75 research outputs found
Computational Analysis of Untapped Natural Compounds of Dodonaea viscosa as a Potential Drug Target against Rheumatoid Arthritis
No full textDocumentos apresentados no âmbito do reconhecimento de graus e diplomas estrangeirosRheumatoid arthritis is an inflammatory condition that damages joints and cartilage over time. It results in swelling of the synovial lining, which makes movement difficult. Although the exact cause of RA is still unknown, it is well established that genetic and
environmental variables have a role in its development. The condition is shown to affect females three times more frequently than males. The WHO estimates that it affects 0.3–1 percent of the world's population. In contrast, the incidence in Pakistan varies from 0.5 to 1.9 percent. There are numerous therapeutic options available for it, including NSAIDs, DMARDs, and biologics. These therapies aid in reducing disease-related symptoms, but their adverse effects have restricted their use. Thus, scientists are looking into herbal
plants as a modern remedy for RA that has a high potential for treatment while minimizing side effects and is non-toxic, affordable, and cost-effective.
The therapeutic qualities of medicinal plants are derived from bioactive metabolites that help them fight pathogenic diseases. Similarly, Dodonaea viscosa (L.) Jacq., an ethnobotanical plant, was used in this study to assess the effectiveness of its components in the treatment of rheumatoid arthritis. D. viscosa is widely distributed close to Margalla Hills in Pakistan. It is an evergreen, blooming hardy shrub with a variety of plant parts that are said to have anti-inflammatory, antibacterial, wound healing, and antioxidant
effects.
Phenols, flavonoids, steroids, sterols, saponins, coumarins, tannins, and terpenoids were all detected in D. viscosa ethanol extract. The DPPH and FRAP experiments demonstrated good antioxidant activity. Similarly, D. viscosa extract exhibited significant anti-inflammatory potential in tests like the protein denaturation assay and the HRBC membrane stabilization experiment.
In silico studies revealed that nine of the 480 compounds found in D. viscosa ethanol extract had drug-like properties. TNF-α, STAT3, and IL-6 were found to be among the top three RA-related genes in a HUB gene analysis of the top 200 RA genes. The signaling pathways of these genes result in the activation of JAK/STAT, Nuclear factor κB (NF-κB), and Mitogen-activated protein kinases (MAPKs) pathways, respectively.
Significant findings were obtained from the molecular docking analysis of three protein targets with nine ligands. The compound 06, 4-(1-Hydroxy-3-oxo-1H-isoindol-2-yl) benzoic acid, had the lowest binding score for TNF-α. Comparatively, compound 7 (3-
(2,3-Dihydro-1,4-benzodioxin-6-yl)-3-hydroxy-2H-isoindol-1-one) displayed the lowest binding energies for STAT3 and IL-6. The docked complex's highest stability is indicated by its lowest binding energy. The MD simulation findings for these three complexes showed that only compound 6-TNF complex remained stable, proving that compound 06, 4-(1-Hydroxy-3-oxo-1H-isoindol-2-yl) benzoic acid, is a good small molecule inhibitor of TNF-α and may one day be employed as a potent drug.
The current study concludes that D.viscosa have excellent inhibitory potential against TNF-α, which plays a significant role in the disease. However, additional in-vitro and invivo testing is strongly advised to assess the efficacy of nine compounds in alleviating the
effects of Rheumatoid arthritis progression
The Mantle of Advanced Glycation End Products in Micro-and Macrovascular Complications of Type 2 Diabetes Mellitus
No full textThymus serpyllum Exhibits Anti-Diabetic Potential in Streptozotocin-Induced Diabetes Mellitus Type 2 Mice: A Combined Biochemical and In Vivo Study
No full textType 2 diabetes mellitus (T2DM) is a complex metabolic disorder that is characterized by hyperglycemia, insulin resistance, and lack of insulin production. It has been previously reported that Thymus serpyllum has therapeutic potential against many diseases. To investigate the antidiabetic action of Thymus serpyllum, this study aimed to analyze its restorative impact in diabetic mice, in which it was administered in diet. Diabetes was induced in BALB/c mice fed with a high-fat diet and two intraperitoneal injections of streptozotocin. With the onset of diabetes, the mice were administered daily with aqueous extract of Thymus serpyllum (500 mg/kg/d and 800 mg/kg/d) for 4 weeks. Body weight and fasting blood glucose levels were measured after every 1 week of the treatment. Subsequently, intraperitoneal glucose tolerance and insulin tolerance tests were conducted. In addition, liver tissue was isolated for assessment in terms of levels of gene expression of the AMPK, IRS1, and GLUT2 gene. Treatment with the aqueous extract of Thymus serpyllum was found to be significantly effective in controlling hyperglycemia and improving glucose and insulin tolerance. Predictable with these impacts, the extract of Thymus serpyllum upregulated the AMPK expression at the mRNA level, as well as upregulating the expression of IRS1 and GLUT2 gene. Histopathological examination of the liver, kidney, and pancreas also revealed the restorative impact in terms of cellular morphology. The results hence demonstrated that oral administration of aqueous extract of Thymus serpyllum can potentially attenuate hyperglycemia in the liver muscle of streptozotocin (STZ)-induced diabetic mice via AMPK and IRS1 upregulation
Evaluation of Antidiabetic Activity of Biogenic Silver Nanoparticles Using Thymus serpyllum on Streptozotocin-Induced Diabetic BALB/c Mice
No full textType 2 Diabetes Mellitus is one of the most common metabolic disorders, and is characterized by abnormal blood sugar level due to impaired insulin secretion or impaired insulin action—or both. Metformin is the most commonly used drug for the treatment of Type 2 Diabetes Mellitus, but due to its slow mode of action and various side effects it shows poor and slow therapeutic response in patients. Currently, scientists are trying to tackle these limitations by developing nanomedicine. This research reports novel synthesis of silver nanoparticles using aqueous extract of Thymus serpyllum and aims to elucidate its therapeutic potential as an antidiabetic agent on streptozotocin induced diabetic BALB/c mice. Thymus serpyllum mediated silver nanoparticles were characterized through UV, SEM, XRD, and FTIR. The alpha amylase inhibition and antioxidant activity were checked through [Formula: see text] amylase and DPPH radical scavenging assay, respectively. To check the effect of silver nanoparticles on blood glucose levels FBG, IPGTT, ITT tests were employed on STZ induced BALB/c mice. To assess the morphological changes in the anatomy of liver, pancreas, and kidney of BALB/c mice due to silver nanoparticles, histological analysis was done through H&E staining system. Finally, AMPK and IRS1 genes expression analysis was carried out via real time PCR. Silver nanoparticles were found to be spherical in shape with an average size of 42 nm. They showed an IC50 of 8 [Formula: see text] g/mL and 10 [Formula: see text] g/mL for [Formula: see text] amylase and DPPH assay, respectively. Our study suggests that silver nanoparticles—specifically 10 mg/kg—cause a significant increase in the expression of AMPK and IRS1, which ultimately increase the glucose uptake in cells. Thymus serpyllum mediated silver nanoparticles possess strong antioxidant and antidiabetic potential and can further be explored as an effective and cheaper alternative option for treatment of Type 2 Diabetes Mellitus
Molecular Link between Glo-1 Expression and Markers of Hyperglycemia and Oxidative Stress in Vascular Complications of Type 2 Diabetes Mellitus
No full textChronic hyperglycemia and oxidative stress in Type 2 Diabetes Mellitus trigger cellular dysfunction via the formation of Advanced Glycation End Products (AGEs), resulting in dicarbonyl stress. Glyoxalase-1 (Glo-1) is the main defense against dicarbonyl stress. The aim of this study was to explore any cross-talk between Glo-1 and markers of hyperglycemia and oxidative stress. The siRNA-mediated downregulation of Glo-1 was performed in human microvascular endothelial cell line (HMEC-1). A Glo-1 transgenic rat model was developed. Glo-1 activity, as determined spectrophotometrically, and methylglyoxal were quantified using UPLC-MS/MS and the expression of representative markers of hyperglycemia and oxidative stress was performed using quantitative real-time PCR. A significant increase in the expression of Vascular Cell Adhesion Molecule-1 (VCAM-1) was observed in the case of the siRNA-mediated downregulation of Glo-1 in the microvasculature model under hyperglycemic conditions (p-value p-value = 0.0125). The expression of thioredoxin interacting protein (TXNIP) was found to be significantly upregulated in wildtype diabetic conditions vs. Glo-1 transgenic control conditions (p-value = 0.008), whereas the downregulation of Glo-1 had no impact on TXNIP expression. These findings substantiate the role of VCAM as an important marker of dicarbonyl stress (represented by Glo-1 downregulation), as well as of hyperglycemia, in diabetic vascular complications. Our findings also suggest a potential feedback loop that may exist between Glo-1 and TXNIP, as the highest expression of TXNIP is observed in cases of wildtype diabetic conditions, and the lowest expression of TXNIP is observed when Glo-1 transgene is being expressed in absence of dicarbonyl stress
Identification and in silico analysis of functional SNPs of human TAGAP protein: A comprehensive study.
No full textGenetic polymorphisms in TAGAP gene have been associated with many diseases including rheumatoid arthritis, multiple sclerosis and other autoimmune disorders. Identifying functional SNPs in such disease associated genes is an uphill task hence before planning larger population study, it is better to scrutinize putative functional SNPs. In this study we used various computational approaches to identify nsSNPs which are deleterious to the structure and/or function of TAGAP protein that might be causing these diseases. Computational analysis was performed by five different in silico tools including SIFT, PROVEAN, PolyPhen-2, PhD-SNP and SNPs&GO. The study concludes that mutations of Glycine → Glutamic Acid at position 120, Glycine → Tryptophan at position 141 and Valine → Methionine at position 151 are major mutations in native TAGAP protein which might contribute to its malfunction and ultimately causing disease. The study also proposed 3D structures of native TAGAP protein and its three mutants. Future studies should consider these nsSNPs as main target mutations in various diseases involving TAGAP malfunction. This is the first comprehensive study, where TAGAP gene variants were analyzed using in silico tools hence will be of great help while considering large scale studies and also in developing precision medicines for cure of diseases related to these polymorphisms. Furthermore, animal models of various autoimmune diseases and having these mutations might be of help in exploring their precise roles
Regulatory MicroRNAs in T2DM and Breast Cancer
No full textMicroRNAs orchestrate the tight regulation of numerous cellular processes and the deregulation in their activities has been implicated in many diseases, including diabetes and cancer. There is an increasing amount of epidemiological evidence associating diabetes, particularly type 2 diabetes mellitus, to an elevated risk of various cancer types, including breast cancer. However, little is yet known about the underlying molecular mechanisms and even less about the role miRNAs play in driving the tumorigenic potential of the cell signaling underlying diabetes pathogenesis. This article reviews the role of miRNA in bridging the diabetes–breast cancer association by discussing specific miRNAs that are implicated in diabetes and breast cancer and highlighting the overlap between the disease-specific regulatory miRNA networks to identify a 20-miRNA signature that is common to both diseases. Potential therapeutic targeting of these molecular players may help to alleviate the socioeconomic burden on public health that is imposed by the type 2 diabetes mellitus (T2DM)–breast cancer association
Identification and in silico analysis of functional SNPs of human TAGAP protein: A comprehensive study
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