Cannabinoid 2 Receptor Activation Protects against Diabetic Cardiomyopathy through Inhibition of AGE/RAGE-Induced Oxidative Stress, Fibrosis, and Inflammasome Activation.

Oxidative stress, fibrosis, and inflammasome activation from advanced glycation end product (AGE)-receptor of advanced glycation end product (RAGE) interaction contribute to diabetic cardiomyopathy (DCM) formation and progression. Our study revealed the impact of ß-caryophyllene (BCP) on activating cannabinoid type 2 receptors (CB2Rs) against diabetic complication, mainly cardiomyopathy and investigated the underlying cell signaling pathways in mice. The murine model of DCM was developed by feeding a high-fat diet with streptozotocin injections. After the development of diabetes, the animals received a 12-week oral BCP treatment at a dose of 50 mg/kg/body weight. BCP treatment showed significant improvement in glucose tolerance and insulin resistance and enhanced serum insulin levels in diabetic animals. BCP treatment effectively reversed the heart remodeling and restored the phosphorylated troponin I and sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a expression. Ultrastructural examination showed reduced myocardial cell injury in DCM mice treated with BCP. The preserved myocytes were found to be associated with reduced expression of AGE/RAGE in DCM mice hearts. BCP treatment mitigated oxidative stress by inhibiting expression of NADPH oxidase 4 and activating phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. Also, BCP suppressed cardiac fibrosis and endothelial-to-mesenchymal transition in DCM mice by inhibiting transforming growth factor ß (TGF-ß)/suppressor of mothers against decapentaplegic (Smad) signaling. Further, BCP treatment suppressed nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome activation in DCM mice and alleviated cellular injury to the pancreatic tissues evidenced by significant elevation of the number of insulin-positive cells. To demonstrate a CB2R-dependent mechanism of BCP, another group of DCM mice were pretreated with AM630, a CB2R antagonist. AM630 was observed to abrogate the beneficial effects of BCP in DCM mice. Taken together, BCP demonstrated the potential to protect the myocardium and pancreas of DCM mice mediating CB2R-dependent mechanisms. SIGNIFICANCE STATEMENT: BCP, a CB2R agonist, shows protection against DCM. BCP attenuates oxidative stress, inflammation, and fibrosis in DCM via activating CB2Rs. BCP mediating CB2R activation favorably modulates AGE/RAGE, PI3K/AKT/Nrf2ß and TGF-ß/Smad and (NLRP3) inflammasome in diabetic cardiomyopathy.

Effects of long-term dehydration and quick rehydration on the camel kidney: pathological changes and modulation of the expression of solute carrier proteins and aquaporins.

BACKGROUND: Recurrent dehydration causes chronic kidney disease in humans and animal models. The dromedary camel kidney has remarkable capacity to preserve water and solute during long-term dehydration. In this study, we investigated the effects of dehydration and subsequent rehydration in the camel's kidney histology/ultrastructure and changes in aquaporin/solute carrier proteins along with gene expression. RESULTS: In light microscopy, dehydration induced few degenerative and necrotic changes in cells of the cortical tubules with unapparent or little effect on medullary cells. The ultrastructural changes encountered in the cortex were infrequent during dehydration and included nuclear chromatin condensation, cytoplasmic vacuolization, mitochondrial swelling, endoplasmic reticulum/ lysosomal degeneration and sometimes cell death. Some mRNA gene expressions involved in cell stability were upregulated by dehydration. Lesions in endothelial capillaries, glomerular membranes and podocyte tertiary processes in dehydrated camels indicated disruption of glomerular filtration barrier which were mostly corrected by rehydration. The changes in proximal tubules brush borders after dehydration, were accompanied by down regulation of ATP1A1 mRNA involved in Na + /K + pump that were corrected by rehydration. The increased serum Na, osmolality and vasopressin were paralleled by modulation in expression level for corresponding SLC genes with net Na retention in cortex which were corrected by rehydration. Medullary collecting ducts and interstitial connective tissue were mostly unaffected during dehydration. CKD, a chronic nephropathy induced by recurrent dehydration in human and animal models and characterized by interstitial fibrosis and glomerular sclerosis, were not observed in the dehydrated/rehydrated camel kidneys. The initiating factors, endogenous fructose, AVP/AVPR2 and uric acid levels were not much affected. TGF-ß1 protein and TGF-ß1gene expression showed no changes by dehydration in cortex/medulla to mediate fibrosis. KCNN4 gene expression level was hardly detected in the dehydrated camel's kidney; to encode for Ca + + -gated KCa3.1 channel for Ca + + influx to instigate TGF-ß1. Modulation of AQP 1, 2, 3, 4, 9 and SLC protein and/or mRNAs expression levels during dehydration/rehydration was reported. CONCLUSIONS: Long-term dehydration induces reversible or irreversible ultrastructural changes in kidney cortex with minor effects in medulla. Modulation of AQP channels, SLC and their mRNAs expression levels during dehydration/rehydration have a role in water conservation. Cortex and medulla respond differently to dehydration/rehydration.

Adropin Is Expressed in Pancreatic Islet Cells and Reduces Glucagon Release in Diabetes Mellitus.

Diabetes mellitus affects 537 million adults around the world. Adropin is expressed in different cell types. Our aim was to investigate the cellular localization in the endocrine pancreas and its effect on modulating pancreatic endocrine hormone release in streptozotocin (STZ)-induced diabetic rats. Adropin expression in the pancreas was investigated in normal and diabetic rats using immunohistochemistry and immunoelectron microscopy. Serum levels of insulin, glucagon pancreatic polypeptide (PP), and somatostatin were measured using a Luminex® χMAP (Magpix®) analyzer. Pancreatic endocrine hormone levels in INS-1 832/3 rat insulinoma cells, as well as pancreatic tissue fragments of normal and diabetic rats treated with different concentrations of adropin (10-6, 10-9, and 10-12 M), were measured using ELISA. Adropin was colocalized with cells producing either insulin, glucagon, or PP. Adropin treatment reduced the number of glucagon-secreting alpha cells and suppressed glucagon release from the pancreas. The serum levels of GLP-1 and amylin were significantly increased after treatment with adropin. Our study indicates a potential role of adropin in modulating glucagon secretion in animal models of diabetes mellitus.

Comparative Evaluation of the Effects of Amorphous Silica Nanoparticles on the Erythrocytes of Wistar Normotensive and Spontaneously Hypertensive Rats.

Silica nanoparticles (SiNPs) are one of the most widely used nanomaterials. SiNPs can encounter erythrocytes and hypertension is strongly linked to abnormalities in the functional and structural characteristics of erythrocytes. As little is known about the combinatorial effect of SiNP-hypertension interactions on erythrocytes, the aim of this work was to study the effects triggered by hypertension on SiNPs induced hemolysis and the pathophysiological mechanism underlying it. We compared the interaction of amorphous 50 nm SiNPs at various concentrations (0.2, 1, 5 and 25 µg/mL) with erythrocytes of normotensive (NT) and hypertensive (HT) rats in vitro. Following incubation of the erythrocytes, SiNPs induced significant and dose-dependent increase in hemolysis. Transmission electron microscopy revealed erythrocyte deformity in addition to SiNPs taken up by erythrocytes. The erythrocyte susceptibility to lipid peroxidation was significantly increased. The concentration of reduced glutathione, and activities of superoxide dismutase, and catalase were significantly increased. SiNPs significantly increased intracellular Ca2+. Likewise, the concentration of the cellular protein annexin V and calpain activity was enhanced by SiNPs. Concerningly, all the tested parameters were significantly enhanced in erythrocytes from HT rats compared to NT rats. Our results collectively demonstrate that hypertension can potentially exacerbate the in vitro effect induced by SiNPs.

An Update on the Molecular and Cellular Basis of Pharmacotherapy in Type 2 Diabetes Mellitus.

Diabetes mellitus (DM) is a chronic illness with an increasing global prevalence. More than 537 million cases of diabetes were reported worldwide in 2021, and the number is steadily increasing. The worldwide number of people suffering from DM is projected to reach 783 million in 2045. In 2021 alone, more than USD 966 billion was spent on the management of DM. Reduced physical activity due to urbanization is believed to be the major cause of the increase in the incidence of the disease, as it is associated with higher rates of obesity. Diabetes poses a risk for chronic complications such as nephropathy, angiopathy, neuropathy and retinopathy. Hence, the successful management of blood glucose is the cornerstone of DM therapy. The effective management of the hyperglycemia associated with type 2 diabetes includes physical exercise, diet and therapeutic interventions (insulin, biguanides, second generation sulfonylureas, glucagon-like peptide 1 agonists, dipeptidyl-peptidase 4 inhibitors, thiazolidinediones, amylin mimetics, meglitinides, α-glucosidase inhibitors, sodium-glucose cotransporter-2 inhibitors and bile acid sequestrants). The optimal and timely treatment of DM improves the quality of life and reduces the severe burden of the disease for patients. Genetic testing, examining the roles of different genes involved in the pathogenesis of DM, may also help to achieve optimal DM management in the future by reducing the incidence of DM and by enhancing the use of individualized treatment regimens.

Adropin's Role in Energy Homeostasis and Metabolic Disorders.

Adropin is a novel 76-amino acid-peptide that is expressed in different tissues and cells including the liver, pancreas, heart and vascular tissues, kidney, milk, serum, plasma and many parts of the brain. Adropin, encoded by the Enho gene, plays a crucial role in energy homeostasis. The literature review indicates that adropin alleviates the degree of insulin resistance by reducing endogenous hepatic glucose production. Adropin improves glucose metabolism by enhancing glucose utilization in mice, including the sensitization of insulin signaling pathways such as Akt phosphorylation and the activation of the glucose transporter 4 receptor. Several studies have also demonstrated that adropin improves cardiac function, cardiac efficiency and coronary blood flow in mice. Adropin can also reduce the levels of serum triglycerides, total cholesterol and low-density lipoprotein cholesterol. In contrast, it increases the level of high-density lipoprotein cholesterol, often referred to as the beneficial cholesterol. Adropin inhibits inflammation by reducing the tissue level of pro-inflammatory cytokines such as tumor necrosis factor alpha and interleukin-6. The protective effect of adropin on the vascular endothelium is through an increase in the expression of endothelial nitric oxide synthase. This article provides an overview of the existing literature about the role of adropin in different pathological conditions.

Diabetes Mellitus Alters the Immuno-Expression of Neuronal Nitric Oxide Synthase in the Rat Pancreas.

Nitric oxide is generated from nitric oxide synthase following hyperglycemia-induced oxidative stress during the course of diabetes mellitus (DM). We examined the temporal immuno-expression of neuronal nitric oxide synthase (nNOS) in the pancreas of diabetic and non-diabetic rats using immunohistochemical, immunofluorescence and western blot techniques 12 h, 24 h, 1 week, 2 weeks, 1, 8 and 15 months after induction of DM. nNOS co-localized with pancreatic beta cells but disappears 12 h after the onset of DM. In contrast, the nNOS content of pancreatic nerves increased significantly (p < 0.001) 24 h after the induction of DM, and decreased sharply thereafter. However, nNOS-positive ganglion cells were observed even 15 months post-diabetes. ROS increased by more than 100% two months after the onset of DM compared to non-diabetic control but was significantly (p < 0.000001) reduced at 9 months after the induction of DM. The pancreatic content of GSH increased significantly (p < 0.02) after 9 months of DM. Although, TBARS content was significantly (p < 0.009; p < 0.002) lower in aged (9 months) non-diabetic and DM rats, TBARS rate was markedly (p < 0.02) higher 9 months after the induction of DM when compared to younger age group. In conclusion, nNOS is present in pancreatic beta cell, but disappears 12 h after the onset of diabetes. In contrast, the tissue level of nNOS of pancreatic nerves increased in the first week of diabetes, followed by a sharp reduction. nNOS may play important roles in the metabolism of pancreatic beta cell.

Lycopodium Mitigates Oxidative Stress and Inflammation in the Colonic Mucosa of Acetic Acid-Induced Colitis in Rats.

Inflammatory bowel diseases (IBDs) such as ulcerative colitis (UC) and Crohn's disease (CD) are diseases of the gastrointestinal system involving genetic and environmental factors attributed to oxidative stress and inflammation. Targeting oxidative stress and inflammation by novel dietary compounds of natural origin convincingly appears to be one of the important therapeutic strategies to keep the disease in remission. As there is no permanent cure for IBD except for chronic long-term treatment or surgery, it is therefore imperative to investigate plant-based agents that are receiving attention for their therapeutic benefits to overcome the debilitating clinical conditions of IBD. Lycopodium (LYCO), a plant of tropical and subtropical origin and known by numerous names such as ground pine, club moss, or devil's claw, has been popularly used for centuries in traditional medicine including Chinese and Indian medicines. In the present study, the effect of LYCO has been investigated in an acetic acid (AA)-induced colitis model in Wistar rats. LYCO was orally administered at the dose of 50 mg/kg/day either 3 days before or 30 min after the induction of IBD and continued for 7 days by intrarectal administration of AA. The changes in body weight and macroscopic and microscopic analysis of the colon of rats of different experimental groups were observed on days 0, 2, 4, and 7. The levels of myeloperoxidase (MPO), reduced glutathione (GSH), and malondialdehyde (MDA) were measured. AA caused a significant reduction in body weight and increased macroscopic and microscopic ulcer scores along with a significant decline in antioxidant enzymes, superoxide dismutase (SOD), and catalase and antioxidant substrate, glutathione (GSH). There was a concomitant increased formation of malondialdehyde (MDA), a marker of lipid peroxidation, and raised myeloperoxidase (MPO) activity, a marker of neutrophil activation. Treatment with LYCO significantly improved IBD-induced reduction in body weight, improved histology, inhibited MDA formation, and restored antioxidants along with reduced MPO activity. AA also caused the release of proinflammatory cytokines such as interleukin-1ß (IL-1ß) and interleukin-23 (IL-23). Furthermore, AA also increased the levels of calprotectin, a protein released by neutrophils under inflammatory conditions of the gastrointestinal tract. LYCO treatment significantly reduced the release of calprotectin and proinflammatory cytokines. The results demonstrate that LYCO treatment has the potential to improve disease activity by inhibiting oxidative stress, lipid peroxidation, and inflammation along with histological preservation of colonic tissues.

Mechanisms of COVID-19-induced heart failure: a short review.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19) has infected more than 42.5 million people globally resulting in the death of over 1.15 million subjects. It has inflicted severe public health and economic hardships across the world. In addition to acute respiratory distress syndrome, respiratory failure, sepsis, and acute kidney injury, COVID-19 also causes heart failure (HF). COVID-19-induced HF is manifested via different mechanisms, including, but not limited to, (1) virus-induced infiltration of inflammatory cells, which could impair the function of the heart; (2) pro-inflammatory cytokines (monocyte chemoattractant protein-1, interleukin-1ß; interleukin-6; tumor necrosis factor-α) that could cause necrosis and death of the myocardium; (3) endothelial injury coupled with micro-thrombosis which could damage the endocardium; and (4) acute respiratory distress syndrome and respiratory failure that could lead to heart failure due to severe hypoxia. It is concluded that the etiology of COVID-19-induced HF is multifactorial and mitigation of the development of HF in patients with COVID-19 will require different approaches such as social distancing, drug therapy, and the urgent development of a vaccine to eradicate the disease.

Nerolidol, a sesquiterpene, attenuates oxidative stress and inflammation in acetic acid-induced colitis in rats.

Targeting oxidative stress and inflammation by novel dietary compounds of natural origin convincingly appears to be one of the most important therapeutic strategies to keep inflammatory bowel diseases (IBD) such as ulcerative colitis disease in remission. It is imperative to investigate naturally occuring plant-derived dietary phytochemicals that are receiving attention for their therapeutic benefits to overcome the debilitating conditions of IBD. In the present study, the effect of nerolidol (NRD), a monocyclic sesquiterpene found in German Chamomile tea, was investigated in acetic acid-induced colitis model in Wistar rats. NRD was orally administered at a dose of 50 mg/kg/day either for 3 days before or 30 min after induction of IBD for 7 days, after intrarectal administration of acetic acid. The body weight, macroscopic, and microscopic analyses of the colon in different experimental groups were observed on days 0, 2, 4, and 7. Acetic acid caused significant reduction in body weight and induced macroscopic and microscopic ulcer along with a significant decline of antioxidants, concomitant to increased malondialdehyde (MDA), a marker of lipid peroxidation, and myeloperoxidase (MPO) activity, a marker of neutrophil activation. Treatment with NRD significantly improved IBD-induced reduction in body weight, improved histology, inhibited MDA formation, and restored antioxidants along with reduced MPO activity. Acetic acid also induced the release of pro-inflammatory cytokines and increased calprotectin, released by neutrophils under inflammatory conditions. NRD treatment significantly reduced calprotectin and pro-inflammatory cytokines. NRD treatment showed potential to improve disease activity and inhibit oxidative stress, lipid peroxidation, and inflammation along with histological preservation of the colon tissues.

Effects of obesity and diabesity on heart rhythm in the Zucker rat.

Obesity and type 2 diabetes mellitus are risk factors for hypertension, coronary heart disease, cardiac arrhythmias including atrial fibrillation, heart failure and sudden cardiac death. The effects of obesity and diabesity on heart rhythm were investigated in the Zucker diabetic fatty (ZDF) and Zucker fatty (ZF) compared to the Zucker lean (ZL) control rat. In vivo biotelemetry techniques were used to assess the electrocardiogram and other cardiac and metabolic parameters. ZDF rats were characterized by age-dependent elevations in fasting and non-fasting blood glucose, glucose intolerance and weight gain and ZF rats were characterized by smaller elevations in fasting and non-fasting blood glucose and greater weight gain compared to ZL rats. Heart rate (HR) was progressively reduced in ZDF, ZF and ZL rats. At 195 days (6.5 months) of age there were significant differences in HR between ZDF (265 ± 8 bpm, n = 10), ZF (336 ± 9 bpm, n = 10) and ZL (336 ± 10 bpm, n = 10) rats and significant differences in HRV between ZDF (22 ± 1 bpm, n = 10), ZF (27 ± 1 bpm, n = 10) and ZL (31 ± 1 bpm, n = 10) rats. Power spectral analysis revealed no significant (P > 0.05) differences in HRV at low frequencies, reduced HRV at high frequencies and increased sympathovagal balance in ZDF compared to ZF and ZL rats. HR was reduced by ageing and additionally reduced by diabesity in the absence of changes in physical activity and body temperature. Reductions in HRV associated with altered sympathovagal drive might partly underlie disturbed HR in the ZDF rat. Possible explanations for reduced HR and future mechanistic studies are discussed.

The metabolic sensor PASK is a histone 3 kinase that also regulates H3K4 methylation by associating with H3K4 MLL2 methyltransferase complex.

The metabolic sensor Per-Arnt-Sim (Pas) domain-containing serine/threonine kinase (PASK) is expressed predominantly in the cytoplasm of different cell types, although a small percentage is also expressed in the nucleus. Herein, we show that the nuclear PASK associates with the mammalian H3K4 MLL2 methyltransferase complex and enhances H3K4 di- and tri-methylation. We also show that PASK is a histone kinase that phosphorylates H3 at T3, T6, S10 and T11. Taken together, these results suggest that PASK regulates two different H3 tail modifications involving H3K4 methylation and H3 phosphorylation. Using muscle satellite cell differentiation and functional analysis after loss or gain of Pask expression using the CRISPR/Cas9 system, we provide evidence that some of the regulatory functions of PASK during development and differentiation may occur through the regulation of these histone modifications.

Hypocretin/orexin modulates body weight and the metabolism of glucose and insulin.

The hypocretin/orexin (Hcrt/orexin) unit affects the functions of the nervous, cardiovascular, gastrointestinal, and reproductive systems. Hcrt/orexin ligands and receptors have been localized to different parts of the central and peripheral nervous systems, cerebrospinal fluid and blood, exocrine (pancreas, salivary, lacrimal) as well as endocrine (pancreatic islets, pituitary, adrenal) glands. Several factors including stress, glucagon-like peptide-1 agonists, glutamate, nicotine, glucose, and hypoglycaemia stimulate the expression of Hcrt/orexin system, but it is inhibited by ageing, bone morphogenetic protein, hypoxia/hypercapnia, melanocortin receptor accessory protein 2, and glucagon. Literature reports show that Hcrt/orexin can significantly increase insulin secretion from normal and diabetic rat pancreata. Hcrt/orexin decreases blood glucose concentration and reduces insulin resistance partly via increased tissue expression of glucose transporter type 4. It reduces obesity by increasing browning of fat cells and energy expenditure. Taken together, Hcrt/orexin modulates obesity and the metabolism of glucose and insulin. The Hcrt/orexin system may thus be a target in the development of new therapies for the treatment of diabetes mellitus.

Antagonism of Histamine H3 receptors Alleviates Pentylenetetrazole-Induced Kindling and Associated Memory Deficits by Mitigating Oxidative Stress, Central Neurotransmitters, and c-Fos Protein Expression in Rats.

Histamine H3 receptors (H3Rs) are involved in several neuropsychiatric diseases including epilepsy. Therefore, the effects of H3R antagonist E177 (5 and 10 mg/kg, intraperitoneal (i.p.)) were evaluated on the course of kindling development, kindling-induced memory deficit, oxidative stress levels (glutathione (GSH), malondialdehyde (MDA), catalase (CAT), and superoxide dismutase (SOD)), various brain neurotransmitters (histamine (HA), acetylcholine (ACh), γ-aminobutyric acid (GABA)), and glutamate (GLU), acetylcholine esterase (AChE) activity, and c-Fos protein expression in pentylenetetrazole (PTZ, 40 mg/kg) kindled rats. E177 (5 and 10 mg/kg, i.p.) significantly decreased seizure score, increased step-through latency (STL) time in inhibitory avoidance paradigm, and decreased transfer latency time (TLT) in elevated plus maze (all P < 0.05). Moreover, E177 mitigated oxidative stress by significantly increasing GSH, CAT, and SOD, and decreasing the abnormal level of MDA (all P < 0.05). Furthermore, E177 attenuated elevated levels of hippocampal AChE, GLU, and c-Fos protein expression, whereas the decreased hippocampal levels of HA and ACh were modulated in PTZ-kindled animals (all P < 0.05). The findings suggest the potential of H3R antagonist E177 as adjuvant to antiepileptic drugs with an added advantage of preventing cognitive impairment, highlighting the H3Rs as a potential target for the therapeutic management of epilepsy with accompanied memory deficits.

Effect of nociceptin on insulin release in normal and diabetic rat pancreas.

Nociceptin (NC), also known as Orphanin FQ, is a brain peptide involved in the regulation of pain, but its role in the endocrine pancreas is poorly understood. The present study examines the pattern of distribution of NC and its effect on insulin and glucagon secretion after the onset of diabetes mellitus (DM). Male Wistar rats weighing 150-200 g were made diabetic with streptozotocin (60 mg/kg body weight, intraperitoneally). Four weeks after the induction of DM, pancreatic tissues were retrieved and processed for immunofluorescence, immunoelectron microscopy, and insulin and glucagon secretion. Isolated islets from non-diabetic and diabetic rats were used to determine the effect of NC on insulin release. NC was discerned in islet cells of non-diabetic control and diabetic rat pancreata. NC co-localized only with insulin in pancreatic beta cells. NC did not co-localize with either glucagon or somatostatin or pancreatic polypeptide. The number of NC-positive cells was markedly (p < 0.001) reduced after the onset of DM. Electron microscopy study showed that NC is located with insulin in the same secretory granules of the beta cells of both non-diabetic and diabetic rat pancreas. NC inhibits insulin release markedly (p < 0.05) from pancreatic tissue fragments of non-diabetic and diabetic rats. In contrast, NC at 10-12 M stimulates insulin release in isolated islets of DM rats. In conclusion, NC co-localizes with insulin only in the islet of Langerhans. The co-localization of NC with insulin suggests a role for NC in the regulation of pancreatic beta cell function.

Hyperglycemia-induced cardiac contractile dysfunction in the diabetic heart.

The development of a diabetic cardiomyopathy is a multifactorial process, and evidence is accumulating that defects in intracellular free calcium concentration [Ca2+]i or its homeostasis are related to impaired mechanical performance of the diabetic heart leading to a reduction in contractile dysfunction. Defects in ryanodine receptor, reduced activity of the sarcoplasmic reticulum calcium pump (SERCA) and, along with reduced activity of the sodium-calcium exchanger (NCX) and alterations in myofilament, collectively cause a calcium imbalance within the diabetic cardiomyocytes. This in turn is characterized by cytosolic calcium overloading or elevated diastolic calcium leading to heart failure. Numerous studies have been performed to identify the cellular, subcellular, and molecular derangements in diabetes-induced cardiomyopathy (DCM), but the precise mechanism(s) is still unknown. This review focuses on the mechanism behind DCM, the onset of contractile dysfunction, and the associated changes with special emphasis on hyperglycemia, mitochondrial dysfunction in the diabetic heart. Further, management strategies, including treatment and emerging therapeutic modalities, are discussed.

Type 1 diabetes mellitus induces structural changes and molecular remodelling in the rat kidney.

There is much evidence that diabetes mellitus (DM)-induced hyperglycemia (HG) is responsible for kidney failure or nephropathy leading to cardiovascular complications. Cellular and molecular mechanism(s) whereby DM can damage the kidney is still not fully understood. This study investigated the effect of streptozotocin (STZ)-induced diabetes (T1DM) on the structure and associated molecular alterations of the isolated rat left kidney following 2 and 4 months of the disorder compared to the respective age-matched controls. The results revealed hypertrophy and general disorganized architecture of the kidney characterized by expansion in glomerular borders, tubular atrophy and increased vacuolization of renal tubular epithelial cells in the diabetic groups compared to controls. Electron microscopic analysis revealed ultrastructural alterations in the left kidney highlighted by an increase in glomerular basement membrane width. In addition, increased caspase-3 immunoreactivity was observed in the kidney of T1DM animals compared to age-matched controls. These structural changes were associated with elevated extracellular matrix (ECM) deposition and consequently, altered gene expression profile of ECM key components, together with elevated levels of key mediators (MMP9, integrin 5α, TIMP4, CTGF, vimentin) and reduced expressions of Cx43 and MMP2 of the ECM. Marked hypertrophy of the kidney was highlighted by increased atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) gene expression. These changes also correlated with increased TGFß1 activity, gene expression in the left kidney and elevated active TGFß1 in the plasma of T1DM rats compared to control. The results clearly demonstrated that TIDM could elicit severe structural changes and alteration in biochemical markers (remodelling) in the kidney leading to diabetic nephropathy (DN).

Effect of turmeric on colon histology, body weight, ulcer, IL-23, MPO and glutathione in acetic-acid-induced inflammatory bowel disease in rats.

BACKGROUND: This study investigates the protective effects of turmeric (Curcuma longa, CL) on acetic acid-induced colitis in rats. METHOD: Inflammatory bowel disease (IBD) was induced in male Wistar rats by intra-rectal administration of 1 ml of 4% acetic acid at 8 cm proximal to the anus for 30 s. Curcuma longa (CL) powder, (1, 10, or 100 mg/kg/day) was administered for either 3 days before or after IBD for 7 days. The body weight, macroscopic and microscopic analysis of the colon of CL-treated IBD rats and that of control rats (no IBD, no CL) were performed on 0 day, 2, 4 and 7th day. Myeloperoxidase (MPO), IL-23 and glutathione levels in control, untreated and treated rats were measured by ELISA. RESULTS: CL significantly (P < 0.05) improved IBD-induced reduction in mean body weight and mean macroscopic ulcer score. Administration of CL also significantly (P < 0.01) reduced the mean microscopic ulcer score when compared to untreated IBD control. Intake of CL by rats resulted in a significant (P < 0.05) increase in the mean serum glutathione level compared to untreated control. CL reduced both MPO and IL-23 levels in the colonic mucosa of the rat. CONCLUSION: CL improved body weight gain, mean macroscopic and microscopic ulcer scores in the colon of rats suffering from acetic acid-induced IBD. CL reduced both MPO and IL-23 in the mucosa of the colon. The increase in the mean serum glutathione level may help in the reduction of oxidative stress associated with IBD.

Enhanced Glucose Tolerance and Pancreatic Beta Cell Function by Low Dose Aspirin in Hyperglycemic Insulin-Resistant Type 2 Diabetic Goto-Kakizaki (GK) Rats.

BACKGROUND/AIM: Type 2 diabetes is the most common metabolic disorder, characterized by insulin resistance and pancreatic islet beta-cell failure. The most common complications associated with type 2 diabetes are hyperinsulinemia, hyperglycemia, hyperlipidemia, increased inflammatory and reduced insulin response. Aspirin (ASA) and other non-steroidal anti-inflammatory drugs (NSAIDs) have been associated with the prevention of diabetes, obesity and related cardiovascular disorders. Aspirin has been used in many clinical and experimental trials for the prevention of diabetes and associated complications. METHODS: In this study, five month old Goto-Kakizaki (GK) rats, which showed signs of mild hyperglycemia (fasting blood glucose 80-95 mg/dl vs 55-60 mg/dl Wistar control rats) were used. Two subgroups of GK and Wistar control rats were injected intraperitoneally with 100 mg aspirin/kg body weight/ day for 5 weeks. Animals were sacrificed and blood and tissues were collected after performing glucose tolerance (2 h post 2g IP glucose ingestion) tests in experimental and control groups. RESULTS: Aspirin caused a moderate decrease in hyperglycemia. However, we observed a significant improvement in glucose tolerance after ASA treatment in GK rats compared to the nondiabetic Wistar rats. Also, the ASA treated GK rats exhibited a significant decrease in insulinemia. ASA treatment also caused a marked reduction in the pro-inflammatory prostaglandin, PGE2, which was significantly higher in GK rats. On the other hand, no significant organ toxicity was observed after ASA treatment at this dose and time period. However, the total cholesterol and lipoprotein levels were significantly increased in GK rats, which decreased after ASA treatment. Immunofluorescence staining for insulin/glucagon secreting pancreatic cells showed improved beta-cell structural and functional integrity in ASA-treated rats which was also confirmed by SDS-PAGE and Western blot analysis. CONCLUSION: The improved glucose tolerance in ASA-treated GK rats may be associated with increased insulin responses due to the anti-inflammatory properties of ASA and enhanced nitric oxide (NO) level which facilitated insulin signaling and energy utilization in target tissues. These results may have implications in determining the therapeutic use of ASA in insulin-resistant type 2 diabetes.

Anti-hyperlipidemic effect of methanol bark extract of Terminalia chebula in male albino Wistar rats.

CONTEXT: Hyperlipidemia is known to be a major risk factor for the development of cardiovascular diseases (CVDs) which include atherosclerosis, coronary heart disease, and stroke. Although there are a large number of anti-hyperlipidemic drugs available, unfortunately, they all have side effects. OBJECTIVE: Terminalia chebula Retz. (Combretaceae) is a plant used to treat cardiac disorders in the traditional Ayurveda medicine in India. The objective of this study was to assess the anti-hyperlipidemic properties of a methanol (MeOH) bark extract of T. chebula. MATERIALS AND METHODS: Acute toxicity studies were performed according to the Organisation for Economic Cooperation and Development (OECD) guideline no. 423 using various doses (5, 50, 300, and 2000 mg/kg) of T. chebula bark. Anti-hyperlipidemic effect of MeOH bark extract of T. chebula at doses of 200, 400, and 600 mg/kg and fasting glucose levels after treatment with MeOH bark extract of T. chebula at doses of 200, 400, and 600 mg/kg were analyzed using commercially available kits. RESULTS: Acute toxicity studies did not show any morbidity and mortality at various doses. The MeOH extract of T. chebula bark at doses of 200, 400, and 600 mg/kg significantly lowered serum cholesterol and triglyceride levels. Moreover, the extract of T. chebula and the positive control atorvastatin-treated groups of animals showed a significant increase in the serum high-density lipoprotein (HDL) cholesterol levels in diet-induced hypercholesterolemic animals. CONCLUSION: The overall results confirm that the bark extract of T. chebula possesses significant anti-hyperlipidemic activity.