Atheroprotective and hepatoprotective effects of trans-chalcone through modification of eNOS/AMPK/KLF-2 pathway and regulation of COX-2, Ang-II, and PDGF mRNA expression in NMRI mice fed HCD.

BACKGROUND: The effects of trans-chalcone on atherosclerosis and NAFLD have been investigated. However, the underlying molecular mechanisms of these effects are not completely understood. This study aimed to deduce the impacts of trans-chalcone on the eNOS/AMPK/KLF-2 pathway in the heart tissues and the expression of Ang-II, PDFG, and COX-2 genes in liver sections of NMRI mice fed HCD. METHODS AND RESULTS: Thirty-two male mice were divided into four groups (n = 8): control group; fed normal diet. HCD group; fed HCD (consisted of 2% cholesterol) (12 weeks). TCh groups; received HCD (12 weeks) besides co-treated with trans-chalcone (20 mg/kg and 40 mg/kg b.w. dosages respectively) for 4 weeks. Finally, the blood samples were collected to evaluate the biochemical parameters. Histopathological observations of aorta and liver sections were performed by H&E staining. The real-time PCR method was used for assessing the expression of the aforementioned genes. Histopathological examination demonstrated atheroma plaque formation and fatty liver in mice fed HCD which were accomplished with alteration in biochemical factors and Real-time PCR outcomes. Administration of trans-chalcone significantly modulated the serum of biochemical parameters. These effects were accompanied by significant increasing the expression of eNOS, AMPK, KLF-2 genes in heart sections and significant decrease in COX-2, Ang-II, and PDGF mRNA expression in liver sections. CONCLUSION: Our findings propose that the atheroprotective and hepatoprotective effects of trans-chalcone may be attributed to the activation of the eNOS/AMPK/KLF-2 pathway and down-regulation of Ang-II, PDFG, and COX-2 genes, respectively.

Investigating the indirect therapeutic effect of hAMSCs utilizing a novel scaffold (PGS-co-PCL/PGC/PPy/Gelatin) in myocardial ischemia-reperfusion-induced renal failure in male Wistar rats.

BACKGROUND: Myocardial ischemia-reperfusion (MI/R) occurs due to temporary or permanent interruptions in the coronary and circulatory system, indirectly affecting kidney function through reduced cardiac output for metabolic needs. In this study, the aim was to explore the indirect effects of using human amniotic membrane mesenchymal stem cells (hAMSCs) with the PGS-co-PCL/PGC/PPy/Gelatin scaffold in male rats with renal failure induced by miocardial ischemia-reperfusion. METHODS: MI/R injury was induced in 48 male Wistar rats through left anterior descending artery ligation, divided into four groups (n=12); control group, cell group, scaffold group, and celss+scaffold group. Evaluations were conducted at two and thirty days post MI/R injury, encompassing echocardiography, biochemical, inflammatory markers analysis, and histological assessment. RESULTS: Echocardiographic findings exhibited notable enhancement in ejection fraction, fractional shortening, and stroke volume of treated groups compared to controls after 30 days (P< 0.05). Serum creatinine (P< 0.001) and urea (P< 0.05) levels significantly decreased in the scaffold+cells group) compared to the control group. The treated cells+ scaffold group displayed improved kidney structure, evidenced by larger glomeruli and reduced Bowman's space compared to the control group (P< 0.01). Immunohistochemical analysis indicated reduced TNF-α protein in the scaffold+ cells group (P< 0.05) in contrast to the control group (P< 0.05). Inflammatory factors IL-6, TNF-α, and AKT gene expression in renal tissues were improved in scaffold+ cells-treated animals. CONCLUSION: Our research proposes the combination of hAMSCs and the PGS-co-PCL/PGC/PPy/Gelatin scaffold in MI/R injured rats appears to enhance renal function and reduce kidney inflammation by improving cardiac output.

The power of Punica granatum: A natural remedy for oxidative stress and inflammation; a narrative review.

ETHNOPHARMACOLOGICAL RELEVANCE: Pomegranate 'Punica granatum' offers multiple health benefits, including managing hypertension, dyslipidemia, hyperglycemia, insulin resistance, and enhancing wound healing and infection resistance, thanks to its potent antioxidant and anti-inflammatory properties. It has been symbolized by life, health, femininity, fecundity, and spirituality. AIM OF THE STUDY: Although laboratory and animal studies have been conducted on the healing effects of pomegranate, there needs to be a comprehensive review on its anti-oxidative and anti-inflammatory effects in chronic disorders. We aim to provide a comprehensive review of these effects based on in-vitro, in-vivo, and clinical studies conducted in managing various disorders. MATERIALS AND METHODS: A comprehensive search of in-vitro, in-vivo, and clinical findings of pomegranate and its derivatives focusing on the highly qualified original studies and systematic reviews are carried out in valid international web databases, including Web of Science, PubMed, Scopus, and Cochrane Library. RESULTS: Relevant studies have demonstrated that pomegranate and its derivatives can modulate the expression and activity of several genes, enzymes, and receptors through influencing oxidative stress and inflammation pathways. Different parts of pomegranate; roots, bark, blossoms, fruits, and leaves contain various bioactive compounds, such as polyphenols, flavonoids, anthocyanins, and ellagitannins, that have preventive and therapeutic effects against many disorders such as cardiovascular diseases, diabetes, neurological diseases, and cancers without any serious adverse effects. CONCLUSIONS: Most recent scientific evidence indicates that all parts of the pomegranate can be helpful in treating a wide range of chronic disorders due to its anti-oxidative and anti-inflammatory activities. Since the safety of pomegranate fruit, juice, and extracts is established, further investigations can be designed by targeting its active antioxidant and anti-inflammatory constituents to discover new drugs.

Combined Application of Human Amniotic Membrane Mesenchymal Stem Cells and a Modified PGS-co-PCL Film in an Experimental Model of Myocardial Ischemia-Reperfusion Injury.

According to the World Health Organization (WHO), about 3.9 million people die annually of ischemic heart disease (IHD). Several clinical trials have shown that stem cell therapy is a promising therapeutic approach to IHD. Human amniotic membrane mesenchymal stem cells (hAMSCs) positively affect the repair of myocardial ischemia-reperfusion (MI/R) injury by stimulating endogenous repair mechanisms. The differentiated hAMSCs with and without modified PGS-co-PCL film were applied in the myocardium. MI/R injury was induced by ligating the left anterior descending artery in 48 male Wistar rats. The rats were divided into four groups, (n = 12) animals: heart failure (HF) as the control group, HF + MSCs, HF + MSCs + film, and HF + film. Echocardiography was performed 2 and 4 weeks after MI/R injury moreover the expression of the VEGF protein was assessed in the rat heart tissue via immunohistochemistry. In vitro, our result shows fantastic cell survival when seeded on film. In vivo, the left ventricle ejection fraction (LEVD), fractional shortening (FS), end-diastolic (EDV), and stroke volume (SV) have been increased and systolic volumes decreased in all treatment groups in comparison with control. Although combination therapy has a more positive effect on hemodynamic parameters, there is no significant difference between HF + MSCs + film with other treatment groups. Also, In the IHC assay, expression of the VEGF protein significantly increased in all intervention groups. The implantation of MSCs and the modified film significantly enhanced the cardiac functional outcome; in this regard, enhancement in cell survival and VEGF expression are involved as underlying mechanisms in which cardiac film and MSCs exert a beneficial effect.

Hepatoprotective and antifibrotic effects of trans-chalcone against bile duct ligation-induced liver fibrosis in rats.

Objectives: Several lines of research have shown that hepatic fibrosis is one of the leading causes of death worldwide. Trans-chalcone is a flavonoid precursor with anti-oxidant and anti-inflammatory effects. The present study was conducted to examine the antifibrotic properties of trans-chalcone on bile duct ligation (BDL)-induced liver cholestasis in rats. Materials and Methods: Following the BDL operation, trans-chalcone at doses of 12, 24, and 50 mg/kg was administered orally once a day for 45 consecutive days. Serum levels of liver indices, including alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total and direct bilirubin, and lipid profile in addition to blood urea nitrogen (BUN) and creatinine, were measured. Additionally, catalase (CAT) and superoxide dismutase (SOD) activities were assessed in liver homogenates. Histopathological evaluations were performed using Masson trichrome (MT) and hematoxylin and eosin (H&E) staining. Results: The elevated levels of liver enzymes, total and direct bilirubin, BUN, creatinine, cholesterol, triglyceride, and low-density lipoprotein (LDL) induced by BDL were significantly reduced following trans-chalcone administration; while serum level of high-density lipoprotein (HDL) increased. Besides, treatment with trans-chalcone elevated the activities of CAT and SOD in the liver tissues of the animals with BDL surgery. According to MT and H&E staining, BDL-induced histopathological changes, including infiltration of inflammatory cells, hepatocyte necrosis, ductal hyperplasia, and collagen deposition were ameliorated using trans-chalcone administration. Conclusion: It can be concluded from the present study that trans-chalcone, possibly by its anti-oxidant and anti-inflammatory properties, may exert hepatoprotective and antifibrotic effects in BDL-induced liver fibrosis.

The interaction mechanism of plasma iron transport protein transferrin with nanoparticles.

In the biological systems, exposure to nanoparticles (NPs) can cause complicated interactions with proteins, the formation of protein corona and structural changes to proteins. These changes depend not only on NP physicochemical properties, but also on the intrinsic stability of protein molecules. Although, the formation of protein corona on the surface of NPs and the underlying mechanisms have been fully explored in various studies, no comprehensive review has discussed the direct biochemical and biophysical interactions between NPs and blood proteins, particularly transferrin. In this review, we first discussed the interaction of NPs with proteins to comprehend the effects of physicochemical properties of NPs on protein structure. We then overviewed the transferrin structure and its direct interaction with NPs to explore transferrin stability and its iron ion (Fe3+) release behavior. Afterwards, we surveyed the various biological functions of transferrin, such as Fe3+ binding, receptor binding, antibacterial activity, growth, differentiation, and coagulation, followed by the application of transferrin-modified NPs in the development of drug delivery systems for cancer therapy. We believe that this study can provide useful insight into the design and development of bioconjugates containing NP-transferrin for potential biomedical applications.

Hydrothermal method-based synthesized tin oxide nanoparticles: Albumin binding and antiproliferative activity against K562 cells.

The interaction of nanoparticles with protein and cells may provide important information regarding their biomedical implementations. Herein, after synthesis of tin oxide (SnO2) nanoparticles by hydrothermal method, their interaction with human serum albumin (HSA) was evaluated by multispectroscopic and molecular docking (MD) approaches. Furthermore, the selective antiproliferative impact of SnO2 nanoparticles against leukemia K562 cells was assessed by different cellular assays, whereas lymphocytes were used as control cells. TEM, DLS, zeta potential and XRD techniques showed that crystalline SnO2 nanoparticles have a size of less than 50 nm with a good colloidal stability. Fluorescence and CD spectroscopy analysis indicated that the HSA undergoes some slight conformational changes after interaction with SnO2 nanoparticles, whereas the secondary structure of HSA remains intact. Moreover, MD outcomes revealed that the charged residues of HSA preferentially bind to SnO2 nanoclusters in the binding pocket. Antiproliferative examinations displayed that SnO2 nanoparticles can selectively cause the mortality of K562 cells through induction of cell membrane leakage, activation of caspase-9, -8, -3, down regulation of Bcl-2 mRNA, the elevation of ROS level, S phase arrest, and apoptosis. In conclusion, this data may indicate that SnO2 nanoparticles can be used as promising particles to be integrated into therapeutic platforms.

The effects of nickel oxide nanoparticles on structural changes, heme degradation, aggregation of hemoglobin and expression of apoptotic genes in lymphocytes.

Nickel oxide nanoparticles (NiO NPs) have received great interests in medical and biotechnological applications. However, their adverse impacts against biological systems have not been well-explored. Herein, the influence of NiO NPs on structural changes, heme degradation and aggregation of hemoglobin (Hb) was evaluated by UV-visible (Vis) spectroscopy, circular dichroism (CD) spectroscopy, fluorescence spectroscopy, transmission electron microscopy (TEM), and molecular modeling investigations. Also, the morphological changes and expression of Bax/Bcl-2 mRNA in human lymphocyte cell exposed to NiO NPs were assayed by DAPI staining and quantitative real-time PCR (qPCR), respectively. The UV-Vis study depicted that NiO NPs resulted in the displacement of aromatic residues and heme groups and production of the pro-aggregatory species. Intrinsic and Thioflavin T (ThT) fluorescence studies revealed that NiO NPs resulted in heme degradation and amorphous aggregation of Hb, respectively, which the latter result was also confirmed by TEM study. Moreover, far UV-CD study depicted that NiO NPs lead to substantial secondary structural changes of Hb. Furthermore, near UV-CD displayed that NiO NPs cause quaternary conformational changes of Hb as well as heme displacement. Molecular modelling study also approved that NiO NPs resulted in structural alterations of Hb and heme deformation. Moreover, morphological and genotoxicity assays revealed that the DNA fragmentation and expression ratio of Bax/Bcl-2 mRNA increased in lymphocyte cells treated with NiO NPs for 24 hr. In conclusion, this study indicates that NiO NPs may affect the biological media and their applications should be limited.Communicated by Ramaswamy H. Sarma.

Tau folding and cytotoxicity of neuroblastoma cells in the presence of manganese oxide nanoparticles: Biophysical, molecular dynamics, cellular, and molecular studies.

Manganese oxide nanoparticles (Mn2O3 NPs) have been widely used in the medical and biological applications. However, few studies have been undertaken to investigate the cytotoxicity of Mn2O3 NPs against nervous system. Herein, we studied the toxicity of Mn2O3 NPs against tau protein and neuroblastoma cells (SH-SY5Y) in vitro. Circular dichroism (CD) spectroscopy, fluorescence spectroscopy, molecular docking, and molecular dynamic studies were used to explore the conformational changes of protein. The cell-based experiments, such as viability, activation of caspases-3/9, apoptosis, and gene (Bax and Bcl-2) expression assays were performed in vitro. Spectroscopic methods and molecular dynamic studies revealed that Mn2O3 NPs can fold the structure of tau toward a more packed structure. The Mn2O3 NPs also decreased the cell viability in a dose-dependent manner. Indeed, caspase-3 and caspase-9 activation, Bax/Bcl-2 ratio elevation and apoptosis induction were observed after exposure of SH-SY5Y to Mn2O3 NPs. In conclusion, tau folding and cytotoxicity against SH-SY5Y cells may be involved in adverse effects induced by Mn2O3 NPs.

Parental morphine exposure affects repetitive grooming actions and marble burying behavior in the offspring: Potential relevance for obsessive-compulsive like behavior.

Family, adoption and twin studies have highlighted the significant role of heritable influences on individual differences in opioid addiction. Meanwhile, obsessive-compulsive disorder (OCD) is a disorder wherein the individual experiences recurring thoughts that cause irrational fears and anxiety. In the present study, adult male and female rats received morphine solution for 21 days and were drug-free for 10 days. Offspring were used in 4 distinct groups; (1) paternal morphine-exposed, (2) maternal morphine-exposed, (3) maternal and paternal morphine-exposed, and (4) drug-naïve subjects. We assessed the grooming behavior and marble burying test as an indicator of obsessive-compulsive behavior. To clarify the mechanisms underlying these changes, the mRNA level of BDNF, the phosphorylation level of CREB and the protein level of D2 dopamine receptor (DR) were evaluated in the nucleus accumbens (NAc). The grooming behavior in male offspring with one or two morphine-abstinent parent(s) increased compared with the offspring of drug naïve rats. In addition, the offspring of morphine-exposed parents buried more marbles when compared with the offspring of drug-naïve parents. Also, the BDNF mRNA was down-regulated in the NAC. However, the levels of phospho-CREB and D2 DR were elevated. Previous studies indicated that exposure to morphine in adulthood enhances the risk of psychiatric disorders in offspring. OCD is one the comorbid disorders with addiction and increases the risk of substance abuse disorder in patients. In this survey, we found that morphine exposure in parents before gestation can encourage obsessive-compulsive behavior in offspring.

The interaction of silica nanoparticles with catalase and human mesenchymal stem cells: biophysical, theoretical and cellular studies.

AIM: Nanoparticles (NPs) have been receiving potential interests in protein delivery and cell therapy. As a matter of fact, NPs may be used as great candidates in promoting cell therapy by catalase (CAT) delivery into high oxidative stress tissues. However, for using NPs like SiO2 as carriers, the interaction of NPs with proteins and mesenchymal stem cells (MSCs) should be explored in advance. METHODS: In the present study, the interaction of SiO2 NPs with CAT and human MSCs (hMSCs) was explored by various spectroscopic methods (fluorescence, circular dichroism (CD), UV-visible), molecular docking and dynamics studies, and cellular (MTT, cellular morphology, cellular uptake, lactate dehydrogenase, ROS, caspase-3, flow cytometry) assays. RESULTS: Fluorescence study displayed that both dynamic and static quenching mechanisms and hydrophobic interactions are involved in the spontaneous interaction of SiO2 NPs with CAT. CD spectra indicated that native structure of CAT remains stable after interaction with SiO2 NPs. UV-visible study also revealed that the kinetic parameters of CAT such as Km, Vmax, Kcat, and enzyme efficiency were not changed after the addition of SiO2 NPs. Molecular docking and dynamics studies showed that Si and SiO2 clusters interact with hydrophobic residues of CAT and SiO2 cluster causes minor changes in the CAT structure at a total simulation time of 200 ps. Cellular assays depicted that SiO2 NPs induce significant cell mortality, change in cellular morphology, cellular internalization, ROS elevation, and apoptosis in hMSCs at higher concentration than 100 µg/mL (170 µM). CONCLUSION: The current results suggest that low concentrations of SiO2 NPs induce no substantial change or mortality against CAT and hMSCs, and potentially useful carriers in CAT delivery to hMSC.

The effects of nickel oxide nanoparticles on tau protein and neuron-like cells: Biothermodynamics and molecular studies.

Herein, the thermodynamic parameters of tau upon interaction with NiO NPs were determined by fluorescence spectroscopy. Also, molecular docking studies were run to explore the binding affinities of NiO NPs clusters with different sizes of 30 Šand 50 Štoward tau. Also, cytotoxic activity of NiO NPs against SH-SY5Y was determined by MTT, LDH, caspase-9/3 activity, and expression of apoptotic Bax and Bcl-2 genes assays. DLS study showed that NiO solution had a good colloidal stability. Fluorescence study revealed that KSV values were 2.95 ±â€¯0.35 × 104, 3.31 ±â€¯0.59 × 104 and 3.92 ±â€¯0.65 × 104 at 298 K, 310 K and 315 K, respectively. Also, ∆G° (kJ/mol), ∆H° (kJ/mol) and T∆S° (kJ/mol) values were - 13.27 ±â€¯1.57, 1.98 ±â€¯0.14, 15.25 ±â€¯2.01, respectively at 298 K. Theoretical studies depicted that affinity of 5O3T segment toward NiO NP (30 Å) is higher than NiO NP (50 Å) and the proportion of Lys residues are higher in the docked pose of NiO NP (30 Å)/5O3T complex than NP (50 Å)/5O3T complex. Moreover, NiO NPs demonstrated a significant increase in the mortality of SH-SY5Y cells in an apoptotic manner. This study determined that NiO NPs may mediate the formation of electrostatic interactions with tau and induction of undesired harmful effects on neurons.

Morphine exposure before conception affects anxiety-like behavior and CRF level (in the CSF and plasma) in the adult male offspring.

It has been proven that exposure to some drugs even before gestation had transgenerational effects. To investigate the changes which induced by parental morphine exposure before gestation; mainly the anxiety-like behavior, Corticotropin Releasing Factor (CRF) level in the CSF and plasma, CRF Receptor 1 (CRFR1), and the level of protein kinase C (PKC-α) were evaluated in the male offspring. Male and female Wistar rats were exposed to morphine for 21 following days. Ten days after last drug exposure, animals were prepared for mating in 4 distinct groups as follow: drug-naïve female and male (used as control), drug-naïve female and morphine-abstinent male, drug-naïve male and morphine-abstinent female, and morphine abstinent male and female. Offspring were subjected to assess anxiety-like behavior (using elevated plus maze test). CSF and plasma were gathered, and the CRF level was evaluated by ELISA. Using real-time PCR, the CRFR1 level in the brain was evaluated. Results showed that anxiety-like behavior increased in the offspring of morphine-abstinent parent(s) compared with the control group. CRF level in the plasma and CSF also increased in the litter of morphine-abstinent parent(s). CRFR1 mRNA level was upregulated in the brain of offspring with one and/or two morphine-abstinent parent(s). Furthermore, the level of PKC-α was decreased in the brain of offspring which had one and/or two morphine-abstinent parent(s). Taken together, our findings indicated that morphine exposure even before gestation induced transgenerational effects via dysregulation of HPA axis which results in anxiety in the adult male offspring.

Hepatoprotective and antifibrotic effects of sodium molybdate in a rat model of bile duct ligation.

PROJECT: Cholestasis liver fibrosis has been increasingly recognized as a cause of high morbidity and mortality in humans. The accumulation of toxic bile salts in a bile duct ligation (BDL) animal model plays a pivotal role in the induction of liver fibrosis. Cholestatic liver fibrosis is characterized by excessive collagen production and deposition, which is mediated by reactive oxygen species (ROS). Molybdenum is an essential micronutrient trace element which acts as a cofactor in many detoxification system enzymes. The aim of the present study was to evaluate the antifibrotic effect of sodium molybdate on liver cholestasis induced by bile duct ligation in rats. PROCEDURE: After BDL, rats were given sodium molybdate (0.05 or 0.1 or 0.2g/kg) or urosodeoxycholic acid (UDCA, 25mg/kg) via intragastric gavage for 45 consecutive days (once per day). RESULTS: BDL drastically increased the serum levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin and direct bilirubin, whereas it reduced the levels of antioxidant enzymes, superoxide dismutase and catalase in the liver. Treatment of BDL rats with sodium molybdate significantly attenuated these changes. As determined by Masson's trichrome staining, BDL markedly induced the liver fibrosis. These alterations were also significantly attenuated by sodium molybdate administration. CONCLUSIONS: The results of this study indicate the hepatoprotective and antifibrotic effect of sodium molybdate in the cholestatic liver. Sodium molybdate, by inhibiting the activation of Ito cells, decreases the collagen production in the liver. The antifibrotic effect of sodium molybdate is likely due to the antioxidative and free radical scavenging effects of this trace element.