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(1) Background: Cardiovascular complications are a leading cause of morbidity and mortality in diabetic patients. The effects of obesity and diabesity on the function and structure of ventricular myocytes in the Zucker fatty (ZF) rat and the Zucker diabetic fatty (ZDF) rat compared to Zucker lean (ZL) control rats have been investigated. (2) Methods: Shortening and intracellular Ca2+ were simultaneously measured with cell imaging and fluorescence photometry, respectively. Ventricular muscle protein expression and structure were investigated with Western blot and electron microscopy, respectively. (3) Results: The amplitude of shortening was increased in ZF compared to ZL but not compared to ZDF myocytes. Resting Ca2+ was increased in ZDF compared to ZL myocytes. Time to half decay of the Ca2+ transient was prolonged in ZDF compared to ZL and was reduced in ZF compared to ZL myocytes. Changes in expression of proteins associated with cardiac muscle contraction are presented. Structurally, there were reductions in sarcomere length in ZDF and ZF compared to ZL and reductions in mitochondria count in ZF compared to ZDF and ZL myocytes. (4) Conclusions: Alterations in ventricular muscle proteins and structure may partly underlie the defects observed in Ca2+ signaling in ZDF and ZF compared to ZL rat hearts.

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-1β (IL-1β) 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.

Cisplatin (CP) treatment has been long associated with the development of acute kidney injury (AKI) through mechanisms involving inflammation and oxidative stress. α-Bisabolol (BIS), a sesquiterpene alcohol isolated from the essential oil of various plants, including chamomile, has garnered popularity lately due to its antioxidant, anti-inflammatory, and anticancer properties. Therefore, we investigated the nephroprotective effects of BIS in the murine model of CP-induced AKI and the underlying mechanism of action. BALB/c mice were given BIS orally at 25 mg/kg for 7 days. On day 7, they were given a single dose of CP at 20 mg/kg intraperitoneally. BIS treatment continued for 3 more days. The animals were sacrificed at the end of the experiment (day 11). Kidneys, plasma, and urine were collected, and subsequently, various physiological, biochemical, and histological parameters were assessed. BIS has significantly normalized the alterations of water intake, urine volume, relative kidney weight, and the concentrations of urea and creatinine, as well as the creatinine clearance induced by CP treatment. BIS significantly mitigated the effects of CP-induced kidney injury by reducing kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, adiponectin, and cystatin C. Likewise, the renal concentrations of proinflammatory cytokines, tumor necrosis factor α, interleukin (IL)-6 and IL-1β that were elevated in CP group were significantly reduced in mice treated with BIS and CP. A similar significant reduction was also observed in the CP-induced augmented levels of markers of oxidative stress, as well as the metabolite pteridine. Moreover, BIS significantly reduced the CP–induced renal DNA damage, and markedly lessened the acute tubular necrosis observed in kidney histology. Additionally, BIS significantly reduced the CP-induced increase in the phosphorylated nuclear factor κB (NFκB) in the kidney. These data strongly suggest that BIS exerts a protective action against CP-induced nephrotoxicity by mitigating inflammation and oxidative stress through the inhibition of NFκB activation. No overt adverse effects were noted with BIS treatment. Additional investigations should be done to consider BIS as an efficacious nephroprotective agent against CP.

Our recent studies have demonstrated that aspirin treatment prevents inflammatory and oxidative stress-induced alterations in mitochondrial function, improves glucose tolerance and pancreatic endocrine function and preserves tissue-specific glutathione (GSH)-dependent redox homeostasis in Goto-Kakizaki (GK) diabetic rats. In the current study, we have investigated the mechanism of action of aspirin in maintaining mitochondrial bioenergetics and redox metabolism in the liver and kidneys of GK rats. Aspirin reduced the production of reactive oxygen species (ROS) and oxidative stress-induced changes in GSH metabolism. Aspirin treatment also improved mitochondrial respiratory function and energy metabolism, in addition to regulating the expression of cell signaling proteins that were altered in diabetic animals. Ultrastructural electron microscopy studies revealed decreased accumulation of glycogen in the liver of aspirin-treated diabetic rats. Hypertrophic podocytes with irregular fusion of foot processes in the renal glomerulus and detached microvilli, condensed nuclei and degenerated mitochondria observed in the proximal convoluted tubules of GK rats were partially restored by aspirin. These results provide additional evidence to support our previous observation of moderation of diabetic complications by aspirin treatment in GK rats and may have implications for cautious use of aspirin in the therapeutic management of diabetes.

The effects of early (5-day) onset of diabetes mellitus (DM) on retina ultrastructure and cellular bioenergetics were examined. The retinas of streptozotocin-induced diabetic rats were compared to those of non-diabetic rats using light and transmission electron microscopy. Tissue localization of glucagon-like-peptide-1 (GLP-1), exendin-4 (EXE-4), and catalase (CAT) in non-diabetic and diabetic rat retinas was conducted using immunohistochemistry, while the retinal and plasma concentration of GLP-1, EXE-4, and CAT were measured with ELISA. Lipid profiles and kidney and liver function markers were measured from the blood of non-diabetic and diabetic rats with an automated biochemical analyzer. Oxygen consumption was monitored using a phosphorescence analyzer, and the adenosine triphosphate (ATP) level was determined using the Enliten ATP assay kit. Blood glucose and cholesterol levels were significantly higher in diabetic rats compared to control. The number of degenerated photoreceptor cells was significantly higher in the diabetic rat retina. Tissue levels of EXE-4, GLP-1 and CAT were significantly (p = 0.002) higher in diabetic rat retina compared to non-diabetic controls. Retinal cellular respiration was 50% higher (p = 0.004) in diabetic (0.53 ± 0.16 µM O2 min−1 mg−1, n = 10) than in non-diabetic rats (0.35 ± 0.07 µM O2 min−1 mg−1, n = 11). Retinal cellular ATP was 76% higher (p = 0.077) in diabetic (205 ± 113 pmol mg−1, n = 10) than in non-diabetic rats (116 ± 99 pmol mg−1, n = 12). Thus, acute (5-day) or early onslaught of diabetes-induced hyperglycemia increased incretins and antioxidant levels and oxidative phosphorylation. All of these events could transiently preserve retinal function during the early phase of the progression of diabetes.

Nociceptin (NC) consists of 17 amino acids (aa) and takes part in the processing of learning and memory. The role of NC in the induction of endogenous antioxidants in still unclear. We examined the effect of NC on the expression of endogenous antioxidants in kidney, liver, cerebral cortex (CC), and hippocampus after the onset of diabetes mellitus, using enzyme-linked immunosorbent assay and immunohistochemistry. Exogenous NC (aa chain 1–17; 10 µg/kg body weight) was given intraperitoneally to normal and diabetic rats for 5 days. Our results showed that catalase (CAT) is present in the proximal (PCT) and distal (DCT) convoluted tubules of kidney, hepatocytes, and neurons of CC and hippocampus. The expression of CAT was significantly (p < 0.05) reduced in the kidney of normal and diabetic rats after treatment with NC. However, NC markedly (p < 0.001) increased the expression CAT in the liver and neurons of CC of diabetic rats. Superoxide dismutase (SOD) is widely distributed in the PCT and DCT of kidney, hepatocytes, and neurons of CC and hippocampus. NC significantly (p < 0.001) increased the expression of SOD in hepatocytes and neurons of CC and the hippocampus but not in the kidney. Glutathione reductase (GRED) was observed in kidney tubules, hepatocytes and neurons of the brain. NC markedly increased (p < 0.001) the expression of GRED in PCT and DCT cells of the kidney and hepatocytes of liver and neurons of CC. In conclusion, NC is a strong inducer of CAT, SOD, and GRED expression in the kidney, liver and brain of diabetic 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.