Biomechanical analysis of stress around the tilted implants with different cantilever lengths in all-on-4 concept.

BACKGROUND: Many clinical studies have reported the high success rate of the All-on-4 concept. In the present study, we aimed to compare the stress distribution with different tilted distal implants and cantilever lengths in an All-on-4 system using the two-dimensional photoelastic method and to establish the All-on-4 implant photoelastic model by computer-aided design (CAD) and rapid prototyping (RP).  METHODS: The data of the human edentulous mandible were acquired by computed tomography (CT). Three human edentulous mandible All-on-4 implant models with different distally inclined implant holes were fabricated using Mimic, Geomagic Studio software, and a light solidifying fast shaping machine. Then the final photoelastic models were established through the traditional method. Each of the three models had four NobelSpeedy Replace implants between the interforaminal regions. The two posterior implants were placed 0, 15, and 45 degrees distally before the mental foramen. The four implants were splinted by wrought cobalt-chromium alloy frameworks. Each of the three photoelastic models was submitted to a 150 N vertical load at five points on the framework: the central fossa of the mandibular first molar, and 0 mm, 5 mm, 10 mm, and 15 mm of the cantilever length. The stress produced in the models was photographed with a digital camera, and the highest value of the stressed fringe pattern was recorded. RESULTS: The All-on-4 implant photoelastic model established by CAD and RP was highly controllable and easy to modify. The position and inclination of implants were accurate, and the frameworks could be passively emplaced. The stress values were higher around a single tilted implant compared with the distal implant in All-on-4 with the same inclination. The 0-degree distal implant and 45-degree distal implant demonstrated the highest and lowest stress when loading at the central fossa of the mandibular first molar, respectively. With the same inclination of distal implant, the peri-implant bone stress increased as the length of cantilever increased. CONCLUSION: The method of establishing the All-on-4 implant photoelastic model by CAD and RP was highly controllable, convenient, fast, and accurate. The tilted implants splinted in the fully fixed prosthesis with reduced cantilever lengths did not increase the stress level compared with the vertical distal implants.And this illustrated that the influence of cantilever on stress distribution was greater than the influence of implant inlination.

Tripchlorolide May Improve Spatial Cognition Dysfunction and Synaptic Plasticity after Chronic Cerebral Hypoperfusion.

Chronic cerebral hypoperfusion (CCH) is a common pathophysiological mechanism that underlies cognitive decline and degenerative processes in dementia and other neurodegenerative diseases. Low cerebral blood flow (CBF) during CCH leads to disturbances in the homeostasis of hemodynamics and energy metabolism, which in turn results in oxidative stress, astroglia overactivation, and synaptic protein downregulation. These events contribute to synaptic plasticity and cognitive dysfunction after CCH. Tripchlorolide (TRC) is an herbal compound with potent neuroprotective effects. The potential of TRC to improve CCH-induced cognitive impairment has not yet been determined. In the current study, we employed behavioral techniques, electrophysiology, Western blotting, immunofluorescence, and Golgi staining to investigate the effect of TRC on spatial learning and memory impairment and on synaptic plasticity changes in rats after CCH. Our findings showed that TRC could rescue CCH-induced spatial learning and memory dysfunction and improve long-term potentiation (LTP) disorders. We also found that TRC could prevent CCH-induced reductions in N-methyl-D-aspartic acid receptor 2B, synapsin I, and postsynaptic density protein 95 levels. Moreover, TRC upregulated cAMP-response element binding protein, which is an important transcription factor for synaptic proteins. TRC also prevented the reduction in dendritic spine density that is caused by CCH. However, sham rats treated with TRC did not show any improvement in cognition. Because CCH causes disturbances in brain energy homeostasis, TRC therapy may resolve this instability by correcting a variety of cognitive-related signaling pathways. However, for the normal brain, TRC treatment led to neither disturbance nor improvement in neural plasticity. Additionally, this treatment neither impaired nor further improved cognition. In conclusion, we found that TRC can improve spatial learning and memory, enhance synaptic plasticity, upregulate the expression of some synaptic proteins, and increase the density of dendritic spines. Our findings suggest that TRC may be beneficial in the treatment of cognitive impairment induced by CCH.

Luteolin Could Improve Cognitive Dysfunction by Inhibiting Neuroinflammation.

Neuroinflammation and oxidative stress play an important role in cognition deficit following chronic cerebral hypoperfusion (CCH). Luteolin, a natural flavonoid found in many plants, is known for a variety of pharmacological activities, such as its anti-inflammatory, anti-allergy, urate, anti-tumor, antibacterial, and antiviral effects. To assess whether luteolin could prevent CCH-induced cognitive dysfunction, through its anti-inflammatory and anti-oxidative-stress effects, we used enzyme-linked immunosorbent assays, enzyme activity assays, behavioral methods, immunohistochemistry, and electrophysiology to detect neuroinflammation and oxidative stress, cognition alterations, and long-term potential (LTP), in a bilateral common carotid arteries ligation (2VO) rat model. We demonstrated that CCH increased tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), interleukin 6 (IL-6), and malondialdehyde (MDA), and decreased superoxide dismutase (SOD) and glutathione peroxidase (GPx) levels. Further, it caused microglia over-activation and astrogliosis, learning and short-term memory dysfunction, and an LTP deficit. Luteolin treatment reversed CCH-induced changes. Specifically, luteolin prevented the increase of TNF-α and IL-1ß, IL-6, and MDA, improved the activity of SOD and GPx, inhibited microglia over-activation and astrogliosis (particularly in the hippocampus and cortex), and ameliorated learning and short-term memory dysfunction, and LTP deficit. Thus, our study suggested that luteolin could be a preferable anti-inflammatory agent to protect cognitive function and synaptic plasticity following CCH. Luteolin could also be putative therapeutic candidate for other inflammation-related brain diseases.

[Analysis on the disease burden and its impact factors of coal worker's pneumoconiosis inpatients].

OBJECTIVE: To obtain the baseline data and decision of quantitative analysis for the allocation of scarce health care resources,and for the health policymaking about easing the disease burden, to provide estimation of the economic costs and the disability-adjusted life years (DALYs) loss of the coal worker's pneumoconiosis (CWP) and to explore the influencing factors of the disease burden. METHODS: The CWP inpatients from the Institute of Occupational Diseases Prevention and Control of a Coal Mining Group for 2011 were recruited in the study. Multiple dimensions of the disease burden were measured in the inception cohort of the 194 CWP inpatients: the direct economic burden, the indirect economic burden and the DALYs loss. The direct economic burden of the inpatients included hospitalization expenses and food allowances and nutritional supplements. The indirect economic burden was estimated using the DALYs and human capital approach,and the influencing factors of hospitalization expenses were analyzed in this study. RESULTS: The estimated direct economic burden for the 194 CWP inpatients for 2011 was approximately 4.68 million yuan and direct burden per capita was 24 108.05 yuan, and their indirect burden about 6.98 million yuan and indirect burden per capita 35 977.36 yuan. The study discovered that 1 681.53 health years were lost for the CWP inpaitents and per capita health years loss (8.67±3.65) years. CONCLUSION: The medical cost, the indirect cost and the DALYs loss of CWP are all sizable. Age and length of stay in the hospital are the major influencing factors for high hospitalization expenses. The hospitalization expenses of the CWP inpatients increase with their age and length of stay in the hospital. Taking effective measures to reduce the morbility is the key point to reduce the CWP burden.

[Epigenetics of plant vernalization regulated by non-coding RNAs].

Many higher plants must experience a period of winter cold to accomplish the transition from vegetative to reproductive growth. This biological process is called vernalization. Some crops such as wheat (Triticum aestivum L.) and oilseed rape (Brassica napus L.) produce seeds as edible organs, and therefore special measures of rotation and cultivation are necessary for plants to go through an early vernalization for flower differentiation and development, whereas the other crops such as Chinese cabbage (B rapa ssp. pekinenesis) and cabbage (Brassica napus L.) produce leafy heads as edible organs, and additional practice should be taken to avoid vernalization for a prolonged and fully vegetative growth. Before vernalization, flowering is repressed by the action of a gene called Flowering Locus C (FLC). This paper reviewed the function of non-coding RNAs and some proteins including VRN1, VRN2, and VIN3 in epigenetic regulation of FLC during vernalization.

[The effects of monocyte-macrophages on malignant transformation of human bronchial epithelial cells induced by extracts from coal tar pitch].

OBJECTIVE: To study the effects of monocyte-macrophages (THP-1) in malignant transformation of human bronchial epithelial cells (BEAS-2B) cells induced by coal tar pitch (CTP) and the expression of TNF-α in the process of the cell malignant transformation. METHODS: BEAS-2B cells and THP-1 Cells were divided into four groups: coal tar pitch (CTP) group, benzo(a)pyrene [B(a)P] group, dimethyl sulfoxide (DMSO) group, BEAS-2B and THP-1 co-culture (co-culture group) group. Carcinogenesis model was established. The soft agar colony formation, chromosome aberrations and cell cycle tests were used to detect the cellular malignant transformation. The ELISA assay was utilized to measure the levels of TNF-α in the supernatant of CTP group and co-culture group. RESULTS: The chromosome number abnormalities could be observed in early stage of the experiment (the 10th generation cells), which showed the increased ratio of aneuploid to polyploid, and the decreased number of diploid. The colony formation rate of co-culture group (the 20th generation cells) was 17.63‰ ± 0.97‰, which was significantly higher than that (13.94‰ ± 0.84‰) of CTP group and that (12.96‰ ± 1.62‰) of B(a)P group (P < 0.05). The proportion of S phase cells in the co-culture group was 44.49% ± 0.68%, which was significantly higher than that (38.19% ± 1.26%) of CTP group and that (36.41% ± 1.19%) of B(a)P group (P < 0.05). The TNF-α level in the co-culture group was significantly higher than that in CTP group (P = 0.001). CONCLUSION: Monocyte-Macrophages can accelerate the malignant transformation of BEAS-2B cells induced by CTP and increase the expression level of TNF-α.

Erratum: Resveratrol counteracts bone loss via mitofilin-mediated osteogenic improvement of mesenchymal stem cells in senescence-accelerated mice: Erratum.

[This corrects the article DOI: 10.7150/thno.23620.].

[Tolterodine tartrate combined with alpha-receptor blocker for benign prostatic hyperplasia with detrusor overactivity].

OBJECTIVE: To evaluate the efficacy and safety of Tolterodine Tartrate combined with the alpha-receptor blocker in the treatment of benign prostatic hyperplasia with detrusor overactivity (BPH-DO). METHODS: A total of 113 patients with BPH-DO were randomly assigned to receive Tolterodine Tartrate combined with Cardura (Group A) and Cardura alone (Group B), both for 12 weeks. Then we recorded and compared their average 24 h urinary frequency, IPSS and QOL score, maximum urinary flow rate, residual urine volume and urinary retention times before and after the treatment. RESULTS: After the treatment, Group A showed significantly better improvement in the average 24 h urinary frequency and scores on IPSS and QOL than Group B. No significant differences were found between the two groups in the maximum urinary flow rate and residual urine volume. No acute urinary retention occurred in either group. CONCLUSION: The combined use of Tolterodine Tartrate and the alpha-receptor blocker can effectively relieve the symptoms of dysuria, urinary frequency and urinary urgency in patients with BPH-DO, with neither significant adverse effects on the maximum flow rate and residual urine volume nor increase in the incidence of acute urinary retention.

[Investigation on correlation between ratio of xylem to phloem of Radix Isatidis and efficacy, chemical composition].

OBJECTIVE: Explore contribution of ratio of xylem to phloem(RXP) to evaluate the quality of Radix Isatidis. METHODS: Antivirus activity and chemical compositions of xylem, phloem and Radix Isatidis of different RXP were determined by RBC agglutination test and unique chromatogram. Meanwhile, correlation between RXP and bioactivity,components was investigated. RESULTS: the activity of medical material of Radix Isatidis whose RXP was 1:2 or 1:1 is equal to that of phloem sample, while is stronger than that of cylem sample. There was a good consistency among the chemical figureprints of three samples (Radix Isatidis, xylem and phloem). When the RXP was 2:1, the medical material of Radix Isatidi and its xylem had the same activity. But the activity of phloem was not obvious. Their consistency of chemical fingerprint was bad, and the activity of Radix Isatidis which had RXP of 1:2 or 1:1 was better than that formed by xylem and phloem of 2:1. The Radix Isatidis of RXP of 1:2 or 1:1 had less similarity of chemical figureprint with that having RXP of 2:1. CONCLUSION: The quality of Radix Isatidis made up by the various RXP had significant difference. Radix Isatidis whose RXP is less than 1:1 had good quality and better activity. As a characteristic parameter of biologic morpha, the RXP can be applied to identifying the quality of Radix Isatidis, and also provided a reference to evaluation of other medical material of roots.

EGB761 ameliorates chronic cerebral hypoperfusion-induced cognitive dysfunction and synaptic plasticity impairment.

Chronic cerebral hypoperfusion (CCH) may lead to the cognitive dysfunction, but the underlying mechanisms are unclear. EGB761, extracted from Ginkgo biloba and as a phytomedicine widely used in the world, has been showed to have various neuroprotective roles and mechanisms, and therapeutic effects in Alzheimer's disease and other cognitive dysfunctions. However, improvements in cognitive function after CCH, following treatment with EGB761, have not been ascertained yet. In this study, we used the behavior test, electrophysiology, neurobiochemistry, and immunohistochemistry to investigate the EGB761's effect on CCH-induced cognitive dysfunction and identify its underlying mechanisms. The results showed that EGB761 ameliorates spatial cognitive dysfunction occurring after CCH. It may also improve impairment of the long-term potentiation, field excitable potential, synaptic transmission, and the transmission synchronization of neural circuit signals between the entorhinal cortex and hippocampal CA1. EGB761 may also reverse the inhibition of neural activity and the degeneration of dendritic spines and synaptic structure after CCH; it also prevents the downregulation of synaptic proteins molecules and pathways related to the formation and stability of dendritic spines structures. EGB761 may inhibit axon demyelination and ameliorate the inhibition of the mTOR signaling pathway after CCH to improve protein synthesis. In conclusion, EGB761 treatment after CCH may improve spatial cognitive function by ameliorating synaptic plasticity impairment, synapse degeneration, and axon demyelination by rectifying the inhibition of the mTOR signaling pathway.

[Quality control of shuanghuanglian freeze-dried powder for injection based on its HPLC-ELSD fingerprints and biological profiles].

This paper is aimed to provide the methods of quality control and bioassay of traditional Chinese medicine injections including bioassay method. Shuanghuanglian freeze-dried powder for injection (SFPI) was chosen as study object. HPLC-ELSD fingerprints of SFPI had been established and the samples were differentiated by similarity calculation. Meanwhile, biological profiles of SFPI on Escherichia coli had been established by microcalorimetry. The similarity values were calculated using the correlation coefficient, based on quantitative thermo-kinetic parameters (T2m, Tj, I%). The results indicated that HPLC-ELSD fingerprints, which showed content changes of chemical components, could not monitor minimal variation of different samples, especially that of biological pollutants, while biological profiles could sensitively detect antibiotic activity alterations of the samples, which were kept under specific conditions. In conclusion, characterized by two-dimension, microcalorimetry could supply thermograms as biological profiles characterized to describe the bioactivity of drugs. This study could clearly demonstrate that the correlative detection was proposed as an efficient strategy for quality control of SFPI, based on HPLC-ELSD fingerprints and biological profiles, which could detect quality fluctuation of samples early and quickly and predict the potential adverse drug events (ADE) for ensuring clinical safety.

[Agglutinated activity bioassay method for the determination of antivirus potency of Banlangen granula].

To establish a bioassay method and quality standard of Banlangen granula, agglutinated activity assay was used in the analysis of the traditional Chinese medicine, Banlangen granula. It showed that masculined effect could be picked up effectively and the products quality of different pharmaceutical factories and different batch numbers from the same factory could be revealed conveniently, accurately, quickly and directly with this method (valence value was between 2 and 11). The established bioassay method had a good reproducibility with RSD = 2%. The dependablity of the activity of red cell agglutination and restrainting influenza virus NA was conspicuous (r2 = 0.878 3). In conclusion, this bioassay method is suitable to control and evaluate the quality of Banlangen granula. Thus the method may provide a simple and effective technique in supervising and examining the quality of other traditional Chinese medicine.

[Kinetic spectrophotometric study on hemolytic process of polysorbate 80].

To establish kinetic assay method for the analysis of hemolysis and to investigate dynamic hemolytic process of polysorbate 80. The UV-VIS spectrum of heme changes when hemoglobin is released continuously during the hemolytic process. Therefore, dynamic hemolytic curve was determined as a new way to characterize the kinetic process of interaction between polysorbate 80 and red blood cells. The effect of polysorbate 80 on blood cells could be perfectly investigated by the hemolytic dynamics. Dynamic hemolytic parameters of polysorbate 80 were calculated according to the hemolytic curves. The constants of hemolytic rate and maximum hemolytic rate of polysorbate 80 had fine linear relationships at the range of 1-20 mg x mL(-1) and 5-20 mg x mL(-1), respectively. In comparison with the present official method such as macroscopic observation and static spectrophotometric methods, kinetic spectrophotometry has the advantages of real time, on-line determination, sensitive, objective, good reproducibility and 2-dimensional information acquired. Therefore, as a biological technique, kinetic spectrophotometry could be applied to evaluate the quality of polysorbate 80 and to screen other solubilizing excipients.

Identification of a hippocampal lncRNA-regulating network in cognitive dysfunction caused by chronic cerebral hypoperfusion.

Cognitive dysfunction caused by chronic cerebral hypoperfusion is a common underlying cause of many cognition-related neurodegenerative diseases. The mechanisms of cognitive dysfunction caused by CCH are not clear. Long non-coding RNA is involved in synaptic plasticity and cognitive function, but whether lncRNA is involved in cognitive dysfunction caused by CCH has not yet been reported. In the present study, we identified the altered lncRNAs and mRNAs by deep RNA sequencing. A total of 128 mRNAs and 91 lncRNAs were up-regulated, and 108 mRNAs and 98 lncRNAs were down-regulated. Real-time reverse transcription-polymerase chain reaction verified the reliability of the lncRNA and mRNA sequencing. Gene Ontology and KEGG pathway analyses showed that differentially-expressed mRNAs were related to peptide antigen binding, the extracellular space, the monocarboxylic acid transport, and tryptophan metabolism. The co-expression analysis showed that 161 differentially expressed lncRNAs were correlated with DE mRNAs. By predicting the miRNA in which both DE lncRNAs and DE mRNAs bind together, we constructed a competitive endogenous RNA network. In this lncRNAs-miRNAs-mRNAs network, 559 lncRNA-miRNA-mRNA targeted pairs were identified, including 83 lncRNAs, 67 miRNAs, and 108 mRNAs. Through GO and KEGG pathway analysis, we further analyzed and predicted the regulatory function and potential mechanism of ceRNA network regulation. Our results are helpful for understanding the pathogenesis of cognitive dysfunction caused by CCH and provide direction for further research.

[Determination of colistin based on biothermal activity detection method].

A biothermal activity detection method has been established to determine the potency of colistin. The biothermal activity fingerprints of E. coli with colistin were determined. There was a good linear relationship (r = 0.993) between logarithm concentration of colistin (lgC) and lag rate of growing time (Deltat%) when the concentrations of colistin ranged from 17.0 to 41.6 u x mL(-1). The average recovery rate was 100.3% (n = 9). Using this method, there was no significant difference between results of colistin potency measurement and those using cup-plate method (P > 0.05). As a result, biothermal activity detection method is sensitive, accurate, rapid, convenient and feasible to determine the potency of colistin. This method can also be applied in real time and online to monitor the process of bacterial growth and could be complementary to the cup-plate method.

[Study on selecting the suitable solubilizing excipients for Shengmai injection].

OBJECTIVE: To select the suitable solubilizing excipients for Shengmai injection by the mean of hemolysis. METHODS: The hemolysis ratio of Shengmai injection, solubilizing excipients and different proportion of them were determined by absorption spectrometry. RESULTS: In the experimental concentration, Shengmai injection itself had no hemolytic effect. Polysorbate 80, Polyethylene glycol 400, Polyethylene glycol 600, Poloxamer 188 solution had no hemolytic effect to appear, but all the experimental concentrations of Polysorbate 20 had hemolytic effect. When combining with different proportion of Polysorbate 20, Polyethylene glycol 400, Polyethylene glycol 600, Poloxamer 188 and Polysorbate 80 of high concentration (0.75% - 1%), Shengmai injection had hemolytic effect. CONCLUSIONS: The absorption spectrometry is more reliable for the judgement of hemolysis than macroscopic observation, and it is helpful to improve the accuracy to select the solubilizing excipients for the TCM injection. Polysorbate 80 can be used as solubilizing excipient of Shengmai injection, which is safe in the concentration range of 0.1% to 0.5%.

[Preparation of Sulfonated Graphene Oxide Modified Composite Nanofiltration Membrane and Application in Salts Separation].

In recent years, water resources are in short supply and seriously polluted. Increasingly more attention has been paid to the process of salt separation. The surface of the nanofiltration (NF) membrane is usually charged and can selectively allow the permeation of different ions. Based on the different charges on the NF membrane surface, in order to achieve a good separation of salt, the prepared graphene oxide with the sulfonic acid group was introduced into NF membrane material. Additionally, the SGO modified composite NF membrane was prepared by interfacial polymerization. Zeta potential analysis showed that the charge on the surface of the prepared NF membrane was more negative than that of the NF membrane without SGO. The peak of the ester group in the FT-IR analysis indicated that the sulfonate group was involved in the polymerization reaction. A Turing structure present on the surface of the membrane was evident through SEM pictures of the membrane surface. At a pressure of 0.2 MPa, the pure water flux can reach 45.85 L·(m2·h)-1. The rejection of Na2SO4 was 98.23%, while that of NaCl was 24.93%. The 10 h operation can effectively separate SO42- and Cl-, which realized the salt recycling.

[Effect of Signal Molecule Combined with Thiobacillus denitrificans on Simultaneous Removal of Nitrogen and Sulfur].

The effects of Thiobacillus denitrificans combined with signal molecules on the removal of sulfide and nitrate was investigated. By adding signal molecules and T. denitrificans at the same, the total number of microorganisms increased, the removal of sulfide and nitrate was accelerated, and an increase in nitrogen gas and more stable accumulation of elemental sulfur was observed. The total number of microorganisms after the reaction was detected using fluorescence in situ hybridization (FISH) technique. In this experiment, the optimal concentration for the stable accumulation of elemental sulfur from six concentrations of signal molecules was revealed. Further, the effects of adding signal molecules, T. denitrificans, and their combination were analyzed at this concentration. The results showed that it was easier to accumulate elemental sulfur after the addition of 1.0 µmol·L-1 signal molecule. After adding both T. denitrificans and 1.0 µmol·L-1 signal molecules at a sulfide concentration of 200 mg·L-1, the removal of sulfide and nitrate increased to 99.8% and 96.9% at 72 h, respectively, and increases in nitrogen gas and sulfur were observed. The amounts of elemental sulfur and nitrogen gas reached to 59.0 mg and 80.0 mL, respectively, after adding 2.5 µmol·L-1 signal molecules at 72 h when the sulfide concentration was 300 mg·L-1. Under those conditions, the removal efficiency of sulfide and nitrate reached 99.0% and 93.9%, and the production of elemental sulfur and nitrogen reached 63.1 mg and 79.5 mL, respectively.

Cinchonine activates endoplasmic reticulum stress-induced apoptosis in human liver cancer cells.

Cinchonine is a natural compound present in Cinchona bark. It exerts multidrug resistance reversal activity and synergistic apoptotic effect with paclitaxel in uterine sarcoma cells. Whether cinchonine is effective against human liver cancer, however, remains elusive. A total of five liver cancer cell lines including Bel-7402, MHCC97H, HepG2, Hep3B and SMCC7721 were used. The anti-proliferative effects of cinchonine on these liver cancer cell lines were assessed by MTT assay. The apoptotic effects of cinchonine on liver cancer cell lines were assessed by flow cytometry with Annexin V/propidium iodide assay. Caspase-3 activation, poly (ADP-Ribose) polymerase (PARP) cleavage as well as the endoplasmic-reticulum (ER) stress response was detected by western blotting. Balb/c-nude mice bearing HepG2 xenograft tumors were used to evaluate the in vivo antitumor effect of cinchonine. It was demonstrated that cinchonine inhibited cell proliferation and promoteed apoptosis in liver cancer cells in a dose-dependent manner. Cinchonine promoted caspase-3 activation and PARP1 cleavage in liver cancer cells. Furthermore, cinchonine activated the ER stress response by upregulating GRP78 and promoting PERK and Eukaryotic Translation Initiation Factor 2 α phosphorylation. The Balb/c-nude mice experiment revealed that cinchonine suppressed HepG2 xenograft tumor growth in mice. The findings indicated that cinchonine promoted ER stress-induced apoptosis in liver cancer cells and suggested that cinchonine may have a potential beneficial effect for liver cancer treatment.

Resveratrol counteracts bone loss via mitofilin-mediated osteogenic improvement of mesenchymal stem cells in senescence-accelerated mice.

Rational: Senescence of mesenchymal stem cells (MSCs) and the related functional decline of osteogenesis have emerged as the critical pathogenesis of osteoporosis in aging. Resveratrol (RESV), a small molecular compound that safely mimics the effects of dietary restriction, has been well documented to extend lifespan in lower organisms and improve health in aging rodents. However, whether RESV promotes function of senescent stem cells in alleviating age-related phenotypes remains largely unknown. Here, we intend to investigate whether RESV counteracts senescence-associated bone loss via osteogenic improvement of MSCs and the underlying mechanism. Methods: MSCs derived from bone marrow (BMMSCs) and the bone-specific, senescence-accelerated, osteoblastogenesis/osteogenesis-defective mice (the SAMP6 strain) were used as experimental models. In vivo application of RESV was performed at 100 mg/kg intraperitoneally once every other day for 2 months, and in vitro application of RESV was performed at 10 µM. Bone mass, bone formation rates and osteogenic differentiation of BMMSCs were primarily evaluated. Metabolic statuses of BMMSCs and the mitochondrial activity, transcription and morphology were also examined. Mitofilin expression was assessed at both mRNA and protein levels, and short hairpin RNA (shRNA)-based gene knockdown was applied for mechanistic experiments. Results: Chronic intermittent application of RESV enhances bone formation and counteracts accelerated bone loss, with RESV improving osteogenic differentiation of senescent BMMSCs. Furthermore, in rescuing osteogenic decline under BMMSC senescence, RESV restores cellular metabolism through mitochondrial functional recovery via facilitating mitochondrial autonomous gene transcription. Molecularly, in alleviating senescence-associated mitochondrial disorders of BMMSCs, particularly the mitochondrial morphological alterations, RESV upregulates Mitofilin, also known as inner membrane protein of mitochondria (Immt) or Mic60, which is the core component of the mitochondrial contact site and cristae organizing system (MICOS). Moreover, Mitofilin is revealed to be indispensable for mitochondrial homeostasis and osteogenesis of BMMSCs, and that insufficiency of Mitofilin leads to BMMSC senescence and bone loss. More importantly, Mitofilin mediates resveratrol-induced mitochondrial and osteogenic improvements of BMMSCs in senescence. Conclusion: Our findings uncover osteogenic functional improvements of senescent MSCs as critical impacts in anti-osteoporotic practice of RESV, and unravel Mitofilin as a novel mechanism mediating RESV promotion on mitochondrial function in stem cell senescence.