gCTRP3 inhibits oophorectomy­induced osteoporosis by activating the AMPK/SIRT1/Nrf2 signaling pathway in mice.

C1q/tumor necrosis factor­related protein 3 (CTRP3) expression is markedly reduced in the serum of patients with osteoporosis. The present study aimed to investigate whether CTRP3 reduces bone loss in oophorectomy (OVX)­induced mice via the AMP­activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/nuclear factor E2­related factor 2 (Nrf2) signaling pathway. Female C57BL/6J mice and MC3T3­E1 cells were used to construct in vivo and in vitro models of osteoporosis, respectively. The left femurs of mice were examined using micro­computed tomography scans and bone­related quantitative morphological evaluation was performed. Pathological changes and the number of osteoclasts in the left femurs of mice were detected using hematoxylin and eosin, and tartrate­resistant acid phosphatase (TRAP) staining. Runt­related transcription factor­2 (RUNX2) expression in the left femurs was detected using immunofluorescence analysis, and the serum levels of bone resorption markers (C­telopeptide of type I collagen and TRAP) and bone formation markers [osteocalcin (OCN) and procollagen type 1 N­terminal propeptide] were detected. In addition, osteoblast differentiation and calcium deposits were examined in MC3T3­E1 cells using alkaline phosphatase (ALP) and Alizarin red staining, respectively. Moreover, RUNX2, ALP and OCN expression levels were detected using reverse transcription­quantitative PCR, and the expression levels of proteins associated with the AMPK/SIRT1/Nrf2 signaling pathway were detected using western blot analysis. The results revealed that globular CTRP3 (gCTRP3) alleviated bone loss and promoted bone formation in OVX­induced mice. gCTRP3 also facilitated the osteogenic differentiation of MC3T3­E1 cells through the AMPK/SIRT1/Nrf2 signaling pathway. The addition of an AMPK inhibitor (Compound C), SIRT1 inhibitor (EX527) or Nrf2 inhibitor (ML385) reduced the osteogenic differentiation of MC3T3­E1 cells via inhibition of gCTRP3. In conclusion, gCTRP3 inhibits OVX­induced osteoporosis by activating the AMPK/SIRT1/Nrf2 signaling pathway.

Association of Overweight and Inflammatory Indicators with Breast Cancer: A Cross-Sectional Study in Chinese Women.

Objective: This cross-sectional study aimed to explore the association of overweight and inflammatory indicators with breast cancer risk in Chinese patients. Methods: Weight, height, and peripheral blood inflammatory indicators, including white blood cell count (WBC), neutrophil count (NE), lymphocyte count (LY), platelet count (PLT) and the concentration of hypersensitivity C-reactive protein (hsCRP), were collected in 383 patients with benign breast lumps (non-cancer) and 358 patients with malignant breast tumors (cancer) at the First Affiliated Hospital of Soochow University, China, from March 2018 to July 2020. Body mass index (BMI), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) were determined according to the ratio equation. The correlations among overweight, inflammatory indicators, and the proportion of non-cancer or cancer cases were analyzed. Results: BMI is associated with an increased breast cancer risk. Compared with non-cancer patients, the average WBC count, NE count, NLR, and level of hsCRP were significantly higher in cancer patients. The level of hsCRP was closely associated with the size of malignant breast tumors. Conclusion: We conclude that overweight and high levels of hsCRP may serve as putative risk factors for malignant breast tumors in Chinese women.

Palmitoylation of KSHV pORF55 is required for Golgi localization and efficient progeny virion production.

Kaposi's sarcoma-associated herpesvirus (KSHV) is a double-stranded DNA virus etiologically associated with multiple malignancies. Both latency and sporadic lytic reactivation contribute to KSHV-associated malignancies, however, the specific roles of many KSHV lytic gene products in KSHV replication remain elusive. In this study, we report that ablation of ORF55, a late gene encoding a tegument protein, does not impact KSHV lytic reactivation but significantly reduces the production of progeny virions. We found that cysteine 10 and 11 (C10 and C11) of pORF55 are palmitoylated, and the palmytoilation is essential for its Golgi localization and secondary envelope formation. Palmitoylation-defective pORF55 mutants are unstable and undergo proteasomal degradation. Notably, introduction of a putative Golgi localization sequence to these palmitoylation-defective pORF55 mutants restores Golgi localization and fully reinstates KSHV progeny virion production. Together, our study provides new insight into the critical role of pORF55 palmitoylation in KSHV progeny virion production and offers potential therapeutic targets for the treatment of related malignancies.

Non-canonical regulation of the reactivation of an oncogenic herpesvirus by the OTUD4-USP7 deubiquitinases.

Deubiquitinases (DUBs) remove ubiquitin from substrates and play crucial roles in diverse biological processes. However, our understanding of deubiquitination in viral replication remains limited. Employing an oncogenic human herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) to probe the role of protein deubiquitination, we found that Ovarian tumor family deubiquitinase 4 (OTUD4) promotes KSHV reactivation. OTUD4 interacts with the replication and transcription activator (K-RTA), a key transcription factor that controls KSHV reactivation, and enhances K-RTA stability by promoting its deubiquitination. Notably, the DUB activity of OTUD4 is not required for K-RTA stabilization; instead, OTUD4 functions as an adaptor protein to recruit another DUB, USP7, to deubiquitinate K-RTA and facilitate KSHV lytic reactivation. Our study has revealed a novel mechanism whereby KSHV hijacks OTUD4-USP7 deubiquitinases to promote lytic reactivation, which could be potentially harnessed for the development of new antiviral therapies.

Hypophysitis Induced by Sintilimab in the Treatment of Bladder Cancer: A Case Report.

BACKGROUND: Immune checkpoint inhibitors (ICIs), as novel antitumor drugs, have been widely used in the clinic and have shown good antitumor effects. However, their widespread use has also led to the emergence of various immune-related adverse events (IrAEs). Hypophysitis is a rare but serious IrAE. Due to its complex and changeable clinical manifestations, hypophysitis may be easily overlooked, leading to delayed diagnosis and treatment. CASE PRESENTATION: A 68-year-old male patient was diagnosed with bladder cancer (T2bNXM0) in October 2021. He received two cycles of immunotherapy with sintilimab and chemotherapy with gemcitabine and cisplatin (GC). One month after the second treatment, he gradually developed recurrent fever, anorexia, drowsiness, and delirium. Laboratory examination revealed hyponatremia, decreased adrenocorticotropic hormone, and hypocortisolemia. The pituitary MRI showed no abnormality. The patient was diagnosed with immunotherapy-induced hypophysitis (IH) caused by sintilimab, leading to downstream endocrine disorders. With hormone replacement therapy, he was in a good mood, had a good appetite, and made an overall recovery. CONCLUSION: Immunotherapy-induced hypophysitis (IH) can result in a severe adrenal crisis, and prompt recognition and diagnosis are crucial. Clinicians must remain vigilant for the possibility of IH in patients who exhibit recurrent fever, anorexia, cognitive decline, and personality changes following ICI treatment. It is imperative to consider this diagnosis early to initiate appropriate management promptly.

STING is a cell-intrinsic metabolic checkpoint restricting aerobic glycolysis by targeting HK2.

Evasion of antitumour immunity is a hallmark of cancer. STING, a putative innate immune signalling adaptor, has a pivotal role in mounting antitumour immunity by coordinating innate sensing and adaptive immune surveillance in myeloid cells. STING is markedly silenced in various human malignancies and acts as a cell-intrinsic tumour suppressor. How STING exerts intrinsic antitumour activity remains unclear. Here, we report that STING restricts aerobic glycolysis independent of its innate immune function. Mechanistically, STING targets hexokinase II (HK2) to block its hexokinase activity. As such, STING inhibits HK2 to restrict tumour aerobic glycolysis and promote antitumour immunity in vivo. In human colorectal carcinoma samples, lactate, which can be used as a surrogate for aerobic glycolysis, is negatively correlated with STING expression level and antitumour immunity. Taken together, this study reveals that STING functions as a cell-intrinsic metabolic checkpoint that restricts aerobic glycolysis to promote antitumour immunity. These findings have important implications for the development of STING-based therapeutic modalities to improve antitumour immunotherapy.

Genome-Wide CRISPR-Cas9 Screen Identifies SMCHD1 as a Restriction Factor for Herpesviruses.

Intrinsic immunity is the frontline of host defense against invading pathogens. To combat viral infection, mammalian hosts deploy cell-intrinsic effectors to block viral replication prior to the onset of innate and adaptive immunity. In this study, SMCHD1 is identified as a pivotal cellular factor that restricts Kaposi's sarcoma-associated herpesvirus (KSHV) lytic reactivation through a genome-wide CRISPR-Cas9 knockout screen. Genome-wide chromatin profiling revealed that SMCHD1 associates with the KSHV genome, most prominently the origin of lytic DNA replication (ORI-Lyt). SMCHD1 mutants defective in DNA binding could not bind ORI-Lyt and failed to restrict KSHV lytic replication. Moreover, SMCHD1 functioned as a pan-herpesvirus restriction factor that potently suppressed a wide range of herpesviruses, including alpha, beta, and gamma subfamilies. SMCHD1 deficiency facilitated the replication of a murine herpesvirus in vivo. These findings uncovered SMCHD1 as a restriction factor against herpesviruses, and this could be harnessed for the development of antiviral therapies to limit viral infection. IMPORTANCE Intrinsic immunity represents the frontline of host defense against invading pathogens. However, our understanding of cell-intrinsic antiviral effectors remains limited. In this study, we identified SMCHD1 as a cell-intrinsic restriction factor that controlled KSHV lytic reactivation. Moreover, SMCHD1 restricted the replication of a wide range of herpesviruses by targeting the origins of viral DNA replication (ORIs), and SMCHD1 deficiency facilitated the replication of a murine herpesvirus in vivo. This study helps us to better understand intrinsic antiviral immunity, which may be harnessed to develop new therapeutics for the treatment of herpesvirus infection and the related diseases.

Preparation of esterified biomass waste hydrogels and their removal of Pb2+, Cu2+ and Cd2+ from aqueous solution.

The treatment of polluted water is a serious environmental problem in the world. Biomass is easily modified and can be prepared into adsorbent materials, which is expected to solve the problem of heavy metal ion adsorption in sewage. In this paper, esterified tobacco straw based hydrogels (ETS-PAA) were synthesized from waste tobacco straw biomass. The structure and thermal stability of these hydrogels were characterized by FTIR, SEM, EDS, XPS and TG. The adsorption of metal ions by the hydrogel was measured by ICP-MS. The effects of initial ion concentration, adsorption time, pH, and temperature on the heavy metal adsorption were investigated. The results showed that ETS-PAA possessed more pores, which led to a better adsorption capacity. The maximum adsorption amounts of Pb2+, Cu2+ and Cd2+ were 2.41 mmol·g-1, 1.93 mmol·g-1 and 1.77 mmol·g-1, respectively. Finally, the adsorption mechanism and kinetics were analyzed. The adsorption was mainly accomplished by ion exchange of -COOK on the monomer chain with heavy metal ions, coordination of -OH and -CONH with heavy metal ions and interaction of ester bond, -COOH with heavy metal ions. The adsorption process was in accordance with the pseudo-second-order kinetic model and Freundlich model. The adsorption process belonged to multilayer chemisorption. This work shows that ETS-PAA was a promising material for the removal of heavy metal pollutants from aqueous solution.

Association of metformin exposure with low risks of frailty and adverse outcomes in patients with diabetes.

BACKGROUND: Diabetes is an independent risk factor of frailty, which increases adverse outcomes in patients with diabetes. Metformin is a common antidiabetic drug in clinical practice. Insulin resistance and chronic inflammation are the two common mechanisms of diabetes and frailty, as well as the main targets of metformin. Research suggested that metformin has anti-aging potential. However, few studies focus on the relationship between metformin and frailty. Thus, we aimed to explore whether metformin was associated with a low risk of frailty and other adverse outcomes in diabetic patients. METHODS: A total of 422 patients (≥ 40 years old) with type 2 diabetes were recruited. Frailty was defined by the Fried phenotype. General information and metformin exposure data were collected, and comprehensive geriatric assessment and laboratory tests were performed. Follow-up was conducted after 4.5 years. The primary outcome was the combined endpoint of cardiovascular events, cerebrovascular events, readmission, and death. Binary logistic regression analysis was used to analyze the association of metformin with frailty. Survival analysis was performed using Cox proportional hazards models. RESULTS: The total prevalence of frailty was 19.4% among the participants with diabetes. 13.1% of patients in the metformin group and 28.2% in the non-metformin group had frailty. Metformin was inversely associated with frailty after adjusting for age, sex, duration, blood glucose levels, target organ damage, comorbidities, and polypharmacy. Further longitudinal analysis showed that metformin was also independently associated with a low risk of combined primary outcomes after adjusting for multiple covariables, while frailty was related to an increased risk of the combined primary outcomes. In the non-frail group, metformin was associated with a decreased risk of combined primary outcomes after adjustment for age and sex. However, the protective effect of metformin on adverse outcomes was not found in frail participants with diabetes. CONCLUSIONS: Metformin use is associated with a reduced risk of frailty. In addition, frailty may attenuate the protective effects of metformin on adverse outcomes in diabetic patients. The early identification and prevention of frailty progression may help enhance the benefits of metformin in patients with diabetes.

Preparation of biomass-based hydrogels and their efficient heavy metal removal from aqueous solution.

In this work, a porous tobacco straw-based polyacrylic acid hydrogel STS-PAA with high adsorption performance was prepared by polymerizing pretreated waste tobacco straw (TS) with acrylic acid/potassium acrylate by UV radiation initiation. The adsorption performance of metal ions was investigated. The effects of different temperatures (25°C, 35°C, and 45°C), adsorption times (1-420 min), pH values (2.0-6.0) and initial concentrations (0.25-4.0 mmol L-1) of metal ions on the adsorption amount of heavy metal ions were investigated. The results showed that the hydrogel had a high removal rate of Pb2+, Cd2+ and Hg2+ in aqueous solution. The adsorption of Pb2+ was particularly effective. When C0 = 4.0 mmol L-1, pH = 6, the equilibrium adsorption amount of Pb2+, Cd2+ and Hg2+ reached 1.49 mmol g-1, 1.02 mmol L-1 and 0.94 mmol g-1, respectively. The chemical structure and morphology of the hydrogels were characterized by FT-IR, EDS, SEM and XPS. The Langmuir model fits well with the adsorption system. The kinetic data suggest the adsorption of Pb2+, Cd2+ and Hg2+ follow the pseudo-first-order model. This indicates that STS-PAA adsorption of three heavy metal ions is monolayer physical adsorption. Thermodynamic analysis shows that the adsorption of Pb2+, Cd2+ and Hg2+ by STS-PAA is an endothermic (ΔH>0) entropy increase (ΔS>0) non-spontaneous reaction.

Long non­coding RNA MALAT1 is involved in retinal pigment epithelial cell damage caused by high glucose treatment.

The present study aimed to explore the role of long non­coding RNA metastasis associated lung adenocarcinoma transcript 1 (lncRNA MALAT1) in high glucose (HG)­induced ARPE­19 cell damage. ARPE­19 cells were cultured and treated with HG (25 mmol/l glucose). MALAT1 expression was silenced following transfection of small interfering RNA. Cell apoptosis was measured using flow cytometry. The cellular levels of reactive oxygen species (ROS), malondialdehyde and superoxide dismutase activity were all measured to examine oxidative stress. Gene expression levels of MALAT1 were determined by reverse transcription­quantitative (RT­q)PCR, while expression of tumor necrosis factor (TNF)­α, monocyte chemotactic protein 1 (MCP­1), intercellular cell adhesion molecule 1 (ICAM­1) and vascular endothelial growth factor (VEGF) was detected using RT­qPCR and western blotting. MALAT1 expression was markedly increased in ARPE­19 cells treated with HG. HG treatment caused increased apoptosis and elevated ROS­induced stress in ARPE­19 cells and these effects could be partly attenuated by MALAT1 knockdown. Increased gene expression levels of TNF­α, MCP­1, ICAM­1 and VEGF induced by HG were also alleviated by MALAT1 inhibition. Therefore, lncRNA MALAT1 is the key factor in ARPE­19 cell damage caused by HG and may be a promising therapeutic target for clinical DR therapy. However, further studies are still required to reveal the detailed mechanisms underlying lncRNA MALAT1 function.

A review on the treatment of multiple myeloma with small molecular agents in the past five years.

Multiple myeloma is currently incurable, and the incidence rate is increasing year by year worldwide. Although in recent years the combined treatment plan based on proteasome inhibitors and immunomodulatory drugs has greatly improved the treatment effect of multiple myeloma, most patients still relapse and become resistant to current treatments. To solve this problem, scientists are committed to developing drugs with higher specificity, such as iberdomide, which is highly specific to ikaros and aiolos. This review aims to focus on the small molecular agents that are being researched/clinically used for the treatment of multiple myeloma, including the target mechanism, structure-activity relationship and application prospects of small molecular agents.

Effects of probiotics on nonalcoholic fatty liver disease: a systematic review and meta-analysis.

OBJECTIVES: Several studies have suggested that the gut-liver axis is closely related to nonalcoholic fatty liver disease (NAFLD). This study was designed to conduct a meta-analysis based on a randomized controlled trial (RCT) to systematically evaluate the efficacy of probiotics in the treatment of NAFLD. METHODS: This study carried out a literature search of published scientific data (up to April 2021) on probiotic therapies of NAFLD. The quality of the included literature was evaluated, and the corresponding data were extracted using the RevMan5.4 software. RESULTS: A total of 9 randomized clinical trials involving 352 patients with NAFLD were included in this study. Results of the meta-analysisstudy showed that probiotic therapy group have significant reduction in the levels of serum indices: alanine aminotransferase (ALT), aspartate transaminase (AST) and total cholesterol (TC) in comparison with the control group. Probiotic therapy was not associated with changes in body mass index (BMI) homeostasis model assessment of insulin resistance (HOMA-IR) and tumor necrosis factor (TNF) Subgroup analyses of BMI indicated that three or more composite probiotics or probiotic treatment for more than three months can significantly reduce the BMI level. CONCLUSION: This systematic review and meta-analysis demonstrated that modulating gut microbiota may be utilized as an effective method to improve liver function and reduce blood lipid levels in patients with NAFLD.

Angptl7 promotes insulin resistance and type 2 diabetes mellitus by multiple mechanisms including SOCS3-mediated IRS1 degradation.

Angptl7 is a secreted and circulating cytokine that belongs to Angiopoietin-like family. The current knowledge about the function of Angptl7 is still limited, and its biological role is only marginally known, such as in the promotion of angiogenesis and inflammation. Here, we demonstrated that Angptl7 promotes insulin resistance and type 2 diabetes mellitus (T2DM). We found that the circulating Angptl7 levels in T2DM patient and mouse models were significantly elevated. Artificial overexpression of Angptl7 in hepatic cells inhibited glucose uptake and impaired insulin signaling pathway. Furthermore, in vivo overexpression of Angptl7 in experimental healthy mice also caused insulin resistance-like characteristics. Mechanistic studies revealed that Angptl7 can upregulate SOCS3 expression, leading to the IRS1 degradation in proteasome. Furthermore, over-expressed Angptl7 inhibited the phosphorylation of Akt and promoted the phosphorylation of ERK1/2, which was known to be associated with insulin resistance. Taken together, our study provided strong evidence that Angptl7 promotes insulin resistance and T2DM by multiple mechanisms, which made Angptl7 a new potential therapeutic target for treatment of insulin resistance and T2DM.

Hypobaric hypoxia regulates iron metabolism in rats.

Intermittent hypobaric hypoxia can produce a protective effect on both the nervous system and non-nervous system tissues. Intermittent hypobaric hypoxia preconditioning has been shown to protect rats from cardiac ischemia-reperfusion injury by decreasing cardiac iron levels and reactive oxygen species (ROS) production, thereby decreasing oxidative stress to achieve protection. However, the specific mechanism underlying the protective effect of hypobaric hypoxia is unclear. To shed light on this phenomenon, we subjected Sprague-Dawley rats to hypobaric hypoxic preconditioning (8 hours/day). The treatment was continued for 4 weeks. We then measured the iron content in the heart, liver, spleen, and kidney. The iron levels in all of the assessed tissues decreased significantly after hypobaric hypoxia treatment, corroborating previous results that hypobaric hypoxia may produce its protective effect by decreasing ROS production by limiting the levels of catalytic iron in the tissue. We next assessed the expression levels of several proteins involved in iron metabolism (transferrin receptor, L-ferritin, and ferroportin1 [FPN1]). The increased transferrin receptor and decreased L-ferritin levels after hypobaric hypoxia were indicative of a low-iron phenotype, while FPN1 levels remained unchanged. We also examined hepcidin, transmembrane serine proteases 6 (TMPRSS6), erythroferrone (ERFE), and erythropoietin (EPO) levels, all of which play a role in the regulation of systemic iron metabolism. The expression of hepcidin decreased significantly after hypobaric hypoxia treatment, whereas the expression of TMPRSS6 and ERFE and EPO increased sharply. Finally, we measured serum iron and total iron binding capacity in the serum, as well as red blood cell count, mean corpuscular volume, hematocrit, red blood cell distribution width SD, and red blood cell distribution width CV. As expected, all of these values increased after the hypobaric hypoxia treatment. Taken together, our results show that hypobaric hypoxia can stimulate erythropoiesis, which systemically draws iron away from nonhematopoietic tissue through decreased hepcidin levels.

Iron regulatory protein 2 deficiency may correlate with insulin resistance.

Iron is known to be a crucial regulator of glucose, and several studies have demonstrated that iron overload is one of the risk factors for insulin resistance and diabetes; however, the mechanism has not yet been clarified. To investigate the effect of iron overload on glucose metabolism and the underlying mechanism, Irp2 knockout (Irp2-/-) mice (endogenous iron overload model) were used. We found that Irp2-/- mice exhibited hyperglycemia and iron overload in the liver and skeletal muscle. Increased MDA, decreased SOD levels, and increased cell apoptosis were also found in the liver and muscle of Irp2-/- mice. Glucose concentrations were significantly higher in Irp2-/- mice in insulin tolerance tests. However, early-phase insulin secretion was not altered in Irp2-/- mice. The expression of hepatic IRS2 and muscle GLUT4 was declined in Irp2-/- mice at both mRNA and protein levels when compared with those of wild-type control. In conclusions, Irp2-/- mice showed hyperglycemia, which might due to insulin resistance rather than due to impaired insulin secretion.

Efficacy, safety and influencing factors of intra-calf muscular injection of bone marrow mononuclear cells in the treatment of type 2 diabetes mellitus-induced lower extremity vascular disease.

The efficacy, safety and impact of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) associated with the intra-calf muscular injection of bone marrow mononuclear cells (BMMCs) in the treatment of type 2 diabetes mellitus (T2DM)-induced lower extremity vascular disease (LEVD) were evaluated. Patients with T2DM-LEVD were randomly divided into a control group and BMMCs group to assess the efficacy and safety of the treatment; serum VEGF and bFGF levels were detected. The BMMCs group was divided into superior genicular artery (SGA) and inferior genicular artery (IGA) subgroups as well as low-dose and high-dose subgroups for the comparison of efficacy indices. The BMMCs group exhibited significantly improved indices (P<0.05) compared with the control group and no fatalities or cancer occurred. There were no significant changes in serum VEGF and bFGF levels (P>0.05). The claudication distance in the IGA subgroup was significantly greater that in the SGA subgroup (P<0.05); the low-dose subgroup and the high-dose subgroup did not demonstrate any significant differences in each index (P>0.05). BMMC treatment for T2DM-LEVD was found to be safe and effective and had no significant impact on serum VEGF and bFGF levels in the short term; However, the degree of LEVD may affect its efficacy.

Resveratrol reverses chronic restraint stress-induced depression-like behaviour: Involvement of BDNF level, ERK phosphorylation and expression of Bcl-2 and Bax in rats.

Chronic stress occurs in everyday life and induces depression-like behaviors, associated with proteins alterations and apoptosis in brain. Resveratrol is a natural polyphenol enriched in polygonum cuspidatum and has diverse biological activities, including potent antidepressant-like effects. The aim of this study was to determine whether resveratrol administration influences chronic restraint stress (CRS) - induced depression-like behaviors and explores underlying mechanisms. Male Wistar rats were subjected to CRS protocol for a period of 3 weeks to induce depressive-like behavior. The results showed that resveratrol (80mg/kg/i.p) administrated for 3 weeks significantly reversed the CRS-induced behavioral abnormalities (reduced sucrose preference and increased immobility time) in stressed rats. CRS exposure significantly decreased BDNF levels and phosphorylation of extracellular signal-regulated kinase (pERK) in hippocampus and prefrontal cortex (PFC), accompanied by decreased Bcl-2 mRNA expression and increased Bax mRNA expression, while resveratrol treatment normalized these levels. All of these effects of resveratrol were essentially identical to that observed with fluoxetine. In conclusion, our studies showed that resveratrol exerted antidepressant-like effects in CRS rats, mediated in part by the apoptotic machinery and up-regulating BDNF and pERK levels in the brain region.

Differences and Similarities in the Clinicopathological Features of Pancreatic Neuroendocrine Tumors in China and the United States: A Multicenter Study.

The presentation, pathology, and prognosis of pancreatic neuroendocrine tumors (PNETs) in Asian patients have not been studied in large cohorts. We hypothesized that the clinicopathological features of PNETs of Chinese patients might be different from those of US patients. The objectives of this study were to address whether PNETs in Chinese patients exhibit unique clinicopathological features and natural history, and can be graded and staged using the WHO/ENETS criteria. This is a retrospective review of medical records of patients with PNETs in multiple academic medical centers in China (7) and the United States (2). Tumor grading and staging were based on WHO/ENETS criteria. The clinicopathological features of PNETs of Chinese and US patients were compared. Univariate and multivariate analyses were performed to find associations between survival and patient demographics, tumor grade and stage, and other clinicopathological characteristics. A total of 977 (527 Chinese and 450 US) patients with PNETs were studied. In general, Chinese patients were younger than US patients (median age 46 vs 56 years). In Chinese patients, insulinomas were the most common (52.2%), followed by nonfunctional tumors (39.7%), whereas the order was reversed in US patients. Tumor grade distribution was similar in the 2 countries (G1: 57.5% vs 55.0%; G2: 38.5% vs 41.3%; and G3: 4.0% vs 3.7%). However, age, primary tumor size, primary tumor location, grade, and stage of subtypes of PNETs were significantly different between the 2 countries. The Chinese nonfunctional tumors were significantly larger than US ones (median size 4 vs 3 cm) and more frequently located in the head/neck region (54.9% vs 34.8%). The Chinese and US insulinomas were similar in size (median 1.5 cm) but the Chinese insulinomas relatively more frequently located in the head/neck region (48.3% vs 26.1%). Higher grade, advanced stage, metastasis, and larger primary tumor size were significantly associated with unfavorable survival in both countries. Several clinicopathological differences are found between Chinese and US PNETs but the PNETs of both countries follow a similar natural history. The WHO tumor grading and ENETS staging criteria are applicable to both Chinese and US patients.

α-Internexin: a novel biomarker for pancreatic neuroendocrine tumor aggressiveness.

PURPOSE: We aimed to test whether α-internexin could be a molecular biomarker of tumor aggressiveness and prognosis in pancreatic neuroendocrine tumors (PNETs). PATIENTS AND METHODS: Using immunohistochemical staining and Western blot, we detected the expression of α-internexin in 350 tumors from 343 patients, of whom 257 were followed up. Methylation of α-internexin promoter was examined by bisulfite sequencing to identify the crucial region that determines gene expression. Methylation of gene promoter in tumors was quantitatively measured by denaturing high performance liquid chromatography (DHPLC). We correlated α-internexin expression with clinicopathological characteristics. RESULTS: α-Internexin was expressed in 53% of 350 PNETs. The reduced expression of α-internexin was significantly associated with advanced stage (P < .0001), metastases (P < .0001), and recurrence (P = .003). α-Internexin expression was found in 57.1% of 212 surviving patients and in 17.1% of 35 deceased patients (P < .0001). Reduced expression of α-internexin was associated with shorter overall survival in PNET patients (log rank P < .0001) as well as in patients with noninsulinoma and nonfunctional (NF)-PNETs (log rank P = 0.0073 and P = 0.010, respectively). The crucial region of α-internexin promoter (-149 to +96 nucleotides [nt]) was identified, and the hypomethylation of this area in PNETs was significantly associated with gene expression (P = .015). CONCLUSION: α-Internexin can be a useful prognostic biomarker for PNETs.