Effect of decentration and tilt on the in vitro optical quality of monofocal and trifocal intraocular lenses.

PURPOSE: To evaluate and compare the effect of decentration and tilt on the optical quality of monofocal and trifocal intraocular lenses (IOL). METHODS: Optical quality of a monofocal IOL (AcrySof IQ SN60WF; Alcon Laboratories, Inc., USA) and a trifocal IOL (AcrySof IQ PanOptix; Alcon Laboratories, Inc., USA) was assessed using an in vitro optical bench (OptiSpheric IOL R&D; Trioptics GmbH, Germany). At apertures of 3.0 mm and 4.5 mm, modulation transfer function (MTF) at spatial frequency of 50 lp/mm, MTF curve and the United States Air Force (USAF) resolution test chart of the two IOLs were measured and compared at their focus with different degrees of decentration and tilt. Optical quality at infinity, 60 cm and 40 cm and the through-focus MTF curves were compared when the two IOLs were centered at apertures of 3.0 mm and 4.5 mm. Spectral transmittance of the two IOLs was measured by the UV-visible spectrophotometer (UV 3300 PC; MAPADA, China). RESULTS: The SN60WF and the PanOptix filtered blue light from 400 to 500 nm. Both IOLs at the far focus and the PanOptix at the intermediate focus showed a decrease in optical quality with increasing decentration and tilt. The PanOptix demonstrated enhanced optical quality compared to the previous gradient at the near focus at a decentration range of 0.3-0.7 mm with a 3.0 mm aperture, and 0.5 mm with a 4.5 mm aperture, whereas other conditions exhibited diminished optical quality with increasing decentration and tilt at the focus of both IOLs. When the two IOLs were centered, the SN60WF had better optical quality at infinity, while the PanOptix had better optical quality at 60 cm and 40 cm defocus. The optical quality of the SN60WF exceeded that of the PanOptix at far focus, with a 3 mm aperture decentration up to 0.7 mm and a 4.5 mm aperture decentration up to 0.3 mm; this observation held true for all tilts, irrespective of aperture size. As both decentration and tilt increased, the optical quality of the SN60WF deteriorated more rapidly than that of the PanOptix at the far focal point. CONCLUSIONS: The SN60WF showed a decrease in optical quality with increasing decentration and tilt. Optical quality of the PanOptix at the near focus increased in some decentration conditions and decreased in some conditions, while it showed a decrease at the other focuses with increasing decentration. While tilt only had a negative effect on optical quality. When both IOLs were centered, the PanOptix provided a wider range of vision, while the SN60WF provided better far distance vision. At the far focus, the SN60WF has better resistance to tilt than the PanOptix, but the optical quality degrades more quickly when decentered and tilted.

Human Placenta-Derived Mesenchymal Stem Cells Improve Neurological Function in Rats with Intrauterine Hypoxic-Ischaemic Encephalopathy by Reducing Apoptosis and Inflammatory Reactions.

BACKGROUND: Hypoxic-ischaemic encephalopathy (HIE) is a major cause of neonatal disability and mortality. Although hypothermia therapy offers some neuroprotection, the recovery of neurological function is limited. Therefore, new synergistic therapies are necessary to improve the prognosis. Mesenchymal stem cell-based therapy is emerging as a promising treatment option for HIE. In this study, we studied the therapeutic efficacy of human placenta-derived mesenchymal stem cells (PD-MSCs) in the HIE rat model and analyzed the underlying therapeutic mechanisms. METHODS: Rats were divided into 6 groups (n = 9 for each) as follows: control, HIE model, HIE + normal saline, and HIE + PD-MSC transplantation at days 7, 14 and 28 postpartum. Following PD-MSC transplantation, neurological behavior was evaluated using rotarod tests, traction tests, and the Morris water maze test. The degree of brain tissue damage was assessed by histological examination and Nissl staining. Expression levels of apoptosis-related proteins and inflammatory factors were quantified by Western blotting and enzyme-linked immunosorbent assays. Immunofluorescence was used to investigate the ability of PD-MSCs to repair the morphology and function of hippocampal neurons with hypoxic-ischaemic (HI) injury. RESULTS: PD-MSC transplantation enhanced motor coordination and muscle strength in HIE rats. This treatment also improved spatial memory ability by repairing pathological damage and preventing the loss of neurons in the cerebral cortex. The most effective treatment was observed in the HIE + PD-MSC transplantation at day 7 group. Expression levels of microtubule-associated protein-2 (MAP-2), B-cell lymphoma-2 (BCL-2), interleukin (IL)-10, and transforming growth factor (TGF -ß1) were significantly higher in the HIE + PD-MSC treatment groups compared to the HIE group, whereas the levels of BCL-2-associated X protein (BAX), BCL-2-associated agonist of cell death (BAD), IL-1ß and tumour necrosis factor α (TNF-α) were significantly lower. CONCLUSIONS: We demonstrated that intravenous injection of PD-MSC at 7, 14 and 28 days after intrauterine HI damage in a rat model could improve learning, memory, and motor function, possibly by inhibiting apoptosis and inflammatory damage. These findings indicate that autologous PD-MSC therapy could have potential application for the treatment of HIE.

Prevalence and Predictors of Hemorrhagic Foci on Long-term Follow-up MRI of Recent Single Subcortical Infarcts.

Hemorrhagic foci surrounding the lacune in the long-term evolution of recent single subcortical infarcts (RSSIs) remains largely unexplored. We aimed to determine the prevalence, characteristics, and predictors of hemorrhagic foci in patients with RSSI. From a prospective, longitudinal study of RSSIs, we recruited patients who underwent multimodal MRI assessments both at baseline and approximately one year after the stroke onset. Hemorrhagic foci were identified using susceptibility-weighted imaging (SWI). Among 101 patients with RSSI, nearly half (n = 45, 44.6%) had hemorrhagic foci within the index RSSI lesions on follow-up SWI. RSSIs with hemorrhagic foci formation were associated with a longer time to follow-up imaging (median 449 versus 401 days, P = 0.005) and higher likelihood of being located in the anterior circulation compared to those without hemorrhagic foci (88.9% versus 64.3%, P = 0.003). Hemorrhagic foci were also associated with larger lesion size (P < 0.001), a higher proportion of cavitation formation (P = 0.003), higher baseline NIHSS scores (P = 0.004), and poorer functional outcomes (P = 0.001). In the subset of RSSIs in the lenticulostriate artery (LSA) territory, after adjustment for covariates, larger initial lesion volume (OR 1.80, 95% CI 1.13-2.87; P = 0.014) and greater decreases in LSA total length (OR 0.59, 95% CI 0.36-0.96; P = 0.035) were independently associated with hemorrhagic foci formation. The extent of ischemia in the initial infarct is predictive of the presence of hemorrhagic residues. Our findings contribute to the current understanding of the mechanisms underlying the evolution of RSSIs.

Analysis of titer stability and inactivation kinetics of harvest solution of SARS-CoV-2 / 中国生物制品学杂志

@#Objective To investigate the titer stability of the harvest solution of severe acute respiratory syndrome coronavirus2(SARS-CoV-2)at 2 ～ 8 ℃ and the inactivation effect of β-propiolactone inactivator on the virus.Methods Three batches of SARS-CoV-2 harvest solution(batch numbers:202111001,202111002 and 202111003)were stored at 2 ～ 8 ℃ for 12 d and sampled every 3 d(0,3,6,9 and 12 d)for detection of the titers by Karber method;Three batches of virus harvest solution equilibrated overnight at 2 ～ 8 ℃ were inactivated by adding β-propiolactone at a volume fraction of 1∶4 000 and detected for the titers at different inactivation time points(0,0.5,1,1.5,2,3,4,8,16 and 24 h),of which samples inactivated for 8,16 and 24 h were taken for inactivation verification,and samples inactivated for 24 h were observed by transmission electron microscope.Results The titers of SARS-CoV-2 decreased with the prolongation of storage time at 2 ～8 ℃,which showed no obvious decrease during 0 ～ 3 d,while decreased from the initial 7.75,6 and 7.5 lgCCID_(50)/mL to5.75,4.625 and 6.25 lgCCID_(50)/mL on day 12,indicating that the virus activity showed a gradual decrease trend at 2 ～8 ℃；With the inactivation time,the virus titer decreased continuously and could not be detected after inactivation for 3 h.Transmission electron microscope observation showed that the inactivated virus particles were intact and the spike protein was evenly distributed.Conclusion The virulence of SARS-CoV-2 stored at 2 ～ 8 ℃ was unstable,so the subsequent inactivation and purification process should be carried out as soon as possible;The titer of virus could not be detected after3 h of inactivation,which provided a reference for the determination of the inactivation process.

Light Quality Modulates Growth, Triggers Differential Accumulation of Phenolic Compounds, and Changes the Total Antioxidant Capacity in the Red Callus of Vitis davidii.

Light quality is one of the key elicitors that directly affect plant cell growth and biosynthesis of secondary metabolites. In this study, the red callus of spine grape was cultured under nine light qualities (namely, dark, white, red, yellow, blue, green, purple, warm-yellow, and warm-white light). The effects of different light qualities were studied on callus growth, accumulation of phenolic compounds, and total antioxidant capacity of the red callus of spine grape. The results showed that blue and purple light induced increased red coloration in the callus, whereas yellow light induced the greatest callus proliferation. Among all of the light quality treatments, darkness treatment downregulated the contents of phenolic compounds, whereas blue light was the treatment most conducive to the accumulation of total phenolics. White, blue, and purple light induced increased anthocyanin accumulation. Mixed-wavelength light was beneficial to the accumulation of flavonoids. Blue and purple light were conducive to the accumulation of proanthocyanidins. A further study showed that cyanidin 3-glucoside (Cy3G) and peonidin 3-glucoside (P3G) were the main anthocyanin components in the callus, and blue, purple, and white light treatments promoted their accumulation, whereas flavan-3-ols and flavonols were the main components of non-anthocyanin phenolics, and their accumulation changed in response to not only light quality but also culture duration. The total antioxidant capacity of the callus cultures changed significantly in response to different light qualities. These results will provide evidence for an abiotic elicitor strategy to stimulate callus growth and enhance the accumulation of the main phenolic compounds in the red callus of spine grape.

The Single-Stranded DNA-Binding Gene Whirly (Why1) with a Strong Pathogen-Induced Promoter from Vitis pseudoreticulata Enhances Resistance to Phytophthora capsici.

Vitis vinifera plants are disease-susceptible while Vitis pseudoreticulata plants are disease-resistant; however, the molecular mechanism remains unclear. In this study, the single-stranded DNA- and RNA-binding protein gene Whirly (VvWhy1 and VpWhy1) were cloned from V. vinifera "Cabernet Sauvignon" and V. pseudoreticulata "HD1". VvWhy1 and VpWhy1 promoter sequences (pVv and pVp) were also isolated; however, the identity of the promoter sequences was far lower than that between the Why1 coding sequences (CDSs). Both Why1 gene sequences had seven exons and six introns, and they had a C-terminal Whirly conserved domain and N-terminal chloroplast transit peptide, which was then verified to be chloroplast localization. Transcriptional expression showed that VpWhy1 was strongly induced by Plasmopara viticola, while VvWhy1 showed a low expression level. Further, the GUS activity indicated pVp had high activity involved in response to Phytophthora capsici infection. In addition, Nicotiana benthamiana transiently expressing pVp::VvWhy1 and pVp::VpWhy1 enhanced the P. capsici resistance. Moreover, Why1, PR1 and PR10 were upregulated in pVp transgenic N. benthamiana leaves. This research presented a novel insight into disease resistance mechanism that pVp promoted the transcription of Why1, which subsequently regulated the expression of PR1 and PR10, further enhancing the resistance to P. capsici.

[Effects of SmacN7 inducing apoptosis of breast cancer cell MDA-MB-157 and its mechanism].

Objective: To investigate the effects and molecular mechanisms of Second mitochondria-derived activator of caspase N7 (SmacN7) on the apoptosis of breast cancer cells MDA-MB-157. Methods: Breast cancer cells MDA-MB-157 were treated with SmacN7 at the concentrations of 0-20 µmol/L. The proliferation activity of the cells was detected by MTS method, apoptosis and cell cycle were analyzed by flow cytometry, karyotypic changes of MDA-MB-157 cells were observed by Hoechst33342 staining, mitochondrial membrane potential was detected by JC-1 staining, and LDH release experiment was used to detect the drug cytotoxicity. Real time PCR was used to analyze the transcription levels of genes in MDA-MB-157 cells. The effect of inhibiting breast cancer proliferation was confirmed by tumor inhibition experiments. Results: After treated with SmacN7, the inhibition rate of proliferation and apoptosis rate of breast cancer cells MDA-MB-157 were increased (P＜0.01), the karyotype changed significantly, the mitochondrial membrane potential in cells was decreased, and the LDH release was increased. The transcription levels of TRAIL, DR4, DR5, p53, PARP-1, Bax, Bid, BAK, caspase-3, caspase-8 and caspase-9 were up-regulated (P＜0.01), and the transcription levels of Ras, PI3K, AKT, mTOR, Bcl-2, Bcl-xL, MCL-1, Survivin, cIAP-1 and cIAP-2 were inhibited (P＜0.01). Conclusion: SmacN7 induces apoptosis of breast cancer cell MDA-MB-157 through TRAIL-mediated death receptor pathway and mitochondrial-mediated endogenous apoptosis pathway, and plays a role in anti-breast cancer.

[Effects of 2-12alkyl-6-methoxycyclohexa-2, 5-diene-1, 4-dione(DMDD)on diffuse large B lymphoma and its mechanism].

OBJECTIVE: To investigate the effects and molecular mechanisms of 2-12alkyl-6-methoxycyclohexa-2,5-diene-1,4-dione(DMDD) on diffuse large B lymphoma (DLBCL). METHODS: In animal experiments, 4-week-aged BALB/C mice were divided into 5 groups, 20 mice in each group. Mice were inguinal injected with DLBCL cell line OCI-LY19 cells 0.1 ml at the concention of 1 × 107 /ml. Two days later, mice were treated with DMDD at the doses of 0, 1, 5, 25 and 125 mg/kg by intragastric administration respectively, once /2 days. Ten mice of each group were killed on the 18th day of administration, and the tumor tissues were weighed. The survival time of the remaining mice were recorded. In cell experiments, OCI-LY19 cells were added to 96-well culture plates, 100 µl 1×105 cells/ml per well, then 100 µl DMDD was added to the well and the final concentrations were 0, 1, 5, 25 and 125 µmol/L respectively. The cells were treated with DMDD for 0, 24, 48 and 72 h, three wells in each group. The cell proliferation activity was detected by MTS assay. According to the results of cell proliferation experiments, OCI-LY19 cells were treated with DMDD at the concentrations of 0 µmol/L, 5 µmol/L and 25 µmol/L for 24 h. The apoptosis rate was analyzed by flow cytometry, the nuclear type was observed by hoechst staining, the mitochondrial membrane potential was observed by JC-1 staining, cytotoxicity of drugs was evaluated by LDH release experiment, gene expression and transcription were analyzed by qPCR and Western blot. RESULTS: Compared with 0 mg/kg drug group, DMDD at the dose of 1～125 mg/kg could inhibit the growth of tumor tissue in mice and prolong their survival time (P＜0.01). Cell experiments showed: in DMDD group, the proliferation activity of OCI-LY19 cells was decreased significantly and the level of apoptosis was increased significantly (P＜0.01), nuclear fragmentation, agglutination, apoptotic bodies occurred and mitochondrial membrane potential was decreased, the LDH release rate was increased significantly (P＜0.01), the expressions of caspase-3 and bax genes and the phosphorylation level of Ikappa B alpha in cells were up-regulated significantly, the protein expression levels of bcl-2, bcl-xL, jak2 and stat3 were inhibited significantly (P＜0.01). CONCLUSION: DMDD can inhibit the expressions of JAK2, STAT3 and p-Ikappa B alpha in JAK2/STAT3 and NF-kappa B signal pathways, down-regulate BCL-2/BAX and activate Caspase-3, finally, activate the endogenous pathway of mitochondrial apoptosis in OCI-LY19 cells and promote the apoptosis of DLBCL cells, inhibit proliferation of OCI-LY19 cells. It has inhibitive effects on DLBCL.

[The effects of tectochrysin on prostate cancer cells apoptosis and its mechanism].

OBJECTIVE: To investigate the effects of tectochrysin on prostate cancer cell line 22Rv.1 and reveal its molecular mechanism. METHODS: Tectochrysin at the concentrations of 0～20 µg/ml was applied to 22Rv.1 cells and normal prostate cell RWPE-1. The proliferation activity of the cells was detected by MTS assay. Flow cytometry and hoechst 33342 staining were used to analyze the effects of drugs on cell apoptosis, death, cell cycle and nuclear type changes. LDH release test was used to analyze the cytotoxicity of the drug to 22Rv.1 cells. QPCR and Western blot were used to analyze the effects of the drug on the expressions of genes in 22Rv.1 cells. Finally, the tumor inhibited effect of the drug on the bearing tumor BALB/c mice were confirmed though anti-tumor experiment. RESULTS: Tectochrysin could significantly inhibit the proliferation activity of 22Rv.1 cells and induced their apoptosis, and promoted the expressions of genes dr4, dr5, trail, p53, caspase-3, caspase-8, caspase-9, bid, bax and foxo3, inhibited the expressions of anti-apoptotic genes akt, pi3k and bcl-2. CONCLUSION: Tectochrysin can induce prostate cancer cells apoptosis through affecting TRAIL and PI3K/AKT signaling pathways, and has anti-prostate cancer effect.

Effects of 2-12alkyl-6-methoxycyclohexa-2, 5-diene-1, 4-dione(DMDD)on diffuse large B lymphoma and its mechanism / 中国应用生理学杂志

OBJECTIVE@#To investigate the effects and molecular mechanisms of 2-12alkyl-6-methoxycyclohexa-2,5-diene-1,4-dione(DMDD) on diffuse large B lymphoma (DLBCL).@*METHODS@#In animal experiments, 4-week-aged BALB/C mice were divided into 5 groups, 20 mice in each group. Mice were inguinal injected with DLBCL cell line OCI-LY19 cells 0.1 ml at the concention of 1 × 10 /ml. Two days later, mice were treated with DMDD at the doses of 0, 1, 5, 25 and 125 mg/kg by intragastric administration respectively, once /2 days. Ten mice of each group were killed on the 18th day of administration, and the tumor tissues were weighed. The survival time of the remaining mice were recorded. In cell experiments, OCI-LY19 cells were added to 96-well culture plates, 100 μl 1×10 cells/ml per well, then 100 μl DMDD was added to the well and the final concentrations were 0, 1, 5, 25 and 125 μmol/L respectively. The cells were treated with DMDD for 0, 24, 48 and 72 h, three wells in each group. The cell proliferation activity was detected by MTS assay. According to the results of cell proliferation experiments, OCI-LY19 cells were treated with DMDD at the concentrations of 0 μmol/L, 5 μmol/L and 25 μmol/L for 24 h. The apoptosis rate was analyzed by flow cytometry, the nuclear type was observed by hoechst staining, the mitochondrial membrane potential was observed by JC-1 staining, cytotoxicity of drugs was evaluated by LDH release experiment, gene expression and transcription were analyzed by qPCR and Western blot.@*RESULTS@#Compared with 0 mg/kg drug group, DMDD at the dose of 1～125 mg/kg could inhibit the growth of tumor tissue in mice and prolong their survival time (P＜0.01). Cell experiments showed: in DMDD group, the proliferation activity of OCI-LY19 cells was decreased significantly and the level of apoptosis was increased significantly (P＜0.01), nuclear fragmentation, agglutination, apoptotic bodies occurred and mitochondrial membrane potential was decreased, the LDH release rate was increased significantly (P＜0.01), the expressions of caspase-3 and bax genes and the phosphorylation level of Ikappa B alpha in cells were up-regulated significantly, the protein expression levels of bcl-2, bcl-xL, jak2 and stat3 were inhibited significantly (P＜0.01).@*CONCLUSION@#DMDD can inhibit the expressions of JAK2, STAT3 and p-Ikappa B alpha in JAK2/STAT3 and NF-kappa B signal pathways, down-regulate BCL-2/BAX and activate Caspase-3, finally, activate the endogenous pathway of mitochondrial apoptosis in OCI-LY19 cells and promote the apoptosis of DLBCL cells, inhibit proliferation of OCI-LY19 cells. It has inhibitive effects on DLBCL.

The effects of tectochrysin on prostate cancer cells apoptosis and its mechanism / 中国应用生理学杂志

OBJECTIVE@#To investigate the effects of tectochrysin on prostate cancer cell line 22Rv.1 and reveal its molecular mechanism.@*METHODS@#Tectochrysin at the concentrations of 0～20 μg/ml was applied to 22Rv.1 cells and normal prostate cell RWPE-1. The proliferation activity of the cells was detected by MTS assay. Flow cytometry and hoechst 33342 staining were used to analyze the effects of drugs on cell apoptosis, death, cell cycle and nuclear type changes. LDH release test was used to analyze the cytotoxicity of the drug to 22Rv.1 cells. QPCR and Western blot were used to analyze the effects of the drug on the expressions of genes in 22Rv.1 cells. Finally, the tumor inhibited effect of the drug on the bearing tumor BALB/c mice were confirmed though anti-tumor experiment.@*RESULTS@#Tectochrysin could significantly inhibit the proliferation activity of 22Rv.1 cells and induced their apoptosis, and promoted the expressions of genes dr4, dr5, trail, p53, caspase-3, caspase-8, caspase-9, bid, bax and foxo3, inhibited the expressions of anti-apoptotic genes akt, pi3k and bcl-2.@*CONCLUSION@#Tectochrysin can induce prostate cancer cells apoptosis through affecting TRAIL and PI3K/AKT signaling pathways, and has anti-prostate cancer effect.

LncRNA CamK-A Regulates Ca2+-Signaling-Mediated Tumor Microenvironment Remodeling.

Cancer cells entail metabolic adaptation and microenvironmental remodeling to survive and progress. Both calcium (Ca2+) flux and Ca2+-dependent signaling play a crucial role in this process, although the underlying mechanism has yet to be elucidated. Through RNA screening, we identified one long noncoding RNA (lncRNA) named CamK-A (lncRNA for calcium-dependent kinase activation) in tumorigenesis. CamK-A is highly expressed in multiple human cancers and involved in cancer microenvironment remodeling via activation of Ca2+-triggered signaling. Mechanistically, CamK-A activates Ca2+/calmodulin-dependent kinase PNCK, which in turn phosphorylates IκBα and triggers calcium-dependent nuclear factor κB (NF-κB) activation. This regulation results in the tumor microenvironment remodeling, including macrophage recruitment, angiogenesis, and tumor progression. Notably, our human-patient-derived xenograft (PDX) model studies demonstrate that targeting CamK-A robustly impaired cancer development. Clinically, CamK-A expression coordinates with the activation of CaMK-NF-κB axis, and its high expression indicates poor patient survival rate, suggesting its role as a potential biomarker and therapeutic target.

[Anti-hepatoma effects of Smac analogue Birinapant and its related molecular mechanism].

OBJECTIVE: To investigate the effects of Birinapant on hepatocellular carcinoma cells and its related molecular mechanisms. METHODS: Human hepatocellular carcinoma cells QGY-7701 were treated with 0, 1, 5, 25 and 125 nmol/L Birinapant for 24, 48 and 72 hours respectively, each experiment 3 wells.The proliferation activity of cells, the apoptosis levels, the cells nuclear type, the mitochondrial membrane potential, the transcription and expression levels of genes and the cytotoxicity of Birinapant were analyzed.At the same time, 4-week-old male BALB/C mice were randomly divided into 5 groups, with 20 mice in each group.The mice were inguinal injected with QGY-7701 cells, and then subcutaneous injected with Birinapant (concentrations ranging from 0, 1, 5, 25, 125 µg/kg) in each group after two days, once every other day.On 18th day since first Birinapant injection, 10 mice were killed in each group to weigh tumor tissue and survival time was recorded from the remaining 10 mice.The effects of Birinapant on the growth of the tumor and the survival time of tumor-bearing mice were observed. RESULTS: Compared with the negative control (NC) group, the proliferation activity of QGY-7701 was inhibited significantly after Birinapant treatment and the apoptosis levels were increased significantly (P<0.01).The cell mitochondrial membrane potential was decreased and the karyotype was changed (P<0.01).At the same time, the transcription and expression levels of genes cellular inhibitor of apoptosis protein 1(cIAP-1), cellular inhibitor of apoptosis protein 2(cIAP-2), ras, raf, mek and erk were significantly decreased (P<0.01), while the expression levels of caspase-3 and caspase-9 genes were up-regulated (P<0.01).Compared with the model group (MG), the growth of the tumor was inhibited significantly and the survival time of the tumor-bearing mice was prolonged after Birinapant treatment (P<0.01). CONCLUSIONS: Birinapant can inhibit the expression of cIAP-1, cIAP-2 and the proteins of Ras-Raf-MEK-ERK signal pathways, so as to activate the mitochondria mediated endogenous apoptosis pathway.Birinapant shows a certain inhibitory effect on liver cancer.

Anti-hepatoma effects of Smac analogue Birinapant and its related molecular mechanism / 中国应用生理学杂志

OBJECTIVE@#To investigate the effects of Birinapant on hepatocellular carcinoma cells and its related molecular mechanisms.@*METHODS@#Human hepatocellular carcinoma cells QGY-7701 were treated with 0, 1, 5, 25 and 125 nmol/L Birinapant for 24, 48 and 72 hours respectively, each experiment 3 wells.The proliferation activity of cells, the apoptosis levels, the cells nuclear type, the mitochondrial membrane potential, the transcription and expression levels of genes and the cytotoxicity of Birinapant were analyzed.At the same time, 4-week-old male BALB/C mice were randomly divided into 5 groups, with 20 mice in each group.The mice were inguinal injected with QGY-7701 cells, and then subcutaneous injected with Birinapant (concentrations ranging from 0, 1, 5, 25, 125 μg/kg) in each group after two days, once every other day.On 18 day since first Birinapant injection, 10 mice were killed in each group to weigh tumor tissue and survival time was recorded from the remaining 10 mice.The effects of Birinapant on the growth of the tumor and the survival time of tumor-bearing mice were observed.@*RESULTS@#Compared with the negative control (NC) group, the proliferation activity of QGY-7701 was inhibited significantly after Birinapant treatment and the apoptosis levels were increased significantly (<0.01).The cell mitochondrial membrane potential was decreased and the karyotype was changed (<0.01).At the same time, the transcription and expression levels of genes cellular inhibitor of apoptosis protein 1(cIAP-1), cellular inhibitor of apoptosis protein 2(cIAP-2), ras, raf, mek and erk were significantly decreased (<0.01), while the expression levels of caspase-3 and caspase-9 genes were up-regulated (<0.01).Compared with the model group (MG), the growth of the tumor was inhibited significantly and the survival time of the tumor-bearing mice was prolonged after Birinapant treatment (<0.01).@*CONCLUSIONS@#Birinapant can inhibit the expression of cIAP-1, cIAP-2 and the proteins of Ras-Raf-MEK-ERK signal pathways, so as to activate the mitochondria mediated endogenous apoptosis pathway.Birinapant shows a certain inhibitory effect on liver cancer.

LncRNA wires up Hippo and Hedgehog signaling to reprogramme glucose metabolism.

The Hippo pathway plays essential roles in organ size control and cancer prevention via restricting its downstream effector, Yes-associated protein (YAP). Previous studies have revealed an oncogenic function of YAP in reprogramming glucose metabolism, while the underlying mechanism remains to be fully clarified. Accumulating evidence suggests long noncoding RNAs (lncRNAs) as attractive therapeutic targets, given their roles in modulating various cancer-related signaling pathways. In this study, we report that lncRNA breast cancer anti-estrogen resistance 4 (BCAR4) is required for YAP-dependent glycolysis. Mechanistically, YAP promotes the expression of BCAR4, which subsequently coordinates the Hedgehog signaling to enhance the transcription of glycolysis activators HK2 and PFKFB3. Therapeutic delivery of locked nucleic acids (LNAs) targeting BCAR4 attenuated YAP-dependent glycolysis and tumor growth. The expression levels of BCAR4 and YAP are positively correlated in tissue samples from breast cancer patients, where high expression of both BCAR4 and YAP is associated with poor patient survival outcome. Taken together, our study not only reveals the mechanism by which YAP reprograms glucose metabolism, but also highlights the therapeutic potential of targeting YAP-BCAR4-glycolysis axis for breast cancer treatment.

Low-molecular-weight fibroblast growth factor 2 attenuates hepatic fibrosis by epigenetic down-regulation of Delta-like1.

UNLABELLED: Liver fibrosis, a major cause of end-stage liver diseases, is closely regulated by multiple growth factors and cytokines. The correlation of fibroblast growth factor 2 (FGF2) with chronic liver injury has been reported, but the exact functions of different FGF2 isoforms in liver fibrogenesis remain unclear. Here, we report on the differential expression patterns and functions of low- and high-molecular-weight FGF2 (namely, FGF2(lmw) and FGF2(hmw) , respectively) in hepatic fibrogenesis using a CCl4 -induced mouse liver fibrosis model. FGF2(hmw) displayed a robust increase in CCl4 -induced hepatic fibrosis and promoted fibrogenesis. In contrast, endogenous FGF2(lmw) exhibited a slight increase in hepatic fibrosis and suppressed this pathological progression. Moreover, exogenous administration of recombinant FGF2(lmw) potently ameliorated CCl4 -induced liver fibrosis. Mechanistically, we showed that FGF2(lmw) treatment attenuated hepatic stellate cell activation and fibrosis by epigenetic down-regulation of Delta-like 1 expression through the p38 mitogen-activated protein kinase pathway. CONCLUSION: FGF2(lmw) and FGF2(hmw) have distinct roles in liver fibrogenesis. These findings demonstrate a potent antifibrotic effect of FGF2(lmw) administration, which may provide a novel approach to treat chronic liver diseases.

The immunogenicity and protection effect of the BPL-inactivated CA16 vaccine in different animal systems.

We evaluated the effect of a ß-propiolactone (BPL)-inactivated coxsackievirus A16 (CA16) vaccine, using three immunogenicity evaluation and two animal challenge systems. A CA16 virus strain, named 419, was used as the production strain. Another CA16 strain, named 1131, was isolated and used as the challenge strain in intracerebral inoculation of neonatal mice for the calculation of median lethal dose (LD 50). In the passive and maternal antibody-protection challenge systems, all results indicated that the vaccine could protect mouse pups from lethal challenge with the CA16 virus. In the immunogenicity systems, three types of animal (mouse, rat, and cynomolgus monkey), were immunized with the 419/CA16 vaccine. The dose-effect relationship and the antibody-generation routine were described. The CA16 vaccine induced a more potent serum antibody effect in rat than in mouse. The serum antibody titer was detectable more than 63 days after the initial vaccination. We also identified tools to evaluate the effect of the BPL-inactivated CA16 vaccine.

Delta-like 1 serves as a new target and contributor to liver fibrosis down-regulated by mesenchymal stem cell transplantation.

Chronic liver injury always progresses to fibrosis and eventually to cirrhosis, a massive health care burden worldwide. Delta-like 1 (Dlk1) is well known as an inhibitor of adipocyte differentiation. However, whether it is involved in liver fibrosis remains unclear. Here, we provide the first evidence that Dlk1 is a critical contributor to liver fibrosis through promoting activation of hepatic stellate cells (HSCs) during chronic liver injury. We found that upon liver injury, Dlk1 was dramatically induced and initially expressed in hepatocytes and then into the HSCs by a paracrine manner. It leads to the activation of HSCs, which is considered to be a pivotal event in liver fibrogenesis. Two forms (∼50 and ∼25 kDa) of the Dlk1 protein were detected by Western blot analysis. In vitro administration of Dlk1 significantly promoted HSC activation, whereas in vivo knockdown of Dlk1 dramatically inhibited HSC activation and the subsequent fibrosis. The large soluble form (∼50 kDa) of Dlk1 was shown to contribute to HSC activation. We were encouraged to find the Dlk1-promoted HSC activation and liver fibrosis can be depressed by transplantation of bone marrow-mesenchymal stem cells (BM-MSCs). Furthermore, we demonstrated that FGF2 was up-regulated in BM-MSCs under injury stimulation, and it probably participated in the inhibition of Dlk1 by BM-MSCs. Our findings provide a novel role of Dlk1 in liver fibrosis leading to a better understanding of the molecular basis in fibrosis and cirrhosis and also give insights into the cellular and molecular mechanisms of MSC biology in liver repair.