Evaluation of tumor-educated platelet long non-coding RNAs (lncRNAs) as potential diagnostic biomarkers for colorectal cancer.

INTRODUCTION: Cancer-derived circulating components are increasingly considered as candidate sources for non-invasive diagnostic biomarkers. This study aimed to investigate the expression of tumor-educated platelet (TEP) long non-coding RNAs (lncRNAs) in colorectal cancer (CRC) patients and determine whether it could be served as a potential tool for CRC diagnosis. MATERIALS AND METHODS: Relative quantitative real-time PCR (qRT-PCR) was used to detect the expression levels of three cancer-related platelet-derived lncRNAs CCAT1, HOTTIP, and XIST in 75 CRC patients and 42 healthy controls. Quantitative data were analyzed by SPSS (IBM Corp., Armonk, NY, USA) for comparison of cancer and non-cancer individuals. The receiver operating characteristic (ROC) curve analysis was further performed to assess the diagnostic values of lncRNAs within the CRC patients. RESULTS: The expression levels of lncRNAs colon cancer associated transcript 1 (CCAT1) (P = 0.006) and HOXA transcript at the distal tip (HOTTIP) (P = 0.049), but not X-inactive specific transcript (XIST) (P = 0.12), were significantly upregulated in CRC patients compared to healthy individuals. However, there were no significant correlations between platelet lncRNAs and clinicopathological characteristics, including sex, age, tumor location, differentiation, and size (all at P > 0.05). The area under the ROC curve (AUC) of the lncRNA CCAT1 was 0.61 (sensitivity, 71%; specificity, 50%). CONCLUSION: TEP lncRNA CCAT1 is detectable in the circulation of CRC patients and could be considered as a potential diagnostic biomarker.

Associations of the Paleolithic Diet Pattern Scores and the Risk of Breast Cancer among Adults: A Case-Control Study.

Evidence suggests the role of changing traditional lifestyle patterns such as Paleolithic to modern lifestyle in the incidence and epidemic of chronic diseases. Thus, this study aimed to investigate the association between Paleolithic diet (PD) and risk of Breast Cancer (BC) in adult Iranian women. This matched case-control study included 253 women with BC and 267 healthy women aged >18 years. PD score was evaluated using a validated 168-item quantitative food frequency questionnaire. Conditional logistic regression model was used to estimate odds ratios (ORs) and 95% confidence intervals (95%CIs), and dose-response was investigated. Mean of PD score was 39.00 ± 6.39. Among the food groups of the PD components, BC patients significantly had lower consumption of healthy food groups as vegetables, fruits, fish, and nuts, higher intakes of sugar-sweetened beverages as well as grains and starches. After adjustment for potential confounders, comparing the highest quartile of PD scores with the lowest quartile, a decrease in the risk of BC was observed for all women (OR: 0.26; 95% CI: 0.13-0.53), as well as those premenopausal (OR: 0.29; 95% CI: 0.11), and postmenopausal (OR: 0.17; 95% CI: 0.05 - 0.56). Our findings show that adherence to the PD pattern significantly reduces the risk of BC in the population studied. However, prospective studies are needed to further investigate this association.

Adherence to Oxidative Balance Scores is Associated with a Reduced Risk of Breast Cancer; A Case-Control Study.

We aimed to examine whether anthropometric indices, dietary factors, and nutrient intakes of women with and without breast cancer (BrCa) are associated with the oxidative balance score (OBS). This case-control study was carried out among 253 patients with BrCa and 267 healthy subjects aged >18 years. The OBS was calculated by using the following 13 dietary and non-dietary anti- and prooxidant components: dietary antioxidants (selenium, fiber, ß-carotene, vitamin D, vitamin C, vitamin E, and folate), dietary prooxidants (iron and saturated and polyunsaturated fatty acids), and nondietary anti- (physical activity) and prooxidants (smoking and obesity). The binary logistic regression was used to determine the association OBS with BrCa. After adjusting for potential confounders in the final model, there was evidence that the odds of BrCa decreased with increasing categories of the OBS (OR = 0.53, 95% CI 0.28 - 0.98; P-trend = 0.021). When we made stratified analysis by menopausal status, OBS was inversely associated with odds of BrCa in premenopausal women after adjusting for potential confounders. No significant association was found between OBS and odds of BrCa among post-menopausal women. Our data suggest that OBS scores were associated with decreased BrCa risk in the overall population.

Adherence to Lifelines Diet Score (LLDS) Is Associated with a Reduced Risk of Breast Cancer (BrCa): A Case-Control Study.

Background: Previous evidence suggests a link between diet quality and breast cancer (BrCa); however, the link between the Lifelines Diet Score (LLDS)-a fully food-based score that uses the 2015 Dutch Dietary Guidelines-and risk of BrCa has not yet been evaluated. Therefore, the aim of this study was to observe the relationship between adherence to an LLDS and risk of BrCa in Iranian adults. Methods: In the hospital-based case-control study, 253 patients with BrCa and 267 non-BrCa controls were enrolled. Individual's food consumption was recorded to calculate LLDS using a semiquantitative food frequency questionnaire. In adjusted models, the association between the inflammatory potential of the diet and the risk of BrCa was estimated by using binary logistic regression. Results: Compared with control individuals, BrCa patients significantly had higher waist circumference (WC), first pregnancy age, abortion history, and number of children. In addition, the mean intake of vitamin D supplements and anti-inflammatory drugs in the case group was significantly lower than the control group. Furthermore, after adjusted potential confounders, individuals in the highest vs. lowest quartiles of LLDS showed statistically significant lower risk of BrCa in overall population (OR: 0.21; 95% CI: 0.11-0.43; P trend <0.001), premenopausal (OR: 0.26; 95% CI: 0.10-0.68; P trend = 0.003), and post-menopausal women (OR: 0.20; 95% CI: 0.06-0.60; P trend = 0.015). Conclusion: Findings of this study reflected that higher LLDS decreased risk of BrCa, but need further investigation in later studies.

Trends in insulin-like growth factor-1 levels after bariatric surgery: a systematic review and meta-analysis.

According to studies, there are many inconsistencies in how IGF-1 levels change after bariatric surgery compared to before surgery, as well as its effects. These discrepancies can be attributed to various factors such as age, body mass index (BMI), and duration of intervention. Therefore, the aim of this study was to evaluate the level of insulin-like growth factor-1 (IGF-1) after bariatric surgery. A systematic review and meta-analysis based on the PRISMA guidelines was conducted from inception until 2021. From 1871 articles initially selected, 24 studies with 28 treatment arms met the eligible criteria and were included. Pooled findings from the random-effects model indicated that IGF-1 levels increased significantly [weighted mean difference (WMD) = 8.84 ng/ml; 95% confidence interval (CI) 0.30-17.39; p = 0.043] after bariatric surgery compared to before surgery. No significant heterogeneity was noted among the studies (Cochran Q test, p = 0.90, I2 = 0.0%). In subgroup analysis, bariatric surgery significantly increased IGF-1 levels at age <40 years but not at age ≤40 years. Bariatric surgery is capable of increasing the IGF-1 levels compared to the period prior to surgery but with a modest clinical magnitude.

Carbamylated erythropoietin improves recognition memory by modulating microglia in a rat model of pain.

Patients with chronic pain often complain about memory impairments. Experimental studies have shown neuroprotective effects of Carbamylated erythropoietin (Cepo-Fc) in the treatment of cognitive dysfunctions. However, little is currently known about its precise molecular mechanisms in a model of inflammatory pain. Therefore, this study aimed to investigate neuroprotective effects of Cepo-Fc against cognitive impairment induced by the inflammatory model of Complete Freund's Adjuvant (CFA). Carbamylated erythropoietin was administrated Intraperitoneally (i.p) on the day CFA injection, continued for a 21-days period. After conducting the behavioral tests (thermal hyperalgesia and novel object recognition test), western blot and ELISA were further preformed on days 0, 7, and 21. The results of this study indicate that Cepo-Fc can effectively reverse the CFA induced thermal hyperalgesia and recognition memory impairment. Additionally, Cepo-Fc noticeably decreased the hippocampal microglial expression, production of hippocampal IL-1ß, and hippocampal apoptosis and necroptosis induced by the inflammatory pain. Therefore, our findings suggest that neuroprotective effects of Cepo-Fc in the treatment of pain related recognition memory impairment may be mediated through reducing hippocampal microglial expression as well as IL-1ß production.

Retraction notice to "Noopept; a nootropic dipeptide, modulates persistent inflammation by effecting spinal microglia dependent Brain Derived Neurotropic Factor (BDNF) and pro-BDNF expression throughout apoptotic process" [Heliyon (2021) e06219].

[This retracts the article DOI: 10.1016/j.heliyon.2021.e06219.].

Noopept; a nootropic dipeptide, modulates persistent inflammation by effecting spinal microglia dependent Brain Derived Neurotropic Factor (BDNF) and pro-BDNF expression throughout apoptotic process.

There are largely unknown associations between changes in pain behavior responses during persistent peripheral inflammation and spinal cell alteration such as apoptosis. Some evidence suggests that microglia and microglia related mediators play notable roles in induction and maintenance of central nervous system pathologies and inflammatory pain. By considering those relationships and microglia related nootrophic factors, such as the Brain Derived Neurotrophic Factor (BDNF) in CNS, we attempted to assess the relationship between microglia dependent BDNF and its precursor with pain behavior through spinal cell apoptosis as well as the effect of Noopept on this relationship. Persistent peripheral inflammation was induced by a single subcutaneous injection of Complete Freund's Adjuvant (CFA) on day 0. Thermal hyperalgesia, paw edema, microglial activity, microglia dependent BDNF, pro-BDNF expression, and apoptosis were assessed in different experimental groups by confirmed behavioral and molecular methods on days 0, 7, and 21 of the study. Our findings revealed hyperalgesia and spinal cell apoptosis significantly increased during the acute phase of CFA-induced inflammation but was then followed by a decrement in the chronic phase of the study. Aligned with these variations in spinal microglial activity, microglia dependent BDNF significantly increased during the acute phase of CFA-induced inflammation. Our results also indicated that daily administration of Noopept (during 21 days of the study) not only caused a significant decrease in hyperalgesia and microglia dependent BDNF expression but also changed the apoptosis process in relation to microglia activity alteration. It appears that the administration of Noopept can decrease spinal cell apoptosis and hyperalgesia during CFA-induced inflammation due to its direct effects on microglial activity and microglia dependent BDNF and pro-BDNF expression.

Maternal sciatic nerve administered bupivacaine induces hippocampal cell apoptosis in offspring.

BACKGROUND: Bupivacaine, an amid-type local anesthetic, is widely used for clinical patients especially in pregnant women. In addition to neurotoxicity effect of bupivacaine, it can cross the placenta, accumulates in this tissue and retained in fetal tissues. Nevertheless, whether bupivacaine can cause neurotoxicity in fetus remains unclear. Hence, this study was design to investigate the effects of maternal bupivacaine use on fetus hippocampal cell apoptosis and the possible related mechanism. METHODS: On day 15 of pregnancy, sciatic nerve of pregnant wistar rat (180-200 g) were exposed by lateral incision of the right thigh and 0.2 ml of bupivacaine was injected. After their delivery, we randomly selected one male offspring of every mother. On day 30 after of their birth, the rat's hippocampi were isolated for molecular studies. Western blotting was used to examine the expression of cleaved caspase-3, caspase-8 and p-Akt in fetal hippocampus. RESULTS: Our results showed that maternal bupivacaine use caused a significant increment of cleaved caspase-3 and caspase-8 expression in fetal hippocampus compared with the sham group. In addition, maternally administered bupivacaine could significantly decrease hippocampal P.Akt/T.Akt ratio which was concurrent with an increment of cleaved caspase-3 and caspase-8 expression. CONCLUSION: Our data suggest that maternal bupivacaine use increases fetal hippocampal cell apoptosis markers such as caspase 8 and cleaved caspase 3, at least in part, via inhibiting the Akt activation.

Microglia dependent BDNF and proBDNF can impair spatial memory performance during persistent inflammatory pain.

Inflammatory pain is commonly associated with cognitive impairment. However, its molecular mechanisms are poorly understood. Thus, this study was conducted to investigate the molecular mechanisms of behavioral changes associated with inflammatory pain. Briefly, 36 Wistar rats were randomly divided into two main groups: CFA group treated with 100 µL of Complete Freunds' Adjuvant (CFA) and CFA + Minocycline group treated with 100 µL of CFA+40 mg/kg/day of minocycline). After that, each group was divided into three subgroups based on different time points of the study. The pain was induced using CFA and subsequent behavioral changes (i.e., hyperalgesia and learning and spatial memory) were analyzed by the Morris Water Maze (MWM) task and Radiant Heat. Then, the cellular and molecular changes were assessed using Western Blotting, Immunohistochemistry, and Terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) techniques. Results of the study indicated that CFA-induced pain impaired spatial learning and memory functions. Studying the cellular changes showed that persistent inflammatory pain increased the microglial activity in CA1 and Dentate Gyrus (DG) regions. Furthermore, an increase was observed in the percentage of TUNEL-positive cells. Also, pro-Brain-Derived Neurotrophic Factor (BDNF)/BDNF ratio, Caspase3, and Receptor-Interacting Protein kinase 3 (RIP3) levels increased in the rats' hippocampus following induction of persistent inflammatory pain. These changes were reversed following the cessation of pain as well as the injection of minocycline. Taking together, the results of the current study for the first time revealed that an increase in the microglia dependent proBDNF/BDNF ratio following persistent inflammatory pain leads to cell death of the CA1 and DG neurons that subsequently causes a cognitive deficit in the learning and spatial memory functions.

Microglial-induced apoptosis is potentially responsible for hyperalgesia variations during CFA-induced inflammation.

AIMS: Activated microglia is known as a main mediator of inflammatory pain, but the possible mechanisms of its operation are poorly understood. Microglial cells have considered as one of the main sources of pro-inflammatory cytokines in the CNS. PTEN is one of the important targets of pro-inflammatory cytokines and the main mediator of apoptotic cell death. In this study, we investigated the possible effect of microglial activation on PTEN/PI3K/Akt signaling pathway and apoptosis in an inflammatory rat model of Complete Freund's adjuvant (CFA). METHODS: Persistent peripheral inflammation was induced by a subcutaneous injection of CFA into the rats' right hind paw on day 0. Minocycline (a potent selective inhibitor of microglial) was administered intraperitoneally during days 1-21 after CFA injection. Hyperalgesia was assessed on days 0, 7, and 21 using plantar test, then lumbar spinal cord segments were isolated, and the amount of spinal Iba1 (microglial marker), PTEN, P.Akt, and cleaved caspase-3 (a marker of apoptosis activation) were analyzed using Western blot. The spinal TNF-α levels were assayed by ELISA and the microglia numbers were determined using immunohistochemical technique. RESULTS: Results revealed that increased hyperalgesia was concurrent with an increment of Iba1 (P < 0.001), TNF-α (P < 0.001), PTEN (P < 0.01), cleaved caspase-3 (P < 0.001), and a decrement of P.Akt (P < 0.01) during the acute phase of CFA-induced inflammation, while, at the same time as decreasing hyperalgesia during the chronic phase of study, Iba1 and TNF-α expression significantly decreased and PTEN, cleaved caspase-3, and P.Akt restored to baseline on day 0. Minocycline administration reduced the elevation of spinal Iba1 (P < 0.001), TNF-α (0.001), PTEN (P < 0.01), and cleaved caspase-3 (P < 0.001) expression induced by CFA injection, and also restored Akt activity to the baseline on day 0 (P < 0.001). CONCLUSIONS: These results suggest that microglial-mediated pain following CFA injection might be related in part to increased spinal cell apoptosis which probably is mediated by PTEN/PI3K/Akt deregulation.

Alterations in nitric oxide synthase-expressing neurons in the forebrain regions of rats after developmental exposure to organophosphates.

Several mechanisms have been addressed as contributors to the long lasting behavioral deficits after developmental exposure to organophosphate (OP) compounds. Here, the effects of developmental exposure to two common OP insecticides, chlorpyrifos (CPF) and diazinon (DZN), on nitric oxide synthase (NOS)-expressing neurons in the rat forebrain are reported. A daily dose of 1mg/kg of either CPF or DZN was administered to rats during gestational days 15-18 or postnatal days (PND) 1-4. We then assessed NADPH-diaphorase and neuronal NOS (nNOS) immunohistochemistry in forebrain sections on different postnatal days. Prenatal exposure to CPF and DZN induced a transient reduction of NADPH-d(+)/nNOS-immunoreactive (IR) neurons in most cortical regions on PND 4 but exceptionally increased them in the entorhinal/piriform cortex. On PND 15, NADPH-d(+)/nNOS-IR neurons showed morphological abnormalities within entorhinal/piriform cortex of the rats that gestationally exposed to CPF. Postnatal exposure to CPF and DZN did not induce widespread effects on the number of NADPH-d(+)/nNOS-IR neurons on PNDs 7 and 15 but significantly reduced them in most cortical regions and hippocampal subfields on PND 60. The OPs affected NADPH-d(+)/nNOS-IR neurons in a sex independent manner and apparently spared them in the striatum. While the NADPH-d reactivity of microvessels was normally diminished by age, OP treated rats evidently preserved the NADPH-d reactivity of microvessels in the cerebral cortex and hippocampus. The effects of OPs on NADPH-d(+)/nNOS-IR neurons may contribute to the long-lasting behavioral outcomes and expand the neurotransmitter system that need to be considered in OP neurotoxicity evaluations.

Developmental exposure to chlorpyrifos and diazinon differentially affect passive avoidance performance and nitric oxide synthase-containing neurons in the basolateral complex of the amygdala.

Chronic exposure to low doses of organophosphates during brain development can induce persistent neurochemical and behavioral effects. This study sought to determine the long-lasting effects of developmental exposure to chlorpyrifos (CPF) and diazinon (DZN) on passive avoidance (PA) performance and neuronal nitric oxide synthase (nNOS)-containing neurons in the subnuclei within basolateral complex of amygdala (BLC). Developing rats were exposed to daily dose (1mg/kg) of CPF or DZN during gestational days 15-18 and postnatal days (PND) 1-4. PA performance was assessed in young adulthood (PND 60). Brain sections were also processed by NADPH-diaphorase (NADPH-d) and nNOS immunohistochemistry. Gestational exposure to CPF increased NADPH-d(+)/nNOS-immunoreactive (IR) neurons within the basolateral nucleus (BL) and medial paracapsular intercalated cluster, which was along with PA retention impairment in both male and female rats. Prenatal exposure to DZN did not significantly change the number of NADPH-d(+)/nNOS-IR neurons in the BLC while impaired PA retention in females. Postnatal exposure to CPF decreased NADPH-d(+)/NOS-IR neurons in the BL without affecting PA performance. Exposure to DZN during early postnatal period impaired PA retention in both sexes, albeit to a lesser extent in females, and was along with a considerable sex independent reduction of NADPH-d(+)/NOS-IR neurons in all BLC subnuclei. Our data suggest that developmental exposure to apparently subtoxic dose of CPF and DZN elicit long-lasting impairment in PA retention that are associated, but not necessarily correlated with effects on NADPH-d(+)/NOS-IR neurons in BLC of the amygdala.