Effect of Prunetin on Streptozotocin-Induced Diabetic Nephropathy in Rats - a Biochemical and Molecular Approach.

In the modern era, chronic kidney failure due to diabetes has spread across the globe. Prunetin (PRU), a component of herbal medicines, has a broad variety of pharmacological activities; these may help to slow the onset of diabetic kidney disease. The anti-nephropathic effects of PRU have not yet been reported. The present study explored the potential nephroprotective actions of PRU in diabetic rats. For 28 days, nephropathic rats were given oral doses of PRU (20, 40, and 80 mg/kg). Body weight, blood urea, creatinine, total protein, lipid profile, liver marker enzymes, carbohydrate metabolic enzymes, C-reactive protein, antioxidants, lipid peroxidative indicators, and the expression of insulin receptor substrate 1 (IRS-1) and glucose transporter 2 (GLUT-2) mRNA genes were all examined. Histological examinations of the kidneys, liver, and pancreas were also performed. The oral treatment of PRU drastically lowered the blood glucose, HbA1c, blood urea, creatinine, serum glutamic-oxaloacetic transaminase, serum glutamic pyruvic transaminase, alkaline phosphatase, lipid profile, and hexokinase. Meanwhile, the levels of fructose 1,6-bisphosphatase, glucose-6-phosphatase, and phosphoenol pyruvate carboxykinase were all elevated, but glucose-6-phosphate dehydrogenase dropped significantly. Inflammatory marker antioxidants and lipid peroxidative markers were also less persistent due to this administration. PRU upregulated the IRS-1 and GLUT-2 gene expression in the nephropathic group. The possible renoprotective properties of PRU were validated by histopathology of the liver, kidney, and pancreatic tissues. It is therefore proposed that PRU (80 mg/kg) has considerable renoprotective benefits in diabetic nephropathy in rats.

Therapeutics in Metabolic Diseases.

Metabolic diseases have important effects on the health and healthcare costs of an individual. It adversely affects various body processes. Metabolic diseases are characterized as the accumulation of many conditions that collectively increase a person's risk of atherosclerotic coronary disease, insulin, and diabetes mellitus intolerance, as well as vascular and neurological complications, such as stroke. Rare metabolic disease has also been reported in literatures and clinical research. Understanding the history and causes of the disease, associated symptoms, disease severity, physical and vital evaluations, etc. is recommended to provide or improve some appropriate therapeutic measure. The experience with patients starts with a critical and general presentation to a healthcare provider that may indicate potential conditions such as dyslipidemia, hypertension, and metabolic diseases. The main factors in the treatment and management of metabolic disorders are lifestyle changes. Whenever behavioral changes are not effective or cannot be implemented, pharmacotherapies should be initiated including for most of the rare diseases. Moreover, pharmaceutical molecules are the very commonly used therapies. The prospect of therapy through gene transfer into somatic cells unlocks a new field of treatment and opportunity for people affected by these genetic conditions. Like other medical treatments, many gene therapies can relieve some, though not every indications of a specific disease, which can increase patients' quality of life. Hormone-based therapies are also implemented in the treatment of metabolic diseases. It has been suggested to use herbal extracts with different forms of nano-drug delivery techniques, such as nanobiocomposites, solid lipid nanoparticles, nanoemulsions, green-synthesized gold, zinc oxide, and silver nanoparticles.

The Trend of Organic Based Nanoparticles in the Treatment of Diabetes and Its Perspectives.

Diabetes is an untreatable metabolic disorder characterized by alteration in blood sugar homeostasis, with submucosal insulin therapy being the primary treatment option. This route of drug administration is attributed to low patient comfort due to the risk of pain, distress, and local inflammation/infections. Nanoparticles have indeed been suggested as insulin carriers to allow the drug to be administered via less invasive routes other than injection, such as orally or nasally. The organic-based nanoparticles can be derived from various organic materials (for instance, polysaccharides, lipids, and so on) and thus are prevalently used to enhance the physical and chemical consistency of loaded bioactive compounds (drug) and thus their bioavailability. This review presents various forms of organic nanoparticles (for example, chitosan, dextron, gums, nanoemulsion, alginate, and so on) for enhanced hypoglycemic drug delivery relative to traditional therapies.

In Vitro Antioxidant, Anti-inflammatory, Antimicrobial, and Antidiabetic Activities of Synthesized Chitosan-loaded p-Coumaric Acid Nanoparticles.

BACKGROUND: p-Coumaric acid is a phenolic compound widely distributed in fruits and vegetables that displays an array of therapeutic properties, including antidiabetic effects. Prominent application in diabetes is limited due to its suboptimal pharmacokinetics, poor aqueous solubility, and poor bioavailability. Nanotechnology-based delivery methods have been developed to address these limitations and improve the therapeutic uses of p-coumaric acid, and the nanoencapsulation method is emerging as a feasible alternative. OBJECTIVE: The objective of this study is to synthesize p-coumaric acid nanoparticles (PCNPs) and to evaluate their In Vitro activities. METHODS: The PCNPs were synthesized by the nanoprecipitation method and characterized by UV-visible spectroscopy, zeta potential, Fourier-transform infrared (FTIR) spectroscopy, and scanning electron microscopy (SEM) with dispersive energy X-ray (EDX) analysis. In addition, the PCNPs were analyzed for In Vitro antioxidant activity using six different free radical scavenging assays and were also analyzed for antimicrobial, anti-inflammatory, antithrombotic, and antidiabetic effects. RESULTS: The formation of PCNPs was confirmed by UV-visible spectra at 283 nm, and FTIR analysis revealed the reduction and capping of the chitosan nanoparticles. SEM was used to assess the size and shape of the PCNPs, and the high absorption property of the PCNPs was investigated using EDX analysis. The PCNPs had significant antioxidant, hydrogen peroxide (H2O2), lipid peroxidation (LPO), superoxide and nitric oxide (NO) radical scavenging power activities, and showed potent antimicrobial, anti-inflammatory, antithrombotic, and antidiabetic activities. CONCLUSION: The present study suggests that PCNPs can be used as a potential medication delivery approach to provide a greater nephroprotective effect in the treatment of diabetic nephropathy. To the best of our knowledge, this is the first attempt at the synthesis of chitosan-loaded PCNPs.

p-Coumaric Acid Nanoparticles Ameliorate Diabetic Nephropathy via Regulating mRNA Expression of KIM-1 and GLUT-2 in Streptozotocin-Induced Diabetic Rats.

Diabetic nephropathy (DN) has become a leading cause of end-stage renal failure worldwide. The goal of the current study was to examine the protective effects of chitosan-loaded p-Coumaric acid nanoparticles (PCNPs) in nephrotoxicity induced by streptozotocin (STZ). Because of the antidiabetic, anti-inflammatory, and antioxidant properties of PCNPs, the development of DN may be considerably decreased. In this study, the rats received a single intraperitoneal injection (i.p.) of STZ (45 mg/kg) to induce DN. PCNPs were given orally 80 mg/kg b.w to the rats for a duration of four weeks. Body weight, kidney weight, blood glucose, and insulin levels were measured at the end of the experiment. Serum and urine parameters were also examined, along with the histological, immunobiological, and tumor necrosis factor (TNF) and interleukin-6 (IL-6) expression of the nephrotic rats. To comprehend the impact of PCNPs, the expression patterns of the kidney injury molecule (KIM-1) and glucose transporter-2 (GLUT-2) were evaluated. Administration of PCNPs significantly increased body weight, decreased kidney weight and also ameliorated blood glucose levels in the nephropathic rats. The administration of PCNPs also reverted the levels of urea, serum creatinine, urinary NAG, ß-glucuronidase and albumin to near-normal levels. The administration of PCNPs also caused the levels of serum and urine parameters to return to near-normal levels. Additionally, the PCNP-treated rats had markedly reduced TNF-α, IL-6, and KIM-1 expressions as well as enhanced GLUT-2 mRNA expression. Our findings clearly showed that PCNP administration prevents the onset of DN in rats by lowering hyperglycemia, decreasing inflammation, and improving the expression of GLUT-2 mRNA in nephropathic rats.

Metabolic Bone Diseases and New Drug Developments.

Metabolic bone diseases are serious health issues worldwide, since several million individuals over the age of 50 are at risk of bone damage and should be worried about their bone health. One in every two women and one in every four men will break a bone during their lifetime due to a metabolic bone disease. Early detection, raising bone health awareness, and maintaining a balanced healthy diet may reduce the risk of skeletal fractures caused by metabolic bone diseases. This review compiles information on the most common metabolic bone diseases (osteoporosis, primary hyperparathyroidism, osteomalacia, and fluorosis disease) seen in the global population, including their symptoms, mechanisms, and causes, as well as discussing their prevention and the development of new drugs for treatment. A large amount of research literature suggests that balanced nutrition and balanced periodic supplementation of calcium, phosphate, and vitamin D can improve re-absorption and the regrowth of bones, and inhibit the formation of skeletal fractures, except in the case of hereditary bone diseases. Meanwhile, new and improved drug formulations, such as raloxifene, teriparatide, sclerostin, denosumab, and abaloparatide, have been successfully developed and administered as treatments for metabolic bone diseases, while others (romososumab and odanacatib) are in various stages of clinical trials.

Preparation and Optimization of Peppermint (Mentha pipertia) Essential Oil Nanoemulsion with Effective Herbal Larvicidal, Pupicidal, and Ovicidal Activity against Anopheles stephensi.

OBJECTIVES: The Plasmodium parasite is transmitted directly to humans through the Anopheles mosquito bite and causes vector-borne malaria, leading to the transmission of the disease in Southeast Asia, including India. The problem of persistent toxicity, along with the growing incidence of insect resistance, has led to the use of green pesticides to control the spread of the disease in a cost-effective and environment-friendly manner. Based on this objective, this work investigated the larvicidal, pupicidal, and ovicidal activity of Mentha pipertia using a natural nanoemulsion technique. METHODS: GC-MS characterized essential oils of Mentha pipertia leaves were formulated as a nanoemulsion for herbal larvicidal, pupicidal, and ovicidal activities. Size of the nanoemulsion was analyzed by photon correlation spectroscopy. The herbal activities against Anopheles Stephensi of nanoemulsion were evaluated in terms of the lethal concentration for 50% (LC50) and 90% (LC90) to prove low cost, pollution free active effective formulation. RESULTS: Chiral, keto, and alcohol groups are obtained from Mentha pipertia leaves' essential oil, and the nanoemulsions have demonstrated good results in the larvicidal probit analysis, with values of LC50=09.67 ppm and LC90=20.60 ppm. Activity results of the most stable nano formulation with 9.89 nm size showed a significant increase when compared to the bulk. CONCLUSION: The nanoemulsion of Mentha pipertia leaves can be a promising eco-friendly widely available, low-cost herbicide against the Anopheles mosquito.

Lipid Metabolism, Disorders and Therapeutic Drugs - Review.

Different lifestyles have an impact on useful metabolic functions, causing disorders. Different lipids are involved in the metabolic functions that play various vital roles in the body, such as structural components, storage of energy, in signaling, as biomarkers, in energy metabolism, and as hormones. Inter-related disorders are caused when these functions are affected, like diabetes, cancer, infections, and inflammatory and neurodegenerative conditions in humans. During the Covid-19 period, there has been a lot of focus on the effects of metabolic disorders all over the world. Hence, this review collectively reports on research concerning metabolic disorders, mainly cardiovascular and diabetes mellitus. In addition, drug research in lipid metabolism disorders have also been considered. This review explores lipids, metabolism, lipid metabolism disorders, and drugs used for these disorders.

Diabetic Nephropathy - a Review of Risk Factors, Progression, Mechanism, and Dietary Management.

Type 2 diabetes mellitus (T2DM) leads to many health problems like diabetic nephropathy (DN). One of the key factors for chronic kidney disease and end-stage renal disease (ESRD) is T2DM. Extensive work is being done to delineate the pathogenesis of DN and to extend possible remedies. This review is intended to understand the nature of DN risk factors, progression, effects of glycemic levels, and stages of DN. We also explored the novel diagnostic and therapeutic approaches for DN such as gene therapy and stem cell treatments.

Ethno-pharmacological insulin signaling induction of aqueous extract of Syzygium paniculatum fruits in a high-fat diet induced hepatic insulin resistance.

ETHNOPHARMACOLOGICAL RELEVANCE: The ethnopharmacological significance of the fruits of Syzygium paniculatum Gaertn (Magenta Cherry) is widely recognized in the Indian traditional medicine system to treat various disorders, such as diabetes, hyperlipidaemia, hypertension, and cardiovascular problems. AIM OF THE STUDY: This research work investigated the supplementation of the aqueous extract of S. paniculatum fruit (AESPF) on liver function; the molecular effects on the expression of the protein of insulin receptor (IR) and insulin receptor substrate 1 (IRS-1) in high-fat diet-induced hepatic insulin resistance in the rat model. MATERIALS AND METHODS: High-fat diet was used to induce obesity in albino Wistar for 120 days. Biochemical, enzymatic, and histopathological analysis, as well as analysis of hepatic insulin resistance proteins and expression of IRS-1, were performed. RESULTS: The supplementation of AESPF with a dose of 100 mg/kg bw significantly reduced bodyweight, blood sugar, insulin, lipid profiles, and liver enzymes. Hepatic insulin resistance was improved with a reduced level of IR and IRS-1 to protein levels. HFD alters the sensitivity of hepatocytes to insulin due to the down-regulation of insulin receptor proteins. CONCLUSIONS: The fruits of S. paniculatum possess biological activities to alleviate all risky effects by regulating hepatic lipogenesis activity that can be used in the progress of medication for HFD-induced hepatic insulin resistance and metabolic disorders.

Pathophysiology of high fat diet induced obesity: impact of probiotic banana juice on obesity associated complications and hepatosteatosis.

The high fat diet alters intestinal microbiota due to increased intestinal permeability and susceptibility to microbial antigens leads to metabolic endotoxemia. But probiotic juices reported for various health benefits. In this background we hypothesized that pectinase treated probiotic banana juice has diverse effects on HFD induced obesity and non-alcoholic steatohepatitis. 20 weeks fed HFD successfully induced obesity and its associated complications in experimental rats. The supplementation of probiotic banana juice for 5 months at a dose of 5 mL/kg bw/day resulted significant decrease (p < 0.05) in body weight (380 ± 0.34), total fat (72 ± 0.8), fat percentage (17 ± 0.07) and fat free mass (165 ± 0.02). Reduction (p < 0.05) in insulin resistance (5.20 ± 0.03), lipid profile (TC 120 ± 0.05; TG 160 ± 0.24; HDL 38 ± 0.03), liver lipid peroxidation (0.7 ± 0.01), hepatic enzyme markers (AST 82 ± 0.06; ALT 78 ± 0.34; ALP 42 ± 0.22), and hepatic steatosis by increasing liver antioxidant potential (CAT 1.4 ± 0.30; GSH 1.04 ± 0.04; SOD 0.82 ± 0.22) with normal hepatic triglycerides (15 ± 0.02) and glycogen (0.022 ± 0.15) contents and also showed normal liver size, less accumulation of lipid droplets with only a few congestion. It is concluded that the increased intestinal S. cerevisiae yeast can switch anti-obesity, antidiabetic, antioxidative stress, antioxidant and anti-hepatosteatosis effect. This study results will have significant implications for treatment of NAFLD.

Chrysin: Sources, beneficial pharmacological activities, and molecular mechanism of action.

In recent years, public and scientific interest in plant flavonoids has tremendously increased because of their postulated health benefits. This review was mainly focuses on the flavone chrysin (5,7-dihydroxyflavone), which occurs naturally in many plants, honey, and propolis. A number of in vitro and in vivo studies have revealed the therapeutic effects of chrysin against various diseases. In general, chrysin exhibits many biological activities and pharmacological effects, including antioxidant, anti-inflammatory, anticancer, and antiviral activities. Moreover, many studies have reported on the bioavailability of chrysin. Because of its compromised bioavailability and enhanced protein stability, chrysin solid lipid nanoparticle (SLN) synthesis avoids proteolytic degradation and sustained release of drug delivery. To clarify the mechanism of action of chrysin, researchers have investigated the structural binding relationship of chrysin through the docking computation method.

Neuroprotective effect of chrysin on hyperammonemia mediated neuroinflammatory responses and altered expression of astrocytic protein in the hippocampus.

Neuroinflammation is an innate immune response in the central nervous system (CNS) against metabolic and pathogenic toxic wastes. The main hypothesis implies that a state of hyperammonemia which is accountable for both direct and indirect modification in ammonia metabolism with an elevated production of inflammatory cytokines. This study was constructed to explore the modulating effect of chrysin on rudimentary pathophysiologic mechanisms of ammonium chloride (NH4Cl) mediated neuroinflammation in the experimental hyperammonemic rats. NH4Cl was injected intraperitonally (i.p) in male albino wistar rats for a time period of thrice a week for eight consecutive weeks. Initially, the levels of brain ammonia and water content were assessed. Immunohistochemical, RT-PCR and western blotting analysis revealed that the expression of glutamine synthetase (GS) activity and glial fibrillar acidic protein (GFAP) were down-regulated, whereas the expression of TNF-α, IL-1ß, IL-6, p65 NF-κB, iNOS and COX-2 were up-regulated in brain tissue of hyperammonemic rats. Oral supplementation of chrysin (100mg/kg b.w) to hyperammonemic rats considerably restored the levels of brain ammonia, water content, and the expressions of GS, GFAP, TNF-α, IL-1ß, IL-6, p65 NF-κB, iNOS and COX-2. Our findings provided substantial evidence that the chrysin synergistically attenuating the neuroinflammatory mechanism by repressing the expression of proinflammatory cytokines and up-regulating the astrocytic protein expressions via ammonia-reducing strategies. This data suggests that chrysin effectively acts as a therapeutic agent to treat hyperammonemia mediated neuroinflammation.

Clinical aspects of urea cycle dysfunction and altered brain energy metabolism on modulation of glutamate receptors and transporters in acute and chronic hyperammonemia.

In living organisms, nitrogen arise primarily as ammonia (NH3) and ammonium (NH4(+)), which is a main component of the nucleic acid pool and proteins. Although nitrogen is essential for growth and maintenance in animals, but when the nitrogenous compounds exceeds the normal range which can quickly lead to toxicity and death. Urea cycle is the common pathway for the disposal of excess nitrogen through urea biosynthesis. Hyperammonemia is a consistent finding in many neurological disorders including congenital urea cycle disorders, reye's syndrome and acute liver failure leads to deleterious effects. Hyperammonemia and liver failure results in glutamatergic neurotransmission which contributes to the alteration in the function of the glutamate-nitric oxide-cGMP pathway, modulates the important cerebral process. Even though ammonia is essential for normal functioning of the central nervous system (CNS), in particular high concentrations of ammonia exposure to the brain leads to the alterations of glutamate transport by the transporters. Several glutamate transporters have been recognized in the central nervous system and each has a unique physiological property and distribution. The loss of glutamate transporter activity in brain during acute liver failure and hyperammonemia is allied with increased extracellular brain glutamate concentrations which may be conscientious for the cerebral edema and ultimately cell death.