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- What is Mechanism of action of Rapamycin for prolonging the age?http://blogs.nature.com/news/2009/07/of_mice_men_and_rapamycin.htmlAuthors_
rofessor Pranab kumar Bhattacharya MD, FIC path(Ind.) , Professor of Pathology, In charge of Histopathology Unit, in charge Blood Bank &VCCTC, in charge of Cytogenetics. Institute of Post Graduate Medical Education & Research, 244a AJC Bose Road, Kolkta-20, West Bengal, India;Miss upasana Bhattacharya of Mahamyatala, Garia kol-86 Mr. Rupak Bhattacharya BSc(Cal)MSc(JU) of 7/51 purbapalli, Sodepur Dist 24 parganas(North) Kol-110, West Bengal, India; Mr Ritwik Bhattacharya; Dr. Tridib Mandal MD cal. Assistant Professor, dept. of Biochemistry, Dr. Hriday Das MD DTM&H(cal) Medical officer, Dept .of nephrology IPGMER, Dr. Jayanta Das Gupta MD DM Asssociate professor, Dept. Gastroenterology Institute of Post Graduate Medical Education & Research, 244a AJC Bose Road, Kolkta-20, West Bengal, India
Rapamycin was originally isolated from a bacterium found on Rapa Nui, the indigenous name for Easter Island. Rapamycin (Rapamune®, Wyeth Ayerst, sirolimus) is a specific inhibitor of the target of rapamycin (TOR). Rapamycin is also a powerful suppressor of the human immune system, as cell anti proliferating drug, so commonly given to organ[Kidney] transplant patients[6mg as soon as after transplant, then 2mg daily for 2-3months as maintenance dose] to help to prevent the rejection of transplanted organs, used with cardiac drug eluting stents[to prevent proliferation of endothelial cells after stent] and may be used as a cancer adjuvant therapy, and also in autosomal dominent polycystic kidney disease. The drug is very costly approximately costs Rs12000/=, in Indian currency a month. Orthologue (mTOR), is also referred to as FKBP12-rapamycin associated protein (FRAP), rapamycin and FKBP12 target (RAFT), rapamycin target (RAPT), or sirolimus effector protein (SEP). mTOR lies downstream of IGF and has been implicated in several pathways that contribute to tumorigenesis, such as translation initiation and cap-dependent translation. The protein kinase TOR genes (TOR1 and TOR2) were first identified in the early 1990s in a screen for rapamycin-resistant yeast mutants1 . Rapamycin forms a complex with the immunophilin FK506 binding protein-12 (FKBP12), which binds to the FKBP12-rapamycin binding (FRB) domain of mTOR and inhibits its kinase activity. Rapamycin thus can inhibit the growth of a broad spectrum of cancers including rhabdomyosarcoma, neuroblastoma, glioblastoma, small cell lung carcinoma, osteosarcoma, pancreatic cancer, leukaemia, B-cell lymphoma, and breast and colon cancer-derived cells2The rapamycin analogues, CCI-779 (Wyeth-Ayerst, PA, USA), RAD001 (Novartis, Switzerland), and AP23573 (Ariad Pharmaceuticals, MA, USA) have shown promise in clinical trials3 .mTOR functions by integrating extracellular signals (growth factors and hormones), with amino-acid availability and intracellular energy status to control translation rates and additional metabolic processes4 .mTOR enhances translation initiation in part by phosphorylating two major targets, the eIF4E binding proteins (4E-BPs) and the ribosomal protein S6 kinases (S6K1 and S6K2) that cooperate to regulate translation initiation rates.5 In Peutz Jeghers syndrome, Tuberous Sclerosis, and other diseases where PTEN is inactivated, the use of rapamycin as a clinical means to reverse the effect of elevated mTOR activity is an attractive option5. These diseases are distinct from other hamartoma-associated disorders (such as VHL syndrome) since they have an established molecular link to mTOR. Earlier studies demonstrated that PTEN-inactivated tumour cells exhibit enhanced sensitivity to the rapamycin analog CCI-7796 More recently, several studies have shown that rapamycin treatment, in combination with other chemotherapeutic drugs, can lead to enhanced selective killing of cancer cells. In particular, the protein tyrosine kinase (PTK) inhibitor, Imatinib (Gleevec, STI571) synergises with rapamycin to inhibit BCR/ABL transformed cells7 . The effect of rapamycin may be enhanced as a result of Imatinib-induced Akt/mTOR signaling, a complication that is thought to lead to Imatinib resistance. Rapamycin can also synergise with paclitaxel, carboplatin, and vinorelbine to induce apoptosis in breast cancer cells8 Cisplatin-induced apoptosis of A549 lung cancer cells is also significantly enhanced when combined with RAD0019 . This could be in part due to reduced translation of p53-activated p21 mRNA in A549 and MCF7 cells treated with RAD001, thereby allowing the dosage of cisplatin to be reduced Also, the use of theEGFR/VEGFR inhibitor, AEE788, in combination with RAD001 greatly decreased tumour growth in glioma xenografts (Goudar et al, 2005). Furthermore, targeting the glycolytic pathway in combination with mTOR inhibition may also be useful in cases where DNA-damaging agents are less efficient in inhibiting growth and promoting apoptosis of cancer cells10 .Aging is the progressive, universal decline first in functional reserve and then in function that occurs in organisms over time. Aging is heterogeneous. It varies widely in different individuals and in different organs within a particular individual. Aging is not a disease; however, the risk of developing disease is increased, often dramatically, as a function of age. The biochemical composition of tissues changes with age; physiologic capacity decreases, the ability to maintain homeostasis in adapting to stressors declines, and vulnerability to disease processes increases with age. After maturation, mortality rate increases exponentially with ageSome Theories of Aging11Hypothesis How It May Work- Genetic Aging is a genetic program activated in post-reproductive life when an individual’s evolutionary mission is accomplishedOxidative stressAccumulation of oxidative damage to DNA, proteins, and lipids interferes with normal function and produces a decrease in stress responsesMitochondrial dysfunction A common deletion in mitochondrial DNA with age compromises function and alters cell metabolic processes and adaptability to environmental changeHormonal changes The decline and loss of circadian rhythm in secretion of some hormones produces a functional hormone deficiency stateTelomere shortening Aging is related to a decline in the ability of cells to replicateDefective host defenses The failure of the immune system to respond to infectious agents and the over activity of natural immunity create vulnerability to environmental stressesAccumulation of senescent cells Renewing tissues become dysfunctional through loss of ability to renewSo it is not well understood how rapamycin actually prolongs life affecting the ageing process and how its connected to calorie restriction and ageing? Through sirolimus effectors protein (SEP)? Then ageing process can be slowed by a drug therapy starting at an advanced age? should healthy individuals over age 50 consider taking rapamycin to slow his/her ageing?. However it is too costly therapy then. Moreover there are many adverse drug reactions of rapamycin like opportunistic infections, lynmhocele lymphoedema, sepsis, tachycardia hepatotoxicity susceptibilities to lymhoma and other malignancies, exfoliative dermatities azospermia to name a few. Mice are known to live longer if fed a calorie-restricted diet that is close to starvation levels, but this would be very difficult for a person to maintain. what should be the dose?References1 Heitman J, Movva NR, Hall MN Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science1991; 253: 905–909 |2Huang S, Houghton PJ Inhibitors of mammalian target of rapamycin as novel antitumor agents: from bench to clinic. Curr Opin Investig Drugs 2002;3: 295–304 |3 Panwalkar A, Verstovsek S, Giles FJ Mammalian target of rapamycin inhibition as therapy for hematologic malignancies. Cancer2004; 100: 657–666 |4 Hay N, Sonenberg N Upstream and downstream of mTOR. Genes Dev2004; 18: 1926–19455E Petroulakis, Y Mamane, O Le Bacquer, D Shahbazian and N Sonenberg mTOR signaling: implications for cancer and anticancer therapy British Journal of Cancer 2006; 94, 195–199. doi:10.1038/sj.bjc.6602902 http://www.bjcancer.com/Published online 13 December 20056 Guertin DA, Sabatini DM An expanding role for mTOR in cancer. Trends Mol Med 2005;11: 353–3617 Mohi MG, Boulton C, Gu TL, Sternberg DW, Neuberg D, Griffin JD, Gilliland DG, Neel BG Combination of rapamycin and protein tyrosine kinase (PTK) inhibitors for the treatment of leukemias caused by oncogenic PTKs. Proc Natl Acad Sci USA2004; 101: 3130–31358 Mondesire WH, Jian W, Zhang H, Ensor J, Hung MC, Mills GB, Meric-Bernstam F Targeting mammalian target of rapamycin synergistically enhances chemotherapy-induced cytotoxicity in breast cancer cells. Clin Cancer Res2004; 10: 7031–70429 Beuvink I, Boulay A, Fumagalli S, Zilbermann F, Ruetz S, O’Reilly T, Natt F, Hall J, Lane HA, Thomas G The mTOR inhibitor RAD001 sensitizes tumor cells to DNA-damaged induced apoptosis through inhibition of p21 translation. Cell 2005;120: 747–75910 Xu RH, Pelicano H, Zhang H, Giles FJ, Keating MJ, Huang P () Synergistic effect of targeting mTOR by rapamycin and depleting ATP by inhibition of glycolysis in lymphoma and leukemia cells. Leukemia2005; 19: 2153–215811 Lisa B. Caruso; Aging; Chapter 9. Geriatric Medicine page at Harrison’s Internal Medicine17th ed edited by© Copy Right- Copy Right of this comment What is Mechanism of action of Rapamycin for prolonging the age?Published in Journal Nature News is Intellectual Property of authors & belongs to Professor Pranab kumar Bhattacharya and his first degree relatives only as per copy right act & rules of Intellectual Property Right Rules 3D/107/1201a,b/ RDF Copy Right rules/ SPARC copy Right rules-2006/ and Protect intellectual Property Right(PIP) copy right rules of USA-2012.Please do not try even to Infringe and be enough careful for your own safety if you are not direct Blood relation to prof Pranab Kumar Bhattacharya . No person, no pharmaceuticals company no NGOS [ except the authors& first degree relatives] in the state of West Bengal or in any other states of India or in any abroad countries are authorized ever to use this article, with any meaning full, scientific sentences or with scientific and meaning full words laid out in this article either in the class room/ or in mass teaching programme including CME or in any form or promotion or self use what so ever it is with any content of this article or while in writing any book or for his/her personal/ home use, or collective works or for any future Research or implementation as a policy matter or,[ except the authors ]or by Xeroxing and distributing the article/ or by printing/saving/broadcasting the article from any website of internet services,displayed without proper copy right clearance from the authors or from his family members or future copy right owner by written forms. by order- Sd/Professor Pranab Kumar Bhattacharya WBMES
Blogson TheoreticalPhysics;Astronomy; MedicalSciences,Pathology; etc.All contents,words, Syllables &;Scientificallymeaning ful sentences of all blogsposted are Strictly Copy Righted material to ProfDr Pranab Kumar Bhattacharya under IPR Copy Right Acts sections-306/301/3D/107/1012/ RDF and Protect Intellectual Property Right ACT of USA-2012. Don't try to infringe, to avoid huge civil/criminal proceedings in IPR Court: Acknowledgement for all my blogs to my Spouse Mrs Sumita Bhattacharya
Tuesday, 19 November 2013
Monday, 18 November 2013
Of mice, men and rapamycin 09 Jul 2009 | 12:15 GMT | Posted by Daniel Cressey | Category: Health and medicine Comment Published in Nature
Totally drug-resistant TB emerges in India Discovery of a deadly form of TB highlights crisis of 'mismanagement' Comment Published in Nature
International weekly journal of science
NATURE | NEWS
International weekly journal of science
- Even in 21st century are we loosing the battle against eradication of an ancient oldest bacterial diseases by M. Tuberculosis due to poverty, unemployment, under nutrition, HIV and inadequate free quality supply of ATD drugs, microscopy, [ through DOTS] cultural confirmation ,delay in rapid diagnosis and high tech based confirmation of Mycobacteria and of emerging MDR and even TDR ?
Authors
*Professor Pranab Kumar Bhattacharya MD(cal), FIC Path(Ind), Professor and Head, Dept. of Pathology, Now in Calcutta School of Tropical Medicine, 108 C.R avenue ,Kolkata-73, W.B , India, In charge Convener DCP &DLT Course of WBUHS **Miss Upasana Bhattacharya Daughter of Prof. P.K. Bhattacharya
Actually in India even after its 69 years of its Independences and 12th such 5th years plan for eradication of poverty and in spite of high economic growth rate near 9 , is probably the highest of killer diseases, like Tuberculosis (M. Tuberculosis) burden country Globally, if the authors is not however wrong, accounting 1/5th of Global incidence of only Pulmonary TB and 1/3rd of in south Asia. According to WHO in 2007, out of total Global 9,3 million cases of TB, 1.4 million cases and 48,000 death is related to HIV and TB co- infections and the epidemiology of MAC TB is modified today by HIV infection which is causing an increase in occurrences of new TB cases and generation of CAT1 & or CAT 2 drug resistances cases(MDR TB) affecting not only individuals but also their close contacts keens and general population of the close community. The Tuberculosis in India and in one of provinces in India like West Bengal ( where Left front party ruled since 1977] are mostly due to extreme level of economic poverty to purchase their minimum required food, lack of necessary calorie, nutrition in the affected family members in low socioeconomic classes , joblessness, lock out in small and medium size industries in the open market mixed economy of India, huge numbers of unemployment amongst economically active youths ( it exceeded more then 1.8 cores general stream graduate level or High school level educated young generation amongst 8.6 cores population in provinces of West Bengal, India census 2001), non workers, laborers, high prices for essential foods purchase , low per capita income in sub urban (bellow poverty line(BPL) Per capita income per month Rs 450 and poverty line people ], urban slum dwellers, colony people, many hawkers maid servants ,watch men and in rural population, illiteracy, and TB is mainly predominant and rampant today within low socioeconomic income group people ( who are the main working /labor forces of the state / India ) of the province of West Bengal, India ( approx.38. population as per author ) and in people BPL (29%) . This ancient Myco Bacterial disease is not usually found in upper middle class and sudden raised middle class and rich class Population with high economic stability (25-30%) having cars, flats with decoration with or without A/c, though other bacterial infections & other diseases for over nutrition { as for example, obesity, metabolic syndrome and sequel, seen in these class. Why?. As the TB is related with CD4 T cell immunity and by delayed type hypersensitivity-Type IV (Th1.and Th2. T cells) which falls with gross level poverty & low calorie consumption for long time. At least, the present first author as a Histo pathologist never encountered in his medical 27 years carrier in hospital’s Lab Set up ,unless that person is some how Immuno compromised for CD4 T cells for some other diseases like Diabetes, taking various kinds of immunosupressive drugs, steroids or under gone any organ transplants or HIV. Nearly 45% population in India is today, affected by TB and in West Bengal alone is house of 1.5 to 3.5 million people per year and in India there are 500,000 deaths occur annually due to TB only?. NTCP followed by RNTCP i.e Revised National TB control program was initiated in the year 1993 by GOI as DOT program strategy. There was political, administrative and organizational commitment too, for short course of DOT (6 months therapy) through which ensuring poor class comprehensive TB control services to reach at Sub center level (SHC) of the country with reliable sputum smear microscopy, good quality anti TB drugs, effective and patient friendly treatment to be given under direct observations and accountability to establish with health care system of the state. Then came revised RNTCP. The objective of revised RNTCP started in 2000, whose objective was to achieve 85% cure rate amongst new/old smear positive cases initiated on treatment and case detection rate raising up to 70% of affected. But there were not really enough existing infrastructure, enough staffs, enough human resources, free essential quality anti TB drugs, human resources to decentralize the activity through creation of Sub-sub divisional level supervisory teams comprising of a senior treatment supervisor, senior laboratory supervisor and designated trained chest Medical officers ,enough reliable microscopy centers with trained persons to examine AFB, free supply of quality Anti TB drugs (CAT-1/CAT-2/CAT-3] and trained personal though some norms and guide line was formulated for these attempts. Result was quite expected and there is raise of TB incidences. TB, HIV, Malaria, MRDM, Diarrhea ARI low birth weight baby and ARI are always diseases of poverty and should be other indicators of Health structure development of a country, or of a state. It is the matter of shame for a welfare government too that TB is raising in the state.
Quite obviously and unexpectedly , very soon ,West Bengal and India faced the challenges of Drug Resistance TB { for long years continued use of these two drugs ] to first INH and then Refampicin ( two drugs) and the real cause was deficient and detoriating TB control program, inefficient administration of effective therapy at free of cost to poor people, use of substandard quality ATD drugs in hospitals, ignorance of health workers about the disease , inadequate admission facility in govt. hospitals during emergency period, replace of blood during severe Hemoptasis; Interruptions of ATD chemotherapy and non adherence due to various reasons ,side effects of toxic drugs and market costs of Anti TB drugs to those people who can not even earn food for them as prevention of TB or non availability, low nutrition status , may have massive bacillary load and delay in identification of TB and lack of uniform laboratory methodology in the state metropolis, prescribing some times of high tech very costly gadgets like Bachtech and PCR identification of the bacteria.
Then came MDR TB in India and in West Bengal too in early 1990s so far author remembers. They are TB which are resistant to two or more effective anti TB drugs available like INH and Refampicin. Those patients who are not MDR TB can be still cured by 6-9 months of treatment if taken regularly. But problem with MDR TB require at least18-24 months treatment and treatment are very toxic for the body itself and are expensive too. In West Bengal, at least stamping a person with MDR TB is equivalent to stamp his death certificate also. The classical threat of TB epidemics started as MDR TB and often that was use or misuse or the antibacterial agents has emerged the evolution towards resistance resulting often treatment failure. There was not stop. There appeared then sporadic XDR TB in India and also in West Bengal . TB in community XDR TB so far authors knowledge is, has been detected in India on an average 1.6% of TB population in India since 2004 to 2007 when MDR was 34% on average. The one possibility of XDR TB may be association with HIV ,though it is only 6% roughly of XDR TB. What about the rest? And now the threat appeared however, Totally drug-resistant tuberculosis (TDR-TB), i.e incurable TB, though are sparse, rare, one or two isolated cases. That are in association with HIV. But so far Knowledge of the author there is no equipped laboratory to diagnose TDR TB except one or two in Delhi. In Maharastra, Mumbai, 2cases of TDR were detected in 2011. Before these Twelve (12) cases of TDR were confirmed. Giovanni Migliori, The Director of the World Health Organization (WHO) Collaborating Centre for Tuberculosis and Lung Diseases in Tradate, Italy, suggests that TDR-TB is a deadlier iteration of the highly resistant forms of TB that have been increasingly reported over the past decade in poor socio economic classes. Totally resistant TB is so not new at all, he said. Since the 1960s, two drugs isoniazid and rifampicin had been standard TB treatment. Although episodes of resistance cropped up periodically, during the 1990s the incidence of multiple drug resistance (MDR) grew significantly, leading researchers in 2006 to refer to it as extensively drug-resistant tuberculosis (XDR-TB). Surveillance data from the WHO indicated that XDR-TB is present in at least in 58 countries, with an estimated 25,000 cases occurring each and every year. WHO till this date describes TB as a disease of poverty and extreme level, poverty who have no purchase capacity for minimum basic need to live as human, drug-resistant varieties might best be understood as resulting from poor treatment. According to a 2011, WHO report, fewer than 5% of newly diagnosed or previously treated patients were tested for drug resistance. And it is estimated that just 16% of patients with drug-resistant TB are receiving appropriate treatment. The cases are a story of mismanagement,said Migliori. Resistance is here man-made, caused by exposure to the wrong treatment, the wrong regimen, the wrong treatment duration. But for author besides the Statement of Migliori, MDR or TDR molecular studies showed drug resistance in M tuberculosis is mutation in the drug target genes and effector pump The pharmaceutical industry has scant interest in TB for decades, together The industry pretty much concluded it wasn't an attractive market, and there was not enough potential profit.
So the Battle for TB is loosing by us. Control of TB must be governmental programmed and that must be based on program ,objective and effectiveness of interventions and applications of resources According this author the first priority to cut of chain of transmission of bacilli by giving food and nutrient to people at BPL or PL level, free early diagnosis, quality sputum microscopy, free provisions of quality anti TB drugs through DOTS ,achieving any how 85% cure rate, universal poor friendly access of free DOTS, to reduce morbidity and mortality and secondary priority expansion of case detection and treatment at free costs in private hospitals, use of free culture for diagnosis of smear negative cases even, formulation of guide line for extra pulmonary cases, identification, surveillance of drug resistance cases at free cost even in private set up hospitals in the country, monitoring of cost effectiveness and rationalizations of care, expansion of tuberculosis packages to care for MDR tuberculosis particularly for immuno suppressive groups and HIV parsons. - Copy Right- Copy Right of this comment in Journal Nature belongs to Professor Pranab kumar Bhattacharya and his first degree relatives only as per copy right act & rules of Intellectual Property Right Rules 3D/107/1201 a,b/ RDF Copy Right rules/ SPARC copy Right rules-2006/ and Protect intellectual Property Right(PIP) copy right rules of USA-2012.Please do not Infringe and be enough careful for your own safety if you are not direct Blood relation to prof Pranab Kumar Bhattacharya . No person, No NGOS [ except the authors& first degree relatives] in the state of West Bengal or in any states of India or in any abroad countries are authorized to use this article, with any meaning full, scientific sentences or with scientific and meaning full words laid out in this article either in the class room/ or in mass teaching programme including CME or in any form what so ever it is with any content of this article or while in writing any book or for his/her personal/ home use, or collective works or for any future Research or implementation as a policy matter or,[ except the authors ]or by Xeroxing and distributing the article/ or by printing/saving/broadcasting the article from any website of internet services,displayed without proper copy right clearance from the authors or from his family members or future copy right owner by written forms.
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