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This study evaluated if the cardioprotective effect of Exendin-4 against ischemia/reperfusion (I/R) injury in male rats involves modulation of AMPK and sirtuins. Adult male rats were divided into sham, sham + Exendin-4, I/R, I/R + Exendin-4, and I/R + Exendin-4 + EX-527, a sirt1 inhibitor. Exendin-4 reduced infarct size and preserved the function and structure of the left ventricles (LV) of I/R rats. It also inhibited oxidative stress and apoptosis and upregulated MnSOD and Bcl-2 in their infarcted myocardium. With no effect on SIRTs 2/6/7, Exendin-4 activated and upregulated mRNA and protein levels of SIRT1, increased levels of SIRT3 protein, activated AMPK, and reduced the acetylation of p53 and PGC-1α as well as the phosphorylation of FOXO-1. EX-527 completely abolished all beneficial effects of Exendin-4 in I/R-induced rats. In conclusion, Exendin-4 cardioprotective effect against I/R involves activation of SIRT1 and SIRT3. Graphical Abstract Exendin-4 could scavenge free radical directly, upregulate p53, and through upregulation of SIRT1 and stimulating SIRT1 nuclear accumulation. In addition, Exendin-4 also upregulates SIRT3 which plays an essential role in the upregulation of antioxidants, inhibition of reactive oxygen species (ROS) generation, and prevention of mitochondria damage. Accordingly, SIRT1 induces the deacetylation of PGC-1α and p53 and is able to bind p-FOXO-1. This results in inhibition of cardiomyocyte apoptosis through increasing Bcl-2 levels, activity, and levels of MnSOD; decreasing expression of Bax; decreasing cytochrome C release; and improving mitochondria biogenesis through upregulation of Mfn-2.

Sirt1 is a potent inhibitor of both poly(ADP-ribose) polymerases1 (PARP1) and NF-kB. This study investigated the cardioprotective effect of exendin-4 on cardiac function and remodeling in rats after an expreimentally-induced myocardial infarction (MI) and explored if this protection involves SIRT1/PARP1 axis. Rats were divided into five groups (n = 10/each): sham, sham + exendin-4 (25 nmol/kg/day i.p.), MI (induced by LAD occlusion), MI + exendin-4, and sham + exendin-4 + EX527 (5 mg/2×/week) (a SIRT1 inhibitor). All treatments were given for 6 weeks post the induction of MI. In sham-operated and MI-induced rats, exendin-4 significantly upregulated Bcl-2 levels, enhanced activity, mRNA, and levels of SIRT1, inhibited activity, mRNA, and levels of PARP1, and reduced ROS generation and PARP1 acetylation. In MI-treated rats, these effects were associated with improved cardiac architectures and LV function, reduced collagen deposition, and reduced mRNA and total levels of TNF-α and IL-6, as well as, the activation of NF-κB p65. In addition, exendin-4 inhibited the interaction of PARP1 with p300, TGF-β1, Smad3, and NF-κB p65 and signficantly reduced mRNA and protein levels of collagen I/III and protein levels of MMP2/9. In conclusion, exendin-4 is a potent cardioprotective agent that prevents post-MI inflammation and cardiac remodeling by activating SIRT1-induced inhibition of PARP1.

In this study, the effect of Euphorbia peplus aqueous extract on human breast cancer cell line MCF7 was examined. The short and long term cytotoxicity were evaluated using sulphorhodamine B and clonogenic assays respectively. Scanning and transmission electron microscopy were employed to examine Euphorbia peplus-induced ultrastructural changes in MCF7 cells. The sulphorhodamine B assay revealed that Euphorbia peplus inhibits the growth of MCF7 with an IC50 of 30.32 μg/ml. The clonogenic assay proved that Euphorbia peplus' growth inhibitory effect is long lasting. The ultrastructural examination demonstrated that Euphorbia peplus extract induces MCF7 cell death. Scanning electron microscopy showed apoptotic blebbing. Transmission electron microscopy displayed cellular shrinkage, the formulation of apoptotic bodies, mitochondrial changes, nuclear shrinkage, chromatin condensation, autophagic vacuoles, and necrotic changes. In summary, Euphorbia peplus has displayed growth inhibitory activity against MCF7 cells and induces cell death predominantly via apoptosis and could be exploited as a breast cancer treatment after further evaluation.

Cardiovascular disease secondary to diabetes represents a significant challenge to the health community. The advanced glycation end products (AGEs) play an important role in diabetes-mediated vascular injury. We tested whether metformin can suppress aortic AGEs production and protect against aortic injuries (aortopathy) and hypertension in streptozotocin-induced type 2 diabetes mellitus (T2DM) animal model. T2DM was induced in rats two weeks after being fed on a high carbohydrate and fat diet (HCFD), and continued on a HCFD until being sacrificed at week 12 (model group). The protective group was put on metformin two weeks before diabetic induction and continued on metformin and HCFD until the end of the experiment, at week 12. Using electron microscopy examinations, we observed in the model group substantial damage to the ultrastructure of aortic endothelial and vascular smooth muscle layers as demonstrated by markedly distorted vacuolated endothelial and vascular smooth muscle cells with pyknotic nuclei detached from the underlying basement membrane, which were protected by metformin. Also, metformin significantly (

Objectives: This study tested the effects of acylated (AG and un-acylated ghrelin (UAG) on hepatic lipid synthesis and insulin resistance (IR) from prospective to their effect on endoplasmic reticulum stress and investigated the possible underlying mechanisms. Methods: Healthy rats were divided as 4 groups (n=12/each) as control, control + AG, control + UAG, and control + AG + UAG (1:1). GA or UAG were given subcutaneously (200 ng/kg/each) for 8 weeks. Results: AG increased fasting levels of glucose and insulin resistance, increased hepatic glucose production, and impaired glucose and insulin tolerance. Besides, it increased serum levels of free fatty acids (FFAs), enhanced serum and hepatic levels of triglycerides and cholesterol, and increased lipid deposition in the livers of rats. Concomitantly, it stimulated the mRNA levels of SREBP1/2, fatty acid synthase, and protein levels of all arms of ER stress including Xbp-1, CHOP, ATF-6, and p-eIF2α, thus activating lipid synthesis and ER stress. It also reduced protein levels of p-IRS (Tyr612), p-Akt (Ser307), and increased levels of ROS, TNF-α, IL-6, and protein levels of cleaved caspase-12, p-IRS (Ser307), and p-JNK (The183/Tyr186) in rats’ livers. Administration of UAG alone or in combination with AG produced contradictory effects. However, both AG and UAG significantly increased mRNA levels of AMPK and PPARα suggesting FAs oxidation. Conclusion: AG induces hepatic steatosis and suppresses hepatic insulin signaling mainly by inducing peripheral IR that is associated with hepatic oxidative stress, inflammation, and ER stress. However, UAG alone or in combination exerts opposite effects.

Diabetic nephropathy (DN) is the most common manifestation of high glucose induced diabetes mellitus. In this study, we report the effects of Cassia auriculata ethanol leaf extract (CALE) on DN-associated cell toxicity and complications. The effects of CALE were screened in vitro using RGE cells. Cell viability was assessed using MTT and flow cytometry. Male Sprague-Dawley rats were divided into control, DN and treatment groups (n = 8). The DN and treatment groups received 60 mg/kg/bw of streptozotocin in citrate buffer, while the treatment group was administered 150 mg/kg/bw of CALE for 10 weeks. Biochemical analysis was conducted using spectrophotometry. Kidney tissues were analyzed using hematoxylin and eosin staining and transmission electron microscopy. CD365-KIM-1 expression was assessed using flow cytometry and signalling proteins were detected using western blotting. Treatment with 30-mM glucose reduced the viability of RGE cells in a time-dependent manner and increased the population of dead RGE cells. Cotreatment with CALE reduced cell death and glucose induced protein expression of LC3-II, RIP-1 and RIP-3 in a dose-dependent manner. In addition, CALE improved the biochemical complications, renal dysfunction and pathophysiology of rats with DN and partially or fully restored the expression of key DN-associated signalling proteins, such as KIM-1 LC3-II, RIP-1, RIP-3 and p-p38MAPK in kidney cells. CALE showed protective effects, and improved DN-associated complications in RGE cells under high glucose stress conditions, potentially by inhibiting autophagic-necroptosis signals. Additionally, CALE improved the biochemical and pathological features of kidney injury while reducing autophagic-necroptosis in rat renal cells via the LC3-II-RIP-p38MAPK pathway. PRACTICAL APPLICATIONS: Results from the current investigation will add information to the literature on glucose induced renal toxicity and the protective effects of CALE over the complications of diabetic nephropathy (DN). The mechanistic investigations of the study will add light on the autophagic/necroptosis signals in DN and open new routes of investigations to study the efficacy of CALE in diabetes-related complications.

Diabetes represents a major public health problem and an estimated 70% of people with diabetes die of cardiovascular complications. The protective effect of insulin treatment against ultrastructural damage to the tunica intima and tunica media of the aorta induced by type 2 diabetes mellitus (T2DM) has not been investigated before using transmission electron microscopy (TEM). Therefore, we induced T2DM in rats using high fat diet and streptozotocin (50 mg/kg) and administered insulin daily by i.v injection for 8 weeks to the treatment group. Whereas, the T2DM control group were left untreated for the duration of the experiment. A comparison was also made between the effect of insulin on aortic tissue and the blood level of biomarkers of vascular injury, inflammation, and oxidative stress. T2DM induced profound ultrastructural damage to the aortic endothelium and vascular smooth muscle cells, which were substantially protected with insulin. Furthermore, insulin returned blood sugar to a control level and significantly (

Aims: We sought to determine whether insulin can protect against type 1 diabetes mellitus (T1DM)-induced cardiac ultrastructural alterations in an animal model of the disease. This has not been investigated before. Methods: Rats were either injected once with 65 mg/kg streptozotocin (STZ) before being sacrificed after 8 weeks or were treated with a daily injection of insulin 2 days by STZ and continued until being sacrificed. Results: Harvested tissues obtained from left ventricles in the untreated T1DM rats showed substantial damage to the cardiomyocyte ultrastructure as demonstrated by disintegrated myofibrils and their sarcomeres, damaged mitochondria and lipid droplets, which was substantially protected by insulin. Insulin also significantly inhibited T1DM-induced hyperglycemia (p < 0.001), dyslipidemia (p < 0.0001), malondialdehyde (MDA; p < 0.0001), tumor necrosis factor-alpha (TNF-α; p < 0.001) and interleukin-6 (p < 0.001). We further demonstrated a significant (p ≤ 0.001) correlation between either sarcomere or mitochondrial injury scoring and the serum levels of glucose, dyslipidemia, and biomarkers of oxidative stress (OxS) and inflammation. Conclusions: These results indicate that insulin effectively suppresses left ventricular cardiomyocyte ultrastructural damage, which substantially slows down the progression of diabetic cardiomyopathy for 8 weeks in a rat model of T1DM, possibly due to the glycemic control and inhibition of dyslipidemia, OxS and inflammation.

Diabetic complications that affect vital organs such as the heart and liver represent a major public health concern. The potential protective effects of the hormone insulin against hepatocyte ultrastructural alterations induced secondary to type 1 diabetes mellitus (T1DM) in a rat model of the disease have not been investigated before. Therefore, rats were injected once with 65 mg/kg streptozotocin (T1DM group) and the protection group (T1DM+Ins) received a daily injection of insulin 48 h post diabetic induction by streptozotocin and continued until being sacrificed at week 8. The harvested liver tissues were examined using transmission electron microscopy (TEM) and blood samples were assayed for biomarkers of liver injury enzyme, glycemia, lipidemia, inflammation, and oxidative stress. TEM images showed that T1DM induced profound hepatocyte ultrastructural alterations as demonstrated by pyknotic nucleus, condensation of chromatin, irregular nuclear membrane, swollen mitochondria, dilated rough endoplasmic reticulum, damaged intercellular space, and accumulation of few lipid droplets inside the hepatocyte cytoplasm, which were substantially protected with insulin. In addition, the blood chemistry profile complements the TEM data as demonstrated by an increase in serum levels of alanine aminotransferase (ALT), dyslipidemia, C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and malondialdehyde (MDA) by T1DM that were significantly (p 0.05) reduced with insulin injections. Thus, we conclude that insulin effectively protects against T1DM-induced liver injury in rats for a period of 8 weeks, possibly due to the inhibition of inflammation, oxidative stress, and dyslipidemia.

This study investigated the effect of ghrelin on cardiomyocytes function, apoptosis and ultra-structural alterations of remote myocardium of the left ventricle (LV) of rats, 21 days post myocardial infarction (MI). Rats were divided into 4 groups as a control, a sham-operated rats, a sham-operated+ghrelin, an MI + vehicle and an MI + ghrelin-treated rats. MI was induced by LAD ligation and then rats were recievd a concomitant doe of either normal saline as a vehicle or treated with ghrelin (100 μg/kg S.C., 2x/day) for 21 consecutive days. Ghrelin enhanced myocardial contractility in control rats and reversed the decreases in myocardial contractility and the increases in the serum levels of CK-MB and LDH in MI-induced rats. Additionally, it inhibited the increases in levels of Bax and cleaved caspase 3 and increased those for Bcl-2 in the remote myocardium of rat's LV, post-MI. At ultra-structural level, while ghrelin has no adverse effects on LV myocardium obtained from control or sham-treated rats, ghrelin post-administration to MI-induced rats reduced vascular formation, restored normal microfilaments appearance and organization, preserved mitochondria structure, and prevented mitochondrial swelling, collagen deposition and number of ghost bodies in the remote areas of their LV. Concomitantly, in remote myocardium of MI-induced rats, ghrelin enhanced endoplasmic reticulum intracellular organelles count, decreased number of atrophied nuclei and phagocytes, diminished the irregularity in the nuclear membranes and inhibited chromatin condensation. In conclusion, in addition to the physiological, biochemical and molecular evidence provided, this is the first study that confirms the anti-apoptotic effect of ghrelin in the remote myocardium of the LV during late MI at the level of ultra-structural changes.

Mechanisms by which ghrelin affords its cardioprotection in mammals remained unclear.To examine if ghrelin confers cardio-protection during cardiac remodelling post-MI by modulating the RAF-1-MEK1/2-ERK1/2 signalling pathway.Rats were divided into control, sham, sham + ghrelin, myocardial infarction (MI), and MI + ghrelin groups. Ghrelin (100 µg/kg) was administered for 21 days, starting one-day post-MI.Ghrelin enhanced cardiac contractility and the activities of antioxidant enzymes, lowered serum levels of enzyme markers of cardiac dysfunction, and lowered inflammatory mediator levels. Ghrelin increased levels of phospho-Raf-1 (SerPost-MI in rats, ghrelin stimulated Raf-1-MEK1/2-ERK1/2-BAD signalling in the LV infarct areas, accounting for its anti-apoptotic effect, enhancing cardiac function, and inhibiting cardiac fibrosis during cardiac remodelling.

Excessive consumption of carbohydrate and fat increases the risk of liver disease. We hypothesized that swim exercise can protect hepatocytes from ultra-structural damage induced by high cholesterol and fructose diets (HCFD). Rats were either fed with HCFD (model group) or a standard laboratory chow (control group) for 15 weeks before being sacrificed. Swim exercise trained rats started the treatment from the 11

Acute renal failure induced by a toxic dose of acetaminophen (also known as paracetamol, or APAP) is common in both humans and experimental animal models. Glomerular ultrastructural alterations induced by APAP overdose associated with the suppression of biomarkers of kidney injury have not been investigated before. Also, we investigated whether the combined polyphenolic antioxidants and anti-inflammatory compounds, resveratrol (RES) and quercetin (QUR) can protect against APAP-induced nephrotoxicity. Rats either received a single dose of APAP (2 g/kg) before being sacrificed after 24 hours or were pretreated for 7 days with combined doses of RES (30 mg/kg) and QUR (50 mg/kg) before being given a single dose of APAP and then sacrificed 24 hours post APAP ingestion. APAP significantly (

This study compared the effect of low-fat diet (LFD) and high-fat diet rich in corn oil (HFD-CO) on left ventricular (LV) fibrosis in rats and examined their effect of angiotensin II (ANG II), JAK/STAT, and TGF-1β/smad3 pathways. As compared to LFD which didn't affect any of the measured parameters, HFD-CO-induced type 2 diabetes phenotype and increased LV collagen synthesis. Mechanistically, it increased LV levels of ROS, ANG II, ACE, IL-6, s-IL-6Rα, TGF-β1, Smad-3, and activities of JAK1/2 and STAT1/3. AG490, a JAK2 inhibitor, partially ameliorated these effect while Losartan, an AT1 inhibitor completely abolished collagen synthesis. However, with both treatments, levels of ANG II, IL-6, and s-IL-6Rα, and activity of JAK1/STAT3 remained high, all of which were normalized by co-administration of NAC or IL-6 neutralizing antibody. In conclusion: HFD-CO enhances LV collage synthesis by activation of JAK1/STAT3/ANG II/TGF-1β/smad3 pathway. PRACTICAL APPLICATIONS: We report that chronic consumption of a high-fat diet rich in corn oil (HFD-CO) induces diabetes mellitus phenotype 2 associated with left ventricular (LV) cardiac fibrosis in rats. The findings of this study show that HFD-CO, and through the increasing generation of ROS and IL-6 levels and shedding, could activate LV JAK1/2-STAT1/3 and renin-angiotensin system (RAS) signaling pathways, thus creating a positive feedback between the two which ultimately leads to activation of TGF-1β/Smad3 fibrotic pathway. Herein, we also report a beneficial effect of the antioxidant, NAC, or IL-6 neutralizing antibody in preventing such adverse effects of such HFD-CO. However, this presents a warning message to the current sudden increase in idiopathic cardiac disorders, especially with the big shift in our diets toward n-6 PUFA.

We recently reported an animal model of osteoarthritis (OA) induced by a combination of the chondrocyte glycolysis inhibitor, monoiodoacetate (MIA) and the agent that induces diabetes mellitus, streptozotocin (STZ). Here we investigated the potential protective effect of the antioxidant and anti-inflammatory agent, vitamin E against MIA+STZ-induced OA. Therefore, rats were either injected once with MIA (2 mg/50 μL) + 65 mg/kg STZ before being sacrificed after 8 weeks (model group) or were treated immediately after MIA+STZ injections with vitamin E (600 mg/kg; thrice a week) before being sacrificed after 8 weeks (treatment group). Using scanning and transmission electron microscopy examinations, we observed in the model group a substantial damage to the articular cartilage of the knee joint as demonstrated by the destruction of the chondrocytes, territorial matrix, disrupted lacunae, collagen fibers, and profound chondrocyte ultrastructural alterations such as degenerated chondrocyte, irregular cytoplasmic membrane, damaged mitochondria and rough endoplasmic reticulum, vacuolated cytoplasm, presence of lipid droplets and different sizes of lysosomes, which were substantially but not completely protected by vitamin E. H&E stained sections of knee joint articular cartilage showed that MIA+STZ induced damage to the chondrocyte and territorial matrix. Vitamin E also significantly (p < .05) inhibited MIA+STZ-induced blood levels of the inflammatory biomarkers, tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) that are known to be modulated in OA and diabetes. We conclude that vitamin E protects against MIA+STZ-induced knee joints injuries in rats, which is associated with the inhibition of biomarkers of inflammation.

This study investigates the effect of chronic consumption of a high-fat diet rich in corn oil (CO-HFD) on atrial cells ultrastructure, antioxidant levels and markers of intrinsic cell death of both control and type 1 diabetes mellitus (T1DM)-induced rats. Adult male rats (10 rats/group) were divided into four groups: control fed standard diet (STD) (3.82 kcal/g, 9.4% fat), CO-HFD (5.4 kcal/g, 40% fat), T1DM fed STD, and T1DM + CO-HFD. CO-HFD and T1DM alone or in combination impaired systolic and diastolic functions of rats and significantly reduced levels of GSH and the activity of SOD, enhanced lipid peroxidation, increased protein levels of P53, Bax, cleaved caspase-3, and ANF and decreased levels of Bcl-2 in their atria. Concomitantly, atrial cells exhibited fragmentation of the myofibrils, disorganized mitochondria, decreased number of atrionatriuretic factor (ANF) granules, and loss of gap junctions accompanied by changes in capillary walls. Among all treatments, the severity of all these findings was more severe in T1DM and most profound in the atria of T1DM + CO-HFD. In conclusion, chronic consumption of CO-HFD by T1DM-induced rats elicits significant biochemical and ultrastructural damage to rat atrial cells accompanied by elevated oxidative stress and mitochondria-mediated cell death.

Diabetic complications such as cardiovascular disease and osteoarthritis (OA) are among the common public health problems. The effect of insulin on OA secondary to diabetes has not been investigated before in animal models. Therefore, we sought to determine whether insulin and the insulin-mimicking agent, vanadium can protect from developing OA in diabetic rats.Type 1 diabetes mellitus (T1DM) was induced in Sprague-Dawley rats and treated with insulin and/or vanadium. Tissues harvested from the articular cartilage of the knee joint were examined by scanning electron microscopy, and blood samples were assayed for oxidative stress and inflammatory biomarkers.Eight weeks following the induction of diabetes, a profound damage to the knee joint compared to the control non-diabetic group was observed. Treatment of diabetic rats with insulin and/or vanadium differentially protected from diabetes-induced cartilage damage and deteriorated fibrils of collagen fibers. The relative biological potencies were insulin + vanadium insulin vanadium. Furthermore, there was about 2- to 5-fold increase in TNF-α (from 31.02 ± 1.92 to 60.5 ± 1.18 pg/ml, p 0.0001) and IL-6 (from 64.67 ± 8.16 to 338.0 ± 38.9 pg/ml, p 0.0001) cytokines and free radicals measured as TBARS (from 3.21 ± 0.37 to 11.48 ± 1.5 µM, p 0.0001) in the diabetic group, which was significantly reduced with insulin and or vanadium. Meanwhile, SOD decreased (from 17.79 ± 8.9 to 8.250.29, p 0.0001) and was increased with insulin and vanadium. The relative potencies of the treating agents on inflammatory and oxidative stress biomarkers were insulin + vanadium insulin vanadium.The present study demonstrates that co-administration of insulin and vanadium to T1DM rats protect against diabetes-induced OA possibly by lowering biomarkers of inflammation and oxidative stress.

Esophageal atresia (EA) with or without tracheo-esophageal fistula (TEF) is a relatively rare congenital anomaly. Despite the advances in the management techniques and neonatal intensive care, esophageal dysmotility remains a very common problem following EA/TEF repair. Our current study aimed to describe the most significant ultrastructural changes of the smooth muscle cells (SMCs) trying to highlight some of the underlying mechanisms of esophageal dysmotility following EA/TEF repair. Twenty-three biopsies were obtained from the tip of the lower esophageal pouch (LEP) of 23 patients during primary repair of EA/TEF. Light microscopic examination was performed with hematoxylin and eosin (HE), and Van Gieson's stains. Ultrastructural examination was done using transmission electron microscopy (TEM). Histopathological examination showed distortion of smooth muscle layer and deposition of an abundant amount of fibrous tissue in-between smooth muscles. Using TEM, SMCs exhibited loss of the cell-to-cell adhesion, mitochondrial vacuolation, formation of myelin figures, and apoptotic fragmentation. There were also plasmalemmal projections and formation of ghost bodies. Interestingly, SMCs were found extending pseudopodia-like projections around adjacent collagen fibers. Engulfed collagen fibers by SMCs underwent degradation within autophagic vacuoles. Degeneration of SMCs and deposition of abundant extracellular collagen fibers are prominent pathological changes in LEP of EA/TEF. These changes might contribute to the pathogenesis of esophageal dysmotility in patients who have survived EA/TEF.

The molecular mechanisms through which ghrelin exerts its cardioprotective effects during cardiac remodeling post-myocardial infarction (MI) are poorly understood. The aim of this study was to investigate whether the cardioprotection mechanisms are mediated by modulation of JAK/STAT signaling and what triggers this modulation. Rats were divided into six groups (n = 12/group): control, sham, sham + ghrelin (100 µg/kg, s.c., daily, starting 1 day post-MI), MI, MI+ ghrelin, and MI+ ghrelin+ AG490, a potent JAK2 inhibitor (5 mg/kg, i.p., daily). All treatments were administered for 3 weeks. Administration of ghrelin to MI rats improved left ventricle (LV) architecture and restored cardiac contraction. In remote non-infarcted areas of MI rats, ghrelin reduced cardiac inflammation and lipid peroxidation and enhanced antioxidant enzymatic activity. In addition, independent of the growth factor/insulin growth factor-1 (GF/IGF-1) axis, ghrelin significantly increased the phosphorylation of JAK2 and Tyr702 and Ser727 residues of STAT3 and inhibited the phosphorylation of JAK1 and Tyr701 and Ser727 residues of STAT1, simultaneously increasing the expression of BCL-2 and decreasing in the expression of BAX, cleaved CASP3, and FAS. This effect coincided with decreased expression of SOCS3. All these beneficial effects of ghrelin, except its inhibitory action on IL-6 expression, were partially and significantly abolished by the co-administration of AG490. In conclusion, the cardioprotective effect of ghrelin against MI-induced LV injury is exerted via activation of JAK2/STAT3 signaling and inhibition of STAT1 signaling. These effects were independent of the GF/IGF-1 axis and could be partially mediated via inhibition of cardiac IL-6.

Schistosomiasis is the second threatening parasitic disease after malaria and among Schistosoma spp., Schistosoma mansoni (S. mansoni) affects about 100 million people in tropic regions in Africa and South America. The current study was carried out to investigate ultrastructural changes of the kidney in mice infected with cercariae of S. mansoni, in which 20 Swiss albino mice of 60-day-old were assigned into two groups (10 each). Control group received 1 ml normal saline by intraperitoneal route. Model group were intraperitoneally infected with 1 ml normal saline containing 40 cercariae of S. mansoni/mouse. After 60 days of infection, specimens from the kidneys of both control and infected mice were obtained and processed for transmission electron microscopy (TEM) examination. The main ultrastructural changes were observed in both glomeruli and tubules. Glomerular findings included irregular thickening and splitting of the glomerular basement membrane (GBM), flattening and effacement of the foot processes of podocytes, and proliferation of mesangial cells. Tubular changes were in the form of swelling, atrophy and vacuolation of tubular epithelial cells, and presence of autophagic vacuoles. In conclusion, adopting TEM shows a number of ultrastructural changes in the kidneys of mice infected with cercariae of S. mansoni, most notably thickening and splitting of GBM and flattening and effacement of foot processes of podocytes and tubular autophagic vacuoles. These changes are still unraveled well in the literature.

We tested the hypothesis that swim exercise can protect the articular cartilage from damages induced secondary to insulin-dependent diabetes mellitus in rats using the scanning electron microscopy and to monitor the blood levels of oxidative and antioxidative stress biomarkers that are known to be modulated in osteoarthritis (OA). A profound damage to the cartilage was observed in the diabetic rats. Our findings also show that swim exercise protects the knee joints from damage induced by diabetes as well as significantly inhibiting OA-induced upregulation of thiobarbituric acid reactive substances (TBARS) and tumor necrosis factor alpha (TNF-α) and augmented superoxide dismutase (SOD) inhibition by OA. Thus, we demonstrated an effective protection by swim exercise against diabetes-induced OA in a rat model of the disease.

Osteoarthritis (OA) is characterized by degradation of matrix and destruction of articular cartilage. Articular chondrocytes are solely responsible for t he production and maintenance of the extracellular matrix. Therefore, chondrocyte disruption is implic ated in cartilage degeneration. Numerous studies have shown that antioxidant treatments are promisin g therapeutics in cases of OA. This study was designedto examine whether vitamin E protects rat a rticular chondrocytes against increased inflammatory markers and oxidative stress and preve nts cartilage destruction in mono-iodoacetateinduced osteoarthritis rat model. Data showed that osteoarthritis group showed a significant increase in inflammatory markers, Tumor Necrosis Factor-α (TNF-α) (38±1 ng/mL), Interlukin-6 (IL-6) (253±15 ng/mL) and oxidative stress marker, Super Oxide Dis mutase (SOD) (14±1 ng/mL) compared to control (18±1 ng/mL), (121+/-23 ng/mL) and (8±1 ng/mL) respectively. Opposite trend was found when animals were treated with vitamin E where TNF-α (27±2 ng/mL) and SOD (10±1 ng/mL) declined significantly. Electro-microscopic examination docu mented the above results and showed improvement of knee joint after administration of v itamin E. This study supported the notion that OA is a multi factorial complication, caused by inflam mation and increased oxidative stress. Administration of vitamin E decreased the markers o f inflammation and oxidative stress as well asimproved ultra-structure of the knee jointin acut e OA animal model. However, further work id needed to validate reliability in human patients su ffering from osteoarthritis.

Diabetic Nephropathy (DN) is one of most prevalent complications of Diabetes Mellitus (DM), therefore prevention of its development is a important field for researches. Quercetin is a plant flavenoid with hypoglycemic and antioxidant properties that is cla imed to have a reno-protective effect in diabetes. This study was designed to investigate the reno-preventi ve role of Quercetin treatment in terms of biochemi cal and pathological changes in diabetic rats and to de termine whether the effect is mediated through modulation of oxidative stress and Na + , K + ATPase expression and activity. Sixty male Sprague-Dawley rats were distributed equally among 6 groups: (i) Contro l group (C), (ii) Quercetin treated Control group ( CQ), (iii) Diabetic group (D), (iv) Diabetic Insulin tre ated group (DI), (v) Diabetic Quercetin treated gro up (DQ) and (vi) Diabetic Insulin and Quercetin treated gro up (DIQ). Systolic blood pressure was measured at t he end of the experiments (8 weeks). Retro-orbital blo od samples were used to determine the serum levels of glucose, HbA1c, urea, creatinine, Na + and K + . Renal homogenate levels of Na + , K + ATPase activity, Malondialdehyde (MDA0, Superoxide Dismutase (SOD) and Glutathione Peroxidase (GPx) were measured. Semiquantitative reverse transcriptase-PCR Na + , K + ATPase expression assays and kidney histopathological examination were conducted. Treatment with either insulin or Quercetin alone resulted in partial rever sal of the biochemical and histopathological signs of neph ropathy in diabetic rats. This was associated with partial but significant amelioration of indicators of oxida tive stress and Na + , K + ATPase gene expression and activity. However only combined treatment by both insulin and Quercetin significantly improved all of the aforementioned parameters up to the control levels. These results suggested that combined therapy with insulin and Quercetin might be a useful preventive tool aga inst development of DN.

Leishmania, a genus of intracellular protozoan parasites of macrophages, is the etiologic agent of cutaneous and visceral disease in man. In our study, localized cutaneous infections with leishmania were studied by light and transmission electron microscopy in 16 patients at phases ranging from onset to a progressive disease. In early infections, epidermal changes could be detected as deep hemorrhagic ulcer characterized by focal massive necrosis of the epidermal layers. Spongiotic vesicles in the epidermis were prominent containing the amastigotes. The dermal changes appeared in the form of diffuse inflammatory infiltrate predominantly composed of macrophages, epithelioid cells, lymphocytes, mast cells, and few plasma cells and eosinophils. Macrophages laden with the parasites were seen dissociating the striated muscle and the collagen bundles which showed degenerative and necrotic changes. In late stages of the disease, multiple granulomas formed predominantly of macrophages containing promastigotes and amastigotes, giant cells, epithelioid cells, and some mast cells were seen in the dermis. Some macrophages appeared vacuolated and loaded with the parasite. The dermal vasculature showed congestion, swelling of the endothelial cells, and fibrinoid necrosis of the wall. Some congested blood vessels demonstrated margination and diapedesis of inflammatory cells. By transmission electron microscopy, intact and degenerated amastigotes were seen phagocytosed inside the macrophagal parasitophorus vacuoles. Erythrophagocytosis and the reaction of other inflammatory cellular components were also described. These results clarified the lesions of leishmania invasion into the skin of the affected patients and its defensive mechanism. Moreover, the host macrophagal–parasite relationship was shown on ultrastructural level.

Rift Valley fever (RVF) is a zoonotic disease that primarily affects ruminant animals and can also cause fatal disease in humans. In the current report, we present the ultrastructural changes in the liver of a man aged 60 years who died from RVF in the Aseer Central Hospital, Abha, Saudi Arabia. The main hepatic changes by transmission electron microscopy included the presence of 95–115 nm electron-dense particles consistent with RVF virions, nuclear condensation, vacuolar degeneration, lipid droplet accumulation and mitochondrial damage and dilation. There were also viral inclusion bodies with electron-dense aggregates, dilation of intercellular spaces, damage of sinusoidal microvilli with widening of space of Disse, dilation of bile canaliculi and increasing number of phagolysosomes.

Varicocele is a dilatation of the pampiniform venous plexus and internal spermatic veins. It affects about 15-20% of male population and can cause infertility.To describe the most significant ultrastructural changes of the smooth muscle cells in grade 3 varicocele veins.The authors analyzed 2- to 3-cm tracts of pampiniform venous plexus from 20 patients who underwent varicocelectomy for left varicocele. Light microscopic examination was performed with Van Gieson's stain. Ultrastructural examination was done using scanning and transmission electron microscopy.Light microscopic examination revealed irregularity and separation of medial smooth muscle cells by abundant collagen fibers in varicocele veins. On scanning electron microscopy, the medial layer of varicocele veins showed hypertrophy, irregularity, and separation of the outer longitudinal smooth muscle cells and deposition of numerous fatty globules in between muscle fibers. Transmission electron microscopy showed marked indentation and chromatin condensation of the nucleus, presence of clear vacuoles and myelin figures in the cytoplasm and plasmalemmal projections and formation of ghost bodies. Furthermore, smooth muscle cells were found to have pseudopodia-like projections around adjacent elastic and collagen fibers.The degenerative changes observed in smooth muscle cells and presence of abundant collagen fibers in the medial layer may contribute to the development of the varicocele of pampiniform venous plexus. Further molecular studies are required to shed more light for the underlying mechanism.

The repeated chemotherapy of schistosomiasis has resulted in the emergence of drug-resistant schistosome strains. The development of such resistance has drawn the attention of many authors to alternative drugs. Many medicinal plants were studied to investigate their antischistosomal potency. The present work aimed to evaluate antischistosomal activity of crude aqueous extract of ginger against Schistosoma mansoni. Sixteen mice of C57 strain were exposed to 100 ± 10 cercariae per mouse by the tail immersion method; the mice were divided into two groups: untreated group and ginger-treated one. All mice were sacrificed at the end of 10th week post-infection. Worm recovery and egg counting in the hepatic tissues and faeces were determined. Surface topography of the recovered worms was studied by scanning electron microscopy. Histopathological examination of liver and intestine was done using routine histological procedures. The worm burden and the egg density in liver and faeces of mice treated with ginger were fewer than in non-treated ones. Scanning electron microscopical examination revealed that male worms recovered from mice treated with ginger lost their normal surface architecture, since its surface showed partial loss of tubercles' spines, extensive erosion in inter-tubercle tegumental regions and numerous small blebs around tubercles. Histopathological data indicated a reduction in the number and size of granulomatous inflammatory infiltrations in the liver and intestine of treated mice compared to non-treated mice. The results of the present work suggested that ginger has antischistosomal activities and provided a basis for subsequent experimental and clinical trials.

Problem statement: The goal of the current investigation was to clarify the effects of Citrullus colocynthis pulp extract on the structure of the liver of diabetic rats at both light and scanning electron microscopic levels. Approach: Forty-eight adult male albino rats were equally allocated into four groups: Group1: control, Group 2: Citrullus colocynthis-treated, Group 3: diabetic rats and Group4: diabetic rats treated with Citrullus colocynthis. All treatments were administered via an intragastric tube. Diabetes was induced in the rats of groups 3 and 4 by an intraperitoneal injection with alloxan. Results: The liver of Citrullus colocynthis-treated rats revealed minor histological changes versus the control animals. In group 3 animals, diabetes caused degenerative alterations in the form of disorganization of the hepatic cords, cytoplasmic vacuolization and pyknosis of the nuclei of hepatocytes and inflammatory cell infiltration. Scanning electron microscope examination of these livers revealed numerous lipid droplets within hepatocytes, damaged blood sinusoids and hemorrhage of erythrocytes between hepatocytes and inside Disse's spaces. On the other hand, the normal histological and scanning ultrastructural features were nearly resumed in the liver of diabetic rats treated with Citrullus colocynthis pulp extract. Conclusion: The present study proved a lessening effect of Citrullus colocynthis pulp extract on the liver of diabetic rats. In light of these advantageous influences, it is advisable to widen the scale of its use in a trial to alleviate the diabetic hepatic adverse effects.

Native cephalic vein remains the superior dialysis conduit, even thirty years after it was first described. However, up to 37% of hemodialysis patients develop progressive stenosis in the venous circuit of arterio-venous fistula (AVF), which may later cause thrombosis and occlusion. To study the pre-existing morphological changes in the wall of the cephalic vein before AVF construction, we collected 23 cephalic vein specimens from 3 normal, young trauma and twenty renal failure patients. The samples were collected at the time of vascular repair in the first group and AVF construction in the second group. Sections were prepared and stained for both light and transmission electron microscopy (TEM) examination. Compared with normal cephalic vein, all pre-access cephalic veins showed thickening of the wall and intimal hyperplasia. Other changes were loss of internal elastic lamina in 9 (45%) patients, loss of endothelial cell layer in 6 (30%), inflammatory cell infiltration of the wall in 5 (25%), mural calcification in 3 (15%) and telangiectasia in 2 (10%). Other ultrastructural changes observed were intimal hypertrophy, degeneration and loss of the endothelial cells, degeneration and fraying of smooth muscle cells (SMCs) and loss of wall components into the lumen. In conclusion, most of the apparently normal cephalic veins of renal failure patients showed morphological abnormalities at the time of AVF construction, which may well influence the outcome of shunts in terms of future stenosis and failure. It seems likely that the later development of AVF stenosis may be the result of pre-existing disease rather than the direct insult of arterialization.

Many factors have been implicated in the aetiology of varicose veins; however, there is ample evidence implicating that the defect is in the wall of the lower limb veins. In order to know the pathological changes in the tunica intima of varicose veins, the smooth muscle cells (SMCs), collagen and elastin of varicose and control patients were studied by light and electron microscopy. The morphological changes in the SMCs, collagen and elastin point to a possible secretory or phagocytic role of the SMCs in producing abnormal immature collagen or elastin fibres or in modulation of function of SMCs due to excessive production of extracellular matrix (ECM).

Angiomyxolipoma, a lipoma variant with myxoid areas and vascular proliferation was originally described in 1996 and till date has only 12 cases in published literature. Only two cases have been reported in children involving buccal mucosa and knee, respectively. The authors report a case of angiomyxolipoma, on the plantar surface of the left foot, in a 4-year-old male child who presented to our institution in Abha city (Kingdom of Saudi Arabia). The significant differential diagnosis of this neoplasm from other similar lipomatous tumours occurring in adult and paediatric population is discussed. The importance of recognising these tumours lies in their recognition as separate entity and the present case may add to the knowledge, clinical behaviour and prognosis of these less reported lipomatous neoplasms.

Basidiobolus ranarum is a fungus found in the dung of amphibians, reptiles, and insectivorous bats. Its structural elements include both hyphae and zygospores. Patients with B. ranarum infection may present with subcutaneous, gastrointestinal, or systemic lesions. Here we report a case of gastrointesinal badidiomycosis in a 13-year-old male child who presented with acute abdomen. Exploration revealed a mass in the ascending colon. On histology, transmural granulomatous inflammation composed of abundant eosinophils, lymphocytes, histiocytes and giant cells was seen. Histochemical stains revealed broad, non-septate, hyphae-like structures surrounded by an eosinophilic sheath. On an ultrastructural level, fungal hyphae, spores, and macrophage-laden crystalloids were observed. The diagnosis of gastrointestinal basidiobolomycosis was established and the patient received antifungal treatment. This paper reviews the relevant literature regarding basidiomycosis, and discusses its diverse clinicopathological features, as well as distinguishing it from other diseases.

Complications in arteriovenous fistula (AVF) occur in up to 35% of renal failure patients on hemodialysis. The most frequent complication is thrombosis, usually from stenotic lesions in the venous outflow system. To study the pre-existing smooth muscle changes in the cephalic vein of these patients, we prospectively collected a total of 17 cephalic vein specimens from 3 normal controls and 14 renal failure patients undergoing primary AVF construction on the chosen limb. After preparation, ultrathin sections were stained with uranyl and lead acetate and were examined under the transmission electron microscope (TEM). Compared with the normal controls, abnormal fibrous infiltration of the intima and the media and varying degrees of smooth muscle degenerative changes were observed in all the cephalic vein sections of renal failure patients. Smooth muscle cells (SMCs) lost their normal fusiform shape and were widely separated by increased amount of irregularly disposed, extracellular collagen fibers. Other cellular abnormalities included irregular cell membrane, granular cytoplasm, Peri- and Paranuclear vacuoles and mega mitochondria. SMCs also showed morphological expression of phagocytosis of collagen and elastic fibers as a sign of remodeling of the vein wall. In conclusion, pre-existing wall and smooth muscle changes were observed in all the cephalic vein sections of renal failure patients, which may contribute to the later complications of AVFs.

In order to study the structural changes in the intimal layer of varicose veins, we prospectively collected a total of 23 vein specimens from both the normal proximal thigh long saphenous (LSV) in 3 young trauma patients and from the unstripped proximal LSV near the sapheno-femoral junction and the distal calf blowouts in 10 primary varicose veins patients. Paraffin sections stained with hematoxylin and eosin were examined under the light microscope while ultra-thin sections were examined under the transmission electron microscope (TEM). Compared with the normal control LSV, varicose vein sections showed increase in the diameter of the lumen, hypertrophy of the wall and elongation and invagination of the intima. Along these invaginations, endothelial cells were compressed, elongated and thinned out. The cells also showed progressive degeneration and were finally lost into the lumen, leaving only the basal lamina to form the luminal surface. This invited blood components like platelets and red blood cells to stick to the bare intima and to penetrate through the wall. This may form the basis of the clinical condition of superficial thrombophlebitis, which sometimes complicates cases of varicose veins. In conclusion, varicose veins showed increased diameter of the lumen and hypertrophy, elongation and invagination of the intima. There was marked degeneration of the endothelial cells and desquamation of the endothelial layer.