Regulatory Non-coding RNAs Involved in Oxidative Stress and Neuroinflammation: An Intriguing Crosstalk in Parkinson's Disease.

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the accumulation of α-synuclein and the degeneration of dopaminergic neurons in the substantia nigra. Although the molecular bases for PD development are not fully recognized, extensive evidence has suggested that the development of PD is strongly associated with neuroinflammation. It is noteworthy that while neuroinflammation might not be a primary factor in all patients with PD, it seems to be a driving force for disease progression, and therefore, exploring the role of pathways involved in neuroinflammation is of great importance. Besides, the importance of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and competing endogenous RNAs (ceRNAs), has been widely studied with a focus on the pathogenesis of PD. However, there is no comprehensive review regarding the role of neuroinflammation-related ncRNAs as prospective biomarkers and therapeutic targets involved in the pathogenesis of PD, even though the number of studies connecting ncRNAs to neuroinflammatory pathways and oxidative stress has markedly increased in the last few years. Hence, the present narrative review intended to describe the crosstalk between regulatory ncRNAs and neuroinflammatory targets with respect to PD to find and propose novel combining biomarkers or therapeutic targets in clinical settings.

Preclinical study of formulated recombinant nucleocapsid protein, the receptor binding domain of the spike protein, and truncated spike (S1) protein as vaccine candidates against COVID-19 in animal models.

BACKGROUND: In this pre-clinical study, we designed a candidate vaccine based on severe acute respiratory syndrome-related -coronavirus 2 (SARS-CoV-2) antigens and evaluated its safety and immunogenicity. METHODS: SARS-CoV-2 recombinant protein antigens, including truncated spike protein (SS1, lacking the N-terminal domain of S1), receptor-binding domain (RBD), and nucleoprotein (N) were used. Immunization program was performed via injection of RBD, SS1 +RBD, and SS1 +N along with different adjuvants, Alum, AS03, and Montanide at doses of 0, 40, 80, and 120 µg at three-time points in mice, rabbits, and primates. The humoral and cellular immunity were analyzed by ELISA, VNT, splenocyte cytokine assay, and flow cytometry. RESULTS: The candidate vaccine produced strong IgG antibody titers at doses of 80 and 120 µg on days 35 and 42. Even though AS03 and Montanide produced high-titer antibodies compared to Alum adjuvant, these sera did not neutralize the virus. Strong virus neutralization was recorded during immunization with SS1 +RBD and RBD with Alum. AS03 and Montanide showed a strong humoral and cellular immunity; however, Alum showed mild to moderate cellular responses. Ultimately, no cytotoxicity and pathologic change were observed. CONCLUSION: These findings strongly suggest that RBD with Alum adjuvant is highly immunogenic as a potential vaccine.

Low level of adiponectin predicts the development of Nonalcoholic fatty liver disease: is it irrespective to visceral adiposity index, visceral adipose tissue thickness and other obesity indices?

We aimed to study the correlation of adiponectin level with insulin resistance (IR), carotid intima-media thickness (cIMT), and various obesity indices especially visceral adipose tissue (VAT) thickness, and visceral adiposity index (VAI), in patients with NAFLD (n = 41), T2D (n = 22), NAFLD + T2D (n = 41), and healthy subjects (n = 20). Results showed the median level of adiponectin in patients with NAFLD (2.97 µg/mL) and ones with NAFLD + T2D (3.21 µg/mL) is significantly lower rather than in controls (4.39 µg/mL). Moreover, VAI is the only predictor for adiponectin concentration in the combination of patient groups and also in all participants independent of IR and other obesity indices. Adiponectin level had also a positive correlation with cIMT and IR in NAFLD patients. Interestingly, lower level of adiponectin was associated with the presence of T2D, NAFLD, and NAFLD + T2D independent of IR and obesity indices. Collectively, it seems that VAI reflecting visceral adipose tissue function is a possible predictor of adiponectin level.

The interaction between dietary approaches to stop hypertension and MC4R gene variant in predicting cardiovascular risk factors.

Objective: The genetic variants near the melanocortin-4 receptor gene (MC4R), a key protein regulating energy balance and adiposity, have been related to obesity and cardiovascular risk factors. However, qualitative and quantitative aspects of diet may modulate the association of this polymorphism with obesity and cardiovascular diseases (CVDs). The aim of this study was to evaluate interactions among MC4R rs17782313, the Dietary Approaches to Stop Hypertension (DASH) diet and risk factors for CVDs. Method: This cross-sectional study was conducted on 266 Iranian women categorized by body mass index (BMI) range of 25-40 kg/m2 as overweight or obese. CVD risk factors included waist circumference (WC), lipid profile, blood pressure, insulin circulation and fasting blood sugar (FBS). Insulin and FBS were used to calculate homeostatic model assessment insulin resistance (HOMA-IR) Body composition was assessed by a multi-frequency bioelectrical impedance analyzer, InBody 770 scanner. Results: The findings of this study show that high adherence to the DASH diet in the CC groups were associated with decreased SBP and DBP compared to the TT group. In addition, a significant difference between women with high adherence to the DASH diet compared to low adherence was observed for body weight (p < 0.001), fat free mass (FFM) (p = 0.01) and BMI (p = 0.02). Women with the CC genotype had higher insulin (mg/dl) (mean and SD, for TT: 14.6 ± 4.6, TC: 17.3 ± 9.2, CC: 15.3 ± 4.8, p = 0.04) and HOMA-IR (mean for and SD, TT: 3.1 ± 1.07, TC: 3.9 ± 2.4, CC: 3.2 ± 1.1, p = 0.01) than TT group. Inclusion of potential confounding variables (age, physical activity, BMI and daily caloric intake) did not attenuate the difference. Conclusion: Among overweight/obese Iranian women with the CC genotype, incorporating the DASH diet may serve as a dietary prescription to decrease CVD risk. A dietary intervention trial is warranted.

The genetic factors associated with Wnt signaling pathway in colorectal cancer.

Colorectal cancer (CRC) is a common cancer with poor prognosis and high mortality. There is growing information about the factors involved in the pathogenesis of CRC. However, the knowledge of the predisposing factors is limited. The development of CRC is strongly associated with the Wingless/Integrated (Wnt) signaling pathway. This pathway comprises several major target proteins, including LRP5/6, GSK3ß, adenomatous polyposis coli (APC), axis inhibition protein (Axin), and ß-catenin. Genetic variations in these components of the Wnt signaling pathway may lead to the activation of ß-catenin, potentially increasing the proliferation of colorectal cells. Because of the potentially important role of the Wnt signaling pathway in CRC, we aimed to review the involvement of different mutations in the main downstream proteins of this pathway, including LRP5/6, APC, GSK3ß, Axin, and ß-catenin. Determination of the genetic risk factors involved in the progression of CRC may lead to novel approaches for the early diagnosis of CRC and the identification of potential therapeutic targets in the treatment of CRC.

Adipose tissue gene expression of long non-coding RNAs; MALAT1, TUG1 in obesity: is it associated with metabolic profile and lipid homeostasis-related genes expression?

BACKGROUND: Recent studies point toward the possible regulatory roles of two lncRNAs; metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and taurine upregulated gene 1 (TUG1) in the pathogenesis of obesity-related disorders and regulation of lipogenesis and adipogenesis. In an attempt to understand the molecules involved in human obesity pathogenesis, we aimed to evaluate the expression of MALAT1 and TUG1 in visceral adipose tissues (VAT) and subcutaneous adipose tissues (SAT) of obese women, as compared to normal-weight women. The mRNA expression of possible target genes including peroxisome proliferator-activated receptor gamma (PPARγ), PPARγ coactivator-1 alpha (PGC1α), sterol regulatory element-binding protein-1c (SREBP-1c), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC) which are involved in adipogenesis and lipogenesis were also examined. METHODS: This study was conducted on 20 obese [body mass index (BMI) ≥ 30 kg/m 2] female participants and 19 normal-weight (BMI < 25 kg/m 2) female participants. Real-time PCR was performed to investigate the mRNA expression of the above-mentioned genes in VAT and SAT from all participants. RESULTS: The results showed lower mRNA levels of TUG1 in both the VAT and SAT of obese women, compared to normal-weight women. Furthermore, TUG1 expression in SAT positively correlated with BMI, waist circumference (WC), hip circumference, HOMA-IR, and insulin levels, eGFR value, creatinine levels, and hs-CRP in all participants independent of age and HOMA-IR. However, VAT mRNA expression of TUG1 had a positive correlation with obesity indices and HOMA-IR and insulin levels in the whole population. Moreover, SAT mRNA level of TUG1 was positively correlated with SAT gene expression of PGC1α, SREBP-1c, FAS, and ACC independent of age and HOMA-IR. Although mRNA expression of MALAT1 did not differ between two groups for any tissue, it was positively correlated with SAT mRNA levels of SREBP-1c, PPARγ, and their targets; FAS and ACC, as well as with VAT mRNA levels of PGC1α. CONCLUSIONS: It seems likely that TUG1 with distinct expression pattern in VAT and SAT are involved in the regulation of lipogenic and adipogenic genes and obesity-related parameters. However, more studies are necessary to establish this concept.

Acetylation and insulin resistance: a focus on metabolic and mitogenic cascades of insulin signaling.

Insulin resistance is associated with an increased risk of several metabolic disorders including type 2 diabetes, hypertension and cardiovascular diseases. Advances over the last decade have expanded our understanding of the molecular mechanisms underlying insulin resistance; however, many details of the mechanisms causing insulin resistance remain unknown. Recently, attention has shifted toward the role of epigenetics in insulin resistance. In this regard, acetylation of the histone tails has been widely investigated for its role in influencing both metabolic and mitogenic cascades of insulin signaling. More specifically, histone acetyltransferases and histone deacetylases, as major modulators of chromatin accessibility and gene expression, have been studied to determine a possible interconnectivity between the special effects of lysine acetylation status and tyrosine phosphorylation networks on the target proteins of downstream pathways involved in both metabolic and mitogenic cascades of insulin signaling. There is accumulating evidence for the post-translational modification effects of IGFR, InsR, IRS1/2, PI3K, Akt, GLUT4, FoxO, PGC-1α, PPAR, AMPK and MAPKs on insulin resistance and glucose homeostasis. In this paper, we review the importance of acetylation of these factors in the regulation of insulin signaling and glucose metabolism, with a primary focus on the target proteins of downstream signaling of insulin. We also provide an update on the interplay between epigenetic modification and the cellular genome in the context of insulin signaling and describe the possible effect of the environment on this epigenetic regulation.

The role of microRNAs in the regulation of insulin signaling pathway with respect to metabolic and mitogenic cascades: A review.

Insulin resistance (IR) is a shared pathological condition among type 2 diabetes, obesity, cardiovascular disease, and other metabolic disorders. It is growing significantly all over the world and consequently, a substantial effort is needed for developing the potential novel diagnostics and therapeutics. An insulin signaling pathway is tightly modulated by different mechanisms including the epigenetic modifications. Today, a deal of great attention has been shifted towards the regulatory role of noncoding RNAs on target proteins of the insulin signaling pathway. Noncoding RNAs are a major area of the epigenetics which control gene expression at the posttranscriptional levels and include a large class of microRNAs (miRNAs). With this in view, many studies have implicated the mediatory effects of miRNAs on the downstream metabolic and mitogenic proteins of the insulin signaling pathway. Since providing new biomarkers for the early diagnosis of IR and related metabolic traits are very significant, we intended to review the possible role of miRNAs in the regulation of the insulin signaling pathway, with a primary focus on the downstream target proteins of the metabolic and mitogenic cascades.

Circulating exosomal miRNAs in cardiovascular disease pathogenesis: New emerging hopes.

Cardiovascular diseases (CVDs) are one of the leading causes of morbidity and mortality. Standard therapies have failed to significantly increase patients' survival. Moreover, the majority of conventional screening procedures are ineffective for the diagnosis of CVDs at early stages. Accumulating evidence suggests that numerous cell types release a class of nano-sized vesicles named exosomes into the extracellular space. Exosomes are widely distributed in various body fluids and contain a number of diverse biomolecules such as proteins, lipids, and both mRNA and noncoding RNAs which reflect host-cell molecular architecture. MicroRNAs (miRNAs), which can be found in exosomes, could be taken up by both neighboring and distal cells. Not only has recent evidence indicated the regulatory role of exosomal miRNAs in the pathogenesis of CVD, but it has also been shown that differential expression of exosomal miRNAs in CVDs has made them promising biomarkers for early detection of CVDs. Owing to these remarkable features, exosomal miRNAs have emerged as hot spots in research. This review summarizes the role of exosomal miRNAs in the pathogenesis of CVDs and discusses their potential application in the clinical setting as both therapeutic and diagnostic tools.

The role of inflammation and its related microRNAs in breast cancer: A narrative review.

Breast cancer is recognized as the most common type of cancer among women with a high rate of mortality all over the world. Over the past years, growing attention has been regarded to realize more about the mechanisms underlying the disease process. It is revealed that the progression of breast cancer may be strongly linked to chronic inflammation owing to the role of inflammatory factors in genetic instability and subsequent cancer predisposition. Although the association between breast cancer and inflammatory pathways has been well-defined now, only recent evidence pointed towards the inflammation-related microRNAs (miRNAs) as potential biomarkers and therapeutic targets involved in the crosstalk of multiple pathways during breast cancer development. Moreover, the practical interactions between these miRNAs and inflammatory factors are also a little characterized. In this review, we intended to describe the effects of predominant inflammatory pathways such as cytokines, phosphoinositide 3-kinase/protein kinase B, and nuclear factor kappa B in association with tumor promoting and tumor suppressing miRNAs on breast cancer progression. Providing new studies in the field of combining biomarkers for early diagnosis, prognosis, and monitoring breast cancer are very important. Notably, understanding the underlying mechanisms of miRNAs as a possible link between inflammation and tumorigenesis may offer a novel insight for combating this epidemic.

Comparison of glomerular filtration rate estimation using Jaffé and enzymatic creatinine assays in diabetic patients.

BACKGROUND: Diabetic kidney disease (DKD) develops an end-stage renal failure and is a major cause of death in diabetic patients. A GFR below 60 ml/min per 1.73 m2 is one of the main markers of DKD. Therefore, the development of an accurate test for diagnosis and monitoring of the mentioned disease would be essential. Here, we examined the impacts of two different kits with different methods for creatinine measurement on the GFR values. METHODS: Blood samples were collected from 80 diabetic patients referring to the clinical laboratory. The levels of serum creatinine were assessed using Jaffé and enzymatic assays by kits from two different manufacturers. Then to assess the eGFR levels, the MDRD equation was used. Further descriptive parameters of both methods and correlation of methods were also calculated. RESULTS: Descriptive analysis of the data demonstrates a slight increase in the serum creatinine measured by Jaffé assay which leads to a substantial decrease in the levels of eGFR compared to the eGFR calculated by the enzymatic assay. Moreover, eGFR over 60 mL/min/1.73 m 2 in enzymatic assay was observed in 27.5% of participants while eGFR of the same participants was below 60 mL/min/1.73 m 2 when it was measured by Jaffé method. Consequently, 27.5% positive discordant cases were reported by Jaffé assay followed by misclassifying them as DKD patients compared with the enzymatic assay. CONCLUSION: While using Jaffé assay, a low level of eGFR is observed which generates more misclassification into the DKD group and demands to an inclusive consideration by physicians in order to diagnose and monitor the DKD patients.