The role and mechanism of TGF-ß1 in the antidepressant-like effects of tetrahydrocurcumin.

Astrocytes and the activation of inflammatory factors are associated with depression. Tetrahydrocurcumin (THC), the principal metabolite of natural curcumin, is renowned for its anti-inflammatory properties. In this research, we explored the impact of THC on the expression of inflammatory factors, neurotrophins, and transforming growth factor ß1 (TGF-ß1) in the prefrontal cortex after chronic restraint stress (CRS) in mice and in lipopolysaccharide (LPS)-induced TNC1 astrocytes. Our findings indicated that THC mitigated the anxiety and depression-like behaviours observed in CRS mice. It also influenced the expression of TGF-ß1, p-SMAD3/SMAD3, sirtuin 1 (SIRT1), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), inducible nitric oxide synthase (iNOS), and tumour necrosis factor α (TNF-α). Specifically, THC augmented the expressions of TGF-ß1, p-SMAD3/SMAD3, SIRT1, BDNF, and GDNF, whilst diminishing the expressions of iNOS and TNF-α in LPS-induced astrocytes. However, when pre-treated with SB431542, a TGF-ß1 receptor inhibitor, it nullified the aforementioned effects of THC on astrocytes. Our results propose that THC delivers its anti-depressive effects through the activation of TGF-ß1, enhancement of p-SMAD3/SMAD3 and SIRT1 expression, upregulation of BDNF and GDNF, and downregulation of iNOS and TNF-α. This research furnishes new perspectives on the anti-inflammatory mechanism that underpins the antidepressant-like impact of THC.

Basolateral Amygdala Cannabinoid CB1 Receptor Controls Formation and Elimination of Social Fear Memory.

Patients with post-traumatic stress disorder (PTSD) usually manifest persistence of the traumatic memory for a long time after the event, also known as resistance to extinction learning. Numerous studies have shown that the endocannabinoid system, specifically the cannabinoid type-1 receptor (CB1R), plays an important role in traumatic memory. However, the effect of basolateral amygdala (BLA) CB1R in social fear memory formation and elimination is still unclear. Here, we built a mouse model of social avoidance induced by acute social defeat stress to investigate the role of BLA CB1R in social fear memory formation and anxiety- and depression-like behavior. Anterograde knockout of CB1R in BLA neurons facilitates social fear memory formation and manifests an anxiolytic effect but does not influence sociability and social novelty. Retrograde knockout of CB1R in BLA promotes social fear memory formation and shows an anxiogenic effect but does not affect sociability and social novelty. Moreover, intracerebral injection of the CB1R antagonist AM251 in BLA during the memory reconsolidation time window eliminates social fear memory. Our findings suggest the CB1R of BLA can be used as a novel molecular target in social fear memory formation and elimination and potential PTSD therapy with memory retrieval and AM251.

Trends in total cholesterol control among American adults with hypercholesterolemia, 1988-2018.

BACKGROUND AND AIMS: Cholesterol control and management in patients with hypercholesterolemia are significant for the primary and secondary prevention of atherosclerotic cardiovascular disease. This study analyzed the trend of serum total cholesterol (TC) control (<240 mg/dL and <200 mg/dL) in American adults with hypercholesterolemia and thereby make some effective recommendations for the public health measures. METHODS AND RESULTS: Basing on the National Health and Nutrition Examination Survey (NHANES) data from 1988 to 2018 (12 cycles), we calculated the weighted and representative rate of patients with hypercholesterolemia who had controlled TC, and then described the trend. Among the adults with hypercholesterolemia, the age-adjusted rate of those whose TC was less than 240 mg/dL increased from 7.67% (95%CI: 5.94%-9.40%) in 1988-1991 to 58.52% (95%CI: 55.89%-61.15%) in 2013-2014 and then remained stable; and the age-adjusted rate of those whose TC was less than 200 mg/dL increased from 2.49% (95%CI: 1.48%-3.50%) in 1988-1991 to 44.58% (95%CI: 40.00%-49.16%) in 2017-2018. CONCLUSION: We concluded that the rate of controlling TC below 200 mg/dL among all patients had shown an increasing trend from 1988 to 2018 in America, while the rate of controlling TC below 240 mg/dL remained stable in recent years after an increasing.

Competing risks analysis of external versus internal radiation in patients with hepatocellular carcinoma after controlling for immortal time bias.

PURPOSE: In cohort studies on liver cancer, there are often immortal time bias and interference of competing risk events. This study proposes to explore the role of internal and external radiotherapy for hepatocellular carcinoma using SEER data, using a competing risk model and controlling immortal time bias. METHODS: Data of SEER from 2004 till 2015 was included. To analyze whether there was a difference in survival between HCC (hepatocellular carcinoma) patients receiving external radiation and internal radiation, we used a competing risk analysis after excluding immortal time bias, and created a nomogram to assess the risk of cancer-specific death (CSD) in hepatocellular carcinoma patients receiving radiotherapy. RESULTS: Potential confounding factors adjusted, there was no significant difference in CSD between external and internal radiation therapy [HR and its 95% CI = 1.098 (0.874-1.380)]. The constructed nomogram performed better than the traditional AJCC model. The AUC and calibration curve results showed that this well-calibrated nomogram could be used to make clinical decisions regarding the prognosis and personalized treatment of hepatocellular carcinoma treated. There was no difference in the cumulative risk of death between patients with liver cancer treated with external radiation therapy and internal radiation therapy. CONCLUSION: There is no difference in the cumulative risk of death between patients with liver cancer treated with external radiation therapy and internal radiation therapy. The nomogram predicts the results more accurately. These results can be used to guide the choice of treatment options for patients with HCC and to predict their survival prognosis.

The relationship between cadmium and cognition in the elderly: a systematic review.

Context: The relationship between cadmium (Cd) and the cognition of the elderly is indistinct.Objective: To summarise the studies on the relationship between the cognition of the elderly and Cd.Methods: Literatures were searched in PubMed, Web of Science, China National Knowledge Infrastructure (CNKI), and Wan fang database on April 25, 2022. The entries in the STROBE statement were used to evaluate the literature quality; all the quantitative studies that met the requirements were systematically summarised.Results: Blood Cd was negatively correlated with the cognitive ability of the elderly, corresponding to different cognitive ability assessment methods, the regression coefficients were: -0.11 (-0.20, -0.03), -0.46 (-0.71, -0.21), -0.54 (-0.90, -0.17), -0.19 (-0.37, -0.01), and -2.29 (-3.41, -1.16). The regression coefficients between urinary Cd level and cognition score were -1.42 (-2.38, -0.46), and 0.76 (-1.28, -0.23). When dietary Cd increased by 1 µg/kg, the composite z-score decreased by 3.64 (p = 0.001). There was no significant correlation between drinking water Cd, fingernail Cd and cognition (p > 0.05).Conclusion: We concluded that blood Cd (including whole blood and plasma), urine Cd and dietary Cd were negatively correlated with the cognition of the elderly, but the relationship between Cd in drinking water and fingernails and cognition was not statistically significant.

Effect of a fall prevention strategy for the older patients: A quasi-experimental study.

AIM: To explore the effect of a fall prevention strategy on older patients based on the Patient Engagement Framework. DESIGN: A longitudinal quasi-experimental quantitative design. METHODS: Older patients who met the inclusion criteria were recruited from geriatric, oncology, neurology and cardiology departments of a teaching general hospital in China. Development of a fall prevention intervention strategy for older patients was based on the Patient Engagement Framework. Patients in the intervention group were given this fall prevention strategy (N = 58), and those in the control group were given conventional measures (N = 58). The following indicators were compared between the two groups after intervention: (a) number of falls; (b) Knowledge-Attitude-Practice (KAP) score; (c) Modified Fall Efficacy Scale score. RESULTS: After the implementation of an intervention strategy in older patients, the number of falls decreased from 3 to 0; the score of KAP and Modified Fall Efficacy Scale was promoted (p < .05).

Waist Circumference-Years Construct Analysis and the Incidence of Type 2 Diabetes: China Health and Nutrition Survey, 1997-2015.

Background: Few studies have combined the degree and duration of abdominal obesity into a waist circumference-years construct for analysis. The purpose of this study was to investigate the effect of waist circumference-years on the incidence of type 2 diabetes. Methods: A total of 6616 adults from the China Health and Nutrition Survey (CHNS) were enrolled in this study from 1997. The waist circumference-years construct was represented as the sum of the upper and lower area between the waist circumference baseline (men: ≥90 cm, women: ≥85 cm) and the waist circumference line. The correlations in the study were analyzed using logistic regression. Results: The incidence of type 2 diabetes increased with increasing waist circumference-years, with an adjusted risk increase of 38% (95% CI: 31−47%) for each additional 50 waist circumference-years, and this rate was similar across gender and age groups. The area under the curve of waist circumference-years (0.743) was greatest in the receiver operating characteristic curve (ROC) analysis compared to baseline waist circumference (0.731) and the waist-height ratio (0.728) (p < 0.05). Conclusion: The waist circumference-years construct is closely associated with an increased risk of type 2 diabetes and may be a stronger predictor of type 2 diabetes risk than baseline waist circumference or the waist-height ratio.

Relationship between renal and liver function with diabetic retinopathy in patients with type 2 diabetes mellitus: a study based on cross-sectional data.

This study aims to explore the relationship between abnormal renal- and liver-function and diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM). A total of 994 T2DM patients who received inpatient treatment in the Endocrinology Department of Henan Province People's Hospital were included in the study. Logistic regression was performed to identify the relationship between abnormal renal and liver function with DR. Receiver operator characteristic analysis was performed to explore the efficacy of risk factors in predicting DR. Higher urine albumin [OR(95%CI) = 3.344(1.921-5.822), P < 0.001] and urine albumin/creatinine ratio [OR (95%CI) = 2.901(1.911-5.822), P < 0.001] were closely related to the occurrence of DR. People with low TP had a 1.624-times higher risk (95%CI: 1.008-2.617) of developing DR than those with normal total protein (P = 0.046). The more risk factors that are present, the greater the risk of DR. For every one-point incremental increase in the risk-factor score, the risk of DR increased by 31.0% (P < 0.001). The area under receiver operating curve of risk-factor score was 0.839 (0.812, 0.866), with a sensitivity of 81.9% and a specificity of 74.8%. The risk of developing DR increased with an increased risk-factor score. These findings are potentially valuable for DR screening and early diagnosis in patients with T2DM.

Ca2+/calmodulin-dependent protein kinase II inhibition reduces myocardial fatty acid uptake and oxidation after myocardial infarction.

An AMP-activated kinase (AMPK) signaling pathway is activated during myocardial ischemia and promotes cardiac fatty acid (FA) uptake and oxidation. Similarly, the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaMKII) is also triggered by myocardial ischemia, but its function in FA metabolism remains unclear. Here, we explored the role of CaMKII in FA metabolism during myocardial ischemia by investigating the effects of cardiac CaMKII on AMPK-acetyl-CoA carboxylase (ACC), malonyl CoA decarboxylase (MCD), and FA translocase cluster of differentiation 36 (FAT/CD36), as well as cardiac FA uptake and oxidation. Moreover, we tested whether CaMKII and AMPK are binding partners. We demonstrated that diseased hearts from patients with terminal ischemic heart disease displayed increased phosphorylation of CaMKII, AMPK, and ACC and increased expression of MCD and FAT/CD36. AC3-I mice, which have a genetic myocardial inhibition of CaMKII, had reduced gene expression of cardiac AMPK. In post-MI (myocardial infarction) AC3-I hearts, AMPK-ACC phosphorylation, MCD and FAT/CD36 levels, cardiac FA uptake, and FA oxidation were significantly decreased. Notably, we demonstrated that CaMKII interacted with AMPK α1 and α2 subunits in the heart. Additionally, AC3-I mice displayed significantly less cardiac hypertrophy and apoptosis 2 weeks post-MI. Overall, these findings reveal a unique role for CaMKII inhibition in repressing FA metabolism by interacting with AMPK signaling pathways, which may represent a novel mechanism in ischemic heart disease.

IL-17 Inhibits Oligodendrocyte Progenitor Cell Proliferation and Differentiation by Increasing K+ Channel Kv1.3.

Interleukin 17 (IL-17) is a signature cytokine of Th17 cells. IL-17 level is significantly increased in inflammatory conditions of the CNS, including but not limited to post-stroke and multiple sclerosis. IL-17 has been detected direct toxicity on oligodendrocyte (Ol) lineage cells and inhibition on oligodendrocyte progenitor cell (OPC) differentiation, and thus promotes myelin damage. The cellular mechanism of IL-17 in CNS inflammatory diseases remains obscure. Voltage-gated K+ (Kv) channel 1.3 is the predominant Kv channel in Ol and potentially involved in Ol function and cell cycle regulation. Kv1.3 of T cells involves in immunomodulation of inflammatory progression, but the role of Ol Kv1.3 in inflammation-related pathogenesis has not been fully investigated. We hypothesized that IL-17 induces myelin injury through Kv1.3 activation. To test the hypothesis, we studied the involvement of OPC/Ol Kv1.3 in IL-17-induced Ol/myelin injury in vitro and in vivo. Kv1.3 currents and channel expression gradually decreased during the OPC development. Application of IL-17 to OPC culture increased Kv1.3 expression, leading to a decrease of AKT activation, inhibition of proliferation and myelin basic protein reduction, which were prevented by a specific Kv1.3 blocker 5-(4-phenoxybutoxy) psoralen. IL-17-caused myelin injury was validated in LPC-induced demyelination mouse model, particularly in corpus callosum, which was also mitigated by aforementioned Kv1.3 antagonist. IL-17 altered Kv1.3 expression and resultant inhibitory effects on OPC proliferation and differentiation may by interrupting AKT phosphorylating activation. Taken together, our results suggested that IL-17 impairs remyelination and promotes myelin damage by Kv1.3-mediated Ol/myelin injury. Thus, blockade of Kv1.3 as a potential therapeutic strategy for inflammatory CNS disease may partially attribute to the direct protection on OPC proliferation and differentiation other than immunomodulation.

Gastrodin Regulates the Notch Signaling Pathway and Sirt3 in Activated Microglia in Cerebral Hypoxic-Ischemia Neonatal Rats and in Activated BV-2 Microglia.

In response to hypoxic-ischemic brain damage (HIBD), microglia activation and its mediated inflammation contribute to neuronal damage. Inhibition of over-activated microglia is deemed to be a potential therapeutic strategy. Our previous studies showed that gastrodin efficiently depressed the neuroinflammation mediated by activated microglia in HIBD neonatal rats. The underlying mechanisms through which gastrodin acts on activated microglia have not been fully elucidated. This study is designed to determine whether gastrodin would regulate the Notch signaling pathway and Sirtuin3 (Sirt3), which are implicated in regulating microglia activation. The present results showed that gastrodin markedly suppressed the expression of members of Notch signaling pathway (Notch-1, NICD, RBP-JK and Hes-1) in activated microglia both in vivo and in vitro. Conversely, Sirt3 expression was enhanced. In BV-2 microglia treated with a γ-secretase inhibitor of Notch pathway- DAPT, the expression of RBP-JK, Hes-1, and NICD was suppressed in activated microglia. Treatment with DAPT and gastrodin further decreased NICD and Hes-1 expression. Sirt3 expression was also decreased after DAPT treatment. However, Sirt3 expression in activated BV-2 microglia given a combined DAPT and gastrodin treatment was not further increased. In addition, combination of DAPT and Gastrodin cumulatively decreased tumor necrosis factor-α (TNF-α) expression. The results suggest that gastrodin regulates microglia activation via the Notch signaling pathway and Sirt3. More importantly, interference of the Notch signaling pathway inhibited Sirt3 expression, indicating that Sirt3 is a downstream gene of the Notch signaling pathway. It is suggested that Notch and Sirt3 synergistically regulate microglia activation such as in TNF-α production.

On Modeling Ensemble Transport of Metal Reducing Motile Bacteria.

Many metal reducing bacteria are motile with their run-and-tumble behavior exhibiting series of flights and waiting-time spanning multiple orders of magnitude. While several models of bacterial processes do not consider their ensemble motion, some models treat motility using an advection diffusion equation (ADE). In this study, Geobacter and Pelosinus, two metal reducing species, are used in micromodel experiments for study of their motility characteristics. Trajectories of individual cells on the order of several seconds to few minutes in duration are analyzed to provide information on (1) the length of runs, and (2) time needed to complete a run (waiting or residence time). A Continuous Time Random Walk (CTRW) model to predict ensemble breakthrough plots is developed based on the motility statistics. The results of the CTRW model and an ADE model are compared with the real breakthrough plots obtained directly from the trajectories. The ADE model is shown to be insufficient, whereas a coupled CTRW model is found to be good at predicting breakthroughs at short distances and at early times, but not at late time and long distances. The inadequacies of the simple CTRW model can possibly be improved by accounting for correlation in run length and waiting time.