Melatonin exerts neuroprotection in a chronodisrupted rat model through reduction in oxidative stress and modulation of autophagy.

Circadian disruption due to artificial light affects cellular redox homeostasis and may lead to neurodegenerative diseases. The aim of the present study was to investigate the effect of continuous light exposure (CLE) and continuous dark exposure (CDE) along with melatonin supplementation on neuronal redox status, mitochondrial complexes, membrane bound transporters, inflammation, autophagy and neurodegeneration in chronodisrupted model of rat. In the study artificial light of white LED bulb with 500 lux intensity was used. Melatonin (10 mg/kg b.w., orally) was supplemented to control and CLE groups for 10 days. Standard protocols were employed to measure pro-oxidants, non-enzymatic antioxidants, and mitochondrial complexes in brain tissues. Membrane-bound ion transporter activities were evaluated in the crude synaptosomes. Gene expression analysis was performed to assess the expression of inflammatory, autophagy and neuronal marker genes. Histopathological changes in cerebral cortex and different hippocampus regions of the brain were studied. Melatonin exerted a significant normalization of redox status biomarkers in brain tissue. Further melatonin restored the activities of mitochondrial complexes and synaptosomal membrane bound ion transporters. RT-PCR data revealed that melatonin downregulated the expression of inflammatory (TNF-α, IL-6) autophagy (Atg-3, Beclin-1) and neurodegenerative genes (Ngb and NSE) in CLE group. Melatonin also preserved the histology architecture in cerebral cortex and hippocampus. Our results indicate that melatonin exerts a potent neuroprotective effect through reduction of oxidative stress, inflammation and autophagy. Melatonin supplementation might be a promising neurotherapeutic in the treatment neurodegenerative disorders caused by circadian disturbances.

Metformin ameliorates acetaminophen-induced sub-acute toxicity via antioxidant property.

Acetaminophen or N-acetyl-p-amino-phenol (APAP) is a drug which is available over-the-counter for fever and pain. Its overdosing causes oxidative stress and subsequent acute liver damage. In the present study, we scrutinized the protective effect of metformin co-treatment in APAP induced blood and liver sub-acute toxicity. This is a pre-clinical study in which male Wistar Rats (BW: 300 ± 20 g) were orally co-treated with APAP (1 g/kg/day) and metformin (300 mg/kg/day) for 28-days. Pro- and anti-oxidant markers viz reactive oxygen species, protein carbonyl, malondialdehyde (MDA), the ferric reducing ability of plasma (FRAP), plasma membrane redox system(PMRS) and reduced glutathione (GSH) were evaluated in blood. Additionally, in liver tissue, catalase (CAT), superoxide dismutase (SOD), MDA and GST level were also evaluated. Histological study and estimation of alanine aminotransferase (ALT), and aspartate aminotransferase (AST) level in serum were performed. APAP induces pro-oxidant markers as well as reduces anti-oxidant markers in blood and liver. Hepatic tissues degeneration and vacuolization of hepatocytes were evident after APAP treatment. Metformin treatment reduces pro-oxidant markers as well as increases anti-oxidant markers in both tissues. It also improves liver tissue architecture after treatment. The outcome of this study suggests that metformin has protective capability against APAP-induced blood and liver toxicity. Thus, metformin co-treatment with APAP attenuates oxidative stress and its consequences.

Fisetin, a potential caloric restriction mimetic, modulates ionic homeostasis in senescence induced and naturally aged rats.

CONTEXT: Fisetin as a caloric restriction mimetic (CRM) exerts numerous beneficial effects on different aging model systems. The effect of fisetin on erythrocyte membrane functions against induced aging is not very clear. OBJECTIVES: The potential role of fisetin in the modulation of erythrocytes membrane-bound transporters during natural and induced aging in rats was assessed. MATERIALS AND METHODS: Male Wistar rats were used for natural and D-galactose (D-gal) induced aging model. After supplementation with fisetin, the activities of different membrane transporters and biomarkers of oxidative stress were evaluated. RESULTS: Fisetin modulated membrane transporters such as calcium-ATPase, sodium potassium-ATPase and sodium hydrogen exchanger during senescence-induced as well as in natural aging. Fisetin also protected oxidative modifications in rat aging. DISCUSSION AND CONCLUSION: Fisetin supplementation improves the ionic homeostasis, a factor that is involved in the aetiology of several age-associated diseases, in naturally old as well as D-gal induced aged rats.

Promising drug discovery strategies for sirtuin modulators: what lessons have we learnt?

INTRODUCTION: Sirtuins, NAD-dependent protein deacetylases, require NAD+ for enzymatic activity. Recent research has indicated that sirtuins have a key role in the regulation of gene expression, the cell cycle, apoptosis, neurodegeneration and several age-related diseases. In mammals, there are seven sirtuin isoforms (SIRT-1-7) that catalyze specific lysine substrate deacetylation. AREAS COVERED: This review explains the current information on the structure, function and importance of sirtuin modulators. It also explores the possible therapeutic applications of sirtuin modulators and related small molecules in the context of various diseases. EXPERT OPINION: Sirtuin's modulators open a new area of research for targeting pathological conditions. Sirtuin modulators, through their targeted function, may provide a possible tool for the amelioration of various diseases. However, the search of activators/inhibitors for sirtuins needs further research. The structural elucidation of sirtuins will create an understanding for the development of isoform-specific selective modulators. This could be a useful tool to determine the functions of individual sirtuins as potential therapeutic agents.

Spermidine, a caloric restriction mimetic, provides neuroprotection against normal and D-galactose-induced oxidative stress and apoptosis through activation of autophagy in male rats during aging.

Spermidine (SPD) is a natural polyamine present in all living organisms and is involved in the maintenance of cellular homeostasis by inducing autophagy in different model organisms. Its role as a caloric restriction mimetic (CRM) is still being investigated. We have undertaken this study to investigate whether SPD, acting as a CRM, can confer neuroprotection in D-galactose induced accelerated senescence model rat and naturally aged rats through modulation of autophagy and inflammation. Young male rats (4 months), D-gal induced (500 mg/kg b.w., subcutaneously) aging and naturally aged (22 months) male rats were supplemented with SPD (10 mg/kg b.w., orally) for 6 weeks. Standard protocols were employed to measure prooxidants, antioxidants, apoptotic cell death and electron transport chain complexes in brain tissues. Gene expression analysis with reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to assess the expression of autophagy and inflammatory marker genes. Our data demonstrate that SPD significantly (p ≤ 0.05) decreased the level of pro-oxidants and increased the level of antioxidants. SPD supplementation also augmented the activities of electron transport chain complexes in aged brain mitochondria thus proving its antioxidant potential at the level of mitochondria. RT-PCR data revealed that SPD up-regulated the expression of autophagy genes (ATG-3, Beclin-1, ULK-1 and LC3B) and down-regulated the expression of the inflammatory gene (IL-6) in aging brain. Our results provide first line of evidence that SPD provides neuroprotection against aging-induced oxidative stress by regulating autophagy, antioxidants level and also reduces neuroinflammation. These results suggest that SPD may be beneficial for neuroprotection during aging and age-related disorders.

Whey protein concentrate protects against age-dependent alteration in redox biomarkers.

Aging is associated with decreased cellular cysteine uptake, which acts as a precursor for glutathione biosynthesis. Whey protein, a liquid aspect of milk, is an effective cysteine delivery system. The study was undertaken to evaluate the potential role of whey protein concentrate (WPC) on the redox biomarkers during aging. Male Wistar rats were divided into following four groups: young control (4 months old); young treated with WPC (300 mg/kg b.w./day orally); old (24 months old) control; old treated with WPC for 28 days. After treatment, changes in body weight, lipid profile and levels of redox biomarkers were determined. A marked decrease in prooxidants such as reactive oxygen species, lipid peroxidation and protein carbonyl and significant (p ≤ 0.05) increase in antioxidants such as reduced glutathione and GST levels were observed after WPC supplementation in old age rats. We also found marked decrease in the level of sialic acid and AGEs after WPC supplementation. In conclusion, WPC provides protection against age-dependent redox imbalance which might be attributed to its antioxidant activity.

Fisetin, a potential caloric restriction mimetic, attenuates senescence biomarkers in rat erythrocytes.

An imbalanced redox status is a hallmark of the aging process. Caloric restriction mimetics (CRMs) are compounds that produce caloric restriction benefits at the molecular, cellular, and physiological level, translating into health-promoting effects. Fisetin is the least explored CRM, and its role in modulating oxidative stress during aging is not clearly known. This study investigated the antioxidative and protective potential of fisetin in a rat model of d-galactose (D-gal)-induced accelerated senescence, and in naturally aged rat erythrocytes. Young rats (4 months), aged D-gal-induced rats [24 months; 500 mg/kg body mass (b.m.); subcutaneous injection] and naturally aged D-gal-induced rats [24 months; 500 mg/kg b.m.; subcutaneous injection] were supplemented with fisetin (15 mg/kg b.m.; orally) for 6 weeks. The resulting data indicated that supplementation with fisetin suppresses aging-induced increases in the levels of reactive oxygen species, eryptosis, lipid peroxidation, and protein oxidation. Our data also show that fisetin significantly increases the levels of antioxidants and activates the plasma membrane redox system. Taken together, the findings show that a fisetin-rich diet could be an anti-aging intervention strategy.

An Uncommon Cause of Postmenopausal Bleeding.

A 65-year-old multiparous female was evaluated for postmenopausal bleeding. Imaging was strongly suggestive of malignancy. However, hysteroscopic-guided endometrial biopsy revealed tuberculous endometritis. The patient responded to antitubercular therapy and recovered completely. Genital tuberculosis is typically considered a disease of young women presenting with infertility. However, tuberculous endometritis should be considered in a patient of postmenopausal bleeding, particularly in developing countries. It is a rare, but curable cause of postmenopausal bleeding.

Rapamycin Confers Neuroprotection Against Aging-Induced Oxidative Stress, Mitochondrial Dysfunction, and Neurodegeneration in Old Rats Through Activation of Autophagy.

Brain aging is an intricate and natural phenomenon exclusively characterized by oxidative stress, accumulation of oxidatively damaged macromolecules, and alterations in structure and function of neurons that further increase the risk factor for most of the neurodegenerative diseases. In addition, age-dependent defective autophagy has also been implicated to favor the pathogenesis and prevalence of the neurological diseases. Therefore, the development of strategies that delay aging and the concomitant neurological disorders remain elusive. Thus, the present study was undertaken to investigate the effect of rapamycin-induced activation of autophagy on aging-related oxidative stress, cell death, neuroinflammation, and neurodegeneration in rat brain. Our data demonstrated the significant age-related oxidative stress, apoptotic cell death, elevated inflammatory response, and reduced level of markers associated with rejuvenation and neural integrity, including the activities of ion channel transporters (Na+/K+-ATPase and Ca2+-ATPase) and acetylcholinesterase in the brain of old aged rats. Furthermore, rapamycin (0.5 mg/kg b.w. for 28 days) induced activation of autophagy provided significant protection to aging rat brain by reducing the aging-induced oxidative stress, apoptotic cell death, and markers of neurodegeneration. Thus, our data confirmed that autophagy plays a pivotal role in delaying brain aging plausibly by maintaining the cellular homeostasis, and structural and functional integrity of cells in the brain.

N-acetyl-l-cysteine attenuates oxidative damage and neurodegeneration in rat brain during aging.

N-acetyl-l-cysteine (NAC) is a precursor of cysteine, which is known to increase the level of glutathione (GSH) in the brain. Several neurodegenerative changes linked to oxidative stress take place in the aging brain. This study aimed to assess the neuroprotective effect of NAC supplementation on age-dependent neurodegeneration in the rat brain. Young (4 months) and old (24 months) Wistar rats (n = 6 rats/group) were supplemented with NAC (100 mg/kg b.w. orally) for 14 days. Enzymatic and nonenzymatic antioxidants such as superoxide dismutase and catalase, and GSH and total thiol respectively, prooxidants such as protein carbonyl, advanced oxidation protein products, reactive oxygen species, and malondialdehyde were assessed in the brain homogenates. Furthermore, nitric oxide level, acetylcholinesterase activity, and Na+/K+-ATPase activity were measured and gene expression studies were also performed. The results indicated that NAC augmented the level of enzymatic and nonenzymatic antioxidants with a significant reduction in prooxidant levels in old rats. NAC supplementation also downregulated the expression of inflammatory markers (TNF-α, IL-1ß, IL-6) and upregulated the expression of marker genes associated with aging (sirtuin-1) and neurodegeneration (neuron-specific enolase, neuroglobin, synapsin-I, myelin basic protein 2) in old rats. The present findings support a neuroprotective role of NAC which has therapeutic implication in controlling age-related neurological disorders.

Rapamycin mitigates erythrocyte membrane transport functions and oxidative stress during aging in rats.

Erythrocyte membrane is a suitable model to study various metabolic and physiological functions as it undergoes variety of biochemical changes during aging. An age-dependent modulatory effect of rapamycin on erythrocyte membrane functions is completely unknown. Therefore, the present study was undertaken to investigate the effect of rapamycin on age-dependent impaired activities of transporters/exchangers, altered levels of redox biomarkers, viz. protein carbonyl (PC), lipid hydroperoxides (LHs), total thiol (-SH), sialic acid (SA) and intracellular calcium ion [Ca2+]i, and osmotic fragility of erythrocyte membrane. A significant reduction in membrane-bound activities of Na+/K+-ATPase (NKA) and Ca2+-ATPase (PMCA), and levels of -SH and SA was observed along with a simultaneous induction in Na+/H+ exchanger (NHE) activity and levels of [Ca2+]i, PC, LH and osmotic fragility in old-aged rats. Rapamycin was found to be a promising age-delaying drug that significantly reversed the aging-induced impaired activities of membrane-bound ATPases and altered levels of redox biomarkers.

Whey protein concentrate supplementation protects rat brain against aging-induced oxidative stress and neurodegeneration.

Whey protein concentrate (WPC) is a rich source of sulfur-containing amino acids and is consumed as a functional food, incorporating a wide range of nutritional attributes. The purpose of this study is to evaluate the neuroprotective effect of WPC on rat brain during aging. Young (4 months) and old (24 months) male Wistar rats were supplemented with WPC (300 mg/kg body weight) for 28 days. Biomarkers of oxidative stress and antioxidant capacity in terms of ferric reducing antioxidant potential (FRAP), lipid hydroperoxide (LHP), total thiol (T-SH), protein carbonyl (PC), reactive oxygen species (ROS), nitric oxide (NO), and acetylcholinesterase (AChE) activity were measured in brain of control and experimental (WPC supplemented) groups. In addition, gene expression and histopathological studies were also performed. The results indicate that WPC augmented the level of FRAP, T-SH, and AChE in old rats as compared with the old control. Furthermore, WPC-treated groups exhibited significant reduction in LHP, PC, ROS, and NO levels in aged rats. WPC supplementation also downregulated the expression of inflammatory markers (tumor necrosis factor alpha, interleukin (IL)-1ß, IL-6), and upregulated the expression of marker genes associated with autophagy (Atg3, Beclin-1, LC3B) and neurodegeneration (neuron specific enolase, Synapsin-I, MBP-2). The findings suggested WPC to be a potential functional nutritional food supplement that prevents the progression of age-related oxidative damage in Wistar rats.

Fisetin as a caloric restriction mimetic protects rat brain against aging induced oxidative stress, apoptosis and neurodegeneration.

AIM: In the present study, attempts have been made to evaluate the potential role of fisetin, a caloric restriction mimetic (CRM), for neuroprotection in D-galactose (D-gal) induced accelerated and natural aging models of rat. MAIN METHODS: Fisetin was supplemented (15mg/kg b.w., orally) to young, D-gal induced aged (D-gal 500mg/kg b.w subcutaneously) and naturally aged rats for 6weeks. Standard protocols were employed to measure pro-oxidants, antioxidants and mitochondrial membrane potential in brain tissues. Gene expression analysis with reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to assess the expression of autophagy, neuronal, aging as well as inflammatory marker genes. We have also evaluated apoptotic cell death and synaptosomal membrane-bound ion transporter activities in brain tissues. KEY FINDINGS: Our data demonstrated that fisetin significantly decreased the level of pro-oxidants and increased the level of antioxidants. Furthermore, fisetin also ameliorated mitochondrial membrane depolarization, apoptotic cell death and impairments in the activities of synaptosomal membrane-bound ion transporters in aging rat brain. RT-PCR data revealed that fisetin up-regulated the expression of autophagy genes (Atg-3 and Beclin-1), sirtuin-1 and neuronal markers (NSE and Ngb), and down-regulated the expression of inflammatory (IL-1ß and TNF-α) and Sirt-2 genes respectively in aging brain. SIGNIFICANCE: The present study suggests that fisetin supplementation may provide neuroprotection against aging-induced oxidative stress, apoptotic cell death, neuro-inflammation, and neurodegeneration in rat brain.

Synergistic Effect of Rapamycin and Metformin Against Age-Dependent Oxidative Stress in Rat Erythrocytes.

Erythrocytes are particularly vulnerable toward age-dependent oxidative stress-mediated damage. Caloric restriction mimetics (CRMs) may provide a novel strategy for the maintenance of redox balance as well as effective treatment of age-associated diseases. Herein, we have investigated the beneficial effect of cotreatment with CRM-candidate drugs, rapamycin (an immunosuppressant drug and inhibitor of mammalian target of rapamycin) and metformin (an antidiabetic biguanide and activator of adenosine monophosphate kinase), against aging-induced oxidative stress in erythrocytes and plasma of aging rats. Male Wistar rats of age 4 (young) and 24 months (old) were coexposed to rapamycin (0.5 mg/kg body weight [b.w.]) and metformin (300 mg/kg b.w.), and data were compared with the response of rats receiving an independent exposure to these chemicals at similar doses. The exposure of individual candidate drugs significantly reversed the age-dependent alterations in the endpoints associated with oxidative stress such as reactive oxygen species, ferric reducing ability of plasma, malondialdehyde, reduced glutathione, plasma membrane redox system, plasma protein carbonyl, and acetyl cholinesterase in erythrocytes and plasma of aging rats. However, the cotreatment with rapamycin and metformin showed a significant augmented effect compared with individual drug interventions on reversal of these age-dependent biomarkers of oxidative stress, suggesting a synergistic response. Thus, the findings open up further possibilities for the design of new combinatorial therapies to prevent oxidative stress- and age-associated health problems.

Neuroprotection Through Rapamycin-Induced Activation of Autophagy and PI3K/Akt1/mTOR/CREB Signaling Against Amyloid-ß-Induced Oxidative Stress, Synaptic/Neurotransmission Dysfunction, and Neurodegeneration in Adult Rats.

Autophagy is a catabolic process involved in the continuous removal of toxic protein aggregates and cellular organelles to maintain the homeostasis and functional integrity of cells. The mechanistic understanding of autophagy mediated neuroprotection during the development of neurodegenerative disorders remains elusive. Here, we investigated the potential role of rapamycin-induced activation of autophagy and PI3K/Akt1/mTOR/CREB pathway(s) in the neuroprotection of amyloid-beta (Aß1-42)-insulted hippocampal neurons in rat model of Alzheimer's disease (AD) like phenotypes. A single intra-hippocampal injection of Aß1-42 impaired redox balance and markedly induced synaptic dysfunction, neurotransmission dysfunction, and cognitive deficit, and suppressed pro-survival signaling in the adult rats. Rapamycin administration caused a significant reduction of mTOR complex 1 phosphorylation at Ser2481 and a significant increase in levels of autophagy markers such as microtubule-associated protein-1 light chain-3 (LC3), beclin-1, sequestosome-1/p62, unc-51-like kinase 1 (ULK1). In addition, rapamycin induced the activation of autophagy that further activated p-PI3K, p-Akt1 (Ser473), and p-CREB (Ser183) expression in Aß1-42-treated rats. The activated autophagy markedly reversed Aß1-42-induced impaired redox homeostasis by decreasing the levels of prooxidants-ROS generation, intracellular Ca2+ flux and LPO, and increasing the levels of antioxidants-SOD, catalase, and GSH. The activated autophagy also provided significant neuroprotection against Aß1-42-induced synaptic dysfunction by increasing the expression of synapsin-I, synaptophysin, and PSD95; and neurotransmission dysfunction by increasing the levels of CHRM2, DAD2 receptor, NMDA receptor, and AMPA receptor; and ultimately improved cognitive ability in rats. Wortmannin administration significantly reduced the expression of autophagy markers, p-PI3K, p-Akt1, and p-CREB, as well as the autophagy mediated neuroprotective effect. Our study demonstrate that autophagy can be an integrated part of pro-survival (PI3K/Akt1/mTOR/CREB) signaling and autophagic activation restores the oxidative defense mechanism(s), neurodegenerative damages, and maintains the integrity of synapse and neurotransmission in rat model of AD.

Antiaging Effect of Metformin on Brain in Naturally Aged and Accelerated Senescence Model of Rat.

Metformin, a biguanide, is a widely used antidiabetic drug, which inhibits gluconeogenesis and is used to treat hyperglycemia in type 2 diabetes. Through activation of AMPK (AMP-activated protein kinase) pathway, metformin also mimics caloric restriction health benefits. Aging causes substantial molecular to morphological changes in brain, the brain cells being more susceptible toward oxidative stress mediated damages due to the presence of high lipid content and higher oxygen consumption. Wistar rats (naturally aged and d-galactose induced rat model) were supplemented with metformin (300 mg/kg b.w. orally) for 6 weeks. The biomarkers of oxidative stress such as antioxidant capacity (ferric reducing antioxidant potential [FRAP]), malondialdehyde (MDA), reduced glutathione (GSH), protein carbonyl (PCO), reactive oxygen species (ROS), acetylcholinesterase (AChE) activity, and nitric oxide (NO) were measured in brain tissues of control and experimental groups. The results indicate that metformin treatment augmented the levels of FRAP and GSH in naturally aged, and d-gal induced aging model groups compared to the respective controls. In contrast, metformin treated groups exhibited significant reduction in MDA, PCO, ROS, and NO levels and a significant increase in AChE activity in induced aging rats. The administration of d-galactose upregulated the expression of sirtuin-2, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) and downregulated the expression of Beclin-1. Metformin supplementation downregulated the d-galactose induced expressions of sirtuin-2, IL-6, and TNF-α expression, whereas upregulated the Beclin-1 expression. Our data confirm that metformin restores the antioxidant status and improves healthy brain aging through the activation of autophagy and reduction in inflammation.

Metformin Alleviates Altered Erythrocyte Redox Status During Aging in Rats.

Metformin, a biguanide drug commonly used to treat type 2 diabetes, has been noted to function as a caloric restriction mimetic. Its antidiabetic effect notwithstanding, metformin is currently being considered an antiaging drug candidate, although the molecular mechanisms have not yet been unequivocally established. This study aims to examine whether short-term metformin treatment can provide protective effects against oxidative stress in young and old-age rats. Young (age 4 months) and old (age 24 months) male Wistar rats were treated with metformin (300 mg/kg b.w.) for 4 weeks. At the end of the treatment period, an array of biomarkers of oxidative stress were evaluated, including plasma antioxidant capacity measured in terms of ferric reducing ability of plasma (FRAP), reactive oxygen species (ROS), lipid peroxidation (MDA), reduced glutathione (GSH), total plasma thiol (SH), plasma membrane redox system (PMRS), protein carbonyl (PCO), advanced oxidation protein products (AOPPs), and advanced glycation end products (AGEs) in control and experimental groups. Metformin treatment resulted in an increase in FRAP, GSH, SH, and PMRS activities in both age groups compared to respective controls. On the other hand, treated groups exhibited significant reductions in ROS, MDA, PCO, AOPP, and AGE level. Save for FRAP and protein carbonyl, the effect of metformin on all other parameters was more pronounced in old-aged rats. Metformin caused a significant increase in the PMRS activity in young rats, however, the effect was less pronounced in old rats. These findings provide evidence with respect to restoration of antioxidant status in aged rats after short-term metformin treatment. The findings substantiate the putative antiaging role of metformin.

Rapamycin alleviates oxidative stress-induced damage in rat erythrocytes.

An imbalanced cellular redox system promotes the production of reactive oxygen species (ROS) that may lead to oxidative stress-mediated cell death. Erythrocytes are the best-studied model of antioxidant defense mechanism. The present study was undertaken to investigate the effect of the immunosuppressant drug rapamycin, an inducer of autophagy, on redox balance of erythrocytes and blood plasma of oxidatively challenged rats. Male Wistar rats were oxidatively challenged with HgCl2 (5 mg/kg body mass (b.m.)). A significant (p < 0.05) induction in ROS production, plasma membrane redox system (PMRS), intracellular Ca2+ influx, lipid peroxidation (LPO), osmotic fragility, plasma protein carbonyl (PCO) content, and plasma advanced oxidation protein products (AOPP) and simultaneously significant reduction in glutathione (GSH) level and ferric reducing ability of plasma (FRAP) were observed in rats exposed to HgCl2. Furthermore, rapamycin (0.5 mg/kg b.m.) provided significant protection against HgCl2-induced alterations in rat erythrocytes and plasma by reducing ROS production, PMRS activity, intracellular Ca2+ influx, LPO, osmotic fragility, PCO content, and AOPP and also restored the level of antioxidant GSH and FRAP. Our observations provide evidence that rapamycin improves redox status and attenuates oxidative stress in oxidatively challenged rats. Our data also demonstrate that rapamycin is a comparatively safe immunosuppressant drug.

Buccal versus vaginal misoprostol administration for the induction of first and second trimester abortions.

OBJECTIVES: To compare the effectiveness, side effects, and patient satisfaction of buccal versus vaginal misoprostol administration in first and second trimester induced abortions. METHODS: In first trimester, women received oral mifepristone followed by misoprostol either by buccal or vaginal route. In second trimester, women received oral mifepristone followed by repeated doses of misoprostol either by buccal or vaginal route. A comparative analysis using SPSS was done. RESULTS: In first trimester, success rate of medical abortion was 96 % in buccal group and 88 % in vaginal group. Nausea was the most common adverse effect which was similar in both groups. In second trimester, success rate was 96 % in buccal group and 80 % in vaginal group. A statistically higher incidence of nausea was noticed in buccal group. Patient satisfaction level was almost similar in both the groups in both trimesters. CONCLUSIONS: Buccal and vaginal routes of misoprostol administration have similar efficacy and patient satisfaction level for first and second trimester induced abortions. Hence, buccal route may serve as an alternative to vaginal misoprostol.