Screening of natural epigenetic modifiers for managing glycemic memory and diabetic nephropathy.

Short hyperglycaemic episodes trigger metabolic memory (MM) in which managing hyperglycaemia alone is not enough to tackle the progression of Diabetic nephropathy on the epigenetic axis. We used a structural similarity search approach to identify phytochemicals similar to natural epigenetic modifiers and docked with SIRT1 protein and did ADME studies. We found that UMB was 84.3% similar to esculetin. Upon docking, we found that UMB had a binding energy of -9.2 kcal/mol while the standard ligand had -11.8 kcal/mol. ADME showed UMB to be a good lead. 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay showed it to be a good antioxidant with IC50 of 107 µg/mL and MTT stands for 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) showed that it does not promote cell death. Oxidative biomarkers in vitro showed UMB was able to ameliorate glycemic memory induced by high glucose. Western blot revealed decreased histone acetylation under hyperglycaemic conditions and upon treatment with UMB along with DR, its levels increased. This led us to check our hypothesis of whether concomitant diet reversal (DR) together with UMB can alleviate high-fat diet-induced metabolic memory and diabetic nephropathy (DN) in SD rats. UMB was able to decrease blood glucose, lipid, renal, and liver profile concluding UMB was able to ameliorate DN and MM by increasing the histone acetylation level.

Nephro-protective effects of alpha-lipoic acid in type I diabetes.

Type 1 diabetes (T1D) is an insulin-dependent autoimmune condition. Short chain fatty acids (SCFAs) are volatile fatty acids with 1-6 carbon atoms that influence glucose storage in the body and can reduce appetite, potentially decreasing T1D risk. Alpha-lipoic acid (α-LA), a type of SCFA, has previously been used to treat diabetic neuropathy and inflammation due to its antioxidant properties. This study aims to assess α-LA's protective effects against T1D and associated kidney damage in rats induced with streptozotocin. Diabetic rats were treated with α-LA orally for 15 days, resulting in improved blood glucose (56% decrease) and kidney function markers like blood urea nitrogen, creatinine and uric acid. α-LA also showed significant antioxidant effects by decreasing LPO as well as improving activities of antioxidant enzymes like superoxide dismutase, catalase and glutathione-S transferase and alleviated kidney damage caused by diabetes. Docking experiments suggest that α-LA may regulate diabetes-related changes at the epigenetic level through interactions with the SIRT1 protein, indicating its potential as a target for future antidiabetic drug development.

Association between obesity, inflammation and insulin resistance: Insights into signaling pathways and therapeutic interventions.

Obesity, a metabolic disorder, is becoming a worldwide epidemic that predominantly increases the risk for various diseases including metabolic inflammation, insulin resistance, and cardiovascular diseases. However, the mechanisms that link obesity with other metabolic diseases are not completely understood. In obesity, various inflammatory pathways that cause inflammation in adipose tissue of an obese individual become activated and exacerbate the disease. Obesity-induced low-grade metabolic inflammation perturbates the insulin signaling pathway and leads to insulin resistance. Researchers have identified several pathways that link the impairment of insulin resistance through obesity-induced inflammation like activation of Nuclear factor kappa B (NF-κB), suppressor of cytokine signaling (SOCS) proteins, cJun-N-terminal Kinase (JNK), Wingless-related integration site (Wnt), and Toll-like receptor (TLR) signaling pathways. In this review article, the published studies have been reviewed to identify the potential and influential role of different signaling pathways in the pathogenesis of obesity-induced metabolic inflammation and insulin resistance along with the discussion on potential therapeutic strategies. Therapies targeting these signaling pathways show improvements in metabolic diseases associated with obesity, but require further testing and confirmation through clinical trials.

Diabetic Nephropathy: Pathogenesis to Cure.

Diabetic nephropathy (DN) is a leading cause of end-stage renal disorder (ESRD). It is defined as the increase in urinary albumin excretion (UAE) when no other renal disease is present. DN is categorized into microalbuminuria and macroalbuminuria. Factors like high blood pressure, high blood sugar levels, genetics, oxidative stress, hemodynamic and metabolic changes affect DN. Hyperglycemia causes renal damage through activating protein kinase C (PKC), producing advanced end glycation products (AGEs) and reactive oxygen species (ROS). Growth factors, chemokines, cell adhesion molecules, inflammatory cytokines are found to be elevated in the renal tissues of the diabetic patient. Many different and new diagnostic methods and treatment options are available due to the increase in research efforts and progression in medical science. However, until now, no permanent cure is available. This article aims to explore the mechanism, diagnosis, and therapeutic strategies in current use for increasing the understanding of DN.

Targeting epigenetic regulators for treating diabetic nephropathy.

Diabetes is accompanied by the worsening of kidney functions. The reasons for kidney dysfunction mainly include high blood pressure (BP), high blood sugar levels, and genetic makeup. Vascular complications are the leading cause of the end-stage renal disorder (ESRD) and death of diabetic patients. Epigenetics has emerged as a new area to explain the inheritance of non-mendelian conditions like diabetic kidney diseases. Aberrant post-translational histone modifications (PTHMs), DNA methylation (DNAme), and miRNA constitute major epigenetic mechanisms that progress diabetic nephropathy (DN). Increased blood sugar levels alter PTHMs, DNAme, and miRNA in kidney cells results in aberrant gene expression that causes fibrosis, accumulation of extracellular matrix (ECM), increase in reactive oxygen species (ROS), and renal injuries. Histone acetylation (HAc) and histone deacetylation (HDAC) are the most studied epigenetic modifications with implications in the occurrence of kidney disorders. miRNAs induced by hyperglycemia in renal cells are also responsible for ECM accumulation and dysfunction of the glomerulus. In this review, we highlight the role of epigenetic modifications in DN progression and current strategies employed to ameliorate DN.

p-Coumaric acid attenuates high-fat diet-induced oxidative stress and nephropathy in diabetic rats.

The prevalence of persistent hyperglycaemia during diabetes, impair antioxidant defence system and generate reactive oxygen species, which majorly contribute to its progression and associated complications. Phytochemicals were suggested to scavenge-free radicals and exert antioxidant effects required to improve insulin sensitivity and reduce the occurrence of diabetes-associated complications. We hypothesise that a phenolic phytochemical p-coumaric can reduce diabetes-induced oxidative stress and improve diabetes-associated nephropathy in rats. The aim of this study is to analyse the protective effects of p-coumaric acid against diabetes-induced oxidative stress and nephropathy in high-fat diet-induced diabetic rats. The oral feeding of p-coumaric acid (20 mg/kg for 12 weeks) was found to significantly decrease the elevated levels of blood glucose in high-fat diet-induced type 2 diabetic rats. p-Coumaric acid treatment also decreases the kidney weight whilst increasing the total body weight of diabetic rats. Furthermore whilst evaluation of the different renal functioning tests, p-coumaric acid significantly improves histopathological changes and the levels of urea, creatinine and uric acid in serum of diabetic rats, which was otherwise elevated under diabetic conditions. Our results also highlight that p-coumaric acid is an efficient compound with antioxidant properties and improves the diabetes-induced change in lipid peroxidation and activities of antioxidant enzymes: catalase, glutathione-S-transferase and superoxide dismutase. p-Coumaric acid thus possesses the potential to prevent diabetic nephropathy by reducing oxidative stress and can thus serve as a potential drug target for pharmaceutical companies.

Metabolic memory and diabetic nephropathy: Beneficial effects of natural epigenetic modifiers.

Nephropathy is one of the most frequent complications of chronic diabetes. The main reason for nephropathy despite being hyperglycemia, but it progresses even after good glycemic control has been achieved in diabetic patients. The effects of prior exposure to high blood glucose conditions depend upon the severity and duration of this exposure, indicating a "metabolic memory" phenomenon. Hyperglycemia not only increases oxidative stress but is also alleged to start several biochemical anomalies and alter gene expression associated with metabolic homeostasis. High glucose levels induce epigenetic modifications that alter gene expression without changing DNA sequences. These epigenetic modifications have shown to be reversible and have the potential to cease adverse effects if good glycemic control is achieved from initiation of diabetes. However, if good glycemic control is not achieved for months, these modifications stand firm to reversals. Therapies and drugs have been in use to prevent epigenetic modifications and oxidative stress, which also helped in ameliorating diabetic nephropathy. But these synthetic drugs are loaded with side effects like increased body weight, kidney dysfunction etc. So phytochemicals are emerging as alternatives and many of them have already been used to treat nephropathy. But still, there is rigorous need to evaluate phytochemicals which can regulate epigenetic events and have the potential to decelerate the further progression of these life-threatening diseases. In this review article we discuss the potential epigenetic modifiers from plants that can erase metabolic memory and can thus be protective against diabetic nephropathy.

Hybrid nanoparticles for the topical delivery of norfloxacin for the effective treatment of bacterial infection produced after burn.

The present study was designed to investigate the solubility and penetrability of norfloxacin after the topical application of developed lipid-polymer hybrid nanoparticle (LPN) formulation. The core shell of the LPNs formulation was composed of poly (lactic-co-glycolic acid) that is highly lipophilic in nature, thus control the release of drug. The developed formulations were characterised for size, shape (transmission electron microscopy [TEM], scanning electron microscopy [SEM], and atomic force microscopy), entrapment efficiency, Fourier transform infra-red (FTIR) spectroscopy, differential scanning calorimetry (DSC) and thermo gravimetric analysis (TGA). Moreover, in vitro skin permeation studies were performed to determine release profile of the drug. Norfloxacin loaded nanoparticles retained there antimicrobial efficacy against Staphylococcus aureus and Pseudomonas aeruginosa. Stability study was suggested that the suitable storage condition should be at 4 ± 2 °C/60 ± 5% RH for the LPNs. Therefore, these nanoparticles showed a safe and effective long-lasting approach for long treatment of bacterial infections due to burn.

Lipid-polymer hybrid nanoparticles: Development & statistical optimization of norfloxacin for topical drug delivery system.

Poly lactic acid is a biodegradable, biocompatible, and non-toxic polymer, widely used in many pharmaceutical preparations such as controlled release formulations, parenteral preparations, surgical treatment applications, and tissue engineering. In this study, we prepared lipid-polymer hybrid nanoparticles for topical and site targeting delivery of Norfloxacin by emulsification solvent evaporation method (ESE). The design of experiment (DOE) was done by using software to optimize the result, and then a surface plot was generated to compare with the practical results. The surface morphology, particle size, zeta potential and composition of the lipid-polymer hybrid nanoparticles were characterized by SEM, TEM, AFM, and FTIR. The thermal behavior of the lipid-polymer hybrid nanoparticles was characterized by DSC and TGA. The prepared lipid-polymer hybrid nanoparticles of Norfloxacin exhibited an average particle size from 178.6 ± 3.7 nm to 220.8 ± 2.3 nm, and showed very narrow distribution with polydispersity index ranging from 0.206 ± 0.36 to 0.383 ± 0.66. The surface charge on the lipid-polymer hybrid nanoparticles were confirmed by zeta potential, showed the value from +23.4 ± 1.5 mV to +41.5 ± 3.4 mV. An Antimicrobial study was done against Staphylococcus aureus and Pseudomonas aeruginosa, and the lipid-polymer hybrid nanoparticles showed potential activity against these two. Lipid-polymer hybrid nanoparticles of Norfloxacin showed the %cumulative drug release of 89.72% in 24 h. A stability study of the optimized formulation showed the suitable condition for the storage of lipid-polymer hybrid nanoparticles was at 4 ± 2 °C/60 ± 5% RH. These results illustrated high potential of lipid-polymer hybrid nanoparticles Norfloxacin for usage as a topical antibiotic drug carriers.

PEGylated liposomes of anastrozole for long-term treatment of breast cancer: in vitro and in vivo evaluation.

The aim of present study was to develop conventional and PEGylated (long circulating), liposomes containing anastrozole (ANS) for effective treatment of breast cancer. ANS is a third-generation non-steroidal aromatase inhibitor of the triazole class used for the treatment of advanced and late-stage breast cancer in post-menopausal women. Under such disease conditions the median duration of therapy should be prolonged until tumor regression ends (>31 months). Liposomes were prepared by the thin film hydration method by using ANS and various lipids such as soyaphosphatidyl choline, cholesterol and methoxy polyethylene glycol distearoyl ethanolamine in different concentration ratios and evaluated for physical characteristics, in vitro drug release and stability. Optimized formulations of liposome were studied for in vitro cytotoxic activity against the BT-549 and MCF-7 cell lines and in vivo behavior in Wistar rats. Preformulation studies, both Fourier transform infrared study and differential scanning calorimetry analysis showed no interaction between the drug and the excipients used in the formulations. The optimized formulations AL-07 and AL-09 liposomes showed encapsulation efficiencies in the range 65.12 ± 1.05% to 69.85 ± 3.2% with desired mean particle size distribution of 101.1 ± 5.9 and 120.2 ± 2.8 nm and zeta potentials of -43.7 ± 4.7 and -62.9 ± 3.5 mV. All the optimized formulations followed Higuchi-matrix release kinetics and when plotted in accordance with the Korsemeyer-Peppas method, the n-value 0.5 < n < 1.0 suggests an anomalous (non-Fickian) transport. Likewise, the PEGylated liposomes showed greater tumor growth inhibition on BT-549 and MCF-7 cell lines from in vitro cytotoxicity studies (p < 0.05). Pharmacokinetic study of conventional and PEGylated liposomes in Wistar rats demonstrated a 3.33- and 20.28-fold increase in AUC(0-∞) values when compared to pure drug (p < 0.001). Among the formulations, PEGylated liposomes showed encouraging results by way of their long circulation and sustained delivery properties for effective treatment of breast cancer.