Melatonin as an Ameliorative Agent Against Cadmium- and Lead-Induced Toxicity in Fish: an Overview.

Diverse anthropogenic activities and lack of knowledge on its consequences have promoted serious heavy metal contaminations in different aquatic systems throughout the globe. The non-biodegradable nature of most of these toxic heavy metals has increased the concern on their possible bioaccumulation in aquatic organisms as well as in other vertebrates. Among these aquatic species, fish are most sensitive to such contaminated water that not only decreases their chance of survivability in the nature but also increases the probability of biomagnifications of these heavy metals in higher order food chain. After entering the fish body, heavy metals induce detrimental changes in different vital organs by impairing multiple physiological and biochemical pathways that are essential for the species. Such alterations may include tissue damage, induction of oxidative stress, immune-suppression, endocrine disorders, uncontrolled cell proliferation, DNA damage, and even apoptosis. Although uncountable reports have explored the toxic effects of different heavy metals in diverse fish species, but surprisingly, only a few attempts have been made to ameliorate such toxic effects. Since, oxidative stress seems to be the underlying common factor in such heavy metal-induced toxicity, therefore, a potent and endogenous antioxidant with no side effect may be an appropriate therapeutic solution. Apart from summarizing the toxic effects of two important toxicants, i.e., cadmium and lead in fish, the novelty of the present treatise lies in its arguments in favor of using melatonin, an endogenous free radical scavenger and indirect antioxidant, in ameliorating the toxic effects of heavy metals in any fish species.

Desynchrony induced by higher-order interactions in triplex metapopulations.

In a predator-prey metapopulation, two traits are adversely related: synchronization and persistence. A decrease in synchrony apparently leads to an increase in persistence and, therefore, necessitates the study of desynchrony in a metapopulation. In this article, we study predator-prey patches that communicate with one another while being interconnected through distinct dispersal structures in the layers of a three-layer multiplex network. We investigate the synchronization phenomenon among the patches of the outer layers by introducing higher-order interactions (specifically three-body interactions) in the middle layer. We observe a decrease in the synchronous behavior or, alternatively, an increase in desynchrony due to the inclusion of group interactions among the patches of the middle layer. The advancement of desynchrony becomes more prominent with increasing strength and numbers of three-way interactions in the middle layer. We analytically validate our numerical results by performing a stability analysis of the referred synchronous solution using the master stability function approach. Additionally, we verify our findings by taking into account two distinct predator-prey models and dispersal topologies, which ultimately supports that the findings are generalizable across various models and dispersal structures.

Oleic acid as a restorative agent in alleviating adrenaline induced altered morphofunctional milieu of gastric tissue and mitochondria.

The role of oleic acid as a protective antioxidant has recently been recognized. The present study is aimed to explore whether oleic acid can afford protection to rat gastric tissue when challenged with adrenaline. Sixty adult healthy male albino rats were divided into 10 groups comprising of 6 animals each. First group constituted the control. Rats of the second group were injected sub-cutaneously with adrenaline bitartrate at the dose of 0.3mg/kg body weight, every day for a period of 17 days. Rats of the third, to the sixth groups were orally fed with different doses of oleic acid (2.5, 5, 10, 20 mg/kg body weight/day) respectively. The rats of seventh to tenth groups were orally fed with doses of oleic acid as mentioned above and subsequently injected with adrenaline bitartrate at 0.3mg/kg body weight sub-cutaneously. After the treatment period, the animals were euthanized through cervical dislocation following light ether anaesthesia and gastric tissues were collected for morphological and biochemical studies. Subcutaneously administered pharmacological dose of adrenaline bitartrate caused oxidative stress inducing gastric lesion in male albino rats as evident from the altered levels of biomarkers of oxidative stress, activities of antioxidant and mitochondrial enzymes related to energy metabolism with changes in tissue morphology. Pre-treatment of rats with oleic acid dose-dependently protected against these gastric injuries induced by adrenaline indicating the potentiality of oleic acid in protecting against adrenaline induced gastric injury in male albino rats where antioxidant mechanisms appear to play a pivotal role in mediating such protection.

Activation of SIRT1/PGC 1α/SIRT3 pathway by melatonin provides protection against mitochondrial dysfunction in isoproterenol induced myocardial injury.

AIMS: Preventing mitochondrial dysfunction and enhancing mitochondrial health and biogenesis is a crucial therapeutic approach to ameliorate injury following acute myocardial infarction. Although the antioxidant role of melatonin against ischemia/reperfusion injury has been reported, the exact mechanism of protection, in vivo, remains poorly understood. This study aims to identify and elaborate upon mechanism of melatonin protection of rat cardiac mitochondria against acute myocardial infarction. MAIN METHODS: Rats were pre-treated with melatonin (10 mg/kg body weight (b.w.); intraperitoneally, i.p.) before isoproterenol bitartrate (ISO) administration (25 mg/kg body weight (b.w.) subcutaneously,s.c.) and their effect on rat heart mitochondrial structure and function was studied. Biochemical changes in activity of biomarkers of oxidative stress, antioxidant enzymes as well as Krebs' cycle enzymes were analyzed. Gene expression studies and Isothermal titration calorimetric studies with pure catalase and ISO were also carried out. KEY FINDINGS: Melatonin was shown to reduce ISO induced oxidative stress, by stimulating superoxide dismutase activity and removing the inhibition of Krebs' cycle enzymes. Herein we report for the first time in rat model that melatonin activates the SIRT1-PGC-1α-SIRT3 signaling pathways after ISO administration, which ultimately induces mitochondrial biogenesis. Melatonin exhibited significant protection of mitochondrial architecture and topology along with increased calcium ion permeability and reactive oxygen species (ROS) generation induced by ISO. Isothermal calorimetric studies revealed that melatonin binds to ISO molecules and sequesters them from the reaction thereby limiting their interaction with catalase along with occupying the binding sites of catalase themselves. SIGNIFICANCE: Activation of SIRT1-PGC-1α-SIRT3 pathway by melatonin along with its biophysical properties prevents ISO induced mitochondrial injury in rat heart.

Attenuation of arsenic induced high fat diet exacerbated oxidative stress mediated hepatic and cardiac injuries in male Wistar rats by piperine involved antioxidative mechanisms.

The current study explored the efficacy of piperine in attenuating arsenic induced high fat diet aggravated oxidative stress mediated injury in hepatic and cardiac tissues of male Wistar rats. Oral administration of piperine significantly (p < 0.05) reduced the levels of organ specific and oxidative stress biomarkers in arsenic and high fat diet treated rat hepatic and cardiac tissues in a dose dependant manner with the dose of 60 mg/kg b.w. exhibiting maximum protection. Arsenic induced high fat diet aggravated oxidative stress mediated damages in liver and heart tissues led to decreased activities of antioxidant enzymes, ROS generation, diminished activities of Krebs' cycle and respiratory chain enzymes, collapsed mitochondrial membrane potential, mitochondrial DNA damage along with altered lipid metabolism and inflammatory cytokine levels. Histochemical and histopathological studies supported the above findings. Piperine efficiently counteracted the arsenic induced high fat diet aggravated oxidative stress mediated damages by modulating antioxidant defense mechanism along with free radical quenching ability. These findings indicate that piperine protected the arsenic induced high fat diet aggravated hepatic and cardiac injuries which underline the importance of piperine in providing a possible therapeutic regime for the amelioration of arsenic-induced high fat diet aggravated oxidative stress mediated organ damages.

Oleic acid protects against cadmium induced cardiac and hepatic tissue injury in male Wistar rats: A mechanistic study.

AIMS: The aim of the present study was to evaluate the possible antioxidant role of oleic acid (OA) against Cd-induced injuries in the heart and liver tissues of male Wistar rats. MAIN METHODS: Rats were treated with either vehicle (control), or OA (10 mg/kg b.w., fed orally), or Cd (0.44 mg/kg b.w., s.c.), or both (OA + Cd) for 15 days. Following completion of the treatment period, biomarkers of organ damage and oxidative stress including ROS, activities of antioxidant enzymes and their level, activities of Krebs cycle enzymes and respiratory chain enzymes were measured. Levels of interleukins (IL-1ß, IL-6, IL-10), tumor necrosis factor (TNF-α) and nuclear factor kappa B (NFκB) were estimated to evaluate the state of inflammation. In addition, changes in mitochondrial membrane potential and status of cytochrome c (Cyt c) were also studied. KEY FINDINGS: Pre-treatment of rats with OA significantly protected against Cd-induced detrimental changes possibly by decreasing endogenous ROS through regulation of antioxidant defense system, inflammatory responses and activities of metabolic enzymes. Moreover, OA was also found to restore mitochondrial membrane potential possibly by regulating Cyt c leakage thereby increasing mitochondrial viability. SIGNIFICANCE: Our results for the first time demonstrated systematically that OA provided protection against Cd-induced oxidative stress mediated injuries in rat heart and liver tissues through its antioxidant mechanism. The results raise the possibility of using OA singly or in combination with other antioxidants or diet in the treatment of situations arising due to oxidative stress and may have future therapeutic relevance.

Aqueous bark extract of Terminalia arjuna protects against cadmium-induced hepatic and cardiac injuries in male Wistar rats through antioxidative mechanisms.

Cadmium (Cd) is one of the most ubiquitous toxic heavy metal in the environment. The present study was conducted to evaluate the protective role of aqueous bark extract of Terminalia arjuna (TA) against Cd induced oxidative damage in hepatic and cardiac tissues as the TA bark extract has folkloric medicinal use in the treatment of various hepatic and cardiac disorders. Male Wistar rats were divided into 4 groups. The control group was treated with normal saline as the vehicle; the second group orally administered with TA (20 mg/kg bw) daily for 15 days; the third group injected with Cd-acetate (0.44 mg/kg bw, s.c.) every alternate day for a period of 15 days; and the fourth group was administered with TA, 60 min prior to Cd treatment. The biomarkers of organ damage were significantly increased in the Cd treated groups. Besides, a significant alteration in the tissue levels of biomarkers of oxidative stress, the activities and the levels of antioxidant enzymes was observed following treatment with Cd. Additionally, some of the enzymes were found to be inhibited uncompetitively by Cd when tested in an in vitro system. Furthermore, evidence gathered from studies on the histological parameters and mitochondrial membrane potential in both the tissues argue in favour of the possible protective role of TA against Cd induced damage. Finally, gas chromatography-mass spectrometry revealed the presence of eight major bioactive phytochemicals in aqueous bark extract of TA having potent free radical scavenging property. The results indicate that the extract could protect hepatic and cardiac tissues against Cd-induced oxidative stress mediated damages through antioxidant mechanism(s).

Response of gastrointestinal melatonin, antioxidants, and digestive enzymes to altered feeding conditions in carp (Catla catla).

The purpose of present study was to ascertain whether the response of gastrointestinal (gut) melatonin to altered feeding conditions was related to the levels of different antioxidants and digestive enzymes in the same gut tissues of a sub-tropical carp (Catla catla). Accordingly, the fish were subjected to food deprivation for 4 or 8 days and separately to re-feeding for 4 or 8 or 12 days after deprivation of food for 8 days, and their gut tissue homogenates were used to measure the levels of melatonin, both enzymatic [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST)] and non-enzymatic [reduced glutathione (GSH)] antioxidants, as well as different digestive enzymes (α-amylase, cellulase, protease, and lipase). Notably, the gut levels of melatonin, SOD, CAT, GPx, and GST underwent gradual increase with the progress of food deprivation, but a sudden fall after restoration of food supply for 4 days and a rise thereafter. Conversely, the activity of all the digestive enzymes significantly decreased after deprivation of food, but started increasing when food supply was reinforced. Gut melatonin concentrations by showing a positive correlation with the titers of different antioxidants (in both food-deprived and re-fed fish groups) and a negative (in food-deprived fish) or a positive (in re-fed fish) correlation with the activity of each digestive enzyme underlined possible physiological interplay between them. Collectively, our findings lend support to the hypothesis that gut melatonin response to altered feeding conditions in carp might be associated with the oxidative status as well as the digestive functions of the gastrointestinal tissues itself.

Vicinal diaryl azole-based urea derivatives as potential cholesterol lowering agents acting through inhibition of SOAT enzymes.

A novel series of vicinal diaryl azole-urea derivatives were synthesized and evaluated for their potential to inhibit SOAT enzyme. Among the reported compounds, compound (12d) emerged as the most potent compound with an IC50 value of 2.43 µM. In polaxamer-407 induced lipoprotein lipase inhibition model, compound (12d) reduced triglyceride turnover in vivo. Compound (12d) also showed dose-dependent prevention of serum total cholesterol and prevention of LDL-C elevation at a dose of 30 mg/kg. Furthermore, compound (12d) showed potential to stop falling levels of serum HDL-C dose-dependently and improved the atherogenic index. Effect of 12d on body weight, plaque formation and development of atherogenic lesions were studied. Toxicological study of compound (12d) indicated that at a dose of 2000 mg/kg, 12d was devoid of any signs of toxicity or mortality.

Influences of exogenous melatonin on the oocyte growth and oxidative status of ovary during different reproductive phases of an annual cycle in carp Catla catla.

The present study aimed to evaluate antioxidant role of melatonin in determining seasonality of ovarian growth in adult carp Catla catla. Accordingly, an identical regimen of exogenous melatonin administration (100 µg/100 g body weight per day for 15 days) was followed during the preparatory, prespawning, and spawning phases of an annual reproductive cycle. The study did not include postspawning phase, when the ovaries were completely regressed and devoid of any healthy growing follicles. The ovarian response was evaluated by determining relative number of developing oocytes as well as measuring the levels of melatonin, oxidative stress (using malondialdehyde [MDA] as the marker), both enzymatic (superoxide dismutase [SOD], catalase [CAT], glutathione peroxidase [GPx], and glutathione S-transferase [GST]) and nonenzymatic (reduced glutathione [GSH]) antioxidants in the ovarian homogenates. Due to melatonin treatment, oocyte growth was accelerated in the preparatory phase but retarded in the prespawning and spawning phases of annual cycle. Conversely, melatonin administration in each reproductive phase led to a significant reduction of MDA and elevations of SOD, CAT, GPx, GST, GSH, as well as melatonin levels in the ovary. As a result, melatonin titers in the ovary always reported a negative correlation with MDA and a positive correlation with SOD, CAT, GST, GPx, as well as GSH levels. However, melatonin content of ovary and the values of gonosomatic index in melatonin-treated carp displayed a positive correlation in the preparatory phase and a negative correlation in the remaining parts of reproductive cycle. Thus, it seems likely that melatonin by acting as an antioxidant reduces intraovarian oxidative stress throughout the seasons of follicular growth, whereas exogenous melatonin administration exerts progonadal influences during the preparatory phase, but antigonadal effects during the prespawning and spawning phases of reproductive cycle.

Gut melatonin response to microbial infection in carp Catla catla.

The purpose of present study was to demonstrate the response of gut melatoninergic system to Aeromonas hydrophila infection for 3 or 6 days and search for its correlation with the activity of different antioxidative and digestive enzymes to focus their interplay under pathophysiological conditions in carp (Catla catla). Microscopic study of gut in infected fish revealed degenerative changes in the tunica mucosa and lamina propria layers with sloughed off epithelial cells in the lumen. The activity of each digestive enzyme was reduced, but the levels of melatonin, arylalkylamine-N-acetyl transferase protein, the key regulator of melatonin biosynthesis, and different enzymatic antioxidants in gut were gradually and significantly increased with the progress of infection. Gut melatonin concentrations in A. hydrophila challenged carp by showing a positive correlation with the activity of each antioxidative enzyme, and a negative correlation with different digestive enzymes argued in favor of their functional relation, at least, during pathological stress. Moreover, parallel changes in the gut and serum melatonin titers indicated possible contribution of gut to circulating melatonin. Collectively, present carp study provided the first data to suggest that endogenous gut melatonin may be implicated to the mechanism of response to microbial infections in any fish species.

ACAT inhibitors: the search for novel cholesterol lowering agents.

Increased level of serum cholesterol (hyperlipidemia) is the most significant risk factor for the development of atherosclerosis. Cholesterol levels are affected by factors such as rate of endogenous cholesterol synthesis, biliary cholesterol excretion and dietary cholesterol absorption. Acyl CoA: Cholesterol O-acyl transferases (ACAT) are a small family of enzymes that catalyze cholesterol esterification and cholesterol absorption in intestinal mucosal cells and maintain the cholesterol homeostasis in the blood. Inhibition of the ACAT enzymes is one of the attractive targets to treat hyperlipidemia. Literature survey shows that structurally diverse compounds possess ACAT inhibitory properties. In this review, a comprehensive presentation of the literature on diverse ACAT inhibitors has been given.

Triazole incorporated pyridazinones as a new class of antihypertensive agents: design, synthesis and in vivo screening.

A number of 6-(substituted phenyl)-2-(4-substituted phenyl-5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydropyridazin-3(2H)-one derivatives were designed and synthesized by a sequence of reactions starting from respective aryl hydrocarbons. The final compounds (4a-4u) were evaluated for antihypertensive activities by non-invasive method using Tail Cuff method. The compounds 4e, 4i and 4k showed appreciable antihypertensive activity comparable with that of standard hydralazine and propranolol.