The implication of miR-200a and miR-132 expression and their correlations with NF-κB/TNF-alpha signaling in adults with diabetic nephropathy.

Aim: The primary factor causing chronic renal failure is diabetic nephropathy (DN) worldwide. However, the current biomarkers for DN have limited diagnostic utility. Thus, this work aimed to clarify the implications of microRNA-200a (miR-200a) and microRNA-132 (miR-132) and their correlation with NF-κB (nuclear factor- kappa beta), and, TNF-α (tumor necrosis factor -alpha) signaling to identify biomarkers able to distinguish late-stage from early- stage DN. Methods: Fifty healthy controls, and 271 type 2 diabetic (T2D) patients (166 male plus 105 female) were enrolled. Participants were stratified into seven groups according to along with the estimated glomerular filtration rate (eGFR), glycated hemoglobin (HbA1c%), healthy controls, diabetes without DN (G1), diabetes with mild renal impairment (G2), and four DN grades (G3a, G3b, G4, and G5). Results: Compared to healthy controls, the DN groups exhibited linear increases in serum miR-200a, TNF-α, NF-κB, matrix metalloproteinase (MMP-9) and interleukin-6 (IL-6) levels and reductions in miR-132 serum expression. Among the patients, NF-κB and TNF-α produced a negative correlation with miR-132, while, positive correlation has been discovered with miR-200-a. The operating characteristic of the receiver curve (ROC), proved that, miR-200a also miR-132 had good diagnostic performance in distinguishing early from advanced DN. Conclusion: MiR-200a as well as miR-132 expression levels, and their correlations with NF-κB/TNF-alpha signaling, were able to differentiate between DN patients with lower eGFR, suggesting their utility as diagnostic and prognostic biomarkers.

Protective Effects of Propolis and Chitosan Nanoparticles against Ibuprofen-Induced Hepatotoxicity in Albino Rats.

Post-marketing hepatotoxicity findings are more common or occur much later. NSAIDs (non-steroidal anti-inflammatory drugs) like ibuprofen are consumed in large quantities around the world. NSAIDs have a low incidence of hepatotoxicity but their wide use makes them a major contributor to drug-induced liver injury. Hepatitis is linked to systemic oxidative stress which results in cellular necrosis and fibrosis, as well as tissue lipoprotein peroxidation and glutathione depletion. Given the lack of safe and effective anti-hepatitis drugs in medicine today, natural substances appear to be a promising and safe alternative. Propolis and chitosan are considered natural substances that have a protective effect on the hepatocytes. The purpose of this study was to validate the protective effect of propolis/chitosan nanoparticle extracts on ibuprofen-induced hepatotoxicity. Thirty (30) albino rats were used for the experiment. Animals were exposed to ibuprofen (400 mg/kg body weight/day) for 4 weeks (7 days/week) followed by treatment with propolis (200 mg/kg body weight/day) and chitosan extract (200 mg/kg body weight/day) separately and also in combination for consecutive 4 weeks. This study revealed a significant increase in serum transaminases, alkaline phosphatase, albumin, and total bilirubin in serum, as well as an increase in lipid peroxidation (MDA) and nitric oxide (NO). Furthermore, GSH, GST, and SOD decreased significantly in the group that was exposed to ibuprofen. Furthermore, there was a significant increase in pro-inflammatory parameters such as IL-1ß and NF-ĸB, as well as low levels of anti-inflammatory parameters such as IL-6 and BCl-2. These alterations were improved by propolis and chitosan extracts, which was further confirmed in experimental animals. This study demonstrated that propolis and chitosan nanoparticle extracts have the potential to protect against hepatotoxicity induced by ibuprofen, due to their ability to regulate anti-inflammatory and anti-oxidative defense activities.

Relationship between Cytokines and Metabolic Syndrome Components: Role of Pancreatic-Derived Factor, Interleukin-37, and Tumor Necrosis Factor-α in Metabolic Syndrome Patients.

The metabolic syndrome (MetS) is a serious public health issue that affects people all over the world. Notably, insulin resistance, prothrombotic activity, and inflammatory state are associated with MetS. This study aims to explore the relationship between cytokines and tumor necrosis factor-α (TNF-α), pancreatic-derived factor (PANDER), and interleukin (IL-)-37 and the accumulation of MetS components. Eligible participants were divided into four groups as follows: group 1, patients with dyslipidemia; group 2, patients with dyslipidemia and obesity; group 3, patients with dyslipidemia, obesity, and hypertension; and group 4, patients with dyslipidemia, obesity, hypertension, and hyperglycemia. This study exhibited that serum levels of TNF-α and PANDER were significantly elevated (P < 0.001) in the MetS groups, while IL-37 level and IL-37 mRNA expression were significantly decreased (P < 0.001) relative to healthy controls. Moreover, this study has revealed significant correlations (P < 0.001) between MetS components and TNF-α, PANDER, and IL-37 levels in MetS patients. The aforementioned results suggested the association between the proinflammatory cytokine (TNF-α and PANDER) and anti-inflammatory cytokine (IL-37) with the accumulation of MetS components. Hence, the overall outcome indicated that PANDER and IL-37 may be considered novel biomarkers associated with increased risk of MetS and can be used as a promising therapeutic target in preventing, ameliorating, and treating metabolic disorders. Supplementary Information: The online version contains supplementary material available at 10.1007/s12291-022-01079-z.

Box-Behnken Design of Experiments of Polycaprolactone Nanoparticles Loaded with Irinotecan Hydrochloride.

BACKGROUND: The Box-Behnken design of experiments (BBD) is a statistical modelling technique that allows the determination of the significant factors in developing nanoparticles (NPs) using a limited number of runs. It also allows the prediction of the best levels of variables to obtain the desired characteristics (size, charge, and encapsulation efficiency) of the NPs. The aim of this study was to examine the effect of the independent variables (amount of polymer and drug, and surfactant concentration) and their interaction on the characteristics of the irinotecan hydrochloride (IRH)-loaded polycaprolactone (PCL) NPs and to determine the most optimum conditions for producing the desired NPs. METHODS: The development of the NPs was carried out by a double emulsion solvent evaporation technique with yield enhancement. The NPs data were fitted in Minitab software to obtain the best fit model. RESULTS: By using BBD, the most optimum conditions for producing the smallest size, highest magnitude of charge, and highest EE% of PCL NPs were predicted to be achieved by using 61.02 mg PCL, 9 mg IRH, and 4.82% PVA, which would yield 203.01 nm, -15.81 mV, and 82.35% EE. CONCLUSION: The analysis by BBD highlighted that the model was a good fit to the data, confirming the suitability of the design of the experiments.

The Pathogenic Role of Oxidative Stress, Cytokine Expression, and Impaired Hematological Indices in Diabetic Cardiovascular Diseases.

A simultaneous increase in the prevalence of diabetes mellitus (DM), a risk factor for cardiovascular diseases (CVDs), has contributed to the escalation of CVD related mortalities. To date, oxidative stress and inflammation are increasingly recognized as significant drivers of cardiovascular complications in patients with diabetes. Therefore, this study aims to explore the correlation between oxidative stress, inflammation, and hematological indices in diabetic patients with CVDs. Patients were allocated into five groups: healthy controls; nondiabetic patients with myocardial infarction; diabetic patients with myocardial infarction; nondiabetic patients with heart failure; and diabetic patients with heart failure. The results revealed that the malondialdehyde levels were increased; whereas superoxide dismutase enzyme activities were markedly reduced in all CVD groups compared with those of healthy controls. Although the mRNA expression levels of interleukin (IL)-6, IL-18, and IL-38 were significantly increased, those of the anti-inflammatory cytokine, IL-35, have been reduced in all CVD groups compared with healthy controls. Regarding hematological indices, hematocrit, red blood cell distribution width, mean platelet (PLT) volume, plateletcrit, PLT distribution width, leukocyte count, and PLT-to-lymphocyte and neutrophil-to-lymphocyte ratios were markedly increased in the diabetic and nondiabetic CVD groups compared with those of the healthy controls. Oxidative stress and cytokine biomarkers may play a significant role in the complications of diabetic cardiomyopathy. Moreover, hematological indices are particularly sensitive to systemic inflammatory changes and are novel markers for the early detection of diabetic cardiomyopathy.

Cinnamaldehyde Mitigates Atherosclerosis Induced by High-Fat Diet via Modulation of Hyperlipidemia, Oxidative Stress, and Inflammation.

Atherosclerosis is a disease in which plaque builds up inside arteries. Cinnamaldehyde (Ci) has many biological properties that include anti-inflammatory and antioxidant activities. Thus, this study was designed to explore the protective effect of Ci against atherosclerosis induced by a high-fat diet (HFD) in Wistar rats. Atherosclerosis was induced by an oral administration of an HFD for 10 weeks. Atherosclerosis-induced rats were supplemented with Ci at a dose of 20 mg/kg bw dissolved in 0.5% dimethyl sulfoxide (DMSO), daily by oral gavage for the same period. Rats were divided into three groups of 10 rats each fed with (a) ND, (b) HFD, and (c) HFD+Ci, daily for 10 weeks. Treatment of rats with Ci significantly reduced the elevated levels of serum total cholesterol (T.Ch), triglycerides (TG), low-density lipoprotein-cholesterol (LDL-Ch), very low-density lipoprotein-cholesterol (VLDL-Ch), and free fatty acids (FFAs) and significantly increased the lowered levels of high-density lipoprotein-cholesterol (HDL-Ch) level. Ci ameliorated the increased cardiovascular risk indices 1 and 2 and the decreased antiatherogenic index. Moreover, Ci reduced the elevated serum creatine kinase (CK), creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), and aspartate aminotransferase (AST) activities. Ci also improved the heart antioxidant activities by decreasing malondialdehyde (MDA) and increasing glutathione S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), and glutathione peroxidase (Gpx) activities. Furthermore, the supplementation with Ci downregulated the mRNA expression levels of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), interleukin-17 (IL-17), and tumor necrosis factor-α (TNF-α). Thus, Ci successfully elicited a therapeutic impact against atherosclerosis induced by HFD via its hypolipidemic, antioxidant, and anti-inflammatory actions.

The relationship between B-cell lymphoma 2, interleukin-1ß, interleukin-17, and interleukin-33 and the development of diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is among the main complications of diabetes mellitus and has been a major factor of renal failure. This study was designed to address the association between beta-cell lymphoma-2 (Bcl-2), interleukin (IL)-1ß, IL-17, and IL-33 and the development of DN. METHODS: In this study, 20 healthy volunteers and 100 patients were enrolled. According to their biochemical markers, the patients were categorized into five groups: diabetic, chronic renal disease, diabetic chronic renal disease, end-stage renal disease, and diabetic end-stage renal disease. RESULTS: Our results showed a noticeable elevation in IL-1ß and IL-17 levels and a reduction in IL-33 and Bcl-2 levels in all investigated groups compared with those in the healthy group. Positive correlations were found between IL-1ß and fasting blood sugar and between creatinine levels and IL-17, HbA1c%, and sodium levels. However, negative correlations were found between IL-33 and urea and sodium concentrations and between Bcl-2 and HbA1c% and creatinine levels. CONCLUSIONS: The present data revealed a marked relationship between Bcl-2, IL-1ß, IL-17, and IL-33 levels and the onset and progression of DN. Understanding the molecular pathways of these processes could be translated into the development of therapeutic strategies.

The impact of HCV eradication on hyperglycemia, insulin resistance, cytokine production, and insulin receptor substrate-1 and 2 expression in patients with HCV infection.

Virological responses after hepatitis C virus (HCV) treatment may alleviate liver disease and extra-hepatic manifestations. Our study aims to explore the impact of HCV eradication on the glycemic status, insulin resistance, cytokine production, and insulin receptor substrate (IRS)-1 and 2 gene expression levels in HCV-hyperglycemic patients. A total of 90 participants were allocated as follows: Group 1 included 30 healthy subjects as controls, and Group 2 included 60 HCV-hyperglycemic patients treated with a direct-acting antiviral (DAA) regimen and further subdivided into HCV-pre-diabetic and HCV-diabetic groups. Laboratory assays screened patients before and after treatments. Our data showed an excellent rate of virological responses in HCV groups after HCV treatment. Moreover, HCV eradication significantly ameliorated blood glucose levels and insulin resistance biomarkers in HCV-hyperglycemic patients compared with baseline values. Also, interleukin (IL)-6, IL-17, IL-23, and IL-27 levels were significantly ameliorated after viral clearance in HCV-hyperglycemic patients compared with baseline values. Similarly, IRS-1 and 2 mRNA expression levels were upregulated in these patients post-HCV treatment compared with baseline values. HCV clearance ameliorated hyperglycemia, cytokine production, and enhanced insulin sensitivity. Future researches will be needed to explore the effects of cytokines and IRS on HCV infection and treatment on a large cohort.

Development and Optimization of Irinotecan-Loaded PCL Nanoparticles and Their Cytotoxicity against Primary High-Grade Glioma Cells.

BACKGROUND: High-grade gliomas (HGGs) are highly malignant tumors with a poor survival rate. The inability of free drugs to cross the blood-brain barrier and their off-target accumulation result in dose-limiting side effects. This study aimed at enhancing the encapsulation efficiency (EE) of irinotecan hydrochloride trihydrate (IRH) within polycaprolactone (PCL) nanoparticles with optimized size and charge. MATERIALS AND METHODS: IRH-loaded PCL nanoparticles were formulated using either the single emulsion (O/W, W/O and O/O) or double emulsion (W/O/O and W/O/W) solvent evaporation techniques. The nanoparticles were characterized for their size, zeta potential and EE, with the optimized nanoparticles being characterized for their drug release and cytotoxicity. RESULTS: The amorphization of PCL and the addition of electrolytes to the aqueous phases of the W/O/W emulsion produced spherical nanoparticles with a mean diameter of 202.1 ± 2.0 nm and an EE of 65.0%. The IRH-loaded nanoparticles exhibited zero-order release and were cytotoxic against primary HGG cells. CONCLUSION: The amorphization of PCL improves its EE of hydrophilic drugs, while the addition of electrolytes to the aqueous phases of the W/O/W emulsion enhances their EE further. IRH-loaded PCL nanoparticles have the potential to deliver cytotoxic levels of IRH over a sustained period of time, enhancing the cell death of HGGs.

Exhibiting the diagnostic face of selenium nanoparticles as a radio-platform for tumor imaging.

Selenium nanoparticles (SeNPs) have become one of the most prospective and promising tools in the course of cancer diagnosis and therapy. Here we describe the synthesis of a novel radioactive platform for tumor imaging using selenium nanoparticles. SeNPs were synthetized using dithionite and glutathione as reducing and capping agent respectively with 5 mmol/L sodium selenite as a precursor and then SeNPs radiolabeled with technetium-99 m, the most common and famous radioactive isotope used for imaging purposes. A characteristic profile for the synthesized SeNPs was performed including size analysis, zeta potential, antioxidant activity, radiochemical yield and in-vivo biodistribution in normal and solid tumor bearing mice. Size analysis showed amorphous SeNP cores of a mean diameter of 21 ± 5 nm with a hydrodynamic size of 43 ± 8 nm and -28 mV zeta potential. The particles also showed a superior antioxidant activity of radical scavenging activity 55.6% according to DPPH assay, in addition, satisfying radiochemical yield up to 97 ± 1.5 was achieved. In vivo studies were applied on male Swiss albino mice that demonstrated a good biodistribution pattern in normal mice with a moderate accumulation in liver at 30 min post injection. Excellent T/NT ratios were obtained in solid tumor bearing mice throughout the experimental time points. The as-synthetized selenium nanoparticles demonstrated surprising and satisfying features which make them promising enough for tumor theranosis.

Polymeric Nanoparticles for the Treatment of Malignant Gliomas.

Malignant gliomas are one of the deadliest forms of brain cancer and despite advancements in treatment, patient prognosis remains poor, with an average survival of 15 months. Treatment using conventional chemotherapy does not deliver the required drug dose to the tumour site, owing to insufficient blood brain barrier (BBB) penetration, especially by hydrophilic drugs. Additionally, low molecular weight drugs cannot achieve specific accumulation in cancerous tissues and are characterized by a short circulation half-life. Nanoparticles can be designed to cross the BBB and deliver their drugs within the brain, thus improving their effectiveness for treatment when compared to administration of the free drug. The efficacy of nanoparticles can be enhanced by surface PEGylation to allow more specificity towards tumour receptors. This review will provide an overview of the different therapeutic strategies for the treatment of malignant gliomas, risk factors entailing them as well as the latest developments for brain drug delivery. It will also address the potential of polymeric nanoparticles in the treatment of malignant gliomas, including the importance of their coating and functionalization on their ability to cross the BBB and the chemistry underlying that.

Correlation between oxidative stress and hematological profile abnormalities in diabetic nephropathy.

AIMS: Diabetes patients with renal impairment commonly have a degree of hematological abnormalities than those non-diabetics with chronic kidney disease. The present study aimed to clarify the association between oxidative stress and hematological abnormalities with the progression of diabetic nephropathy. METHODS: A total of 20 healthy subjects and 100 patients were enrolled in the study. Eligible renal dysfunction patients were classified according to biochemical markers into five groups (20 patients); diabetic patients, pre-renal failure patients, diabetic pre-renal failure patients, renal failure patients, and diabetic renal failure patients. RESULTS: Erythrocytes and platelets count, hemoglobin and hematocrit levels revealed a significant decrease in all renal dysfunction groups, while leukocytes count, red cell distribution width, platelet distribution width, and mean platelet volume showed significant increases in diabetic and renal dysfunction groups as compared to the healthy control. Nitric oxide level increased significantly, while reduced glutathione showed a marked decrease in diabetic and all renal dysfunction groups compared to the healthy control. CONCLUSION: Nitric oxide and reduced glutathione were associated with the inflammatory status in diabetic renal dysfunction patients which reflected by elevation in leukocytes and neutrophils count, red cell distribution width as well as the reduction in values of erythrocytes, platelets count, hemoglobin and hematocrit. Therefore, hematological indices can play a role in predict the progression of diabetic nephropathy.

Relationship of leukocytes, platelet indices and adipocytokines in metabolic syndrome patients.

AIMS: The current study aimed to explore the correlation between leukocytes and platelets indices with adipocytokines (leptin and adiponectin) and MetS components. METHODS: A total of 100 healthy subjects and 200 patients diagnosed with different MetS components were enrolled in the study. Eligible patients were allocated into four groups (50 patients). Group1 include patients with 2 criteria of MetS components, group 2 with 3 criteria, group 3 with 4 criteria and group 4 had patients with 5 criteria. RESULTS: Regarding white blood cell indices, data showed that total leukocyte and neutrophil count as well as neutrophil/lymphocyte (N/L) ratio were significantly increased in all groups of MetS patients when compared to the healthy group. Additionally, platelets count, platelet distribution width (PDW), and main platelet volume (MPV) levels and platelets/lymphocyte (P/L) ratio were significantly higher in all patients with MetS as compared to the healthy subjects. Serum leptin concentration and leptin-to-adiponectin ratio (LAR) were elevated significantly, while adiponectin level was significantly diminished in all MetS groups when compared to the control. CONCLUSION: leukocytes and platelets indices were associated with hyperleptinemia and hypoadiponectinemia as well as MetS components. The study also suggested the necessary role of leukocytes, platelet indices, and LAR as markers in early diagnoses of individuals with MetS components.

Improvement of lipid profile and antioxidant of hypercholesterolemic albino rats by polysaccharides extracted from the green alga Ulva lactuca Linnaeus.

Sulfated polysaccharides from Ulva lactuca were extracted in hot water and precipitated by ethanol then orally gavaged to rats fed on a hypercholesterolemic diet for 21 days to evaluate the antihypercholesterolemic and antioxidant actions. Atorvastatine Ca (Lipitor) was used as a reference drug. The intragastric administration of U. lactuca extract to hypercholesterolemic rats caused significant decrease of serum total lipids, triglycerides, total cholesterol, LDL-cholesterol and vLDL-cholesterol levels. Whereas, HDL-cholesterol concentration was markedly increased by 180%. Aqueous extract showed a significant ameliorative action on elevated atherogenic index, creatine kinase and lactate dehydrogenase activities of hypercholesterolemic group. Furthermore, serum activities of transaminases and alkaline phosphatase were also improved. High fat diet intake caused a highly significantly elevated serum urea, creatinine concentration. These effects were reversed by oral administration of U. lactuca extract. Sulfates polysaccharides extract of U. lactuca ameliorate hepatic enzymatic (catalase, glutathione peroxidase and superoxide dismutase), non-enzymatic (reduced glutathione & total thiol) antioxidant defenses and thiobarbituric acid reactive substances. In conclusion, the tested U. lactuca polysaccharides extract has potent hypocholesterolemic and antioxidant effects in experimentally-induced hypercholesterolemic animal model.