Sirtuins as endogenous regulators of lung fibrosis: A current perspective.

Fibrotic lung diseases qualify among the most dreaded irreversible interstitial pulmonary complications with progressive yet largely unpredictable clinical course. Idiopathic pulmonary fibrosis (IPF) is the most challenging prototype characterized by unknown and complex molecular etiology, severe dearth of non-invasive therapeutic options and average lifespan of 2-5 years in patients post diagnosis. Lung fibrosis (LF) is a leading cause of death in the industrialized world with the propensity to contract, significantly increasing with age. Approximately 45% deaths in US are attributed to fibrotic diseases while around 7% respiratory disease-associated deaths, annually in UK, are actually attributed to IPF. Recent developments in the field of LF have unambiguously pointed towards the pivotal role of Sirtuins (SIRTs) in regulating disease progression, thereby qualifying as potential anti-fibrotic drug targets. These NAD+-dependent lysine deacetylases, deacylases and ADP-ribosyltransferases are evolutionarily conserved proteins, regulated by diverse metabolic/environmental factors and implicated in age-related degenerative and inflammatory disorders. While SIRT1, SIRT6 and SIRT7 are predominantly nuclear, SIRT3, SIRT4, SIRT5 are mainly mitochondrial and SIRT2 is majorly cytosolic with occasional nuclear translocation. SIRT1, SIRT3, SIRT6 and SIRT7 are documented as cytoprotective sirtuins implicated in cardiovascular, pulmonary and metabolic diseases including fibrosis; however functional roles of remaining sirtuins in pulmonary pathologies are yet elusive. Here, we provide a comprehensive recent update on the regulatory role of sirtuins on LF along with discussion on potential therapeutic modulation of endogenous Sirtuin expression through synthetic/plant-derived compounds which can help synthetic chemists and ethnopharmacologists to design new-generation cheap, non-toxic Sirtuin-based drugs against LF.

Acute mental stress induces mitochondrial bioenergetic crisis and hyper-fission along with aberrant mitophagy in the gut mucosa in rodent model of stress-related mucosal disease.

Psychological stress, depression and anxiety lead to multiple organ dysfunctions wherein stress-related mucosal disease (SRMD) is common to people experiencing stress and also occur as a side effect in patients admitted to intensive care units; however the underlying molecular aetiology is still obscure. We report that in rat-SRMD model, cold restraint-stress severely damaged gut mitochondrial functions to generate superoxide anion (O2•-), depleted ATP and shifted mitochondrial fission-fusion dynamics towards enhanced fission to induce mucosal injury. Activation of mitophagy to clear damaged and fragmented mitochondria was evident from mitochondrial translocation of Parkin and PINK1 along with enhanced mitochondrial proteome ubiquitination, depletion of mitochondrial DNA copy number and TOM 20. However, excess and sustained accumulation of O2•--generating defective mitochondria overpowered the mitophagic machinery, ultimately triggering Bax-dependent apoptosis and NF-κB-intervened pro-inflammatory mucosal injury. We further observed that stress-induced enhanced serum corticosterone stimulated mitochondrial recruitment of glucocorticoid receptor (GR), which contributed to gut mitochondrial dysfunctions as documented from reduced ETC complex 1 activity, mitochondrial O2•- accumulation, depolarization and hyper-fission. GR-antagonism by RU486 or specific scavenging of mitochondrial O2•- by a mitochondrially targeted antioxidant mitoTEMPO ameliorated stress-induced mucosal damage. Gut mitopathology and mucosal injury were also averted when the perception of mental stress was blocked by pre-treatment with a sedative or antipsychotic. Altogether, we suggest the role of mitochondrial GR-O2•--fission cohort in brain-mitochondria cross-talk during acute mental stress and advocate the utilization of this pathway as a potential target to prevent mitochondrial unrest and gastropathy bypassing central nervous system.

The use of neem for controlling gastric hyperacidity and ulcer.

H(2)-receptor blockers and proton pump inhibitors are now used extensively to control gastric and duodenal ulcer, inflammation and pain, but these drugs have limitations and are not always affordable. The development of novel nontoxic antiulcer drugs, including from medicinal plants, is therefore desirable, and Azadirachta indica A. Juss, commonly known as Neem, is known to have potent gastroprotective and antiulcer effects. This review deals with the pharmacological and biochemical studies carried out regarding the antiulcer activities of Neem extracts and their mechanism of action, including the inhibition of acid secretion. A comparison with ranitidine and omeprazole in some animal models has been included and clinical studies, where available, have also been incorporated, along with a safety evaluation. Neem bark extract has the potential for the development of novel medicines for the therapeutic control of gastric hyperacidity and ulcer.

Biological activities of crude extracts and chemical constituents of Bael, Aegle marmelos (L.) Corr.

Bael (Aegle marmelos (L.) Corr.) is an important medicinal plant of India. Leaves, fruits, stem and roots of A. marmelos have been used in ethno medicine to exploit its' medicinal properties including astringent, antidiarrheal antidysenteric, demulcent, antipyretic and anti-inflammatory activities. Compounds purified from bael have been proven to be biologically active against several major diseases including cancer, diabetes and cardiovascular diseases. Preclinical studies indicate the therapeutic potential of crude extracts of A. marmelos in the treatment of many microbial diseases, diabetes and gastric ulcer. This review covers the biological activities of some isolated chemical constituents of A. marmelos and preclinical studies on some crude extracts and pure compounds to explore novel bioactive compounds for therapeutic application.

Clinical studies on the effect of Neem (Azadirachta indica) bark extract on gastric secretion and gastroduodenal ulcer.

We have shown earlier that Neem (Azadirachta indica) bark aqueous extract has potent antisecretory and antiulcer effects in animal models and has no significant adverse effect (Bandyopadhyay et al., Life Sciences, 71, 2845-2865, 2002). The objective of the present study was to investigate whether Neem bark extract had similar antisecretory and antiulcer effects in human subjects. For this purpose, a group of patients suffering from acid-related problems and gastroduodenal ulcers were orally treated with the aqueous extract of Neem bark. The lyophilised powder of the extract when administered for 10 days at the dose of 30 mg twice daily caused a significant (p < 0.002) decrease (77%) in gastric acid secretion. The volume of gastric secretion and its pepsin activity were also inhibited by 63% and 50%, respectively. Some important blood parameters for organ toxicity such as sugar, urea, creatinine, serum glutamate oxaloacetate transaminase, serum glutamate pyruvate transaminase, albumin, globulin, hemoglobin levels and erythrocyte sedimentation rate remained close to the control values. The bark extract when taken at the dose of 30-60 mg twice daily for 10 weeks almost completely healed the duodenal ulcers monitored by barium meal X-ray or by endoscopy. One case of esophageal ulcer (gastroesophageal reflux disease) and one case of gastric ulcer also healed completely when treated at the dose of 30 mg twice daily for 6 weeks. The levels of various blood parameters for organ toxicity after Neem treatment at the doses mentioned above remained more or less close to the normal values suggesting no significant adverse effects. Neem bark extract thus has therapeutic potential for controlling gastric hypersecretion and gastroesophageal and gastroduodenal ulcers.

Mechanism of antiulcer effect of Neem (Azadirachta indica) leaf extract: effect on H+-K+-ATPase, oxidative damage and apoptosis.

The mechanism of the antiulcer effect of Neem leaf aqueous extract to block gastric lesions in rat has been studied with emphasis on acid secretion, oxidative damage and apoptosis. The extract dose-dependently inhibits gastric lesions induced by restraint-cold stress, indomethacin and ethanol. In stress ulcer model, it is more effective than ranitidine but less effective than omeprazole. It also dose-dependently blocks pylorus ligation and mercaptomethylimidazole-induced acid secretion. In the pylorus-ligation model, it is less effective than omeprazole but as effective as ranitidine. It inhibits H+-K+-ATPase activity in vitro in concentration-dependent manner to inhibit acid secretion. Oxidative membrane damage by hydroxyl radical (*OH) as measured by lipid peroxidation in stress ulcer is significantly blocked by leaf extract. Stress-induced apoptotic DNA fragmentation is also protected. The extract also prevents *OH-mediated mucosal DNA damage in vitro by scavenging the *OH. Neem leaf extract, thus, offers antiulcer activity by blocking acid secretion through inhibition of H+-K+-ATPase and by preventing oxidative damage and apoptosis.

Gastroprotective effect of Neem (Azadirachta indica) bark extract: possible involvement of H(+)-K(+)-ATPase inhibition and scavenging of hydroxyl radical.

The antisecretory and antiulcer effects of aqueous extract of Neem (Azadirachta indica) bark have been studied along with its mechanism of action, standardisation and safety evaluation. The extract can dose dependently inhibit pylorus-ligation and drug (mercaptomethylimidazole)-induced acid secretion with ED(50) value of 2.7 and 2 mg Kg(-1) b.w. respectively. It is highly potent in dose-dependently blocking gastric ulcer induced by restraint-cold stress and indomethacin with ED(50) value of 1.5 and 1.25 mg Kg(-1) b.w. respectively. When compared, bark extract is equipotent to ranitidine but more potent than omeprazole in inhibiting pylorus-ligation induced acid secretion. In a stress ulcer model, it is more effective than ranitidine but almost equipotent to omeprazole. Bark extract inhibits H(+)-K(+)-ATPase activity in vitro in a concentration dependent manner similar to omeprazole. It offers gastroprotection against stress ulcer by significantly preventing adhered mucus and endogenous glutathione depletion. It prevents oxidative damage of the gastric mucosa by significantly blocking lipid peroxidation and by scavenging the endogenous hydroxyl radical ((z.rad;)OH)-the major causative factor for ulcer. The (z.rad;)OH-mediated oxidative damage of human gastric mucosal DNA is also protected by the extract in vitro. Bark extract is more effective than melatonin, vitamin E, desferrioxamine and alpha-phenyl N-tert butylnitrone, the known antioxidants having antiulcer effect. Standardisation of the bioactive extract by high pressure liquid chromatography indicates that peak 1 of the chromatogram coincides with the major bioactive compound, a phenolic glycoside, isolated from the extract. The pharmacological effects of the bark extract are attributed to a phenolic glycoside which is apparently homogeneous by HPLC and which represents 10% of the raw bark extract. A single dose of 1g of raw extract per kg b.w. (mice) given in one day and application of 0.6g raw extract per kg b.w. per day by oral route over 15 days to a cumulative dose of 9g per kg was well tolerated and was below the LD(50). It is also well tolerated by rats with no significant adverse effect. It is concluded that Neem bark extract has therapeutic potential for the control of gastric hyperacidity and ulcer.