Mahaneem Mohamed

Melatonin in Bacterial and Viral Infections with Focus on Sepsis: A Review

Melatonin is a versatile molecule, synthesized not only by the pineal gland, but also in small amounts by many other organs like retina, gastrointestinal tract, thymus, bone marrow, lymphocytes etc. It plays an important role in various functions of the body like sleep and circadian rhythm regulation, immunoregulatory mechanism, free radical scavenger, antioxidant functions, oncostatic actions, control of reproductive functions, regulation of mood etc. Melatonin has also been found to be effective in combating various bacterial and viral infections. Its administration has been shown to be effective in controlling chlamydial infections, infections induced by Mycobacterium tuberculosis, and also in many viral infections. Molecular mechanisms of anti microbial actions of melatonin have suggested to be due to effects on free radical formation, direct regulation of duplication of bacteria, depletion of intracellular substrates like iron etc. Besides, it is effective in sepsis as demonstrated in various animal models of septic shock. Melatonins protective action against sepsis is suggested to be due to its antioxidant, immunomodulating and inhibitory actions against the production and activation of pro-inflammatory mediators. Use of melatonin has been beneficial in treating premature infants suffering from severe respiratory distress syndrome and septic shock. It has a potential therapeutic value in treating septic shock and associated multi organ failure in critically ill patients in addition to its antimicrobial and antiviral actions. The patents related to melatonins use for treatment of bacterial infections and its use in clinical disorders are included.

Antioxidant Protective Effect of Honey in Cigarette Smoke-Induced Testicular Damage in Rats

Cigarette smoke (CS) can cause testicular damage and we investigated the possible protective effect of honey against CS-induced testicular damage and oxidative stress in rats. CS exposure (8 min, 3 times daily) and honey supplementation (1.2 g/kg daily) were given for 13 weeks. Rats exposed to CS significantly had smaller seminiferous tubules diameter and epithelial height, lower Leydig cell count and increased percentage of tubules with germ cell loss. CS also produced increased lipid peroxidation (TBARS) and glutathione peroxidase (GPx) activity, as well as reduced total antioxidant status (TAS) and activities of superoxide dismutase (SOD) and catalase (CAT). However, supplementation of honey significantly reduced histological changes and TBARS level, increased TAS level, as well as significantly restored activities of GPx, SOD and CAT in rat testis. These findings may suggest that honey has a protective effect against damage and oxidative stress induced by CS in rat testis.

Metabolic Syndrome, its Pathophysiology and the Role of Melatonin

Metabolic syndrome (MetS) is characterised by symptoms of obesity, insulin resistance, hypertension, dyslipidemia and diabetes mellitus. The pathophysiological mechanisms involved in MetS are complex and involved dysregulation of many biochemical and physiological regulatory mechanisms of the body. Elevated levels of low density lipoproteins like VLDL, and LDL with reduction of HDL seen in patients with MetS contribute to atherogenic dyslipedemia. Melatonin has been suggested to be effective in improving MetS through its anti-hyperlipidemic action. Melatonin reduced both adiposity, and body weight in experimental animal studies and also attenuated weight gain and obesityinduced metabolic alterations and this effect of melatonin is attributed to its anti-oxidative effects. Melatonin administration has been shown to inhibit insulin release by acting through both MT1 and MT2 melatonin receptors present in pancreatic β-cells. Melatonin also increased insulin sensitivity and glucose tolerance in animals fed with either high fat or high sucrose diet. Melatonin exerts most of its beneficial actions by acting through MT1 and MT2 melatonin receptors present in various tissues of the body and some of the metabolic actions of melatonin have been blocked by melatonin antagonist like luzindole. Ramelteon, the newly available melatonin agonist will also have more promising role in the control of MetS. The numbers of patents are available with regard to treatment of MetS. Drug related to antidepressant fluoxetine is used for treatment of MetS (US Patent No. 2008001400450). Anti-oxidants like S-adenosyl-methionine, Vitamin E, and Vitamin C have been found beneficial in treating MetS (US Patent No. 8063024). Melatonin being a powerful Antioxidant will have a promising role in treating patients with metabolic syndrome.

Effect of different doses of Malaysian honey on reproductive parameters in adult male rats

The aim of this study was to evaluate the effect of different doses of Malaysian honey on male reproductive parameters in adult rats. Thirty‐two healthy adult male Sprague–Dawley rats were randomly divided into four groups (eight rats per group). Group 1 (control group) was given 0.5 ml of distilled water. Groups 2, 3 and 4 were given 0.2, 1.2 and 2.4 g kg−1 body weight of honey respectively. The rats were treated orally by gavage once daily for 4 weeks. Honey did not significantly alter body and male reproductive organs weights. The rats in Group 3 which received honey at 1.2 g kg−1 had significantly higher epididymal sperm count than those in Groups 1, 2 and 4. No significant differences were found for the percentage of abnormal sperm, elongated spermatid count, reproductive hormonal levels as well as the histology of the testis among the groups. In conclusion, Malaysian honey at a dose of 1.2 g kg−1 daily significantly increased epididymal sperm count without affecting spermatid count and reproductive hormones. These findings might suggest that oral administration of honey at this dose for 4 weeks may enhance spermiogenesis in adult rats.

Autonomic nervous system mediates the hypotensive effects of aqueous and residual methanolic extracts of Syzygium polyanthum(Wight) Walp.var.polyanthum leaves in anaesthetized rats

Syzygium polyanthum (Wight) Walp. var. polyanthum leaves are consumed as a traditional Malay treatment of hypertension. This study investigates hypotensive potential of aqueous (AESP) and residual methanolic (met-AESP) extracts of S. polyanthum leaves and possible involvement of autonomic receptors. AESP and met-AESP (20 to 100 mg/kg) were intravenously administered into anaesthetized Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. Blood pressure and heart were monitored for 20 min. AESP and met-AESP induced significant dose-dependent hypotension, but only 100 mg/kg AESP caused mild bradycardia (n = 5). AESP-induced hypotension was more potent than that of met-AESP in WKY. AESP has a faster onset time than that of met-AESP in both WKY and SHR. However, met-AESP-induced hypotension was more sustained than that of AESP in SHR. Blockages of autonomic ganglion and α-adrenergic receptors using hexamethonium and phentolamine (n = 5 for each group) partially attenuated AESP-induced hypotension, suggesting involvement of α-adrenergic receptors. Blockages of autonomic ganglion, β-adrenergic, cholinergic receptors, and nitric oxide production using hexamethonium, propranolol, atropine, and N-ω-nitro-l arginine methyl ester (L-NAME) (n = 5 for each group) partially attenuated met-AESP-induced hypotension, suggesting involvement of β-adrenergic and cholinergic receptors via nitric oxide production.

Assessment of hepatic function, oxidant/antioxidant status, and histopathological changes in rats treated with atorvastatin Effect of dose and acute intoxication with acetaminophen

A major disadvantage that may occur in association with atorvastatin (ATV) therapy is elevation of serum transaminases. This study was designed to evaluate the effects of treatment of rats with various doses of ATV (2, 5, and 10 mg/kg/day) on liver function, oxidative stress, and histology and on the severity of acetaminophen (APAP) hepatotoxicity. ATV administration for 21 days resulted in a dose-dependent significant rise in serum activities of alkaline phosphatase, aspartate aminotransferase, and alanine aminotransferase. Only ATV at 10 mg/kg/day decreased reduced glutathione (GSH) levels and superoxide dismutase (SOD) activity, increased malondialdehyde (MDA) levels, and elicited histopathological changes in the liver. In rats challenged with APAP (500 mg/kg), the livers showed centrilobular necrosis with evident oxidative stress and liver dysfunction after 24 h. Rats challenged with APAP after pretreatment with ATV 2 or 5 mg/kg/day showed significantly lower activities of serum enzymes, higher hepatic GSH levels and SOD activities, lower MDA levels and milder histopathological changes compared with rats challenged with APAP after pretreatment with ATV 10 mg/kg/day or without drug pretreatment. In conclusion, the effect of ATV on the liver is dose dependent. Our results showed that ATV, at the highest dose used, induced hepatic lipid peroxidation and injury, suggesting a role for oxidative stress in ATV-induced hepatotoxicity. However, lower doses of ATV attenuated APAP-induced hepatotoxicity via a mechanism related, at least in part, to a reduction of APAP-induced hepatic oxidative stress. These results are of practical interest as both drugs may be used concurrently in clinical practice.

Melatonin Effects on Plasmodium Life Cycle: New Avenues for Therapeutic Approach

Malaria remains a global health problem affecting more than 515 million people all over the world including Malaysia. It is on the rise, even within unknown regions that previous to this were free of malaria. Although malaria eradication programs carried out by vector control programs are still effective, anti-malarial drugs are also used extensively for curtailing this disease. But resistance to the use of anti-malarial drugs is also increasing on a daily basis. With an increased understanding of mechanisms that cause growth, differentiation and development of malarial parasites in rodents and humans, new avenues of therapeutic approaches for controlling the growth, synchronization and development of malarial parasites are essential. Within this context, the recent discoveries related to IP3 interconnected signalling pathways, the release of Ca2+ from intracellular stores of Plasmodium, ubiquitin protease systems as a signalling pathway, and melatonin influencing the growth and differentiation of malarial parasites by its effects on these signalling pathways have opened new therapeutic avenues for arresting the growth and differentiation of malarial parasites. Indeed, the use of melatonin antagonist, luzindole, has inhibited the melatonins effect on these signalling pathways and thereby has effectively reduced the growth and differentiation of malarial parasites. As Plasmodium has effective sensors which detect the nocturnal plasma melatonin concentrations, suppression of plasma melatonin levels with the use of bright light during the night or by anti-melatonergic drugs and by using anti-kinase drugs will help in eradicating malaria on a global level. A number of patients have been admitted with regards to the control and management of malarial growth. Patents related to the discovery of serpentine receptors on Plasmodium, essential for modulating intra parasitic melatonin levels, procedures for effective delivery of bright light to suppress plasma melatonin levels and thereby arresting the growth and elimination of malarial parasites from the blood of the host are all cited in the paper. The purpose of the paper is to highlight the importance of melatonin acting as a cue for Plasmodium faciparum growth and to discuss the ways of curbing the effects of melatonin on Plasmodium growth and for arresting its life cycle, as a method of eliminating the parasite from the host.

Cadmium chloride–induced testicular toxicity in male wistar rats; prophylactic effect of quercetin, and assessment of testicular recovery following cadmium chloride withdrawal

This study assessed the effect of quercetin (QE) on cadmium chloride (CdCl2) - induced testicular toxicity, as well as the effect of withdrawal of CdCl2 treatment on same. Thirty male Wistar rats aged 10 weeks old and weighing 270-300g were assigned into 5 groups and used for this study. Rats in groups 1-4 were administered vehicle, CdCl2 (5mg/kg bwt), CdCl2+QE (5mg/kg bwt and 20mg/kg bwt, respectively) or QE (20mg/kg bwt) orally for 4 weeks. Group 5 rats received CdCl2, with 4 weeks recovery period. Results showed that cadmium accumulated in serum, testis and epididymis, decreased body weight, testicular and epididymal weights, sperm count, motility and viability. Cadmium decreased serum concentrations of reproductive hormones, but increased testicular glucose, lactate and lactate dehydrogenase activity. Cadmium decreased testicular enzymatic (superoxide dismutase, catalase and glutathione peroxidase) and non-enzymatic (glutathione, vitamins C and E) antioxidants, and increased malondialdehyde and hydrogen peroxide. Cadmium down-regulated Bcl-2 protein, up-regulated Bax protein, increased Bax/Bcl-2 ratio and cleaved caspase-3 activity. Histopathology of the testis showed decreased Johnsens score and Leydig cell count. These negative effects were attenuated by QE administration, while withdrawal of CdCl2 did not appreciably reverse toxicity. We conclude that QE better protected the testis from CdCl2 toxicity than withdrawal of CdCl2 administration.

Malaria, anti malarial drugs and the role of melatonin.

Malaria, one of the most deadly diseases of our time affects more than 200 million people across the globe and is responsible for about one million deaths annually. Until recently Plasmodium falciparum has been the main cause for malarial infection in human beings but now Plasmodium knowlesi from Malaysia remains as one of the most virulent parasite spreading fast not only in Malaysia but in different parts of the world. Hence there is urgent need for the global fight to control malaria. Global malaria eradication program by use of insecticide spraying has resulted in good response in the past. Treatment of malaria infected patients with anti-malarial drugs has helped to eliminate malarial infections successfully but with increased resistance displayed by malarial parasites to these drugs there is resurgence of malaria caused both by drug resistance as well as by infection caused by new malarial species like Plasmodium knowlesi. With recent advances on molecular studies on malarial parasites it is now clear that the pineal hormone melatonin acts as a cue for growth and development of Plasmodium falciparum. Same may be true for Plasmodium knowlesi also. Hence treatment modalities that can effectively block the action of melatonin on Plasmodium species during night time by way of using either bright light therapy or use of melatonin receptor blocking can be considered as useful approaches for eliminating malarial infection in man.

Stress Hormone and Reproductive System in Response to Honey Supplementation Combined with Different Jumping Exercise Intensities in Female Rats

This study was performed to determine the effects of 8-week honey supplementation combined with different jumping exercise intensities on serum cortisol, progesterone, estradiol, and reproductive organs. Eighty-four 9-week-old female rats were divided into 7 groups: baseline controls (C0), sedentary group (C), 20 and 80 jumps per day (Ex20J, Ex80J), honey (H), and combined honey with 20 and 80 jumps per day (HEx20J, HEx80J) groups. Jumping exercise was performed at 5 days/week and honey was given at a dosage of 1 g/kg body weight/day for 7 days/week. The level of serum cortisol was higher in Ex20J and Ex80J compared to C. There was significantly lower value of serum cortisol in HEx20J compared to Ex80J. Serum progesterone levels were significantly lower in Ex20J and Ex80J compared to C. However, serum progesterone levels were significantly higher in HEx20J and HEx80J compared to Ex20J and Ex80J. Relative uterine weights were significantly greater in HEx20J compared to C and HEx80J, respectively. There was no significant difference in estradiol level and relative ovarian weights among all the groups. Therefore, honey elicited beneficial effects in reducing the increase of cortisol and in increasing the reduce of progesterone levels induced by different intensities jumping exercise in female rats.