. The activities of exocrine digestive enzymes in the strains were also tested. Four strains with antibacterial and digestive enzyme activities were obtained and the best strains, Bacillus subtilis Y2 and Bacillus amyloliquefaciens Y9, were selected according to their ability to protect epithelial cells from infection. In addition, the effects of strains Y2 and Y9 at the individual level were investigated, finding that the activities of the immune-related enzymes superoxide dismutase, catalase, acid phosphatase, and peroxidase were significantly increased in the sera of the treatment group compared with the control group (p < 0.05). The specific growth rate (SGR, %) was also increased, especially in the Y2 group, and was significantly higher compared with the controls (p < 0.05). The result of the artificial infection test showed that the cumulative mortality within 72 h in the Y2 group was the lowest (50.5%), and in the Y9 group (68.5%) it was significantly lower than that in the control group (100%) (p < 0.05). Analysis of the intestinal microbial communities indicated that Y2 and Y9 could alter the composition of the intestinal flora, increasing both species richness and evenness, and inhibiting the growth of Vibrio in the intestine. These results suggested food supplemented with Y2 and Y9 could improve both immune function and disease resistance, as well as have a positive effect on the growth performance and the intestinal morphology of C. semilaevis.

Design, synthesis and biological evaluation of seco-DSP/DCK derivatives reversing P-glycoprotein-mediated paclitaxel resistance in A2780/T cells.

P-glycoprotein transporter (P-gp, ABCB1) is a major contributor to multidrug resistance, making it a valuable target for the development of novel P-gp inhibitor to overcome multidrug resistance. In this study, forty-nine novel seco-DSPs and seco-DMDCK derivatives were synthesized and evaluated their chemo-sensitize abilities to paclitaxel in A2780/T cell lines. Most of them exhibited a comparable reversal multidrug-resistance activity than verapamil. Especially, compound 27f showed a remarkable chemo-sensitization with more than 425-fold reversal ratio in A2780/T cells. The study of preliminary pharmacological mechanism displayed that compound 27f was more effective to increase the accumulation of paclitaxel and Rhodamine 123 than verapamil via inhibiting P-gp for reversing multidrug-resistance. In addition, a higher than 40 µM IC50 values of hERG potassium channel inhibition concentration suggested that compound 27f hardly had relevant cardiac toxicity. These results indicated that compound 27f might be a potential candidate to further investigate for the development of chemosensitizer with MDR reversal activity.

Eldecalcitol prevented OVX-induced osteoporosis through inhibiting BMSCs senescence by regulating the SIRT1-Nrf2 signal.

Background: Aging and oxidative stress are considered to be the proximal culprits of postmenopausal osteoporosis. Eldecalcitol (ED-71), a new active vitamin D derivative, has shown a good therapeutic effect on different types of osteoporosis, but the mechanism is unclear. This study focused on exploring whether ED-71 could prevent bone loss in postmenopausal osteoporosis by regulating the cell senescence of bone mesenchymal stem cells (BMSCs), and explaining its specific mechanism of action. Materials and methods: An ovariectomized (OVX) rat model was established and 30 ng/kg ED-71 was administered orally once a day. The weight of rats was recorded regularly. Micro-computed tomography (CT) and histochemical staining were used to evaluate bone mass, histological parameters, and aging-related factors. Rat bone mesenchymal stem cells were extracted and cultivated in vitro. Aging cells were marked with senescence-associated ß-gal (SA-ß-gal) dyeing. The mRNA and protein levels of aging-related factors and SIRT1-Nrf2 signal were detected by RT-PCR, Western blot, and immunofluorescence staining. The reactive oxygen species (ROS) levels were detected by DCFH-DA staining. Results: Compared with the Sham group, the bone volume of the ovariectomized group rats decreased while their weight increased significantly. ED-71 prevented bone loss and inhibited weight gain in ovariectomized rats. More importantly, although the expression of aging-related factors in the bone tissue increased in the ovariectomized group, the addition of ED-71 reversed changes in these factors. After extracting and in vitro culturing bone mesenchymal stem cells, the proportion of aging bone mesenchymal stem cells was higher in the ovariectomized group than in the Sham group, accompanied by a significant decrease in the osteogenic capacity. ED-71 significantly improved the bone mesenchymal stem cells senescence caused by ovariectomized. In addition, ED-71 increased the expression of SIRT1 and Nrf2 in ovariectomized rat bone mesenchymal stem cells. Inhibition of SIRT1 or Nrf2 decreased the inhibitory effect of ED-71 on bone mesenchymal stem cells senescence. ED-71 also showed a suppression effect on the reactive oxygen species level in bone mesenchymal stem cells. Conclusion: Our results demonstrated that ED-71 could inhibit the cell senescence of bone mesenchymal stem cells in ovariectomized rats by regulating the SIRT1-Nrf2 signal, thereby preventing bone loss caused by osteoporosis.

Investigation of the separate and simultaneous bindings of warfarin and fenofibrate to bovine serum albumin.

Lipid-lowering drugs are often taken with anticoagulant drugs in hyperlipidemia patients. Fenofibrate (FNBT) and warfarin (WAR) are common clinical lipid-lowering drugs and anticoagulant drugs, respectively. A study of binding affinity, binding force, binding distance, and binding sites was performed to determine the interaction mechanism between drugs and carrier proteins (bovine serum albumin, BSA), as well as their effects on BSA conformation. Both FNBT and WAR can form complexes with BSA by van der Waals force and hydrogen bonds. WAR had a stronger fluorescence quenching effect on BSA, a stronger binding affinity, and greater effects on BSA conformation than FNBT. According to fluorescence spectroscopy and cyclic voltammetry, co-administration of drugs decreased one drug's binding constant to BSA and increased its binding distance. This suggested that each drug's binding to BSA was disturbed by each other, as well as each drug's binding ability to BSA was altered by the other. It was demonstrated that co-administration of drugs had greater effects on the secondary structure of BSA and microenvironment polarity surrounding amino acid residues, using multiple spectroscopy techniques, such as ultraviolet spectroscopy, Fourier transform infrared spectroscopy, and synchronous fluorescence spectroscopy.

Fabrication of Temperature Sensors with High-Performance Uniformity through Thermal Annealing.

It is considered to be of great significance to monitor human health and track the effect of drugs by measuring human temperature mapping through flexible temperature sensors. In this work, we found that the thermal annealing of flexible temperature sensors based on graphite-acrylate copolymer composites can not only improve the temperature coefficient of resistance (TCR) values of the devices, but also greatly improve the uniformity of the performance of the devices prepared in parallel. The best results were obtained when the devices were annealed at 100 °C, which is believed to be due to the rearrangement of graphite particles to generate more uniform and numerous conductive channels within the conductive composite. We believe this finding might promote the practical development of flexible temperature sensors in body temperature sensing for health maintenance and medical applications.