Modulation of cannabinoid receptor 2 alters neuroinflammation and reduces formation of alpha-synuclein aggregates in a rat model of nigral synucleinopathy.

Research into the disequilibrium of microglial phenotypes has become an area of intense focus in neurodegenerative disease as a potential mechanism that contributes to chronic neuroinflammation and neuronal loss in Parkinson's disease (PD). There is growing evidence that neuroinflammation accompanies and may promote progression of alpha-synuclein (Asyn)-induced nigral dopaminergic (DA) degeneration. From a therapeutic perspective, development of immunomodulatory strategies that dampen overproduction of pro-inflammatory cytokines from chronically activated immune cells and induce a pro-phagocytic phenotype is expected to promote Asyn removal and protect vulnerable neurons. Cannabinoid receptor-2 (CB2) is highly expressed on activated microglia and peripheral immune cells, is upregulated in the substantia nigra of individuals with PD and in mouse models of nigral degeneration. Furthermore, modulation of CB2 protects against rotenone-induced nigral degeneration; however, CB2 has not been pharmacologically and selectively targeted in an Asyn model of PD. Here, we report that 7 weeks of peripheral administration of CB2 inverse agonist SMM-189 reduced phosphorylated (pSer129) alpha-synuclein in the substantia nigra compared to vehicle treatment. Additionally, SMM-189 delayed Asyn-induced immune cell infiltration into the brain as determined by flow cytometry, increased CD68 protein expression, and elevated wound-healing-immune-mediator gene expression. Additionally, peripheral immune cells increased wound-healing non-classical monocytes and decreased pro-inflammatory classical monocytes. In vitro analysis of RAW264.7 macrophages treated with lipopolysaccharide (LPS) and SMM-189 revealed increased phagocytosis as measured by the uptake of fluorescence of pHrodo E. coli bioparticles. Together, results suggest that targeting CB2 with SMM-189 skews immune cell function toward a phagocytic phenotype and reduces toxic aggregated species of Asyn. Our novel findings demonstrate that CB2 may be a target to modulate inflammatory and immune responses in proteinopathies.

Downregulated hs-CRP and MAD, upregulated GSH and TAC, and improved metabolic status following combined exercise and turmeric supplementation: a clinical trial in middle-aged women with hyperlipidemic type 2 diabetes.

Background: Aerobic training (AT) and Turmeric Supplementation (TS) are known to exert multiple beneficial effects including metabolic status and Oxidative Stress. To our knowledge, data on the effects of AT and TS on metabolic status and oxidative stress biomarkers related to inflammation in subjects with Hyperlipidemic Type 2 Diabetes Mellitus (HT2DM) are scarce. Objectives: This study was conducted to evaluate the effects of AT and TS on metabolic status and oxidative stress biomarkers related to inflammation in subjects with HT2DM. Methods: This randomized single-blinded, placebo-controlled trial was conducted among 42 subjects with HT2DM, aged 45-60 years old. Participants were randomly assigned to four groups; AT+TS (n = 11), AT+placebo (AT; n = 10), TS (n = 11), and Control+placebo (C; n = 10). The AT program consisted of 60-75% of Maximum heart rate (HRmax), 20-40 min/day, three days/week for eight weeks. The participants in the TS group consumed three 700 mg capsules/day containing turmeric powder for eight weeks. Metabolic status and oxidative stress biomarkers were assessed at baseline and end of treatment. The data were analyzed through paired t-test and one-way analysis of variance (ANOVA) and Bonferroni post hoc test at the signification level of P < 0.05. Results: After eight weeks, significant improvements were observed in metabolic status, oxidative stress biomarkers and high-sensitivity C-reactive protein (hs-CRP) in the AT+TS, TS, and AT compared to C. Additionally, a significant decrease of Metabolic Syndrome (MetS) Z scores (p = 0.001; p = 0.011), hs-CRP (p = 0.028; p = 0.041), Malondialdehyde (MAD) (p = 0.023; p = 0.001), and significantly higher Glutathione (GSH) (p = 0.003; p = 0.001), and Total Antioxidant Capacity (TAC) (p = 0.001; p = 0.001) compared to the AT and TS groups. The results also revealed a significant difference in terms of MetS Z scores (p = 0.001), hs-CRP (p = 0.018), MAD (p = 0.011), GSH (p = 0.001) and TAC (p = 0.025) between the AT and TS. Conclusions: The findings suggest that AT+TS improves metabolic status, oxidative stress biomarkers, and hs-CRP more effectively compared to TS or AT in middle-aged females with T2DM and hyperlipidemia.

When Much Is Too Much-Compared to Light Exercisers, Heavy Exercisers Report More Mental Health Issues and Stress, but Less Sleep Complaints.

BACKGROUND: Physical inactivity has become a global somatic and mental health issue. To counterbalance, promoting regular physical activity appears plausible, above all among adults, where physical inactivity is particularly high. However, some, but sparse, research also indicates that excessive exercising might be associated with unfavorable mental health dimensions. Here, we tested the hypothesis that excessive exercising was associated with more mental health issues. To this end, we assessed mental health issues, stress, mental toughness, and sleep disturbances among heavy and light adult exercisers. METHODS: A total of 200 adults (mean age: 35 years; 62% females) took part in the study. Of those, 100 were heavy exercisers (18-22 h/week), and 100 were light exercisers (1-6 h/week). Participants completed questionnaires covering sociodemographic information, mental health issues, perceived stress, mental toughness, and sleep disturbances. RESULTS: Compared with light exercisers, heavy exercisers reported higher mental health issues, more stress, but also higher mental toughness scores and less sleep disturbances. Higher age, lower mental toughness scores, heavy exerciser-status, and more sleep disturbances predicted higher mental health complaints. CONCLUSIONS: Compared with light exercising, heavy exercising might be associated with more mental health issues. As such, it appears that the association between exercise frequency, intensity, and duration and psychological well-being might be related to an optimum point, but not to a maximum point. In a similar vein, heavily exercising athletes, their coaches, parents, and representatives of sports associations should get sensitized to possible adverse psychological effects of excessive physical activity patterns.

Inhibition of protein tyrosine phosphatase receptor type F suppresses Wnt signaling in colorectal cancer.

Wnt signaling dysregulation promotes tumorigenesis in colorectal cancer (CRC). We investigated the role of PTPRF, a receptor-type tyrosine phosphatase, in regulating Wnt signaling in CRC. Knockdown of PTPRF decreased cell proliferation in patient-derived primary colon cancer cells and established CRC cell lines. In addition, the rate of proliferation as well as colony formation ability were significantly decreased in tumor organoids grown in 3D, whereas the number of differentiated tumor organoids were markedly increased. Consistently, knockdown of PTPRF resulted in a decrease in the expression of genes associated with cancer stem cells downstream of Wnt/ß-catenin signaling. Treating PTPRF knockdown cells with GSK3 inhibitor rescued the expression of Wnt target genes suggesting that PTPRF functions upstream of the ß-catenin destruction complex. PTPRF was found to interact with LRP6 and silencing PTPRF largely decreased the activation of LRP6. Interestingly, this PTPRF-mediated activation of Wnt signaling was blocked in cells treated with clathrin endocytosis inhibitor. Furthermore, knockdown of PTPRF inhibited xenograft tumor growth in vivo and decreased the expression of Wnt target genes. Taken together, our studies identify a novel role of PTPRF as an oncogenic protein phosphatase in supporting the activation of Wnt signaling in CRC.

The Relationship Between Hemodialysis and the Echocardiographic Findings in Patients with Chronic Kidney Disease.

BACKGROUND: The incidence of cardiac morbidity and mortality is high in patients treated with hemodialysis (HD). The aim of this study was to evaluate the relationship between HD and the echocardiographic findings in patients with chronic kidney disease (CKD). METHODS: Between 2012 and 2014, 150 patients with CKD. The echocardiographic data were done based on American Society of Cardiology (ASE). Measurement method for Ejection Fraction was E balling and for Diastolic Function was Tissue Doppler. Anemia, thyroid conditions and dialysis through an arteriovenous fistula or permanent catheter of dialysis for the patients are not considered. RESULTS: The mean age at diagnosis for the patients was 57.8 years, 52.7% were males. Out of 150 patients, 112 patients (74.7%) had diabetes and 117 patients (78%) had a history of hypertension. The prevalence of all echocardiographic findings was more after the first dialysis compared with before the first dialysis in diabetic patients (P<0.05), but in non-diabetic patients, was not for the tricuspid valve stenosis, impaired right ventricular volume, systolic dysfunction and pulmonary hypertension (P>0.05). CONCLUSIONS: According to the findings of this study, seems that more accurate selection of patients for dialysis, paying special attention to hemodynamic change during dialysis, patient education about diet and better control of uremia and diabetes is essential.