The Mitochondrial-Derived Peptide MOTS-c Alleviates Radiation Pneumonitis via an Nrf2-Dependent Mechanism.

Radiation pneumonitis (RP) is a prevalent and fatal complication of thoracic radiotherapy due to the lack of effective treatment options. RP primarily arises from mitochondrial injury in lung epithelial cells. The mitochondrial-derived peptide MOTS-c has demonstrated protective effects against various diseases by mitigating mitochondrial injury. C57BL/6 mice were exposed to 20 Gy of lung irradiation (IR) and received daily intraperitoneal injections of MOTS-c for 2 weeks. MOTS-c significantly ameliorated lung tissue damage, inflammation, and oxidative stress caused by radiation. Meanwhile, MOTS-c reversed the apoptosis and mitochondrial damage of alveolar epithelial cells in RP mice. Furthermore, MOTS-c significantly inhibited oxidative stress and mitochondrial damage in MLE-12 cells and primary mouse lung epithelial cells. Mechanistically, MOTS-c increased the nuclear factor erythroid 2-related factor (Nrf2) level and promoted its nuclear translocation. Notably, Nrf2 deficiency abolished the protective function of MOTS-c in mice with RP. In conclusion, MOTS-c alleviates RP by protecting mitochondrial function through an Nrf2-dependent mechanism, indicating that MOTS-c may be a novel potential protective agent against RP.

Unsupervised low-dose CT denoising using bidirectional contrastive network.

BACKGROUND AND OBJECTIVE: Low-dose computed tomography (LDCT) scans significantly reduce radiation exposure, but introduce higher levels of noise and artifacts that compromise image quality and diagnostic accuracy. Supervised learning methods have proven effective in denoising LDCT images, but are hampered by the need for large, paired datasets, which pose significant challenges in data acquisition. This study aims to develop a robust unsupervised LDCT denoising method that overcomes the reliance on paired LDCT and normal-dose CT (NDCT) samples, paving the way for more accessible and practical denoising techniques. METHODS: We propose a novel unsupervised network model, Bidirectional Contrastive Unsupervised Denoising (BCUD), for LDCT denoising. This model innovatively combines a bidirectional network structure with contrastive learning theory to map the precise mutual correspondence between the noisy LDCT image domain and the clean NDCT image domain. Specifically, we employ dual encoders and discriminators for domain-specific data generation, and use unique projection heads for each domain to adaptively learn customized embedded representations. We then align corresponding features across domains within the learned embedding spaces to achieve effective noise reduction. This approach fundamentally improves the model's ability to match features in latent space, thereby improving noise reduction while preserving fine image detail. RESULTS: Through extensive experimental validation on the AAPM-Mayo public dataset and real-world clinical datasets, the proposed BCUD method demonstrated superior performance. It achieved a peak signal-to-noise ratio (PSNR) of 31.387 dB, a structural similarity index measure (SSIM) of 0.886, an information fidelity criterion (IFC) of 2.305, and a visual information fidelity (VIF) of 0.373. Notably, subjective evaluation by radiologists resulted in a mean score of 4.23, highlighting its advantages over existing methods in terms of clinical applicability. CONCLUSIONS: This paper presents an innovative unsupervised LDCT denoising method using a bidirectional contrastive network, which greatly improves clinical applicability by eliminating the need for perfectly matched image pairs. The method sets a new benchmark in unsupervised LDCT image denoising, excelling in noise reduction and preservation of fine structural details.

Nrf2/PHB2 alleviates mitochondrial damage and protects against Staphylococcus aureus-induced acute lung injury.

Staphylococcus aureus (SA) is a major cause of sepsis, leading to acute lung injury (ALI) characterized by inflammation and oxidative stress. However, the role of the Nrf2/PHB2 pathway in SA-induced ALI (SA-ALI) remains unclear. In this study, serum samples were collected from SA-sepsis patients, and a SA-ALI mouse model was established by grouping WT and Nrf2-/- mice after 6 h of intraperitoneal injection. A cell model simulating SA-ALI was developed using lipoteichoic acid (LTA) treatment. The results showed reduced serum Nrf2 levels in SA-sepsis patients, negatively correlated with the severity of ALI. In SA-ALI mice, downregulation of Nrf2 impaired mitochondrial function and exacerbated inflammation-induced ALI. Moreover, PHB2 translocation from mitochondria to the cytoplasm was observed in SA-ALI. The p-Nrf2/total-Nrf2 ratio increased in A549 cells with LTA concentration and treatment duration. Nrf2 overexpression in LTA-treated A549 cells elevated PHB2 content on the inner mitochondrial membrane, preserving genomic integrity, reducing oxidative stress, and inhibiting excessive mitochondrial division. Bioinformatic analysis and dual-luciferase reporter assay confirmed direct binding of Nrf2 to the PHB2 promoter, resulting in increased PHB2 expression. In conclusion, Nrf2 plays a role in alleviating SA-ALI by directly regulating PHB2 transcription and maintaining mitochondrial function in lung cells.

Aptamer-Based Functionalized SERS Biosensor for Rapid and Ultrasensitive Detection of Gastric Cancer-Related Biomarkers.

Background: Gastric cancer (GC) as is the second deadliest malignancy still lacks rapid, simple and economical detection and early clinical screening techniques. Surface-enhanced Raman spectroscopy (SERS) is a spectroscopic technique based on the surface plasmon resonance of precious metal nanoparticles, which can effectively detect low-abundance tumor markers. Combining SERS technology with sensors has high potential in the diagnosis and screening of GC. Methods: A novel Au/Si nano-umbrella array (Au/SiNUA) was prepared as a SERS substrate and the substrate was functionalized using the corresponding tumor marker aptamers for the detection of clinical biological samples using a one-step recognition release mechanism. Optimization of aptamer and complementary chain concentrations and detection time for optimal sensor preparation. Results: Au/SiNUA were tested to have good SERS enhancement activity. The proposed aptamer biosensor has good specificity and stability, with a low detection time of 18 min and a limit of detection (LOD) at the fM level, which is superior to most of the methods reported so far; and the accuracy of the clinical assay is comparable to that of the ELISA method. The expression levels of PDGF-B and thrombin in the serum of GC patients and healthy individuals can be effectively detected and differentiated. Conclusion: The ultrasensitive and specific aptamer biosensor is highly feasible for the diagnosis and screening of GC and has good application prospects.

The Prognostic Value of Johns Hopkins Hospital Nutrition Support Score in Older Patients Undergoing Cardiovascular Surgery.

OBJECTIVES: Clarify the prognostic value of the Johns Hopkins Hospital Nutrition Support (JHHNS) score on clinical outcomes in older patients undergoing cardiovascular surgery with cardiopulmonary bypass (CPB). DESIGN: A retrospective observational study. SETTING: A teaching and university hospital and tertiary referral center. PARTICIPANTS: The authors analyzed 328 older patients aged ≥65 who underwent cardiovascular surgery with CPB in 2020. INTERVENTIONS: Malnutrition risk was identified by the JHHNS score calculated based on specific preoperative and intraoperative objective parameters. Patients were divided into low- and high-JHHNS groups. Early morbidity, including pneumonia, bacteremia, wound infection, cerebrovascular accident, gastrointestinal bleeding, acute kidney injury, delirium, requirement for extracorporeal membrane oxygenation, and readmission to the intensive care unit (ICU), were the primary outcome; whereas in-hospital mortality, length of ICU and hospital stay, duration of mechanical ventilation and short-term mortality were secondary outcomes. The independent risk factors for postoperative complications were analyzed by logistic regression analyses. MEASUREMENTS AND MAIN RESULTS: The JHHNS score identified 21.0% of patients at risk for malnutrition. Patients in the high-JHHNS group had prolonged median length hospital stay (21 v 24 days, p = 0.002) and mechanical ventilation (13.0 v 16.0 hours, p = 0.038), and more patients in this subgroup stayed longer than 3 days in ICU (30.1% v 43.5%, p = 0.036). Besides, they experienced more postoperative complications (11.2% v 39.1%, p < 0.001). Furthermore, multivariate logistic regression analysis demonstrated that the JHHNS score independently predicted the risk of postoperative complications. No significant intergroup difference was observed for the short-term mortality. CONCLUSIONS: The JHHNS score was an independent predictor for postoperative complications but did not significantly affect short-term mortality in older patients undergoing cardiovascular surgery with CPB.

4-OI ameliorates bleomycin-induced pulmonary fibrosis by activating Nrf2 and suppressing macrophage-mediated epithelial-mesenchymal transition.

OBJECTIVES: Pulmonary fibrosis (PF) is a chronic and refractory interstitial lung disease with limited therapeutic options. 4-octyl itaconate (4-OI), a cell-permeable derivative of itaconate, has been shown to have anti-oxidative and anti-inflammatory properties. However, the effect and the underlying mechanism of 4-OI on PF are still unknown. METHODS: WT or Nrf2 knockout (Nrf2-/-) mice were intratracheally injected with bleomycin (BLM) to establish PF model and then treated with 4-OI. The mechanism study was performed by using RAW264.7 cells, primary macrophages, and conditional medium-cultured MLE-12 cells. RESULTS: 4-OI significantly alleviated BLM-induced PF and EMT process. Mechanism studies have found that 4-OI can not only directly inhibit EMT process, but also can reduce the production of TGF-ß1 by restraining macrophage M2 polarization, which in turn inhibits EMT process. Moreover, the effect of 4-OI on PF and EMT depends on Nrf2. CONCLUSION: 4-OI ameliorates BLM-induced PF in an Nrf2-dependent manner, and its role in alleviating PF is partly due to the direct inhibition on EMT, and partly through indirect inhibition of M2-mediated EMT. These findings suggested that 4-OI has great clinical potential to develop as a new anti-fibrotic agent for PF therapy.

Detection of myeloma cell-derived microvesicles: a tool to monitor multiple myeloma load.

The persistence of tumor load in multiple myeloma (MM) lead to relapse in patients achieving complete remission (CR). Appropriate and effective methods of myeloma tumor load monitoring are important for guiding clinical management. This study aimed to clarify the value of microvesicles in monitoring MM tumor load. Microvesicles in bone marrow and peripheral blood were isolated by differential ultracentrifugation and detected by flow cytometry. Western blotting was applied to assess myosin light chain phosphorylation levels. Flow cytometry to detect Ps+CD41a-, Ps+CD41a-CD138+, Ps+CD41a-BCMA+ microvesicles from bone marrow can be used to predict myeloma burden, furthermore, Ps+CD41a- microvesicles may as a potential index to MRD test. Mechanistically, the releasing of microvesicles from MM cell was regulated by Pim-2 Kinase via Phosphorylation of MLC-2 protein.

Maternal propionate supplementation ameliorates glucose and lipid metabolic disturbance in hypoxia-induced fetal growth restriction.

Intrauterine growth restriction (IUGR), one of the major complications of pregnancy, is characterized by low birth weight and results in higher risks for long-term problems including developing metabolic and cardiovascular diseases. Short-chain fatty acids (SCFAs), especially propionate, have been reported to correct glucose and lipid disorders in metabolic diseases. We hypothesized that maternal propionate supplementation could prevent glucose and lipid metabolic disturbance in hypoxia-induced IUGR. Here, in our study, maternal hypoxia was induced from gestational day (GD) 11 to GD 17.5 to establish an IUGR mouse model. Maternal propionate treatment reversed reduced birth weight in male IUGR offspring. Hepatic transcriptomics demonstrated that SP treatment significantly lowered glucose and lipid metabolism-related genes (Scd1, G6pc, Pck1 and Fasl) in IUGR offspring. KOG enrichment analysis showed that propionate-induced down-regulated differential expressed genes (DEGs) mainly belonged to lipid transport and metabolism. KEGG enrichment results showed that the down-regulated DEGs were mostly enriched in PPAR and FoxO signaling pathways. We also found that maternal oral administration of SP decreased serum lipid content, attenuated hepatic insulin resistance and liver lipid accumulation, reduced hepatic key gene expressions of gluconeogenesis and lipogenesis, increased energy expenditure and improved liver function in 11-week-old male IUGR offspring. These results indicate that maternal propionate supplementation increases birth weight and corrects hepatic glucose and lipid metabolic disturbance and energy expenditure in male mice born with IUGR, which may provide a basis for using propionate to treat IUGR disease.

The Association Between Circulating Trans Fatty Acids and Thyroid Function Measures in U.S. Adults.

Background: There has been controversial evidence regarding the effect of trans fatty acids (TFAs) on thyroid function in animal studies, and the epidemiological studies are lacking. We aimed to investigate the potential associations between circulating TFAs and thyroid function biomarkers in a U.S. adult population sample. Methods: We performed a cross-sectional survey with 626 adults aged ≥20 years who participated in the National Health and Nutrition Examination Survey (NHANES) 2009-2010. Multivariable linear regression models were constructed to elucidate the relationships between circulating concentrations of TFAs (palmitelaidic acid, vaccenic acid, elaidic acid, linoelaidic acid and the sum of the four TFAs) and a panel of thyroid function measures. Results: For 626 adults, positive associations were found between palmitelaidic acid, elaidic acid and total thyroxine (TT4), between palmitelaidic acid and total triiodothyronine (TT3), and between linolelaidic acid and thyroid stimulating hormone (TSH), while linolelaidic acid was negatively associated with free thyroxine (FT4) (all P<0.05). Besides, the four TFAs and the sum TFAs were positively associated with free triiodothyronine (FT3). Vaccenic acid, elaidic acid, linoelaidic acid and the sum TFAs were positively associated with FT3/FT4, while the four TFAs and the sum TFAs were negatively associated with FT4/TT4 (all P<0.05). In stratified analysis, the associations between thyroid function measures and the ratios remained significant in female. For men, linolelaidic acid was negatively associated with FT4 and elaidic acid and the sum TFAs were positively associated with FT3. Furthermore, the associations between TFAs and FT3/FT4 remained significant. Conclusion: Our findings revealed that TFAs exposure was associated with serum biomarkers of thyroid function. More researches are needed to evaluate the long-term health outcomes of these findings.

Roles of LINC01473 and CD74 in osteoblasts in multiple myeloma bone disease.

The suppression of osteoblast (OB) activity is partially responsible for multiple myeloma (MM) bone disease. Long non-coding RNAs (lncRNAs) play a vital role in bone formation and resorption. However, their functions in OBs from patients with MM have rarely been reported. Through high-throughput sequencing of OBs from patients with MM and healthy controls, we identified several lncRNAs and messenger RNAs (mRNAs) with different expression profile and validated them using quantitative real-time PCR. In total, 22 upregulated and 21 downregulated lncRNAs were found in OBs from patients with MM. Moreover, 18 upregulated protein-coding mRNAs were identified. The expression levels of LINC01473 and its associated co-expression mRNA, CD74, were higher in patients with MM than in healthy controls (p=0.047 and p=0.016, respectively). LINC01473 expression demonstrated a negative correlation with serum interleukin-2 and tumor necrosis factor α levels, whereas the expression of mRNA CD74 was positively associated with serum lactic dehydrogenase in patients with MM. Aberrant expression of lncRNAs and mRNAs was observed in OBs from patients with MM. This study identifies new promising targets for further research on imbalanced bone formation and resorption and MM immune escape.

Serum lipid levels in relation to clinical outcomes in pregnant women with gestational diabetes mellitus: an observational cohort study.

BACKGROUND: Research on dyslipidemia during pregnancy in women with gestational diabetes mellitus (GDM) has rarely been conducted in Asia. The present study aimed to evaluate maternal mid-trimester lipid profile in relation to GDM and clinical outcomes in these high-risk populations. METHODS: The medical records of 632 pregnant women in the second trimester were retrospectively analyzed. Maternal fasting serum lipids were assayed for total cholesterol (TC), triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), apolipoprotein A1 (Apo A1) and Apo B concentrations during the second trimester. The atherogenic index of plasma (AIP) was calculated as log (TG/HDL). The clinical outcomes were collected by evaluating delivery mode, postpartum hemorrhage, prematurity, macrosomia, birth weight, body length and neonatal Apgar 5 min score. RESULTS: Levels of TG and AIP were elevated while decreased HDL-C was observed in women with GDM compared with that of the control group. Significant differences were observed in gestational weeks at birth, cesarean section, postpartum hemorrhage, birth weight, body length, prematurity and macrosomia between the two groups. Compared with women with hyperlipidemia, the incidence of GDM and cesarean section was lower in normal lipid group. Women in the hyperlipidemia group had smaller gestational weeks at birth than those in the control group. According to the logistic regression analysis, each unit elevation in AIP increased the risk of GDM by 18.48 times (OR = 18.48, CI: 2.38-143.22). Besides, age (OR = 1.11, CI: 1.06-1.16) and pre-pregnancy BMI (OR = 1.15, CI: 1.07-1.24) were the risk factors of GDM. CONCLUSIONS: These findings suggested that reasonable lipid control in the second trimester might reduce the incidence of GDM and be a potential strategy for improving clinical outcomes in these high-risk women.

Dehydrocostus Lactone Attenuates Methicillin-Resistant Staphylococcus aureus-Induced Inflammation and Acute Lung Injury via Modulating Macrophage Polarization.

Dehydrocostus lactone (DHL), a natural sesquiterpene lactone isolated from the traditional Chinese herbs Saussurea lappa and Inula helenium L., has important anti-inflammatory properties used for treating colitis, fibrosis, and Gram-negative bacteria-induced acute lung injury (ALI). However, the effects of DHL on Gram-positive bacteria-induced macrophage activation and ALI remains unclear. In this study, we found that DHL inhibited the phosphorylation of p38 MAPK, the degradation of IκBα, and the activation and nuclear translocation of NF-κB p65, but enhanced the phosphorylation of AMP-activated protein kinase (AMPK) and the expression of Nrf2 and HO-1 in lipoteichoic acid (LTA)-stimulated RAW264.7 cells and primary bone-marrow-derived macrophages (BMDMs). Given the critical role of the p38 MAPK/NF-κB and AMPK/Nrf2 signaling pathways in the balance of M1/M2 macrophage polarization and inflammation, we speculated that DHL would also have an effect on macrophage polarization. Further studies verified that DHL promoted M2 macrophage polarization and reduced M1 polarization, then resulted in a decreased inflammatory response. An in vivo study also revealed that DHL exhibited anti-inflammatory effects and ameliorated methicillin-resistant Staphylococcus aureus (MRSA)-induced ALI. In addition, DHL treatment significantly inhibited the p38 MAPK/NF-κB pathway and activated AMPK/Nrf2 signaling, leading to accelerated switching of macrophages from M1 to M2 in the MRSA-induced murine ALI model. Collectively, these data demonstrated that DHL can promote macrophage polarization to an anti-inflammatory M2 phenotype via interfering in p38 MAPK/NF-κB signaling, as well as activating the AMPK/Nrf2 pathway in vitro and in vivo. Our results suggested that DHL might be a novel candidate for treating inflammatory diseases caused by Gram-positive bacteria.

Ethyl ferulate protects against lipopolysaccharide-induced acute lung injury by activating AMPK/Nrf2 signaling pathway.

Ethyl ferulate (EF) is abundant in Rhizoma Chuanxiong and grains (e.g., rice and maize) and possesses antioxidative, antiapoptotic, antirheumatic, and anti-inflammatory properties. However, its effect on lipopolysaccharide (LPS)-induced acute lung injury (ALI) is still unknown. In the present study, we found that EF significantly alleviated LPS-induced pathological damage and neutrophil infiltration and inhibited the gene expression of proinflammatory cytokines (TNF-α, IL-1ß, and IL-6) in murine lung tissues. Moreover, EF reduced the gene expression of TNF-α, IL-1ß, IL-6, and iNOS and decreased the production of NO in LPS-stimulated RAW264.7 cells and BMDMs. Mechanistic experiments revealed that EF prominently activated the AMPK/Nrf2 pathway and promoted Nrf2 nuclear translocation. AMPK inhibition (Compound C) and Nrf2 inhibition (ML385) abolished the beneficial effect of EF on the inflammatory response. Furthermore, the protective effect of EF on LPS-induced ALI was not observed in Nrf2 knockout mice. Taken together, the results of our study suggest that EF ameliorates LPS-induced ALI in an AMPK/Nrf2-dependent manner. These findings provide a foundation for developing EF as a new anti-inflammatory agent for LPS-induced ALI/ARDS therapy.

Complement C3a activates osteoclasts by regulating the PI3K/PDK1/SGK3 pathway in patients with multiple myeloma.

OBJECTIVE: Myeloma bone disease (MBD) is the most common complication of multiple myeloma (MM). Our previous study showed that the serum levels of C3/C4 in MM patients were significantly positively correlated with the severity of bone disease. However, the mechanism of C3a/C4a in osteoclasts MM patients remains unclear. METHODS: The formation and function of osteoclasts were analyzed after adding C3a/C4a in vitro. RNA-seq analysis was used to screen the potential pathways affecting osteoclasts, and the results were verified by Western blot, qRT-PCR, and pathway inhibitors. RESULTS: The osteoclast area per view induced by 1 µg/mL (mean ± SD: 50.828 ± 12.984%) and 10 µg/mL (53.663 ± 12.685%) of C3a was significantly increased compared to the control group (0 µg/mL) (34.635 ± 8.916%) (P < 0.001 and P < 0.001, respectively). The relative mRNA expressions of genes, OSCAR/TRAP/RANKL/cathepsin K, induced by 1 µg/mL (median: 5.041, 3.726, 1.638, and 4.752, respectively) and 10 µg/mL (median: 5.140, 3.702, 2.250, and 5.172, respectively) of C3a was significantly increased compared to the control group (median: 3.137, 2.004, 0.573, and 2.257, respectively) (1 µg/mL P = 0.001, P = 0.003, P < 0.001, and P = 0.008, respectively; 10 µg/mL: P < 0.001, P = 0.019, P < 0.001, and P = 0.002, respectively). The absorption areas of the osteoclast resorption pits per view induced by 1 µg/mL (mean ± SD: 51.464 ± 11.983%) and 10 µg/mL (50.219 ± 12.067%) of C3a was also significantly increased (33.845 ± 8.331%) (P < 0.001 and P < 0.001, respectively) compared to the control. There was no difference between the C4a and control groups. RNA-seq analysis showed that C3a promoted the proliferation of osteoclasts using the phosphoinositide 3-kinase (PI3K) signaling pathway. The relative expressions of PIK3CA/phosphoinositide dependent kinase-1 (PDK1)/serum and glucocorticoid inducible protein kinases (SGK3) genes and PI3K/PDK1/p-SGK3 protein in the C3a group were significantly higher than in the control group. The activation role of C3a in osteoclasts of MM patients was reduced by the SGK inhibitor (EMD638683). CONCLUSIONS: C3a activated osteoclasts by regulating the PI3K/PDK1/SGK3 pathways in MM patients, which was reduced using a SGK inhibitor. Overall, our results identified potential therapeutic targets and strategies for MBD patients.

Involvement of MM cell-derived exosomes in T lymphocytes immune responses.

Exosomes were reported to mediate cell communication in the tumor microenvironment; however, the effects of multiple myeloma (MM)-derived exosomes on the quantity and function of T cells remain unknown. Exosomes were extracted from MM cell lines (OPM2 and U266B1) by ultracentrifugation using a Total Exosome Isolation kit. Exosomes were co-cultured with CD4+ T, CD8+ T and regulatory T (Treg) cells that were isolated from healthy donors (HDs) and patients with MM using magnetic beads. Flow cytometry was used to detect T cells apoptosis and expression of perforin and granzyme B in CD8+ T cells. Cell viability was detected using Cell Counting kit-8, and interleukin 10 (IL-10) and transforming growth factor ß (TGF-ß) in cell supernatants were detected by ELISA. The apoptosis of HD-CD4+ T was higher in the OPM2 group, and viability in the U266B1 group was decreased. The apoptosis of HD-CD8+ T decreased in the OPM2 and U266B1 groups, and cell viability increased in the OPM2 and the U266B1 groups. Perforin of HD-CD8+ T in the U266B1 group was lower while perforin of MM-CD8+ T in OPM2 and U266B1 groups was markedly decreased. The apoptosis of HD-Treg was lower in the U266B1 group, but apoptosis of MM-Treg was higher in the U266B1 group. The viability of HD-Treg in U266B1 group increased but the viability of MM-Treg in OPM2 and U266B1 groups decreased. TGF-ß from MM-Treg decreased in the OPM2 and U266B1 groups when compared with the control group (P<0.05). MM-derived exosomes promote apoptosis and inhibit proliferation of HD-CD4+ T, inhibit apoptosis and promote proliferation, but inhibit perforin of HD-CD8+ T, inhibit apoptosis and promote proliferation HD-Treg, and inhibit perforin of MM-CD8+ T and TGF-ß secretion of MM-Treg.

CCN1 stimulated the osteoblasts via PTEN/AKT/GSK3ß/cyclinD1 signal pathway in Myeloma Bone Disease.

BACKGROUNDS: Myeloma-related bone disease (MBD) is a common complication of multiple myeloma (MM), which can both decrease life quality and influence the prognosis of the patients. We have found that CCN1 stimulated proliferation and differentiation of osteoblasts in MM in vitro and in vivo, while its mechanism still remains unknown. METHOD: Bone marrow mononuclear cells were collected from MM patients and differentiated into the osteoblasts. After co-culture with CCN1 in vitro, the intracellular signaling antibody array and western blot were performed to explore the signaling pathway. Furthermore, GSK3ß inhibitor TWS119 was used to check the pathway of CCN1 might have on osteoblasts in vitro. RESULTS: For the protein array kit, the expressions of GSK3ß, 4E-BP1, and PTEN are decreased in CCN1 group. For western blots, the CCN1 group also has lower expression comparing to the control group in PTEN (P = .031). Meanwhile p-AKT and cyclinD1 levels have increased in the CCN1 group (P = .002, P = .039). After adding TWS119 as another group, western blot was performed again to verify the pathway. For upstream proteins PTEN and p-AKT, TWS119 group has higher expression level compared to that in CCN1 group (P = .003, P = .001). And for downstream protein cyclinD1, TWS119 group also presented higher level than the control group (P = .02). CCN1 could have almost the same effect on GSK3ß as the specific inhibitor TWS119 had. CONCLUSIONS: CCN1 can stimulate osteoblasts through PTEN/AKT/GSK3ß/cyclinD1 pathway in MBD, which has the potential to be a novel therapy of MBD.

Effect factors related to a high probability of hemodialysis independence in newly diagnosed multiple myeloma patients requiring hemodialysis.

BACKGROUND: Renal failure is a severe complication of symptomatic myeloma, related to higher mortality. Recovery from dialysis dependence can lead to enormous survival benefits. We investigated the effect factors for probability of dialysis independence. METHODS: Retrospective data on 45 newly diagnosed MM (NDMM) patients with serious renal impairment and requiring hemodialysis were analyzed. The statistical methods including logistic regression analysis, Kaplan-Meier survival curves, the log-rank test and the Cox proportional hazards model for survival analysis were used in our study. RESULTS: Twenty-two of the 45 patients, who were on hemodialysis at diagnosis, became dialysis independence. In the logistic regression analysis, serum level of ß2-microglobulin, kidney disease history, involved free light chain, and achieving at least VGPR were significantly associated with reversibility from dialysis dependence. In addition, achieving hemodialysis discontinuation was related to better survival. The multivariate analyses demonstrated that reversibility from dialysis dependence, proteinuria < 3.5 g/24 h, and achieving at least VGPR were significantly associated with OS among NDMM patients requiring hemodialysis. CONCLUSION: Lower serum level of ß2-microglobulin and lower level of free light chain at diagnosis, achieving at least VGPR, and shorter kidney disease history are related to a high probability of dialysis independence in NDMM patients with serious renal failure requiring dialysis.

The complete mitochondrial genome of Aparapotamon similium (Decapoda: Brachyura), an endemic to China.

In this study, we first obtained the complete mitochondrial genome of Aparapoamon similium (Decapoda: Brachyura). The complete mitochondrial genome is 19,236 bp in length and includes 37 typical genes (13 protein-coding genes, 22 tRNAs genes, 2 rRNAs genes, and 1 putative control region). The whole mitochondrial genome is characterized by the apparent AT bias (72.82%). BI and ML phylogenetic analysis based on 67 mitochondrial genomes of Brachyura species show a highly similar topology structure with high bootstrap supported. The results reveal the close relationship between A. similium and Potamiscus motuoense. This study would establish a solid data foundation for further diversification studies.

Identification of a gene encoding microphthalmia-associated transcription factor and its association with shell color in the clam Meretrix petechialis.

The microphthalmia-associated transcription factor (MITF) is a master regulator of melanocyte development through the direct transcriptional control of related genes, e.g., the phenoloxidase gene. In this study, an MITF gene, MpMITF2, was identified in the clam Meretrix petechialis. The full-length cDNA of MpMITF2 was 2026 bp, and the molecular mass of the predicted protein was 42.6 kDa. A basic helix-loop-helix leucine zipper domain was detected in the deduced protein sequence, which can bind the E-box motif within the promoter of the downstream genes. The mRNA of MpMITF2 was more highly expressed in the mantle compared to the other four tissues. Furthermore, there was a significant difference in the mRNA expression of MpMITF2 among three clam strains with different shell colors. The protein level of MpMITF2 was also different among these strains. These results implied that MpMITF2 was associated with shell color formation in the clam M. petechialis. When the mRNA expression of MpMITF2 was knocked down, the new shell showed discontinuous pigment distribution, suggesting that the reduced expression of MpMITF2 influenced pigment synthesis. A gene encoding phenoloxidase (MpPO) was identified as related to the shell color of the clam and was also a putative downstream gene of MITF. Both the mRNA and protein levels of MpPO decreased significantly at 12 h post-MpMITF-suppression, suggesting that MpMITF2 is required for the expression of MpPO. Our results indicate the close relationships among MpMITF2, MpPO and shell color. This study implicates the role of MITF in shell color formation in the clam M. petechialis.

The Effect and Safety of Bortezomib in the Treatment of AL Amyloidosis: A Systematic Review and Meta-Analysis.

Bortezomib began to be used in the treatment of light chain (AL) amyloidosis in recent years. We performed the first meta-analysis of randomized clinical trials and clinical controlled trials to evaluate the effect and safety of bortezomib treatment for AL amyloidosis. We conducted a search (until July 2016) in electronic databases (PubMed databases and the Cochrane Central Register of Controlled Trials bases from the year 2003). There were 205 records we searched and eight studies was included (n = 617 persons). We demonstrated that bortezomib treatment significantly improved overall response rate (ORR), complete response, a cardiac response rate, 2-year overall survival and the risk of neuropathy and reduced overall mortality compared to controls without bortezomib therapy. From the comparison and subgroup analysis of ORR between bortezomib group and no bortezomib group, the patients with bortezomib had a higher ORR, especially patients pretreated with bortezomib before high-dose melphalan followed by autologous stem cell transplant compared to no pretreatment. In addition, patients with bortezomib in standard dosage had significantly higher ORR. According to our results, bortezomib should be used in AL amyloidosis patients to improve response rate and survival rate and future relevant randomized controlled trials require to be performed.