Ultrasensitive US Microvessel Imaging of Hepatic Microcirculation in the Cirrhotic Rat Liver.

Background Liver microcirculation dysfunction plays a vital role in the occurrence and development of liver diseases, and thus, there is a clinical need for in vivo, noninvasive, and quantitative evaluation of liver microcirculation. Purpose To evaluate the feasibility of ultrasensitive US microvessel imaging (UMI) in the visualization and quantification of hepatic microvessels in healthy and cirrhotic rats. Materials and Methods In vivo studies were performed to image hepatic microvasculature by means of laparotomy in Sprague-Dawley rats (five cirrhotic and five control rats). In vivo conventional power Doppler US and ex vivo micro-CT were performed for comparison. UMI-based quantifications of perfusion, tortuosity, and integrity of microvessels were compared between the control and cirrhotic groups by using the Wilcoxon test. Spearman correlations between quantification parameters and pathologic fibrosis, perfusion function, and hepatic hypoxia were evaluated. Results UMI helped detect minute vessels below the liver capsule, as compared with conventional power Doppler US and micro-CT. With use of UMI, lower perfusion indicated by vessel density (median, 22% [IQR, 20%-28%] vs 41% [IQR, 37%-46%]; P = .008) and fractional moving blood volume (FMBV) (median, 6.4% [IQR, 4.8%-8.6%] vs 13% [IQR, 12%-14%]; P = .008) and higher tortuosity indicated by the sum of angles metric (SOAM) (median, 3.0 [IQR, 2.9-3.0] vs 2.7 [IQR, 2.6-2.9]; P = .008) were demonstrated in the cirrhotic rat group compared with the control group. Vessel density (r = 0.85, P = .003), FMBV (r = 0.86, P = .002), and median SOAM (r = -0.83, P = .003) showed strong correlations with pathologically derived vessel density labeled with dextran. Vessel density (r = -0.81, P = .005) and median SOAM (r = 0.87, P = .001) also showed strong correlations with hepatic tissue hypoxia. Conclusion Contrast-free ultrasensitive US microvessel imaging provided noninvasive in vivo imaging and quantification of hepatic microvessels in cirrhotic rat liver. © RSNA, 2022 Supplemental material is available for this article. See also the editorial by Fetzer in this issue.

A strain induced polar metal phase in a ferromagnetic Fe3GeTe2 monolayer.

The electronic structure and magnetic properties of the ferromagnetic Fe3GeTe2 monolayer have been extensively studied in recent years. Experimentally, external strain can be produced inevitably during the growth on the substrate. However, the impact of strain on the structural, electronic, and magnetic properties remains largely underexplored. Herein, by using density functional theory, we systematically investigate the crystalline configuration and electronic structure of the Fe3GeTe2 monolayer in the presence of external strain. We find that a moderate compressive strain could break the structural vertical symmetry, leading to a sizable out-of-plane dipole moment, while the ferromagnetism can be retained. Surprisingly, strain-induced polarization in the off-center Fe and Ge atoms barely contributes to the energy states at the Fermi level. The efficient decoupling of the conductivity and polarization in the strained Fe3GeTe2 monolayer results in an extremely rare phase with the coexistence of polarization, metallicity, and ferromagnetism, i.e., magnetic polar metals for potential applications in magnetoelectricity and spintronics.

circRNA422 enhanced osteogenic differentiation of bone marrow mesenchymal stem cells during early osseointegration through the SP7/LRP5 axis.

Circular RNAs (circRNAs) play an important role in biological activities, especially in regulating osteogenic differentiation of stem cells. However, no studies have reported the role of circRNAs in early osseointegration. Here we identified a new circRNA, circRNA422, from rat bone marrow mesenchymal stem cells (BMSCs) cultured on sandblasted, large-grit, acid-etched titanium surfaces. The results showed that circRNA422 significantly enhanced osteogenic differentiation of BMSCs with increased expression levels of alkaline phosphatase, the SP7 transcription factor (SP7/osterix), and lipoprotein receptor-related protein 5 (LRP5). Silencing of circRNA422 had opposite effects. There were two SP7 binding sites on the LRP5 promoter, indicating a direct regulatory relationship between SP7 and LRP5. circRNA422 could regulate early osseointegration in in vivo experiments. These findings revealed an important function of circRNA422 during early osseointegration. Therefore, circRNA422 may be a potential therapeutic target for enhancing implant osseointegration.

Postoperative analgesic efficacy and safety of imrecoxib versus celecoxib in hip osteoarthritis patients undergoing total hip arthroplasty: a multi-center, randomized, controlled, non-inferiority study.

BACKGROUND: Imrecoxib, a novel cyclooxygenase-2 inhibitor, possesses a certain postoperative analgesic effect for several orthopedic surgeries. This multi-center, randomized, controlled, non-inferiority study intended to investigate the postoperative analgesic efficacy and safety profile of imrecoxib (versus celecoxib) in hip osteoarthritis patients undergoing total hip arthroplasty (THA). METHODS: 156 hip osteoarthritis patients planned for THA were randomized into imrecoxib (N = 78) and celecoxib (N = 78) groups. Patients were orally administrated with imrecoxib or celecoxib 200 mg at 2 h (h) after THA, 200 mg every 12 h to day (D)3, and 200 mg every 24 h to D7; additionally, each patient received patient-controlled analgesia (PCA) for 2 days. RESULTS: Resting pain visual analogue scale (VAS) score at 6 h, 12 h, D1, D2, D3, and D7 post THA was not varied between imrecoxib and celecoxib groups (all P > 0.050), neither was moving pain VAS score (all P > 0.050). Importantly, the upper of 95% confidence interval of pain VAS score margin between imrecoxib and celecoxib groups was within the non-inferiority threshold (Δ = 1.0), indicating the fact that non-inferiority was established. The additional and total consumption of PCA was not varied between imrecoxib and celecoxib groups (both P > 0.050). Also, no difference was seen in Harris hip score, European Quality of Life 5-Dimensions (EQ-5D) total and VAS scores at month (M)1, M3 between the two groups (all P > 0.050). Besides, the incidences of all adverse events were not different between imrecoxib and celecoxib groups (all P > 0.050). CONCLUSION: Imrecoxib is non-inferior to celecoxib for postoperative analgesia in hip osteoarthritis patients undergoing THA.

Liver Fibrosis Assessment by Viewing Sinusoidal Capillarization: US Molecular Imaging versus Two-dimensional Shear-Wave Elastography in Rats.

Background US elastography is a first-line assessment of liver fibrosis severity; however, its application is limited by its insufficient sensitivity in early-stage fibrosis detection and its measurements are affected by inflammation. Purpose To assess the sensitivity of US molecular imaging (USMI) in early-stage liver fibrosis detection and to determine whether USMI can specifically distinguish fibrosis regardless of inflammation when compared with two-dimensional (2D) shear-wave elastography (SWE). Materials and methods USMI and 2D SWE were performed prospectively (January to June 2021) in 120 male Sprague-Dawley rats with varying degrees of liver fibrosis and acute hepatitis and control rats. Liver sinusoidal capillarization was viewed at CD34-targeted USMI and quantitatively analyzed by the normalized intensity difference (NID). Data were compared by using a two-sided Student t test or one-way analysis of variance. Linear correlation analyses were used to evaluate the relationships between collagen proportionate area values and NID and liver stiffness measurement (LSM) values. Receiver operating characteristic curves were used to assess the diagnostic performance in detecting liver fibrosis. Results Both NID and LSM values showed good linear correlation with collagen proportionate area values (r = 0.91 and 0.87, respectively). No difference was observed between the areas under the receiver operating characteristic curve in detecting stage F0-F1 between USMI and 2D SWE (0.97 vs 0.91, respectively; P = .20). USMI depicted liver fibrosis at an early stage more accurately than 2D SWE (area under the curve, 0.97 vs 0.82, respectively; P = .01). Rats with hepatitis had higher liver stiffness values than control rats (9.83 kPa ± 0.79 vs 6.55 kPa ± 0.38, respectively; P < .001), with no difference in the NID values between control rats and rats with hepatitis (6.75% ± 1.43 vs 6.74% ± 0.86, respectively; P = .98). Conclusion Sinusoidal capillarization viewed at US molecular imaging helped to detect early-stage liver fibrosis more accurately than two-dimensional shear-wave elastography and helped assess fibrosis regardless of inflammation. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Barr in this issue.

Exploring the Role and Mechanism of Adipose Derived Mesenchymal Stem Cells on Reversal of Pigmentation Model Effects.

Interventions for extrinsic aging can be implemented, but these must address photoaging, which is the primary cause of extrinsic aging. Pigmentation due to photoaging depends on the duration and intensity of sun exposure. This study investigated the relationship between adipose-derived mesenchymal stem cells (ASCs) and photoaging pigmentation, and the underlying mechanism of action by establishing a photoaging pigmentation model using various treatments and exposure options in a guinea pigs. The energy dose of each UVB irradiation was 120 mJ/cm2 and the total dose of irradiation was 360 mJ/cm2. After successfully establishing the photoaging model, ASCs (1×106) in an balanced salt solution (0.9 ml), balanced salt solution (0.9 ml), and bFGF (9 µg) mixed with an balanced salt solution (0.9 ml) were injected intradermally in ten guinea pigs. ELISA, macroscopic skin and histological observations, and Masson-Fontana staining were done. At 2 and 4 weeks post-injection, noticeable changes were observed. Guinea pigs receiving ASCs injections displayed significantly lower visible skin scores while the melanin content continued to decrease. Somewhat improved histopathological morphology, including epidermal thinning, dermal thickening, and little inflammatory cell infiltration was observed immediately after and up to 4 weeks of ASCs injection. Melanocortin 1 receptor (MC1R) and alpha-melanocyte test hormone (alpha-MSH) levels reduced significantly, and basic fibroblast growth factor (bFGF) levels increased significantly immediately after and up to 4 weeks of ASCs injection. The MC1R and alpha-MSH levels reduced significantly immediately after and up to 4 weeks of bFGF injection. Briefly, intradermal ASCs injection can notably eliminate pigmentation in a guinea pig photoaging pigmentation model. This may be related to the fact that bFGF secreted by ASCs lowers MC1R and alpha-MSH levels, blocks the cAMP signalling pathway, and inhibits melanin synthesis. This finding may present new options for treating photoaging pigmentation.Level of Evidence: N/A.

Intracolic ultrasound molecular imaging: a novel method for assessing colonic tumor necrosis factor-α expression in inflammatory bowel disease.

BACKGROUND: While anti-tumor necrosis factor alpha (TNF-α) therapy has been proven effective in inflammatory bowel disease (IBD), approximately 40% of patients lose the response. Transmembrane TNF-α (mTNF-α) expression in the intestinal mucosa is correlated with therapeutic efficacy, and quantification of mTNF-α expression is significant for predicting response. However, conventional intravenous application of microbubbles is unable to assess mTNF-α expression in intestinal mucosa. Herein, we proposed intracolic ultrasound molecular imaging with TNF-α-targeted microbubbles (MBTNF-α) to quantitatively detect mTNF-α expression in the intestinal mucosa. METHODS: MBTNF-α was synthesized via a biotin-streptavidin bridging method. TNF-α-targeted ultrasound imaging was performed by intracolic application of MBTNF-α to detect mTNF-α expression in surgical specimens from a murine model and patients with IBD. Linear regression analyses were performed to confirm the accuracy of quantitative targeted ultrasound imaging. RESULTS: On quantitative TNF-α-targeted ultrasound images, a greater signal intensity was observed in the mouse colons with colitis ([1.96 ± 0.45] × 106 a.u.) compared to that of the controls ([0.56 ± 0.21] × 106 a.u., P < 0.001). Targeted US signal intensities and inflammatory lesions were topographically coupled in mouse colons. Linear regression analyses in specimens of mice and patients demonstrated significant correlations between the targeted ultrasound signal intensity and mTNF-α expression (both P < 0.001). Furthermore, TNF-α-targeted ultrasound imaging qualitatively distinguished the varying inflammatory severity in intestinal specimens from IBD patients. CONCLUSION: Intracolic ultrasound molecular imaging with MBTNF-α enables quantitative assessment of mTNF-α expression. It may be a potential tool for facilitating the implementation of personalized medicine in IBD.

Targeted imaging of orthotopic prostate cancer by using clinical transformable photoacoustic molecular probe.

BACKGROUND: To obtain high-yield histological samples by targeted prostate cancer (PCa) biopsy is the current trend compared with transrectal ultrasound (TRUS)-guided systematic histological biopsy, which is regarded as the gold standard for prostate cancer (PCa) diagnosis. In this paper, we present a targeted PCa imaging strategy using a real-time molecular photoacoustic imaging system integrated with a handheld US probe (PAI/US) and synthesized an integrin αvß3 targeted probe based on ICG (cRGD-ICG). METHODS: To prepare cRGD-ICG, ICG-NHS was linked to cRGD through carboxyl-co-reaction. In vitro PA imaging ability of cRGD-ICG was tested. Orthotopic PCa-bearing rats were used as animal models. After injected with either cRGD-ICG or non-targeted probe, rats were implemented with PA imaging to confirm the specific accumulation of cRGD-ICG at tumor region. Moreover, pathological frozen slices were made to observe distribution of the probe in prostate tissue ex vivo. RESULTS: A small molecular PAI probe was synthesized and exhibited excellent targeted imaging ability in vitro. In vivo photoacoustic imaging was carried out after intravenous injection of cRGD-ICG in orthotopic PCa-bearing rats under the facilitation of the PAI/US system. Maximum molecular photoacoustic signals were observed in the tumor area in vivo after the probe injection, which showed 3.8-fold higher signal enhancement than that in the control group (P < 0.05). Significantly higher cRGD-ICG accumulation was observed under confocal microscopy in the tumor region than in normal prostate tissue. CONCLUSIONS: All our results showed that the comprehensive strategy provided a high-yield and reliable method for PCa diagnosis and targeted prostate biopsy, with great clinical translation potential.

Simple structural indocyanine green-loaded microbubbles for dual-modality imaging and multi-synergistic photothermal therapy in prostate cancer.

As problems with the overuse of radical prostate cancer (PCa) treatment are increasingly exposed, focal therapy represents the direction of low- or intermediate-risk PCa management in the future. However, inaccurate diagnosis and low controllability of focal therapy hinder its clinical translation. In this study, we develop simple structural cyclic arginine-glycine-aspartic (cRGD) peptide-modified and indocyanine green (ICG)-loaded microbubbles (cRGD-ICG-MBs) for ultrasound-photoacoustic imaging and multi-synergistic photothermal therapy (PTT) to address the above problems. Precise PCa diagnosis is achieved by molecular ultrasound imaging. cRGD-targeting and low-frequency ultrasound with an amplitude of 500kPa convert MBs into nanoparticles for enhanced ICG delivery. Alow frequency2500 kPa amplitude ultrasound enables temporary vasculature destruction, which minimizes heat loss during PTT. Specifically, ICG in the tumor region is 14-fold higher than the control, resulting in satisfactory PTT. Our study highlights that this theranostic strategy possesses considerable clinical translational potential, especially in mini-invasive and individualized PCa therapy.

Mitochondrial dysfunction in endothelial cells induced by airborne fine particulate matter (<2.5 µm).

Exposure to ambient fine particulate matter (<2.5 µm; PM2.5 ) increases the risk of the physiopathology of vascular diseases. However, the underlying mechanism, particularly the mitochondrial damage mechanism, of PM2.5 -induced vascular dysfunction is still unclear. In this study, we examined PM2.5 -induced alterations of mitochondrial morphology, and further demonstrated the adverse effects on mitochondrial dynamics and function in vascular endothelial cells. Consequently, cultured EA.hy926 cells were subjected to PM2.5 collected from Beijing. A Cell Counting Assay Kit-8 demonstrated that PM2.5 exposure decreased the proliferation of EA.hy926 cells in a dose-dependent manner. The exposure caused an increment of abnormal mitochondria coupled with the decrease of fusion protein MFN2 and the increase of fission protein FIS1, suggesting that PM2.5 inhibits mitochondrial fusion. Further analyses revealed PM2.5 decreased the mitochondrial membrane potential (ΔΨm) and increased the mitochondrial permeability transport pore opening, eventually resulting in impairments in adenosine triphosphate synthesis. Therefore, it is clearly shown that PM2.5 triggered endothelial toxicity through mitochondria as the target, including the damage of mitochondrial homeostasis.

Babesia gibsoni endemic to Wuhan, China: mitochondrial genome sequencing, annotation, and comparison with apicomplexan parasites.

Babesia gibsoni (B. gibsoni), an intracellular apicomplexan protozoan, poses great threat to canine health. Currently, little information is available about the B. gibsoni (WH58) endemic to Wuhan, China. Here, the mitochondrial (mt) genome of B. gibsoni (WH58) was amplified by five pairs of primers and sequenced and annotated by alignment with the reported mt genome sequences of Babesia canis (B. canis, KC207822), Babesia orientalis (KF218819), Babesia bovis (AB499088), and Theileria equi (AB499091). The evolutionary relationships were analyzed with the amino acid sequences of cytochrome c oxidase I (cox1) and cytochrome b (cob) genes in apicomplexan parasite species. Additionally, the mt genomes of Babesia, Theileria, and Plasmodium spp. were compared in size, host infection, form, distribution, and direction of the protein-coding genes. The full size of the mt genome of B. gibsoni (WH58) was 5865 bp with a linear form, containing terminal-inverted repeats on both ends, six large subunit ribosomal RNA fragments, and three protein-coding genes: cox1, cob, and cytochrome c oxidase III (cox3). Babesia, Theileria, and Plasmodium spp. had a similar mt genome size of about 6000 bp. The mt genomes of parasites that cause canine babesiosis showed a slightly smaller size than the other species. Moreover, Babesia microti (R1 strain) was about 11,100 bp in size, which was twice larger than that of the other species. The mt form was linear for Babesia and Theileria spp. but circular for Plasmodium falciparum and Plasmodium knowlesi. Additionally, all the species contained the three protein-coding genes of cox1, cox3, and cob except Toxoplasma gondii (RH strain) which only contained the cox1 and cob genes. The phylogenetic analysis indicated that B. gibsoni (WH58) was more identical to B. gibsoni (AB499087), B. canis (KC207822), and Babesia rossi (KC207823) and most divergent from Babesia conradae in Babesia spp. Despite the highest similarity to B. gibsoni (AB499087) reported in Japan, B. gibsoni (WH58) showed notable differences in the sequence of nucleotides and amino acids and the property in virulence to host and in vitro cultivation. This study compared the mt genomes of the two B. gibsoni isolates and other parasites in the phylum Apicomplexa and provided new insights into their differences and evolutionary relationships.

MiR-193a-3p and miR-224 mediate renal cell carcinoma progression by targeting alpha-2,3-sialyltransferase IV and the phosphatidylinositol 3 kinase/Akt pathway.

Tumor metastasis is a major cause of cancer-related death in renal cell carcinoma (RCC). MicroRNAs (miRNAs) have been widely known to modulate proliferation invasion, metastasis, and apoptosis of cancer cells. In this study, we aimed to investigate the function and novel target of miR-193a-3p and miR-224 in RCC. The levels of miR-193a-3p and miR-224 were significantly increased in RCC tissues and RCC cell lines. Alpha-2,3-Sialyltransferase IV (ST3GalIV) was highly expressed in adjacent nontumor tissues and human normal proximal tubular cell line HK-2 compared to RCC tissues and cell lines. ST3GalIV expression was negatively correlated with miR-193a-3p and miR-224. Further analysis indicated that miR-193a-3p and miR-224 directly targeted ST3GalIV. MiR-193a-3p and miR-224 increased cell proliferation and migration by directly inhibiting ST3GalIV, and this effect was reversed by co-transfection with ST3GalIV in vitro. Overexpression of miR-193a-3p and miR-224 increased RCC cell proliferation in vivo. Furthermore, the phosphatidylinositol 3 kinase (PI3K)/Akt pathway was mediated by miR-193a-3p and miR-224 in RCC cell lines. Collectively, these results suggested that miR-193a-3p and miR-224 played an important role in regulation of RCC by targeting ST3GalIV via PI3K/Akt pathway.

Effect of nutritional supplement on bone marrow-derived mesenchymal stem cells from aplastic anaemia.

Aplastic anaemia (AA) is characterised by pancytopenia resulting from a marked reduction in haemopoietic stem cells (HSC). The regulation of haemopoiesis depends on the interaction between HSC and various cells of the bone marrow (BM) microenvironment, including BM-derived mesenchymal stromal cells (BMSC). The purpose of this study was to analyse the biological effect of nutritional supplement (NS), a dietary supplement consisting of thirty-six compounds: amino acids, nucleotides, vitamins and micronutrients on the BMSC of AA rats. The AA rat model was established by irradiating X-ray (2·5 Gy) and intraperitoneal injections of cyclophosphamide (35 mg/kg; Sigma) and chloramphenicol (35 mg/kg; Sigma). Then AA rats were fed with NS in a dose-dependent manner (2266·95, 1511·3, 1057·91 mg/kg d) by intragastric administration. The effect of NS on the BMSC of AA rats was analysed. As compared with AA rats, NS treatment significantly improved these peripheral blood parameters and stimulated the proliferation of total femoral nucleated cells. NS treatment affected proliferative behaviour of BMSC and suppressed BMSC differentiation to adipocytes. Furthermore, NS treatment of AA rats accelerated osteogenic differentiation of BMSC and enhanced bone mineral density. Co-incubation of HSC with mesenchymal stromal cells and serum from AA rats subjected to high-dose NS markedly improved the yield of CD34+cells. Protein microarray analysis revealed that there were eleven differentially expressed proteins in the NS group compared with the AA rat group. The identified specific NS might be implicated in rehabilitation of BMSC in AA rats, suggesting their potential of nutritional support in AA treatment.

The effects of autophagy on vascular endothelial cells induced by airborne PM2.5.

The purpose of this study was to examine the direct toxicity of PM2.5 collected from Beijing on human umbilical vein endothelial cells (HUVEC). A Cell Counting Kit 8 (CCK8) assay demonstrated that PM2.5 exposure decreased the proliferation of HUVECs in a dose-dependent manner. We also found that PM2.5 exposure induced autophagy in HUVECs, as evidenced by: (1) an increased number of double-membrane vesicles; (2) enhanced conversion and punctuation of the microtubule-associated protein light chain 3 (LC3); and (3) decreased levels of the selective autophagy substrate p62 in a time-dependent manner. Furthermore, promoting autophagy in PM2.5-exposed HUVECs with rapamycin increased the cell survival rate, whereas inhibiting autophagy via 3-methyladenine significantly decreased cell survival. These results demonstrate that PM2.5 exposure can induce cytotoxicity and autophagy in HUVECs and that autophagy play a protective role against PM2.5-induced cytotoxicity. The findings of the present study imply a direct toxic effect of PM2.5 on HUVECs and provide novel insight into the mechanism of cardiovascular diseases caused by PM2.5 exposure.

Effect of ST3GAL 4 and FUT 7 on sialyl Lewis X synthesis and multidrug resistance in human acute myeloid leukemia.

Sialyl Lewis X (sLe X, CD15s) is a key antigen produced on tumor cell surfaces during multidrug resistance (MDR) development. The present study investigated the effect of α1, 3 fucosyltransferase VII (FucT VII) and α2, 3 sialyltransferase IV (ST3Gal IV) on sLe X oligosaccharides synthesis as well as their impact on MDR development in acute myeloid leukemia cells (AML). FUT7 and ST3GAL4 were overexpressed in three AML MDR cells and bone marrow mononuclear cells (BMMC) of AML patients with MDR by real-time polymerase chain reaction (PCR). A close association was found between the expression levels of FUT7 and ST3GAL4 and the amount of sLe X oligosaccharides, as well as the phenotypic variation of MDR of HL60 and HL60/ADR cells both in vitro and in vivo. Manipulation of these two genes' expression modulated the activity of phosphoinositide-3 kinase (PI3K)/Akt signaling pathway, thereby regulating the proportionally mutative expression of P-glycoprotein (P-gp) and multidrug resistance related protein 1 (MRP1), both of which are known to be involved in MDR. Blocking the PI3K/Akt pathway by its specific inhibitor LY294002 or Akt short hairpin RNA (shRNA) resulted in the reduced MDR of HL60/ADR cells. This study indicated that sLe X involved in the development of MDR of AML cells probably through FUT7 and ST3GAL4 regulating the activity of PI3K/Akt signaling pathway and the expression of P-gp and MRP1.

α-2,8-Sialyltransferase Is Involved in the Development of Multidrug Resistance via PI3K/Akt Pathway in Human Chronic Myeloid Leukemia.

Cell surface sialylation is emerging as an important feature of cancer cell multidrug resistance (MDR). We have focused on the influence of 2,8-sialyltransferases in key steps of the development of MDR in chronic myeloid leukemia (CML). The expressional profiles of six α-2,8-sialyltransferases were generated in three pairs of CML cell lines and peripheral blood mononuclear cells (PBMC) of CML patients. Cellular MDR phenotype positively correlated with ST8SIA4 and ST8SIA6 levels. Furthermore, ST8SIA4 mediated the activity of phosphoinositide-3 kinase (PI3K)/Akt signal pathway and the expression of P-glycoprotein (P-gp). Targeting the PI3K/Akt pathway by its specific inhibitor LY294002, or by Akt RNA interfering reversed the MDR phenotype of K562/ADR cells. Inhibition of PI3K/Akt pathway also attenuated the effects caused by the overexpression of ST8SIA4 on MDR. Therefore this study indicated that α-2,8-sialyltransferases involved in the development of MDR of CML cells probably through ST8SIA4 regulating the activity of PI3K/Akt signaling and the expression of P-gp.

Efficiency or equality? The utilitarianism-egalitarianism trade-off determines carbon allocation preference.

International carbon allocation confronts the conflict between efficiency and equality. Previous research based on the intergroup bias perspective has attributed carbon allocation preference to the defence of ingroup interests (i.e., national interests) while overlooking the critical role of trade-offs between competing moral values. Integrating the contingency theory of justice and moral philosophical theories of utilitarianism and egalitarianism, we proposed that the moral-values trade-off between utilitarianism and egalitarianism determines carbon allocation preference through justice reasoning. Analysis of large-scale survey datasets (Study 1) revealed that aggregated national endorsement of utilitarianism over egalitarianism predicted greater efficiency preference in total and per capita carbon emission levels. Study 2 demonstrated that experimentally manipulating endorsement of utilitarianism versus egalitarianism boosted efficiency (vs. equality) preference in carbon allocation, and justice reasoning characterized by enhanced efficiency-focused justice and diminished equality-focused justice accounted for these effects. Using a 'manipulation-of-mediator' design, Study 3 further confirmed the causal link in the mediation model. By highlighting the significance of moral trade-offs in shaping carbon allocation preference, this research not only provides a novel moral perspective in understanding debates on international carbon allocation but also has important implications for fostering international carbon abatement cooperation.

Knockdown of LRP5 Promotes Proliferation and Invasion of Tongue Squamous Cell Carcinoma through Compensatory Activation of Akt Signaling.

The role of LRP5, a critical receptor in the Wnt signaling pathway, remains unexplored in tongue squamous cell carcinoma (TSCC). This study investigates the impact of LRP5 knockdown on the biological behaviors of TSCC cell lines both in vitro and in vivo. Our findings indicate that LRP5 knockdown significantly enhances cell proliferation, migration, and invasion in CAL27 and SCC25 cell lines. RNA-seq analysis reveals compensatory activation of the Akt pathway, with 119 genes significantly upregulated post-LRP5 knockdown. Elevated MMP1 expression suggests its potential involvement in TSCC progression. Western blot analysis demonstrates increased Akt phosphorylation, upregulated proliferation-related PCNA, and downregulated apoptosis-related caspase-3 after LRP5 knockdown. Down-regulation of E-cadherin and ß-Catenin, proteins associated with cell adhesion and invasion, further elucidates the molecular mechanism underlying increased cell migration and invasion. Our study concludes that compensatory Akt pathway activation is essential for the LRP5 knockdown-induced migration and proliferation of CAL27 and SCC25 cells. These results highlight LRP5 as a potential therapeutic target for TSCC. Simultaneous inhibition of Wnt and Akt signaling emerges as a promising approach for TSCC treatment.

Functional roles of glycogene and N-glycan in multidrug resistance of human breast cancer cells.

Drug resistance is a major problem in cancer chemotherapy. Aberrant glycosylation has been known to be associated with cancer chemoresistance. Aim of this work is to investigate the alterations of glycogene and N-glycan involved in multidrug resistance (MDR) in human breast cancer cell lines. Using real-time polymerase chain reaction (PCR) for quantification of glycogenes, fluorescein isothiocyanate (FITC)-lectin binding for glycan profiling, and mass spectrometry for N-glycan composition, the expression of glycogenes, glycan profiling, and N-glycan composition differed between drug-resistant MCF/ADR cells and the parental MCF-7 line. Further analysis of the N-glycan regulation by tunicamycin (TM) application or PNGase F treatment in MCF/ADR cells showed partial inhibition of the N-glycan biosynthesis and increased sensitivity to chemotherapeutic drugs dramatically both in vitro and in vivo. Using an RNA interference strategy, we showed that the downregulation of MGAT5 in MCF/ADR cells could enhance the chemosensitivity to antitumor drugs both in vitro and in vivo. Conversely, a stable high expression of MGAT5 in MCF-7 cells could increase resistance to chemotherapeutic drugs both in vitro and in vivo. In conclusion, the alterations of glycogene and N-glycan in human breast cancer cells correlate with tumor sensitivity to chemotherapeutic drug and have significant implications for the development of new treatment strategies. © 2013 IUBMB Life, 65(5):409-422, 2013.

Cortical thickness of the left parahippocampal cortex links central hearing and cognitive performance in aging.

Hearing impairment is considered a leading modifiable risk factor of cognitive decline and dementia. While most evidence has been established on clinical assessment of peripheral hearing loss, understanding of how central hearing in real-world conditions is associated with cognitive aging is limited. This study analyzed the data of 473 unrelated healthy adults aged 36-100 years old from the Lifespan Human Connectome Project in Aging. Central hearing was evaluated using the Words-in-Noise decibel threshold. Cognitive functions were evaluated by the performance on cognitive tests, and cortical thickness was estimated from magnetic resonance imaging (MRI) data. Here, we show that a higher hearing threshold was associated with a lower performance on immediate and delayed episodic memory retrieval, switching aspect of executive function, working memory, reading decoding, and vocabulary comprehension. Cortical thickness in the left parahippocampal cortex (lPHC) was negatively associated with the hearing threshold and acted as a significant partial mediator in the association of central hearing with immediate recall, switching, reading decoding, and vocabulary comprehension. These findings suggest that cortical thickness in the lPHC, an early target of dementia, partially links central hearing and performance in multiple cognitive domains in aging.