Bmi-1 Epigenetically Orchestrates Osteogenic and Adipogenic Differentiation of Bone Marrow Mesenchymal Stem Cells to Delay Bone Aging.

With the increase in the aging population, senile osteoporosis (SOP) has become a major global public health concern. Here, it is found that Prx1 and Bmi-1 co-localized in trabecular bone, bone marrow cavity, endosteum, and periosteum. Prx1-driven Bmi-1 knockout in bone-marrow mesenchymal stem cells (BMSCs) reduced bone mass and increased bone marrow adiposity by inhibiting osteoblastic bone formation, promoting osteoclastic bone resorption, downregulating the proliferation and osteogenic differentiation of BMSCs, and upregulating the adipogenic differentiation of BMSCs. However, Prx1-driven Bmi-1 overexpression showed a contrasting phenotype to Prx1-driven Bmi-1 knockout in BMSCs. Regarding mechanism, Bmi-1-RING1B bound to DNMT3A and promoted its ubiquitination and inhibited DNA methylation of Runx2 at the region from 45047012 to 45047313 bp, thus promoting the osteogenic differentiation of BMSCs. Moreover, Bmi-1-EZH2 repressed the transcription of Cebpa by promoting H3K27 trimethylation at the promoter region -1605 to -1596 bp, thus inhibiting the adipogenic differentiation of BMSCs. It is also found that Prx1-driven Bmi-1 overexpression rescued the SOP induced by Prx1-driven Bmi-1 knockout in BMSCs. Thus, Bmi-1 functioned as a hub protein in the epigenetic regulation of BMSCs differentiation to delay bone aging. The Prx1-driven Bmi-1 overexpression in BMSCs can be used as an approach for the translational therapy of SOP.

Anti-OX40 Antibody Combined with HBc VLPs Delays Tumor Growth in a Mouse Colon Cancer Model.

Objective: Combination immunotherapy strategies targeting OX40, a co-stimulatory molecule that can enhance antitumor immunity by modulating the proliferation, differentiation, and effector function of tumor-infiltrating T cells, have attracted much attention for their excellent therapeutic effects. In this study, we aimed to evaluate the antitumor efficacy of combined anti-OX40 and hepatitis B core virus-like particles (HBc VLPs) therapy using a mouse colon cancer model. Methods: Humanized B-hOX40 mice were injected subcutaneously with MC38 colon tumor cells and treated with HBc VLPs+anti-hOX40 antibody. Tumor growth was monitored. Flow cytometric analysis was performed to evaluate the populations of T cell subsets in the tumors. Results: The combination of anti-OX40 with HBc VLPs resulted in a significant delay in tumor growth, suggesting that a potent antitumor immunity was induced by the combination therapy. Further studies revealed that HBc VLPs+anti-OX40 treatment induced a significant increase in effector T cells (Teffs) and a significant decrease in regulatory T cells (Tregs) in the tumor microenvironment (TME), which accounted for the synergistic antitumor effect of anti-OX40 in combination with HBc VLPs. Conclusion: Combination therapy of anti-hOX40 and HBc VLPs provides synergistic antitumor activity in colon cancer-bearing mice, which may represent a potential design strategy for cancer immunotherapy.

ACOT7 promotes retinoblastoma resistance to vincristine by regulating fatty acid metabolism reprogramming.

The rate of vincristine (VCR) resistance in the treatment of retinoblastoma (RB) is relatively high, and the exact role and mechanism of autophagy and fatty acid (FA) metabolism in RB are still unknown. The aim of this study was to elucidate the molecular mechanism by which acyl-CoA thioesterase 7 (ACOT7) regulates FA metabolism and autophagy, which may lead to potential therapeutic strategies for RB. In the present study, the relationship between FA metabolism and cellular drug sensitivity was evaluated through ACOT7 overexpression or inhibition tests in RB-resistant cells. The lipase inhibitor orlistat and the autophagy inhibitor CQ were used to determine the effects of ACOT7 on FA metabolism, autophagy, and cellular drug sensitivity, as well as the therapeutic value of ACOT7 targeting. The results showed that ACOT7 was upregulated in VCR-resistant RB cells, significantly enhancing cell resistance and indicating that ACOT7 may serve as a biomarker for VCR resistance in RB cells. Knockdown of ACOT7 inhibited FA metabolism and reduced cell viability in VCR-resistant RB cells. The effect of ACOT7 overexpression was opposite to that of ACOT7 knockdown, and ACOT7 overexpression promoted autophagy in VCR-resistant RB cells. After treatment with orlistat or CQ, FA metabolism in VCR-resistant RB cells decreased, cell viability and autophagy were inhibited, EMT was inhibited, and the sensitivity of RB cells to VCR was increased. In conclusion, ACOT7 knockdown can mediate FA metabolism to inhibit autophagy and the migration of RB cells, thereby improving the sensitivity of RB cells to VCR.

[Correlation between Serum Interleukin-33, ß2-Microglobulin Levels and DS Stage in Patients with Multiple Myeloma].

OBJECTIVE: To investigate the correlation between serum interleukin-33 (IL-33), ß2microglobulin (ß2-MG) levels and Durie-Salmon (DS) stage in patients with multiple myeloma (MM). METHODS: 100 MM patients admitted to the First Affiliated Hospital of Fujian Medical University from March 2019 to January 2021 were selected and divided into stage I, stage II and stage III groups according to the DS staging system. A baseline data questionnaire of patients was designed, then the relevant baseline data and laboratory test results of patients were recorded. The levels of serum IL-33 and ß2-MG of all patients were detected, and the correlation between serum IL-33, ß2-MG levels and DS stage of MM patients was analyzed. RESULTS: Among the 100 patients with MM, there were 32 cases in stage I, 39 cases in stage II and 29 cases in stage III. The levels of serum CRP and ß2-MG of patients in stage III were significantly higher than those of patients in stage I and II, and the levels of serum CRP and ß2-MG of patients in stage II were significantly higher than those of patients in stage I, the differences were statistically significant (P <0.05). The level of serum IL-33 of patients in stage III was significantly lower than that of patients in stage I and II, and the level of serum IL-33 of patients in stage II was significantly lower than that of patients in stage I, the differences were statistically significant (P <0.05). There was no statistical significant difference in other data between groups (P >0.05). Kendall's tau-b correlation analysis showed that the levels of serum CRP and ß2-MG were positively correlated with DS stage in MM patients (r =0.534, 0.776), the level of serum IL-33 was negatively correlated with DS stage in MM patients (r =-0.759). Ordered logistic regression analysis and forest plot showed that the low level of serum IL-33 and the high level of ß2-MG were the influencing factors of high DS stage in MM patients (P <0.05 ). CONCLUSION: DS stage of MM patients is closely related to the levels of serum IL-33 and ß2-MG, that is, the lower the serum IL-33 level and the higher the ß2-MG level, and the higher the DS stage of MM patients.

Circ-MALAT1 accelerates cell proliferation and epithelial mesenchymal transformation of colorectal cancer through regulating miR-506-3p/KAT6B axis.

Colorectal cancer (CRC) is a prevalent malignant tumor of the digestive tract. Circular RNAs may play important roles in the progression of CRC. In this study, we investigated the roles and mechanisms of action of circ-MALAT1 in CRC. Gene expression and protein abundance were determined using qRT-PCR and western blot, respectively. Cell proliferation and migration were assessed by MTT, clone formation, and wound-healing assays. The interactions among the long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (circ-MALAT1), miR-506-3p, and lysine acetyltransferase 6B (KAT6B) were predicted using the StarBase software and confirmed by the luciferase activity assay. Circ-MALAT1 and KAT6B were upregulated, while miR-506-3p was downregulated in CRC cells. We validated that knocking down of circ-MALAT1 suppressed proliferation, migration, and epithelial-mesenchymal transition (EMT) of CRC cells, and these effects were abolished by miR-506-3p downregulation or KAT6B sufficiency. Our study suggests that circ-MALAT1 could sponge miR-506-3p to regulate the expression of KAT6B. Moreover, KAT6B sufficiency could neutralize miR-506-3p-dependent growth arrest, migration, and EMT. Circ-MALAT1 promotes cell proliferation, migration, and EMT of CRC cells via the miR-506-3p/KAT6B axis, thereby acting as a novel potential therapeutic target for the treatment of colorectal cancer.

Babao Dan decreases hepatocarcinogenesis by inhibiting hepatic progenitor cells malignant transformation via down-regulating toll-like receptor 4.

Background: Babao Dan (BBD) is a traditional Chinese medicine that has been widely used as a complementary and alternative medicine to treat chronic liver diseases. In this study, we aimed to observe the effect of BBD on the incidence of diethylnitrosamine (DEN)-initiated hepatocellular carcinoma formation in rats and explored its possible mechanism. Methods: To verify this hypothesis, BBD was administrated to rats at a dose of 0.5g/kg body weight per two days from the 9th to 12th week in HCC-induced by DEN. Liver injury biomarkers and hepatic inflammatory parameters were evaluated by histopathology as well as serum and hepatic content analysis. We applied immunohistochemical analysis to investigate the expression of CK-19 and SOX-9 in liver tissues. The expression of TLR4 was determined by immunohistochemical, RT-PCR, and western blot analysis. Furthermore, we also detected the efficacy of BBD against primary HPCs neoplastic transformation induced by LPS. Results: We observed that DEN could induce hepatocarcinogenesis, and BBD could obviously decrease the incidence. The biochemical and histopathological examination results confirmed that BBD could protect against liver injury and decrease inflammatory infiltration. Immunohistochemistry staining results showed that BBD could effectively inhibit the ductal reaction and the expression of TLR4. The results showed that BBD-serumcould obviously inhibit primary HPCs neoplastic transformation induced by regulating the TLR4/Ras/ERK signaling pathway. Conclusion: In summary, our results indicate that BBD has potential applications in the prevention and treatment of HCC, which may be related to its effect on hepatic progenitor cells malignant transformation via inhibiting the TLR4/Ras/ERK signaling pathway.

Prognostic significance of prognostic nutritional index and systemic immune-inflammation index in patients after curative breast cancer resection: a retrospective cohort study.

BACKGROUND: Nutritional status and inflammation are closely associated with poor outcome in malignant tumors. However, the prognostic impact of postoperative in these variables on breast cancer (BC) remains inconclusive. We aimed to determine whether prognostic nutritional index (PNI), systemic immune-inflammation index (SII), neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) affect two long-term outcomes among patients after curative resection of BC. METHODS: We retrospectively reviewed 508 patients with BC treated with curative surgery between February 5, 2013 and May 26, 2020. All patients were divided into 3 groups based on tertiles (T1-T3) of PNI, SII, NLR, and PLR. The effects of four indexes on disease-free survival (DFS) and overall survival (OS) have been evaluated using Cox proportional hazards models and Kaplan-Meier method. RESULTS: Compared with PNI-lowest cases, patients with highest PNI showed significantly longer DFS (multivariate adjusted hazard ratio [HR] = 0.37, 95% confident interval [CI] 0.19-0.70, P for trend = 0.002), whereas higher PLR seemed to be marginally associated with poorer DFS (P for trend = 0.086 and 0.074, respectively). Subgroup analyses indicate the potential modification effects of family history of BC and radiotherapy on the prognosis value of PNI to DFS in BC patients (P for interaction = 0.004 and 0.025, respectively). In addition, the levels of three inflammatory indices, namely SII, NLR, and PLR might be positively related with increased age at diagnosis (all P for trend < 0.001). CONCLUSIONS: A high PNI was associated with better DFS, supporting its roles as prognostic parameters for patients with BC. The nutritional status and systemic immune may exert great effects on patient prognosis. Further studies are warrant to explore the prognosis value of PLR.

On the Three-dimensionality of Flow in the Neo-sinus and its Implications for Subclinical Leaflet Thrombosis.

OBJECTIVES: Subclinical leaflet thrombosis is a silent phenomenon commonly observed following transcatheter aortic valve implantation (TAVI). Leaflet thrombosis is associated with ischaemic complications and structural valve deterioration. Prior studies have shown that blood stasis in neo-sinus contributes to the initiation and growth of subclinical leaflet thrombosis. This study aimed to quantify temporal and spatial characteristics of the flow field from a fundamental perspective. METHODS: in vitro experimental analysis and fluid-solid interaction simulations were employed to characterize the flow field of a transcatheter aortic valve (TAV) with an intra-annular design in a pulse duplicator. Blood residence time (BRT) and flow-induced viscous shear stress were measured in the neo-sinus and on the surface of TAV leaflets. RESULTS: Temporal and spatial velocity variations were observed in neo-sinus, indicating that the flow is time-dependent and fully three-dimensional. The degree of blood stasis in the neo-sinus (bulk fluid) and on the surface of the TAV leaflets highly depends on the local flow characteristics. Regional flow variation in the neo-sinus resulted in substantial variations in BRT magnitude in the neo-sinus and on the surface of the TAV leaflet. Areas with a high degree of blood stasis were observed near the fixed boundary edge of the leaflets. CONCLUSIONS: The study indicated that leaflet motion is a primary driver of flow in neo-sinus. Considering the substantial variations in BRT magnitude in the neo-sinus (bulk fluid), blood stasis should be quantified locally on the surface of foreign (valve) materials to avoid errors in forecasting the risk of subclinical leaflet thrombosis in patients undergoing TAVI.

Calculation of shielding performance of CRT concrete for proton therapy and optimal shielding design of treatment delivery room.

Proton therapy is becoming increasingly popular worldwide, and its shielding must be considered. The cathode ray tube (CRT) material is a glass containing heavy metal elements, these materials have become a good choice for the production of radiation-proof concrete. In this study, the ability of concrete containing CRT fragments as shielding materials for proton therapy rooms is evaluated in terms of neutron shielding ability, neutron reflection ability, ambient dose equivalent rate, and induced radioactivity. In addition, this concrete is compared with commonly used ordinary concrete, boron-containing concrete, and barite concrete. The results show that with the increase of CRT content (10%-90%), the transmitted neutron fluence decreases continuously (5.06 × 10-10 - 1.77 × 10-10 cm-2/particle), and the reflection of neutrons gradually increases (2.64 × 10-9 - 3.20 × 10-9 cm-2/particle), resulting in an increased potential to patients. When 50% CRT concrete is used, the ambient dose equivalent rate is below 3.80 µSv/h/nA, and 90% CRT concrete is below 3.11 µSv/h/nA. The trend of radionuclide activity of induced radioactivity from 0 to 60 min after irradiation for concrete with different CRT contents is 2.74-5.38 × 10-3 Bq/cm3, and the maximum photon fluence is 8.13 × 102 cm-2. In conclusion, the optimization model of the three-layer shielding structure of ordinary concrete, high CRT content concrete, and boron-containing concrete is proposed with ambient dose equivalent rate less than 1.88 µSv/h/nA, minimizing the reflected neutrons to which the patient is exposed. This study shows the protection performance of CRT concrete is better than ordinary concrete and barite concrete.

CircPTK2 accelerates tumorigenesis of colorectal cancer by upregulating AKT2 expression via miR-506-3p.

With the rapid increase in its incidence in the last decade, colorectal cancer (CRC) is becoming one of the most life-threatening cancers. Circular RNA PTK2 (circPTK2) has multiple functions in oncogenesis, including in CRC. However, it remains elusive if circPTK2 also plays an important role in CRC malignancy. The levels of circPTK2, miR-506-3p, and AKT serine/threonine kinase 2 (AKT2) were measured by qPCR. The protein level of AKT2 was evaluated by western blotting assay. The proliferation, migration, and invasion of CRC cancer cells were evaluated by MTT, colony formation, wound-healing, and transwell assays. The interaction between circPTK2 and miR-506-3p and between miR-506-3p and AKT2 mRNA were verified by dual-luciferase reporter assay. The expressions of circPTK2 and AKT2 were elevated in CRC cells, with a concomitant reduction of miR-506-3p. The knockdown of circPTK2 suppressed the proliferation, migration, and invasion of CRC cells. CircPTK2 targeted miR-506-3p and negatively regulated its expression. Furthermore, miR-506-3p overexpression suppressed the CRC progression by downregulating the AKT2 expression. AKT2 overexpression or miR-506-3p inhibition restored the suppression of growth and invasiveness of CRC cancer cells caused by circPTK2 silencing. The circPTK2/miR-506-3p/AKT2 axis plays a novel and essential role in promoting CRC progression, providing potential targets for CRC therapeutic modality.

Methylation-mediated expression of SPARC is correlated with tumor progression and poor prognosis of breast cancer.

Secreted protein acidic and rich in cysteine (SPARC) plays a crucial role in the formation and progression of tumors. DNA methylation has become increasingly recognized as a frequent event of epigenetic alterations and one of the primary mechanisms of gene inactivation. The study aims to investigate the status of DNA methylation and the biofunction of SPARC in breast cancer. The qRT-PCR, BGS, and MSP methods were respectively employed to measure the relative mRNA expression levels and methylation status of SPARC. Additionally, the effects of SPARC on cell proliferation, migration, and invasion were examined in SPARC overexpression and knockdown cells. Immunohistochemical staining and western blot assay were used to examine the protein expression of genes. The expression levels of SPARC were found to be higher in breast cancer tissues and most breast cancer cells. The expression levels of SPARC in MDA-MB-231 and MCF-7 cells were significantly reversed by 5-Aza-dC treatment. Furthermore, the high expression and promoter DNA hypomethylation of SPARC were detected in triple-negative breast cancer tissues, while no expression changes of SPARC were found in luminal A breast cancer tissues. Overexpression of SPARC dramatically promoted MCF-7 cells migration and invasion, while knockdown of SPARC inhibited MDA-MB-231 cells migration and invasion. SPARC was involved in the epithelial-mesenchymal transition (EMT) process of breast cancer cells. The expression levels of mesenchymal markers N-cadherin, Vimentin, and ß-catenin were upregulated, while E-cadherin was downregulated in SPARC overexpressed breast cancer cells. Conversely, the expression levels of EMT-related genes demonstrated the opposite trend in SPARC knockdown cells. To conclude, high expression of SPARC regulated by promoter hypomethylation promotes breast cancer cells migration and invasion, thus SPARC may act as an oncogene and serve as a potential target for breast cancer therapy.

Dual-targeting vaccine of FGL1/CAIX exhibits potent anti-tumor activity by activating DC-mediated multi-functional CD8 T cell immunity.

Tumor DNA vaccine as an effective therapeutic approach can induce systemic immunity against malignant tumors, but its therapeutic effect is still not satisfactory in advanced renal cancer. Herein, a novel DNA vaccine containing dual antigens of fibrinogen-like protein 1 (FGL1) and carbonic anhydrase IX (CAIX) was developed and intramuscularly delivered by PLGA/PEI nanoparticles for renal cancer therapy. Compared with PLGA/PEI-pCAIX immunization, PLGA/PEI-pFGL1/pCAIX co-immunization significantly inhibited the subcutaneous tumor growth and promoted the differentiation and maturation of CD11c+ DCs and CD11c+CD11b+ DCs subset. Likewise, the increased capabilities of CD8 T cell proliferation, CTL responses, and multi-functional CD8+ T cell immune responses were observed in PLGA/PEI-pFGL1/pCAIX vaccine group. Interestingly, depletion of CD8+ T cells by using CD8 mAb resulted in a loss of anti-tumor function of PLGA/PEI-pFGL1/pCAIX vaccine, suggesting that the anti-tumor activity of the vaccine was dependent on CD8+ T cell immune responses. Furthermore, PLGA/PEI-pFGL1/pCAIX co-immunization also suppressed the lung metastasis of tumor mice by enhancing the multi-functional CD8+ T cell responses. Therefore, these results indicate that PLGA/PEI-pFGL1/pCAIX vaccine could provide an effective protective effect for renal cancer by enhanced DC-mediated multi-functional CD8+ T cell immune responses. This vaccine strategy offers a potential approach for solid or metastatic tumor treatment.

Panax notoginseng saponins induce apoptosis in retinoblastoma Y79 cells via the PI3K/AKT signalling pathway.

This study aimed to investigate the effects of Panax notoginseng saponins (PNS) on the proliferation, apoptosis, and PI3K/AKT signalling pathways of retinoblastoma Y79 cells to explore the possible mechanism of action of PNS on retinoblastoma. The effects of PNS and carboplatin on the proliferation of Y79 cells were examined using cell counting kit-8 assay. And the apoptosis rate, the mRNA and protein levels of apoptosis-related genes and the expression of PI3K/AKT pathway protein were assessed. PNS effectively inhibited the proliferation (P < 0.05) and increased apoptosis of Y79 cells (P < 0.05). Compared with the negative control, the Y79 cells treated with PNS had significantly increased (P < 0.05) mRNA and protein expression of Bax, caspase-3, caspase-8, and caspase-9 and elevated levels of cleaved caspase-3, cleaved caspase-8, and cleaved caspase-9 proteins (P < 0.05). The mRNA and protein expression of the apoptosis suppressor gene Bcl-2 was inhibited (P < 0.05), while the Bax/Bcl-2 values of the cells in the drug group were significantly higher than those in the negative group (P < 0.01). After treatment with PNS, the total protein expression of PI3K and AKT1 in the Y79 cells did not show significant differences compared with the negative group (P > 0.05), although the expression of phosphorylated proteins p-PI3K, p-AKT (Thr308), p-AKT (Ser473), and p-mTOR were significantly reduced (P < 0.05). Meanwhile, the antagonist protein of the pathway phosphatase and tensin homologue deleted on chromosome 10 (PTEN) expression was increased (P < 0.01). Cellular alterations following inhibition of the PI3K/AKT pathway using LY294002 were similar to those of PNS, the proliferation of Y79 cells was also inhibited, and cell apoptosis increased (P < 0.001). The expression of Bax, caspase-3, caspase-8, caspase-9, and activation proteins cleaved caspase-3, cleaved caspase-8, and cleaved caspase-9 was also significantly higher than that in the negative control (P < 0.05). Bcl-2 protein expression was decreased (P < 0.01), and the Bax/Bcl-2 ratio was higher than that in the negative control (P < 0.001). Overall, we demonstrated that PNS effectively inhibited the proliferation and promoted the apoptosis of retinoblastoma Y79 cells. The apoptosis-promoting effect of PNS may involve the inhibition of the PI3K/AKT signalling pathway, which subsequently regulates the expression of apoptosis-related genes.

Dual-tracer PET/CT-targeted, mpMRI-targeted, systematic biopsy, and combined biopsy for the diagnosis of prostate cancer: a pilot study.

PURPOSE: Growing evidence proved the efficacy of multi-parametric MRI (mpMRI) and prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT)-guided targeted biopsy (TB) in prostate cancer (PCa) diagnosis, but there is no direct comparison between mpMRI-TB and PSMA PET/CT-TB. Gastrin-releasing peptide receptor (GRPR) is highly expressed in PCa, which can compensate for the unstable expression of PSMA in PCa. Therefore, we designed a study to compare the efficiency of mpMRI-TB, dual-tracer (GRPR and PSMA) PET/CT-TB, systematic biopsy, and combined biopsy for the diagnosis of prostate cancer. METHODS: One hundred twelve suspicious PCa patients were enrolled from September 2020 to June 2021. Patients with anyone of positive dual-tracer PET/CT or mpMRI underwent TB, and all enrolled patients underwent systematic biopsy (SB) after TB. The primary outcome was the detection rates of PCa in different biopsy strategies. Secondary outcomes were the performance of three imaging methods, omission diagnostic rates, and upgrading and downgrading of biopsy samples relative to those of prostatectomy specimens in different biopsy strategies. McNemar's tests and Bonferroni correction in multiple comparisons were used to compare the primary and secondary outcomes. RESULTS: In 112 men, clinically significant PCa (grade group[GG] ≥ 2) accounted for 34.82% (39/112), and nonclinically significant PCa (GG = 1) accounted for 4.46% (5/112). 68 Ga-PSMA PET/CT-TB achieved higher PCa detection rate (69.77%) and positive ratio of biopsy cores (0.44) compared with SB (39.29% and 0.12) and mpMRI-TB (36.14% and 0.23), respectively (P < 0.005). Dual-tracer PET/CT screen out patients for avoiding 52.67% (59/112) unnecessary biopsy, whereas dual-tracer PET/CT-TB plus SB achieved high detection rate (77.36%) without misdiagnosis of csPCa. CONCLUSION: Dual-tracer PET/CT might screen patients for avoiding unnecessary biopsy. Dual-tracer PET/CT-TB plus SB might be a more effective and promising strategy for the definite diagnosis of clinically significant PCa than mpMRI-TB.

Apple Polyphenols Extract (APE) Alleviated Dextran Sulfate Sodium Induced Acute Ulcerative Colitis and Accompanying Neuroinflammation via Inhibition of Apoptosis and Pyroptosis.

The main aim of this study was to investigate the potent anti-apoptosis and anti-pyroptosis effects of apple polyphenols extract (APE) on dextran sulfate sodium model group (DSS)-induced acute ulcerative colitis (UC) and the protective effect of APE against acute UC-related neuroinflammation and synapse damage. Forty-three C57BL/6 male mice were randomly divided into a control group (CON), a 3% DSS model group (DSS), a 500 mg/(kg·bw·d) APE group (HAP), and a 125 (LD) or 500 (HD) mg/(kg·bw·d) APE treatment concomitantly with DSS treatment group. The results showed that APE significantly ameliorated DSS-induced acute UC through inhibiting intestinal epithelial cell (IEC) apoptosis and the Caspase-1/Caspase-11-dependent pyroptosis pathway, with increased BCL-2 protein expression and decreased protein levels of NLRP3, ASC, Caspase-1/11, and GSDND. Furthermore, APE significantly reduced acute UC-related neuroinflammation and synapse damage, supported by decreased mRNA levels of hypothalamus Cox-2 and hippocampus Gfap and also increased the mRNA levels of hypothalamus Psd-95. The increased protein expression of ZO-1 and Occludin improved the intestinal barrier integrity and improved the function of goblet cells by upregulating the protein level of MUC-2 and TTF3 accounted for the beneficial effects of APE on UC-associated neuroinflammation. Therefore, APE might be a safe and effective agent for the management of acute UC.

Co-immunization with L-Myc enhances CD8+ or CD103+ DCs mediated tumor-specific multi-functional CD8+ T cell responses.

Renal carcinoma shows a high risk of invasion and metastasis without effective treatment. Herein, we developed a chitosan (CS) nanoparticle-mediated DNA vaccine containing an activated factor L-Myc and a tumor-specific antigen CAIX for renal carcinoma treatment. The subcutaneous tumor models were intramuscularly immunized with CS-pL-Myc/pCAIX or control vaccine, respectively. Compared with single immunization group, the tumor growth was significantly suppressed in CS-pL-Myc/pCAIX co-immunization group. The increased proportion and mature of CD11c+ DCs, CD8+ CD11c+ DCs and CD103+ CD11c+ DCs were observed in the splenocytes from CS-pL-Myc/pCAIX co-immunized mice. Furthermore, the enhanced antigen-specific CD8+ T lymphocyte proliferation, cytotoxic T lymphocyte (CTL) responses, and multi-functional CD8+ T cell induction were detected in CS-pL-Myc/pCAIX co-immunization group compared with CS-pCAIX immunization group. Of note, the depletion of CD8 T cells resulted in the reduction of CD8+ T cells or CD8+ CD11c+ DCs and the loss of anti-tumor efficacy induced by CS-pL-Myc/pCAIX vaccine, suggesting the therapeutic efficacy of the vaccine was required for CD8+ DCs and CD103+ DCs mediated CD8+ T cells responses. Likewise, CS-pL-Myc/pCAIX co-immunization also significantly inhibited the lung metastasis of renal carcinoma models accompanied with the increased induction of multi-functional CD8+ T cell responses. Therefore, these results indicated that CS-pL-Myc/pCAIX vaccine could effectively induce CD8+ DCs and CD103+ DCs mediated tumor-specific multi-functional CD8+ T cell responses and exert the anti-tumor efficacy. This vaccine strategy offers a potential and promising approach for solid or metastatic tumor treatment.

[Retracted] In vitro antitumor activity of the ethyl acetate extract Potentilla chinensis in osteosarcoma cancer cells.

Following the publication of the above paper, a concerned reader drew to the Editor's attention that several figures bore striking similarities to other papers that were published at around the same time written by different authors based in different research institutions. Fig. 3 (in colour) was essentially the same as a greyscale figure (Fig. 4) in a paper published in Oncology Reports, which has now been retracted [Wan G, Tao J­G, Wang G­D, Liu S­P, Zhao H­X and Liang Q­D: 3­ß­Εrythrodiol isolated from Conyza canadensis inhibits MKN­45 human gastric cancer cell proliferation by inducing apoptosis, cell cycle arrest, DNA fragmentation, ROS generation and reduces tumor weight and volume in mouse xenograft mode. Oncol Rep 35: 2328­2338, 2016]. Furthermore, Figs. 5 and 6 in the above paper appeared to share data with Figs. 7 and 11, respectively, in a paper published in Phytomedicine [Sui C­G, Meng F­D and Jiang Y­h: Antiproliferative activity of rosamultic acid is associated with induction of apoptosis, cell cycle arrest, inhibition of cell migration and caspase activation in human gastric cancer (SGC­7901) cells. Phyomedicine 22: 796­806, 2015]. After having conducted an independent investigation in the Editorial Office, the Editor of Molecular Medicine Reports has determined that the above paper should be retracted from the Journal on account of a lack of confidence concerning the originality and the authenticity of the data. The authors were asked for an explanation to account for these concerns, but the Editorial Office never received any reply. The Editor regrets any inconvenience that has been caused to the readership of the Journal. [the original article was published in Molecular Medicine Reports 14: 3634­3640, 2016; DOI: 10.3892/mmr.2016.5679].

mascRNA and its parent lncRNA MALAT1 promote proliferation and metastasis of hepatocellular carcinoma cells by activating ERK/MAPK signaling pathway.

MALAT1-associated small cytoplasmic RNA (mascRNA) is a cytoplasmic tRNA-like small RNA derived from nucleus-located long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). While MALAT1 was extensively studied and was found to function in multiple cellular processes, including tumorigenesis and tumor progression, the role of mascRNA was largely unknown. Here we show that mascRNA is upregulated in multiple cancer cell lines and hepatocellular carcinoma (HCC) clinical samples. Using HCC cells as model, we found that mascRNA and its parent lncRNA MALAT1 can both promote cell proliferation, migration, and invasion in vitro. Correspondingly, both of them can enhance the tumor growth in mice subcutaneous tumor model and can promote metastasis by tail intravenous injection of HCC cells. Furthermore, we revealed that mascRNA and MALAT1 can both activate ERK/MAPK signaling pathway, which regulates metastasis-related genes and may contribute to the aggressive phenotype of HCC cells. Our results indicate a coordination in function and mechanism of mascRNA and MALAT1 during development and progress of HCC, and provide a paradigm for deciphering tRNA-like structures and their parent transcripts in mammalian cells.

Effect of Andrographis paniculata polysaccharide on human retinoblastoma Y79 cell proliferation and apoptosis.

AIM: To explore the effect of the Andrographis paniculata (A. paniculata) polysaccharide on the proliferation and apoptosis of human retinoblastoma (RB) Y79 cells and its mechanism. METHODS: The refined A. paniculata polysaccharide was obtained using techniques such as water extraction, ethanol precipitation, and decompression concentration. The inhibition effect of the A. paniculata polysaccharide on the proliferation of Y79 cells was detected by cell proliferation assay. Flow cytometry was used for the detection of cell apoptosis rate and cycle change. Real-time qunatitative polymerase chain reaction (RT qPCR)and Western blotting were used to detect the expression of cell apoptosis signal pathway-related factors (caspase-3, caspase-8, and caspase-9) and cell cycle signal pathway-related factors (CDK1 and cyclinB1) at the transcriptional and translational levels. RESULTS: Infrared and ultraviolet spectrum scanning showed that the extracted drug was a polysaccharide with high purity. After being treated with different concentrations of A. paniculata polysaccharide for different periods of time, the Y79 cells showed different degrees of proliferation inhibition. Flow cytometric observations showed that the cell apoptosis rate and the proportion of cells blocked in the G2/M phase were significantly increased after A. paniculata polysaccharide treatment. Further analysis revealed that the mRNA and protein expression of caspase-3, caspase-8, and caspase-9 in the A. paniculata polysaccharide treatment groups increased significantly compared with that in the control groups, while the expression of CDK1 and cyclinB1 decreased significantly. CONCLUSION: The A. paniculata polysaccharide could inhibit the proliferation and induce apoptosis of Y79 cells. Its possible mechanism is via the upregulation of caspase-3, caspase-8, and caspase-9 expression in the cell apoptotic signaling pathway and the downregulation of CDK1 and cyclinB1 expression in the cell cycle signaling pathway.

Cellular microRNAs influence replication of H3N2 canine influenza virus in infected cells.

MicroRNAs (miRNAs) are known to play important regulatory roles in host-virus interactions. Avian-origin H3N2 canine influenza virus (CIV) has emerged as the most prevalent subtype among dogs in Asia since 2007. To evaluate the roles of host miRNAs in H3N2 CIV infection, here, miRNA profiles obtained from primary canine bronchiolar epithelial cells (CBECs) and canine alveolar macrophages (CAMCs) were compared between infected and mock-infected cells with the H3N2 CIV JS/10. It was found that the expressions of cfa-miR-125b and cfa-miR-151, which have been reported to be associated with innate immunity and inflammatory response, were significantly decreased in CIV-infected canine primary cells. Bioinformatics prediction indicated that 5' seed regions of the two miRNAs are partially complementary to the mRNAs of nucleoprotein (NP) and non-structural protein 1 (NS1) of JS/10. As determined by virus titration, quantitative real-time PCR (qRT-PCR) and western blotting, overexpression of the two miRNAs inhibited CIV replication in cell culture, while their inhibition facilitated this replication, suggesting that the two miRNAs could act as negative regulators of CIV replication. Our findings support the notion that some cellular miRNAs can influence the outcome of virus infection, which helps to elucidate the resistance of host cells to viral infection and to clarify the pathogenesis of H3N2 CIV.