Investigating the association between the tissue expression of miRNA-101, JAK2/STAT3 with TNF-α, IL-6, IL-1ß, and IL-10 cytokines in the ulcerative colitis patients.

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory bowel disease caused by numerous factors, such as immune system dysfunction and genetic factors. MicroRNAs (miRNAs) play a crucial role in UC pathogenesis, particularly via the JAK-STAT pathway. Our aim was to investigate the association between miRNA-101 and JAK2-STAT3 signaling pathway with inflammatory cytokines in UC patients. METHODS: We enrolled 35 UC patients and 35 healthy individuals as the control group, referred to Shariati Hospital, Tehran, Iran. Patients were diagnosed based on clinical, laboratory, histological, and colonoscopy criteria. RNA and protein extracted from tissue samples. Real-time PCR was used to assess the expression levels of miRNA-101, interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, and IL-10 genes, while western blot was employed to measure levels of P-STAT3, total STAT3, and JAK2 proteins. RESULTS: Expression of pro-inflammatory cytokines TNF-α, IL-1ß, and IL-6 significantly increased, while the expression of IL-10 significantly decreased in the case group versus controls. Additionally, miRNA-101 expression was significantly higher in UC patients. A significant correlation between miRNA-101 and IL-6 expression was observed, indicating their relationship and possible impact on cell signaling pathways, JAK2-STAT3. No significant changes were observed in phosphorylated and total STAT3 and JAK2 protein expression. CONCLUSION: This study provides evidence of increased miRNA-101 expression in UC tissue, suggesting a potential correlation between miRNA-101 and IL-6 expression and their involvement in the JAK2-STAT3 pathway. The study confirms alterations in UC patients' pro-inflammatory cytokines and anti-inflammatory IL-10. However, further investigations are needed to understand the exact role of miRNA-101 in UC pathogenesis fully.

Crosstalk between Alzheimer's disease and diabetes: a focus on anti-diabetic drugs.

Alzheimer's disease (AD) and Type 2 diabetes mellitus (T2DM) are two of the most common age-related diseases. There is accumulating evidence of an overlap in the pathophysiological mechanisms of these two diseases. Studies have demonstrated insulin pathway alternation may interact with amyloid-ß protein deposition and tau protein phosphorylation, two essential factors in AD. So attention to the use of anti-diabetic drugs in AD treatment has increased in recent years. In vitro, in vivo, and clinical studies have evaluated possible neuroprotective effects of anti-diabetic different medicines in AD, with some promising results. Here we review the evidence on the therapeutic potential of insulin, metformin, Glucagon-like peptide-1 receptor agonist (GLP1R), thiazolidinediones (TZDs), Dipeptidyl Peptidase IV (DPP IV) Inhibitors, Sulfonylureas, Sodium-glucose Cotransporter-2 (SGLT2) Inhibitors, Alpha-glucosidase inhibitors, and Amylin analog against AD. Given that many questions remain unanswered, further studies are required to confirm the positive effects of anti-diabetic drugs in AD treatment. So to date, no particular anti-diabetic drugs can be recommended to treat AD.

Combination therapy of metformin and p-coumaric acid mitigates metabolic dysfunction associated with obesity and nonalcoholic fatty liver disease in high-fat diet obese C57BL/6 mice.

Metformin (MET) has been demonstrated to have favorable impact on nonalcoholic fatty liver disease (NAFLD); however, the combined effect of this drug with p-coumaric acid (PCA) on liver steatosis is unclear. The aim of the current study was to evaluate the combined effects of MET and PCA on NAFLD in a high-fat diet (HFD)-induced NAFLD mouse model. The obese mice received MET (230 mg/kg), PCA (200 mg/kg) monotherapies, and MET combination with PCA in the diet for 10 weeks. Our results showed that the combination of MET and PCA markedly ameliorated weight gain and fat deposition in HFD fed mice. Furthermore, the combination of MET and PCA lowered liver triglyceride (TG) content which was accompanied by decreased expression of lipogenic and increased expression of ß-oxidation related genes and proteins. In addition, combination therapy of MET and PCA mitigated liver inflammation through inhibiting hepatic macrophage infiltration (F4/80), switching macrophage from M1 into M2 phenotype, and ameliorating nuclear factor-κB (NF-κB) activity in comparison with the monotherapy of MET or PCA. Furthermore, we found that MET and PCA combination therapy upregulated thermogenesis-related genes in BAT and sWAT. Combination therapy results in stimulating brown-like adipocyte (beige) formation in the sWAT of HFD mice. Taken together, these findings indicate that MET combined with PCA can improve NAFLD through decreasing lipid accumulation, inhibiting inflammation and inducing thermogenesis, and adipose tissue browning.

The combination of metformin with morin alleviates hepatic steatosis via modulating hepatic lipid metabolism, hepatic inflammation, brown adipose tissue thermogenesis, and white adipose tissue browning in high-fat diet-fed mice.

AIM: The valuable effects of metformin (MET) and morin (MOR) in the improvement of NAFLD have been proposed, nevertheless, their combination impacts were not investigated so far. We determined the therapeutic effects of combined MET and MOR treatment in high-fat diet (HFD)-induced Non-alcoholic fatty liver disease (NAFLD) mice. METHODS: C57BL/6 mice were fed on an HFD for 15 weeks. Animals were allotted into various groups and supplemented with MET (230 mg/kg), MOR (100 mg/kg), and MET + MOR (230 mg/kg + 100 mg/kg). KEY FINDINGS: MET in combination with MOR reduced body and liver weight in HFD-fed mice. A significant decrease in fasting blood glucose and improvement in glucose tolerance was observed in HFD mice treated with MET + MOR. Supplementation with MET + MOR led to a decline in hepatic triglyceride levels and this impact was associated with diminished expression of fatty-acid synthase (FAS) and elevated expression of carnitine palmitoyl transferase 1 (CPT1) and phospho-Acetyl-CoA Carboxylase (p-ACC). Moreover, MET combined with MOR alleviates hepatic inflammation through the polarization of macrophages to the M2 phenotype, decreasing the infiltration of macrophages and lowering the protein level of NF-kB. MET and MOR in combination reduce the size and weight of epididymal white adipose tissue (eWAT), and subcutaneous WAT (sWAT), whereas improves cold tolerance, BAT activity, and mitochondrial biogenesis. Combination therapy results in stimulating brown-like adipocyte (beige) formation in the sWAT of HFD mice. SIGNIFICANCE: These results suggest that the combination of MET and MOR has a protective effect on hepatic steatosis, which may use as a candidate therapeutic for the improvement of NAFLD.

Bone mass and microarchitecture in T2DM patients and corticosteroids therapy: the Bushehr Elderly Health program.

Purpose: Our study examined whether T2DM and glucocorticoids treatment affect bone quality and quantity that are measured by Bone Mineral Density (BMD) and Trabecular Bone Score (TBS). Materials & methods: Participants in this study were 2294 women and men aged over 60 years who participated in stage II of the Bushehr Elderly Health (BEH) program. Patients with T2DM and those who received glucocorticoids were included. BMD was detected using the DXA method and the TBS of L1-L4 was evaluated by TBS iNsight® software. To evaluate the correlation between TBS and BMD levels with diabetes and taking corticosteroids sex-specific multivariable linear regression models were appplied. Results: TBS and BMD were not significantly different in those who had received glucocorticoids versus those who did not.T2DM revealed a significant association with both BMD and TBS in men (beta = 0.12, p < 0.001 and beta = 0.063, p = 0.03, respectively). BMD values were significantly higher in diabetic women (beta = 0.073, p < 0.01). BMI had a significant association with both TBS and BMD but in an opposite direction, in women and men (BMD: beta = -0.22, -0.24, and regarding TBS: beta = 0.37, 0.25, all p-values < 0.001). Conclusion: Our findings showed that T2DM had major effects on BMD in both men and women. However, T2DM only affects TBS in men. Furthermore, neither BMD nor TBS were affected by GC intake in men or women.Based on the variable importance of covariates, BMI was the most influential factor on both BMD and TBS, although in opposite directions, in both sexes.

The critical role of mesenchymal stromal/stem cell therapy in COVID-19 patients: An updated review.

New coronavirus disease 2019 (COVID-19), as a pandemic disaster, has drawn the attention of researchers in various fields to discover suitable therapeutic approaches for the management of COVID-19 patients. Currently, there are many worries about the rapid spread of COVID-19; there is no approved treatment for this infectious disease, despite many efforts to develop therapeutic procedures for COVID-19. Emerging evidence shows that mesenchymal stromal/stem cell (MSC) therapy can be a suitable option for the management of COVID-19. These cells have many biological features (including the potential of differentiation, high safety and effectiveness, secretion of trophic factors and immunoregulatory features) that make them suitable for the treatment of various diseases. However, some studies have questioned the positive role of MSC therapy in the treatment of COVID-19. Accordingly, in this paper, we will focus on the therapeutic impacts of MSCs and their critical role in cytokine storm of COVID-19 patients.

Finding Appropriate Signal Peptides for Secretory Production of Recombinant Glucarpidase: An In SilicoMethod.

BACKGROUND: Methotrexate (MTX) is a general chemotherapeutic agent utilized to treat a variety of malignancies, woefully, its high doses can cause nephrotoxicity and subsequent defect in the process of MTX excretion. The recombinant form of glucarpidase is produced by engineered E. coli and is a confirmed choice to overcoming this problem. OBJECTIVE: In the present study, in silico analyses were performed to select suitable SPs for the secretion of recombinant glucarpidase in E. coli. METHODS: The signal peptide website and UniProt database were employed to collect the SPs and protein sequences. In the next step, SignalP-5.0 helped us to predict the SPs and the position of cleavage sites. Moreover, physicochemical properties and solubility were evaluated using Prot- Param and Protein-sol online software, and finally, ProtCompB was used to predict the final subcellular localization. RESULTS: Luckily, all SPs could form soluble fusion proteins. At last, it was found that PPB and TIBA could translocate the glucarpidase into the extracellular compartment. CONCLUSION: This study showed that there are only 2 applicable SPs for the extracellular translocation of glucarpidase. Although the findings were remarkable with high degrees of accuracy and precision based on the utilization of bioinformatics analyses, additional experimental assessments are required to confirm and validate it. Recent patents revealed several inventions related to the clinical aspects of vaccine peptides against human disorders.

Metformin in combination with genistein ameliorates skeletal muscle inflammation in high-fat diet fed c57BL/6 mice.

Although the beneficial effects of metformin (MET) and genistein in ameliorating inflammation have been elucidated, their combined impacts on skeletal muscle inflammation have not been clearly understood. This study aimed to examine the possible preventive effect of MET in combination with genistein on skeletal muscle inflammation in high-fat diet (HFD) fed C57BL/6 mice. Fifty C57BL/6 male mice were fed on an HFD for 10 weeks. The mice were categorized into five groups, control, HFD, HFD + MET (0.23%), HFD + genistein (0.2%), and HFD + MET + genistein for 12 weeks. The results showed that treatment with MET and genistein, either alone or in combination, led to reduced weight gain, fasting blood glucose, plasma insulin, HOMA-IR levels, and Area Under the Curves (AUCs) in ipGTT. MET in combination with genistein demonstrated a decreasing effect on macrophages infiltration rate compared to genistein and MET groups alone. The expression of iNOS was reduced, whereas the expression of M2 macrophage markers was increased in combined treatment of MET and genistein. Furthermore, MET in combination with genistein reduced the expression of TNF-α, IL-1ß, MCP-1, and IL-6 and increased the expression of IL-10 in comparison with genistein and MET groups alone. Plasma and skeletal muscle triglycerides and intra-myocellular lipid deposition were reversed by treatment with MET and genistein, alone or in combination. These results imply that the combination therapy of MET and genistein may have therapeutic potential for decreasing obesity-induced skeletal muscle inflammation in the HFD-fed model.

Novel insights into the interaction between long non-coding RNAs and microRNAs in glioma.

Glioma is the most common brain tumor of the central nervous system. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) have been identified to play a vital role in the initiation and progression of glioma, including tumor cell proliferation, survival, apoptosis, invasion, and therapy resistance. New documents emerged, which indicated that the interaction between long non-coding RNAs and miRNAs contributes to the tumorigenesis and pathogenesis of glioma. LncRNAs can act as competing for endogenous RNA (ceRNA), and molecular sponge/deregulator in regulating miRNAs. These interactions stimulate different molecular signaling pathways in glioma, including the lncRNAs/miRNAs/Wnt/ß-catenin molecular signaling pathway, the lncRNAs/miRNAs/PI3K/AKT/mTOR molecular signaling pathway, the lncRNAs-miRNAs/MAPK kinase molecular signaling pathway, and the lncRNAs/miRNAs/NF-κB molecular signaling pathway. In this paper, the basic roles and molecular interactions of the lncRNAs and miRNAs pathway glioma were summarized to better understand the pathogenesis and tumorigenesis of glioma.

The effects of natural compounds on wound healing in Iranian traditional medicine: A comprehensive review.

Wounds are physical and anatomical disruption in healthy skin and represent an important healthcare concern around the world. Wound healing is a complex and dynamic cascade of cellular and molecular interactions which include four main phases: hemostasis, inflammatory, proliferative, and remodeling. Therefore, some pharmacological activities such as anti-inflammatory, antioxidant, and antimicrobial activities can play a key role in the process of wound healing. Iranian Traditional Medicine (ITM) has a rich background of practice and a wealth of ancient medicine scientists from the Old Persian days until today. This paper presents and characterizes pure data from original references of ITM about wound remedies and verifies their function by reviewing articles from three databases (Google Scholar, PubMed, and Scopus), which could be an interesting and comprehensive resource for future researchers interested in traditional medicine (TM) generally and in ITM in particular. Selected natural compounds from the references were divided into 5 groups, including herbs, herbal products, animal products, minerals, and animals. In total, 23 natural compounds with regard to the current state of knowledge and ITM were introduced and verified. The present review will provide better insights into ITM and its extensive experience in topics such as wound healing.

MicroRNA-26a-5p as a potential predictive factor for determining the effectiveness of trastuzumab therapy in HER-2 positive breast cancer patients.

BACKGROUND: Breast cancer (BC) is known as the most prevalent type of cancer among women. Trastuzumab, as an anticancer drug, has been used broadly in human epidermal growth factor receptor 2 (HER-2) positive (+) BC patients. Moreover, accumulating evidence has demonstrated that microRNAs is involved in the pathogenesis BC. Hence, we aimed to investigate the effect of trastuzumab on the expression levels of microRNA-26a in HER-2 positive BC patients. METHODS: This study was conducted among HER-2 + and HER-2 Negative (-) BC patients. Serum expression of microRNA-26a was detected by real-time PCR. Then, we assessed the correlations of microRNA-26a levels with multiple clinico-pathological characteristics of BC. RESULTS: In HER-2 + patients, the microRNA-26a expression significantly increased after treatment with Docetaxel/Trastuzumab in comparison to before the treatment levels (p.value = 0.01). However, this overexpression in HER-2-patients after treatment with Docetaxel was not significant compared to the levels before the treatment (p.value = 0.14). In addition, the expression of microRNA -26a has significantly increased in HER-2 + patients who were ≤48 years old and premenopausal after the treatment with Docetaxel/Trastuzumab when compared to the levels before the treatment (p.value = 0.039 vs. 0.031, respectively). Furthermore, there was a significant correlation between the expression of microRNA -26a and the tumor size, stage, estrogen receptor (ER) and progesterone receptor (PR) status in the HER-2 + group before and after the treatment (p.value = 0.043, 0.042, 0.049 and 0.034 respectively). CONCLUSIONS: Trastuzumab led to overexpression of microRNA-26a in HER-2 + BC patients. It seems that the detecting microRNA -26a expression levels, during or after the trastuzumab therapy could be a useful biomarker for monitoring the therapeutic response in HER-2 + BC patients. However, further studies on large populations of women with HER-2+ BC are needed to explore this possible novel biomarker, in more detail, within various clinical contexts.

Competing Endogenous RNAs (CeRNAs): Novel Network in Neurological Disorders.

Neurological disorders (NDs) comprise a broad range of diseases affecting both central and peripheral nervous systems. These complex multifactorial diseases have a high rate of mortality all over the world, particularly in aged people. Today, new evidence drove our attention to the notable role of noncoding RNAs (ncRNAs) in the progression of NDs. Remarkably, recent studies showed that there are close communication networks among RNA transcripts such as mRNAs, long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), and pseudogenes for regulating each other's expression through competing for shared sequences in microRNAs (miRs). This concept is a new area of ongoing research recognized as competing endogenous RNA (ceRNA) hypothesis. CeRNAs are novel regulatory molecules in a wide range of biological stages and pathological contexts. Indeed, the disruption of ceRNA networks (ceRNETs) may affect neural development genes and induce neuropathological changes leading to the development of NDs. Because of this, identifying the correlation of ceRNETs with NDs will open a new window for expanding our knowledge about this field of science, as well as creating novel roads for developing specific diagnostic biomarkers for NDs management. Owing to these unique features, exploring the exact role of ceRNAs is a hot topic in NDs investigations. Hence, in this review, we will summarize the evidence supporting ceRNETs in the regulation of NDs-related gene expression.

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.

MicroRNAs in breast cancer: Roles, functions, and mechanism of actions.

Breast cancer is one of the most lethal malignancies in women in the world. Various factors are involved in the development and promotion of the malignancy; most of them involve changes in the expression of certain genes, such as microRNAs (miRNAs). MiRNAs can regulate signaling pathways negatively or positively, thereby affecting tumorigenesis and various aspects of cancer progression, particularly breast cancer. Besides, accumulating data demonstrated that miRNAs are a novel tool for prognosis and diagnosis of breast cancer patients. Herein, we will review the roles of these RNA molecules in several important signaling pathways, such as transforming growth factor, Wnt, Notch, nuclear factor-κ B, phosphoinositide-3-kinase/Akt, and extracellular-signal-regulated kinase/mitogen activated protein kinase signaling pathways in breast cancer.

New insights into the role of microRNAs and long noncoding RNAs in most common neurodegenerative diseases.

Neurodegenerative diseases (NDs) are a diversity of neurological disorders characterized by the progressive degeneration of the structure and function of the central nervous system (CNS). The most common NDs are Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Recently, many studies have investigated associations between common NDs with noncoding RNAs (ncRNAs) molecules. ncRNAs are regulatory molecules in the normal functioning of the CNS. Two of the most important ncRNAs are microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). These types of ncRNAs are involved in different biological processes including brain development, maturation, differentiation, neuronal cell specification, neurogenesis, and neurotransmission. Increasing data has demonstrated that miRNAs and lncRNAs have strong correlations with the development of NDs, particularly gene expression. Besides, ncRNAs can be introduced as new biomarkers for diagnosis and prognosis of NDs. Hence, in this review, we summarized the involvement of various miRNAs and lncRNAs in most common NDs followed by a correlation of ncRNAs dysregulation with the AD, PD, and HD.

Multiple functions of p27 in cell cycle, apoptosis, epigenetic modification and transcriptional regulation for the control of cell growth: A double-edged sword protein.

The cell cycle is controlled by precise mechanisms to prevent malignancies such as cancer, and the cell needs these tight and advanced controls. Cyclin dependent kinase inhibitor p27 (also known as KIP1) is a factor that inhibits the progression of the cell cycle by using specific molecular mechanisms. The inhibitory effect of p27 on the cell cycle is mediated by CDKs inhibition. Other important functions of p27 include cell proliferation, cell differentiation and apoptosis. Post- translational modification of p27 by phosphorylation and ubiquitination respectively regulates interaction between p27 and cyclin/CDK complex and degradation of p27. In this review, we focus on the multiple function of p27 in cell cycle regulation, apoptosis, epigenetic modifications and post- translational modification, and briefly discuss the mechanisms and factors that have important roles in p27 functions.

Multiple Functions of Long Non-Coding RNAs in Oxidative Stress, DNA Damage Response and Cancer Progression.

In addition to aberrant alternation of transcriptome, it is now suggested that dysregulation of the non-coding transcripts, particularly long non-coding RNAs (lncRNAs), which comprise the majority of the genome, is contributed to cancer initiation and progression. As the result of recent huge efforts, the possible roles of numerous lncRNAs in the human cancers were characterized, as well as various strategies with inhibitory effects to target these transcripts on the transformed cells. Moreover, DNA damage response (DDR) pathway is a complex regulatory network responsible for the identification of disruptions in DNA structure, integrity and stability- it is reported to be associated with the up-regulation and down-regulation of lncRNAs. This review explores the involvement of the various lncRNAs in different human cancers, afterwards discusses the association of the lncRNAs expression with the DDR and oxidative stress, which are implicated in a myriad pathophysiological and physiological intra- and extracellular damages. J. Cell. Biochem. 119: 223-236, 2018. © 2017 Wiley Periodicals, Inc.