Downregulation of VEGFA accelerates AGEs-mediated nucleus pulposus degeneration through inhibiting protective mitophagy in high glucose environments.

Intervertebral disc degeneration (IVDD) contributes largely to low back pain. Recent studies have highlighted the exacerbating role of diabetes mellitus (DM) in IVDD, mainly due to the influence of hyperglycemia (HG) or the accumulation of advanced glycation end products (AGEs). Vascular endothelial growth factor A (VEGFA) newly assumed a distinct impact in nonvascular tissues through mitophagy regulation. However, the combined actions of HG and AGEs on IVDD and the involved role of VEGFA remain unclear. We confirmed the potential relation between VEGFA and DM through bioinformatics and biological specimen detection. Then we observed that AGEs induced nucleus pulposus (NP) cell degeneration by upregulating cellular reactive oxygen species (ROS), and HG further aggravated ROS level through breaking AGEs-induced protective mitophagy. Furthermore, this adverse effect could be strengthened by VEGFA knockdown. Importantly, we identified that the regulation of VEGFA and mitophagy were vital mechanisms in AGEs-HG-induced NP cell degeneration through Parkin/Akt/mTOR and AMPK/mTOR pathway. Additionally, VEGFA overexpression through local injection with lentivirus carrying VEGFA plasmids significantly alleviated NP degeneration and IVDD in STZ-induced diabetes and puncture rat models. In conclusion, the findings first confirmed that VEGFA protects against AGEs-HG-induced IVDD, which may represent a therapeutic strategy for DM-related IVDD.

Ameliorating Osteoarthritis in Mice Using Silver Nanoparticles.

Knee osteoarthritis (KOA) is one of the most commonly encountered degenerative diseases of the joints in people over 45 years of age. Currently, there are not any effective therapeutics for KOA,and the only end-point strategy is total knee arthroplasty (TKA); therefore, KOA is associated with economic burdens and societal costs. The immune inflammatory response is involved in the occurrence and development of KOA. We previously established a mouse model of KOA using type II collagen. Hyperplasia of the synovial tissue was present in the model, alongside a large number of infiltrated inflammatory cells. Silver nanoparticles have substantial anti-inflammatory effects and have been widely used in tumor therapy and surgical drug delivery. Therefore, we evaluated the therapeutic effects of silver nanoparticles in a collagenase II-induced KOA model. The experimental results showed that silver nanoparticles significantly reduced synovial hyperplasia and the infiltration of neutrophils in the synovial tissue. Hence, this work demonstrates the identification of a novel strategy for OA and provides a theoretical basis for preventing the progress of KOA.

Reproductive endocrine disruption and gonadal intersex induction in male Japanese medaka chronically exposed to betamethasone at environmentally relevant levels.

The broad utilization of betamethasone in medical treatments may pose a significant ecotoxicological risk to aquatic organisms, yet its potential reproductive toxicity remains unclear. The present study examined the impacts of environmental exposure on male reproduction using Japanese medaka (Oryzias latipes). After 110 days of betamethasone exposure at environmentally relevant concentrations (0, 20 and 200 ng/L), LH/FSH synthesis and release in the pituitary was inhibited, and the production of sex hormones and their signaling pathways in the gonads of male medaka were greatly influenced. This synthetic glucocorticoid restrained testosterone (T) synthesis and gave rise to a significant increase in E2/T and E2/11-KT ratios. Furthermore, chronic betamethasone exposure (20 and 200 ng/L) led to the suppression of androgen receptor (AR) signaling and enhancement of estrogen receptors (ERs) signaling. An increase in hepatic vitellogenin contents was also detected, and testicular oocytes were observed in both 20 and 200 ng/L betamethasone-treated groups. It showed that 20 and 200 ng/L betamethasone could induce male feminization and even intersex, triggering abnormal spermatogenesis in medaka males. With its adverse effects on male fertility, betamethasone could potentially influence the fishery productivity and population dynamics in aquatic ecosystems.

Regulative Roles of Metabolic Plasticity Caused by Mitochondrial Oxidative Phosphorylation and Glycolysis on the Initiation and Progression of Tumorigenesis.

One important feature of tumour development is the regulatory role of metabolic plasticity in maintaining the balance of mitochondrial oxidative phosphorylation and glycolysis in cancer cells. In recent years, the transition and/or function of metabolic phenotypes between mitochondrial oxidative phosphorylation and glycolysis in tumour cells have been extensively studied. In this review, we aimed to elucidate the characteristics of metabolic plasticity (emphasizing their effects, such as immune escape, angiogenesis migration, invasiveness, heterogeneity, adhesion, and phenotypic properties of cancers, among others) on tumour progression, including the initiation and progression phases. Thus, this article provides an overall understanding of the influence of abnormal metabolic remodeling on malignant proliferation and pathophysiological changes in carcinoma.

UBE2C mediated radiotherapy resistance of head and neck squamous cell carcinoma by regulating oxidative-stress-relative apoptosis.

PURPOSE: Radiotherapy resistance is the main obstacle in the effective treatment of advanced head and neck squamous cell carcinoma (HNSCC). Increasing scientific opinions present that ubiquitin-conjugating enzyme E2C (UBE2C) might be a target gene acting as an oncogene. METHOD: TCGA database was used to analyze the expression of UBE2C in HNSCC patients, and the relationship between UBE2C expression and prognosis. Western blot and RT-PCR were used to assess UBE2C expression before and after radiation. Then, cell viability experiment and colony formation were used to evaluate proliferation after 2 Gy radiation. Cell viability experiment, migration, and invasion were evaluated in the condition of UBE2C knock-down. Western blot and RT-PCR were used to assess the expression of apoptosis and ROS relative gene expression. Then, the xenograft model was used to evaluate the efficacy of radiation combined with UBE2C suppression. RESULT: The expression of UBE2C was high in tumors of patients with HNSCC and relatives with poor prognoses. Si-UBE2C cells showed proliferation inhibited and apoptosis enhanced after radiation. Furthermore, the mechanism of UBE2C in HNSCC radioresistance was explored. We performed RT-PCR to find the 4-HNE, which increases oxidative-stress-relative apoptosis in Si-UBE2C cells after radiation. CONCLUSIONS: Through the RT-PCR, WB, cell viability experiment, migration, invasion, and in vivo experiment, UBE2C was confirmed to downregulate oxidative-stress-relative apoptosis induced by radiation and promote the development of malignant tumor cells.

Comparison of the Differential Diagnostic Performance of Intravoxel Incoherent Motion Imaging and Diffusion Kurtosis Imaging in Malignant and Benign Thyroid Nodules.

Objective: This study aimed to compare the diagnostic capacity between IVIM and DKI in differentiating malignant from benign thyroid nodules. Material and Methods: This study is based on magnetic resonance imaging data of the thyroid with histopathology as the reference standard. Spearman analysis was used to assess the relationship of IVIM-derived parameters D, f, D* and the DKI-derived parameters Dapp and Kapp. The parameters of IVIM and DKI were compared between the malignant and benign groups. Binary logistic regression analysis was performed to establish the diagnostic model, and receiver operating characteristic (ROC) curve analysis was subsequently performed. The DeLong test was used to compare the diagnostic effectiveness of different prediction models. Spearman analysis was used to assess the relationship of Ki-67 expression and parameters of IVIM and DKI. Results: Among the 93 nodules, 46 nodules were malignant, and 47 nodules were benign. The Dapp of DKI-derived parameter was related to the D (P < 0.001, r = 0.863) of IVIM-derived parameter. The Kapp of DKI-derived parameter was related to the D (P < 0.001, r = -0.831) of IVIM-derived parameters. The malignant group had a significantly lower D value (P < 0.001) and f value (P = 0.013) than the benign group. The malignant group had significantly higher Kapp and lower Dapp values (all P < 0.001). The D+f had an area under the curve (AUC) of 0.951. The Dapp+Kapp had an AUC of 0.943. The D+f+Dapp+Kapp had an AUC of 0.954. The DeLong test showed no statistical significance among there prediction models. The D (P = 0.007) of IVIM-derived parameters and Dapp (P = 0.045) of DKI-derived parameter were correlated to the Ki-67 expression. Conclusions: IVIM and DKI were alternative for each other in in differentiating malignant from benign thyroid nodules.

Osmoregulatory strategies of estuarine fish Scatophagus argus in response to environmental salinity changes.

BACKGROUND: Scatophagus argus, an estuarine inhabitant, can rapidly adapt to different salinity environments. However, the knowledge of the molecular mechanisms underlying its strong salinity tolerance remains unclear. The gill, as the main osmoregulatory organ, plays a vital role in the salinity adaptation of the fish, and thus relative studies are constructive to reveal unique osmoregulatory mechanisms in S. argus. RESULTS: In the present study, iTRAQ coupled with nanoLC-MS/MS techniques were employed to explore branchial osmoregulatory mechanisms in S. argus acclimated to different salinities. Among 1,604 identified proteins, 796 differentially expressed proteins (DEPs) were detected. To further assess osmoregulatory strategies in the gills under different salinities, DEPs related to osmoregulatory (22), non-directional (18), hypo- (52), and hypersaline (40) stress responses were selected. Functional annotation analysis of these selected DEPs indicated that the cellular ion regulation (e.g. Na+-K+-ATPase [NKA] and Na+-K+-2Cl- cotransporter 1 [NKCC1]) and ATP synthesis were deeply involved in the osmoregulatory process. As an osmoregulatory protein, NKCC1 expression was inhibited under hyposaline stress but showed the opposite trend in hypersaline conditions. The expression levels of NKA α1 and ß1 were only increased under hypersaline challenge. However, hyposaline treatments could enhance branchial NKA activity, which was inhibited under hypersaline environments, and correspondingly, reduced ATP content was observed in gill tissues exposed to hyposaline conditions, while its contents were increased in hypersaline groups. In vitro experiments indicated that Na+, K+, and Cl- ions were pumped out of branchial cells under hypoosmotic stress, whereas they were absorbed into cells under hyperosmotic conditions. Based on our results, we speculated that NKCC1-mediated Na+ influx was inhibited, and proper Na+ efflux was maintained by improving NKA activity under hyposaline stress, promoting the rapid adaptation of branchial cells to the hyposaline condition. Meanwhile, branchial cells prevented excessive loss of ions by increasing NKA internalization and reducing ATP synthesis. In contrast, excess ions in cells exposed to the hyperosmotic medium were excreted with sufficient energy supply, and reduced NKA activity and enhanced NKCC1-mediated Na+ influx were considered a compensatory regulation. CONCLUSIONS: S. argus exhibited divergent osmoregulatory strategies in the gills when encountering hypoosmotic and hyperosmotic stresses, facilitating effective adaptabilities to a wide range of environmental salinity fluctuation.

rFOV-DWI and SMS-RESLOVE-DWI in patients with thyroid nodules: Comparison of image quality and apparent diffusion coefficient measurements.

OBJECTIVES: To compare reduced field of view technique diffusion-weighted imaging (rFOV-DWI) and simultaneous multislice readout segmentation of long variable echo-trains diffusion-weighted imaging (SMS-RESOLVE-DWI) in terms of image quality and diagnostic performance of the apparent diffusion coefficient (ADC) for thyroid nodules. MATERIALS AND METHODS: A total of 27 benign thyroid nodules and 26 malignant thyroid nodules were enrolled. rFOV-DWI and SMS-RESOLVE-DWI were performed at b values of 0 and 1000 s/mm2. Subjective image quality was evaluated in terms of sharpness, distortion and artifacts. Objective indices reflecting distortion, the contrast-to-noise ratio and the ADC were measured. Paired-samples t-tests or Wilcoxon U tests were applied to assess whether significant differences existed among different sequences. According to the pathological results, the nodules were divided into the benign and malignant groups. The receiver operating characteristic (ROC) curve of the ADC values was used to predict malignant nodules. The DeLong test was used to compare the diagnostic effectiveness between rFOV-DWI and SMS-RESOLVE-DWI. RESULTS: The rFOV-DWI images exhibited better sharpness (P < 0.001) and fewer artifacts (P = 0.003) for the thyroid than the SMS-RESOLVE-DWI images. The overall image quality of nodules (P < 0.001) was better in rFOV-DWI images than in SMS-RESOLVE-DWI images. The rFOV-DWI images also showed less deformation than the SMS-RESOLVE-DWI images (P = 0.002, 0.006). The ADC values of both rFOV-DWI and SMS-RESOLVE-DWI revealed equivalent excellent diagnostic performance. The DeLong test revealed no statistically significant differences between rFOV-DWI and SMS-RESOLVE-DWI. CONCLUSION: This study suggested that rFOV-DWI exhibited better image quality than SMS-RESOLVE-DWI and similar performance in differential diagnosis.

Effects of environmental salinity on the immune response of the coastal fish Scatophagus argus during bacterial infection.

The coastal aquaculture is characterized with environmental salinity fluctuation, and the effects of salinity stress on the immunity of cultured fish are needed to be further explored. Scatophagus argus is an important species in the wild fisheries and aquaculture industry, it would be of great value to reveal the impact of salinity change on the immune response in this species. Understanding the effects of salinity stress on immune response can provide valuable insights into salinity management in the aquacultural process. The head kidney, which is an organ unique for teleost fish, functions not only as a central immune organ but also as a crucial role in the stress response during which the secretion of immunoregulatory molecules i.e. cytokines is facilitated. In the present study, Individuals of S. argus acclimated to 3 different salinities [0‰ (FW), 10‰ (BW), and 25‰ (SW)] were injected intraperitoneally with A. hydrophila, and then monitored throughout one week. The effects of environmental salinity on the immune response in S. argus stimulated by A. hydrophila infection were investigated. mRNA expression profiles of cytokine genes IL-1ß, IL-6, IL-10 and TNF-α in different salinity groups was quite different. mRNA expression of cytokine genes in BW group and SW group rose more quickly and significantly higher than FW group (p < 0.05) at early stages (6-24 hpi) after bacterial injection, and before 96 hpi, the highest value of cytokine expression at each time point was recorded in SW group. Immune parameters such as lysozyme level, complement C3 activity and IgM content in BW and FW groups were lower than SW group at each time point from 24 to 144 hpi after bacterial injection. In addition, leukocyte profiles in the head kidney and blood were also investigated. Although hypoosmotic acclimation could temporarily stimulate monocyte and neutrophil proliferation, it was observed that the number of monocytes, neutrophils and lymphocytes of the head kidney and blood in SW group increased more quickly than BW and FW groups after bacterial infection. Our results indicate that hypoosmotic stress due to the decrease of environmental salinity has suppressive immunoregulatory effects on the immune response of S. argus.

An Efficient Probe-Based Routing for Content-Centric Networking.

With the development of new technologies and applications, such as the Internet of Things, smart cities, 5G, and edge computing, traditional Internet Protocol-based (IP-based) networks have been exposed as having many problems. Information-Centric Networking (ICN), Named Data Networking (NDN), and Content-Centric Networking (CCN) are therefore proposed as an alternative for future networks. However, unlike IP-based networks, CCN routing is non-deterministic and difficult to optimize due to frequent in-network caching replacement. This paper presents a novel probe-based routing algorithm that explores real-time in-network caching to ensure the routing table storing the optimal paths to the nearest content provider is up to date. Effective probe-selections, Pending Interest Table (PIT) probe, and Forwarding Information Base (FIB) probe are discussed and analyzed by simulation with different performance measurements. Compared with the basic CCN, in terms of qualitative analysis, the additional computational overhead of our approach is O(NCS + Nrt + NFIB ∗ NSPT) and O(NFIB) on processing interest packets and data packets, respectively. However, in terms of quantitative analysis, our approach reduces the number of timeout interests by 6% and the average response time by 0.6 s. Furthermore, although basic CCN and our approach belong to the same Quality of Service (QoS) category, our approach outperforms basic CCN in terms of real values. Additionally, our probe-based approach performs better than RECIF+PIF and EEGPR. Owing to speedup FIB updating by probes, our approach provides more reliable interest packet routing when accounting for router failures. In summary, the results demonstrate that compared to basic CCN, our probe-based routing approach raises FIB accuracy and reduces network congestion and response time, resulting in efficient routing.

Stimulator of interferon response cGAMP interactor overcomes ERBB2-mediated apatinib resistance in head and neck squamous cell carcinoma.

PURPOSE: Apatinib resistance is the main obstacle to the effective treatment of advanced head and neck squamous cell carcinoma (HNSCC). This study aimed to evaluate the function of Erb-B2 receptor tyrosine kinase 2 (ERBB2) and stimulator of interferon response cGAMP interactor (STING) in apatinib resistance in HNSCC. METHOD: The Cancer Genome Atlas database of HNSCC was used to analyze the relationship between vascular endothelial growth factor receptor 2 (VEGFR2) expression and prognosis. An apatinib resistant (AR) HNSCC cell line was constructed based on the CAL27 cell line. RNA sequencing was performed to explore the differentially expressed mRNAs. Quantitative real-time reverse transcription PCR (qRT-PCR) and western blotting were used to evaluate the expression and phosphorylation level VEGFR2, ERBB2, STING, and related proteins. Apatinib resistance was evaluated by colony formation and cell viability assays. A mouse subcutaneous tumor formation model was established to evaluate the efficiency of combination treatment and vascularization was evaluated by assessing CD31 immunofluorescence. RESULT: The expression of VEGFR2 was high in tumor of patients with HNSCC. Western blotting and qRT-PCR revealed that in AR cells, ERBB2 expression was high, whereas the expression of STING was low. Targeted treatment of ERBB2 using lapatinib could attenuate apatinib resistance. Further research confirmed that overexpressing STING could decrease ERBB2 expression. CONCLUSION: STING could sensitize AR cells to apatinib by decreasing ERBB2 expression. The combination of lapatinib or a STING agonist with apatinib ameliorated acquired apatinib resistance in a synergistic manner.

Inflammatory responses associated with hyposaline stress in gill epithelial cells of the spotted scat Scatophagus argus.

The molecular processes of immune responses in mucosal tissues such as fish gills under environmental stress are poorly understood. In the present study, pro-inflammatory response under hyposaline stress and its regulation by cortisol/corticosteroid receptors (CRs) in gill epithelial cells of the spotted scat Scatophagus argus were analyzed. The fish were transferred to freshwater for 6 days (144 h) of acclimation. Following freshwater exposure, the cortisol concentration increased transiently before returning to the control level over time. mRNA expression of pro-inflammatory cytokines (TNF-a, IL-1b and IL-6) was stimulated by cortisol through CR signals at early stages of acclimation, but hyposaline stress inhibited their levels by the end of the experimental period. The transcriptional profile of anti-inflammatory cytokine IL-10 was quite different from these pro-inflammatory cytokines, and its value fluctuated within a narrow range during the experimental period. Full-length cDNAs of mineralocorticoid receptor (MR) and glucocorticoid receptor 1 (GR1) (different kinds of CRs) were cloned from the gills. Our results showed that MR and GR displayed mutually antagonistic effects during hyposaline stress. MR responded quickly at early stages, and its expression decreased with the drop of cortisol concentration. By contrast, GR expression was maintained at high levels after the acclimation of freshwater exposure. The tight coordination of GR and MR helps to shape the effects of stress on the immune system, which in turn, regulates the stress response. Our results confirm the interaction between endocrine and cytokine messengers and a clear difference in the sensitivity of GR and MR during the hyposaline challenge in gill epithelial cells of the spotted scat Scatophagus argus.

IL-17 promotes proliferation, inflammation and inhibits apoptosis of HaCaT cells via interacting with the TRAF3 interacting protein 2.

The present study aimed to investigate the effects of interleukin-17 (IL-17) on the function of keratinocytes and to further investigate its associated mechanism. Human immortalized epidermal cells (HaCaT) were divided into sham control group (Sham), TRAF3 interacting protein 2 (TRAF3IP2)-knockdown with lentivirus group (si-TRAF3IP2), sham control+IL-17 group (Sham+IL-17) and TRAF3IP2-knockdown with lentivirus+IL-17 group (si-TRAF3IP2+IL-17). MTT and flow cytometry assays demonstrated that IL-17 promoted proliferation and inhibited apoptosis of HaCaT cells, while this effect was reversed following knockdown of TRAF3IP2 with lentiviral vectors. In addition, a marked increase in the levels of IL-6, IL-8, IL-23, TNF-α and VEGF was observed in the Sham+IL-17 group compared with that noted in the Sham group (P<0.05). Furthermore, reverse transcription-quantitative polymerase chain reaction and western blotting indicated that the mRNA and protein expression levels of caspase-3 in the si-TRAF3IP2+IL-17 group were significantly increased compared with those of the Sham+IL-17 group (P<0.05). Taken together, the results indicated that IL-17 promoted proliferation and inflammation and inhibited apoptosis of HaCaT cells by interacting with the TRAF3IP2 adaptor protein, while knockdown of the expression of TRAF3IP2 reduced the effects of IL-17 in HaCaT cells.

ß-Arrestin-2 attenuates hepatic ischemia-reperfusion injury by activating PI3K/Akt signaling.

Hepatic ischemia-reperfusion injury (IRI) remains a common complication during liver transplantation (LT), partial hepatectomy and hemorrhagic shock in patients. As a member of the G protein-coupled receptors adaptors, ARRB2 has been reported to be involved in a variety of physiological and pathological processes. However, whether ß-arrestin-2 affects the pathogenesis of hepatic IRI remains unknown. The goal of the present study was to determine whether ARRB2 protects against hepatic IR injury and elucidate the underlying mechanisms. To this end, 70% hepatic IR models were established in ARRB2 knockdown mice and wild-type littermates, with blood and liver samples collected at 1, 6 and 12 h after reperfusion to evaluate liver injury. The effect of ARBB2 on PI3K/Akt signaling during IR injury was evaluated in vivo, and PI3K/Akt pathway regulation by ARRB2 was further assessed in vitro. Our results showed that ARRB2 knockdown aggravates hepatic IR injury by promoting the apoptosis of hepatocytes and inhibiting their proliferation. In addition, ARRB2 deficiency inhibited PI3K/Akt pathway activation, while the administration of the PI3K/Akt inhibitor PX866 resulted in severe IR injury in mice. Furthermore, the liver-protecting effect of ARRB2 was shown to depend on PI3K/Akt pathway activation. In summary, our results suggest that ß-Arrestin-2 protects against hepatic IRI by activating PI3K/Akt signaling, which may provide a novel therapeutic strategy for treating liver ischemia-reperfusion injury.

Modulation of inflammatory response by cortisol in the kidney of spotted scat (Scatophagus argus) in vitro under different osmotic stresses.

Salinity changes on renal osmoregulation have often been investigated while the immune response of the kidney under osmotic stress is poorly understood in teleosts. Acute stress is generally associated with enhancement of circulating cortisol. The effects of osmotic stress on renal immune response and its regulation by cortisol deserve more attention. In the present study, the effects of exogenous cortisol treatment on the lipopolysaccharide (LPS)-induced immune response were analyzed in renal masses of Scatophagus argus under different osmotic stresses in vitro. mRNA expression of pro-inflammatory cytokines (TNF-α, IL1-ß and IL-6) and immune-regulatory related genes (GR and SOCS1) was measured over a short course (15 h). Comprehensive analysis reveals that transcript abundances of pro-inflammatory cytokine genes such as TNF-α, IL-1ß, and IL-6 induced by LPS, alone or in the combination of cortisol, are tightly associated with osmoregulation under acute osmotic stress. Our results showed that osmotic challenge could significantly enhance mRNA expression levels of pro-inflammatory cytokines in renal masses in vitro. Based on our analysis, it can be inferred that cortisol suppresses the magnitude of renal inflammatory response and attenuates LPS-induced immune response through GR signaling in the face of challenging environmental conditions.

Prognostic Value of the Combination of CEA and Fibrinogen/Albumin Ratio in Resectable Gastric Cancer.

PURPOSE: To investigate the prognostic value of combined serum carcinoembryonic antigen (CEA) levels and fibrinogen/albumin ratio (FAR) in patients with resectable gastric cancer (GC). INTRODUCTION: This retrospective study evaluated the CEA, fibrinogen, and albumin levels and other clinicopathological features of GC patients. The prognostic significance of these factors for overall survival (OS) was assessed using Kaplan-Meier curves and univariate and multivariate Cox proportional models. PATIENTS AND METHODS: A total of 267 patients were included. The optimal cutoff values of CEA and FAR were 3.2 ng/mL and 0.086, respectively. Patients were stratified into three groups based on this cutoff value: CEA-FAR=0 (CEA <3.2 ng/mL and FAR <0.086), CEA-FAR=1 (CEA ≥3.2 ng/mL or FAR ≥0.086), and CEA-FAR=2 (CEA ≥3.2 ng/mL and FAR ≥0.086). RESULTS: Higher CEA-FAR was strongly associated with age, tumor size, tumor invasion, lymph node status, and TNM stage (all P<0.05). The OS rates differed significantly between these 3 groups (88.9% vs 65.0% vs 46.9%, P<0.001). Multivariate analysis showed that CEA-FAR was an independent prognostic factor for OS (P<0.001). The area under the curve was larger for CEA-FAR than for either CEA or FAR alone (0.683, 0.644, and 0.669, respectively). CONCLUSION: Preoperative CEA-FAR could be a potential blood marker for predicting tumor progression and the prognosis of GC patients. Patients with a higher CEA-FAR should undergo extensive follow-up.

Combining the Fibrinogen/Albumin Ratio and Systemic Inflammation Response Index Predicts Survival in Resectable Gastric Cancer.

AIMS: Predicting the prognosis of gastric cancer using tumour-node-metastasis (TNM) staging is difficult as patients with the same TNM stage exhibit different prognoses. METHODS: This study investigated the prognostic value of the preoperative fibrinogen/albumin ratio (FAR)-systemic inflammation response index (SIRI) score in resectable gastric cancer (rGC). RESULTS: Clinicopathological features of 231 rGC patients were analysed retrospectively. Patients were divided into three groups: FAR-SIRI score 2 (FAR ≥ 0.071 and SIRI ≥ 0.84), 1 (FAR < 0.071 and SIRI ≥ 0.84), and 0 (SIRI < 0.84). Higher FAR-SIRI scores were associated with larger tumours, poorer differentiation, and advanced TNM stage (P < 0.05). Compared to those with FAR-SIRI scores of 0, patients with scores of 2 had poorer overall survival (OS). The FAR-SIRI score was an independent prognostic factor for OS in rGC. CONCLUSION: The present data demonstrated that FAR-SIRI scores predicted radical gastric cancer surgical outcomes and may serve as a blood marker for identifying high-risk patients.

Transcriptional analysis of renal dopamine-mediated Na+ homeostasis response to environmental salinity stress in Scatophagus argus.

BACKGROUND: To control the osmotic pressure in the body, physiological adjustments to salinity fluctuations require the fish to regulate body fluid homeostasis in relation to environmental change via osmoregulation. Previous studies related to osmoregulation were focused primarily on the gill; however, little is known about another organ involved in osmoregulation, the kidney. The salinity adaptation of marine fish involves complex physiological traits, metabolic pathways and molecular and gene networks in osmoregulatory organs. To further explore of the salinity adaptation of marine fish with regard to the role of the kidney, the euryhaline fish Scatophagus argus was employed in the present study. Renal expression profiles of S. argus at different salinity levels were characterized using RNA-sequencing, and an integrated approach of combining molecular tools with physiological and biochemical techniques was utilized to reveal renal osmoregulatory mechanisms in vivo and in vitro. RESULTS: S. argus renal transcriptomes from the hyposaline stress (0‰, freshwater [FW]), hypersaline stress (50‰, hypersaline water [HW]) and control groups (25‰) were compared to elucidate potential osmoregulatory mechanisms. In total, 19,012 and 36,253 differentially expressed genes (DEGs) were obtained from the FW and HW groups, respectively. Based on the functional classification of DEGs, the renal dopamine system-induced Na+ transport was demonstrated to play a fundamental role in osmoregulation. In addition, for the first time in fish, many candidate genes associated with the dopamine system were identified. Furthermore, changes in environmental salinity affected renal dopamine release/reuptake by regulating the expression of genes related to dopamine reuptake (dat and nkaα1), vesicular traffic-mediated dopamine release (pink1, lrrk2, ace and apn), DAT phosphorylation (CaMKIIα and pkcß) and internalization (akt1). The associated transcriptional regulation ensured appropriate extracellular dopamine abundance in the S. argus kidney, and fluctuations in extracellular dopamine produced a direct influence on Na+/K+-ATPase (NKA) expression and activity, which is associated with Na+ homeostasis. CONCLUSIONS: These transcriptomic data provided insight into the molecular basis of renal osmoregulation in S. argus. Significantly, the results of this study revealed the mechanism of renal dopamine system-induced Na+ transport is essential in fish osmoregulation.

Aquaporin-3 Attenuates Oxidative Stress-Induced Nucleus Pulposus Cell Apoptosis Through Regulating the P38 MAPK Pathway.

BACKGROUND/AIMS: Previous studies have shown that oxidative damage is a main contributor to disc nucleus pulposus (NP) cell apoptosis. Aquaporin-3 (AQP-3) facilitates reactive oxygen species (ROS) scavenging and thus alleviates oxidative injury in other cells. This study aims to investigate the role and mechanism of AQP-3 in regulating NP cell apoptosis under oxidative damage. METHODS: Rat NP cells were treated with H2O2 for 48 hours, while control NP cells were free of H2O2. Recombinant AQP-3 lentiviral vectors were used to investigate the effect of enhanced AQP-3 expression levels in NP cells. NP cell apoptosis was assessed by flow cytometry, caspase-3 activity, gene expression of apoptosis-related molecules (Bax, Bcl-2 and caspase-3), and protein expression of cellular apoptosis markers (cleaved PARP and cleaved caspase-3). Additionally, intracellular ROS content and activity of the p38 MAPK pathway were evaluated. RESULTS: Compared with the control NP cells, oxidative damage in the treatment cells significantly increased cell apoptosis ratios and caspase-3 activity, upregulated gene expression of Bax and caspase-3, downregulated gene expression of Bcl-2, and increased protein expression of cleaved PARP and cleaved caspase-3, as well as increased intracellular ROS content and activity of the p38 MAPK pathway. However, AQP-3 overexpression partly alleviated cell apoptosis, decreased intracellular ROS content, and inhibited the p38 MAPK pathway in NP cells under oxidative damage. CONCLUSION: Oxidative damage can significantly downregulate AQP-3 expression. Enhancing AQP-3 expression in NP cells partly attenuates cellular apoptosis through regulating the p38 MAPK pathway under oxidative damage.

N-Cadherin Attenuates High Glucose-Induced Nucleus Pulposus Cell Senescence Through Regulation of the ROS/NF-κB Pathway.

BACKGROUND/AIMS: Diabetes mellitus (DM) is a potential etiology of disc degeneration. N-cadherin (N-CDH) helps maintain the cell viability, cell phenotype and matrix biosynthesis of nucleus pulposus (NP) cells. Here, we mainly aimed to investigate whether N-CDH can attenuate high glucose-induced NP cell senescence and its potential mechanism. METHODS: Rat NP cells were cultured in a base culture medium and base culture medium with a 0.2 M glucose concentration. Recombinant lentiviral vectors were used to enhance N-CDH expression in NP cells. Senescence-associated ß-galactosidase (SA-ß-Gal) activity was measured by SA-ß-Gal staining. NP cell proliferation was evaluated by CCK-8 assay. Telomerase activity and intracellular reactive oxygen species (ROS) content were tested by specific chemical kits according to the manufacturer's instructions. G0/G1 cell cycle arrest was evaluated by flow cytometry. Real-time PCR and Western blotting were used to analyze mRNA and protein expressions of senescence markers (p16 and p53) and matrix macromolecules (aggrecan and collagen II). Additionally, p-NF-κB expression was also analyzed by Western blotting to evaluate NF-κB pathway activity. RESULTS: High glucose significantly decreased N-CDH expression, increased ROS generation and NF-κB pathway activity, and promoted NP cell senescence, which was reflected in the increase in SA-ß-Gal activity and senescence marker (p16 and p53) expression, compared to the control group. High glucose decreased telomerase activity and cell proliferation potency. However, N-CDH overexpression partially attenuated NP cell senescence, decreased ROS content and inhibited the activation of the NF-κB pathway under the high glucose condition. CONCLUSION: High glucose decreases N-CDH expression and promotes NP cell senescence. N-CDH overexpression can attenuate high glucose-induced NP cell senescence through the regulation of the ROS/ NF-κB pathway. This study suggests that N-CDH is a potential therapeutic target to slow DM-mediated disc NP degeneration.