Indian Institute of Integrative Medicine

Jammu, India

Indian Institute of Integrative Medicine

Jammu, India
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Kour K.,Indian Institute of Integrative Medicine | Bani S.,Indian Institute of Integrative Medicine
Neuropharmacology | Year: 2011

This study demonstrates the protective effect of chicoric acid (CA) on chronic restraint stress-induced altered T lymphocyte subset distribution and corresponding cytokine secretion patterns in experimental Swiss albino mice. CA has the potential to restore diminished immune response and Th1/Th2 homeostasis in chronically stressed mice as evident by significant increase in lymphocyte proliferation and CD3+, CD4+ and CD8+ T cell population. Interestingly, chicoric acid imparted immunostimulation mainly by upregulating the expression of CD28 and CD80 and downregulating CTLA-4. It exerted stimulatory effect on IL-12, IFN-gamma and IL-2 and suppressed the increased IL-10 levels in chronically stressed mice. It also exhibited a significant lowering effect on raised corticosterone levels and reversed the chronic stress-induced hypertrophy of adrenal glands and atrophy of thymus and spleen, thereby showing its normalizing effect on HPA axis. Our results reveal that CA has the potential to reverse the impact of chronic restraint stress on immune status by normalizing corticosterone levels and augmenting Th1 cytokine profile along with the co-stimulatory molecules particularly CD28/CTLA-4 pathway that plays a very important role in generation of an effective immune response in immune compromised situations. © 2011 Elsevier Ltd. All rights reserved.

Jain S.K.,Indian Institute of Integrative Medicine | Bharate S.B.,Indian Institute of Integrative Medicine | Vishwakarma R.A.,Indian Institute of Integrative Medicine
Mini-Reviews in Medicinal Chemistry | Year: 2012

Chromone alkaloids and flavoalkaloids are an important group of natural products possessing promising medicinal properties. A chromone alkaloid rohitukine is a major bioactive chemical constituent of plant Dysoxylum binectariferum (Meliaceae) Hook. which is phylogenetically related to the Ayurvedic plant, D. malabaricum Bedd. used for treatment of rheumatoid arthritis. This chromone alkaloid led to discovery of two synthetic flavoalkaloids: flavopiridol (Sanofi) and P-276-00 (Piramal) which have reached to advanced stages of clinical development for cancer treatment. Flavopiridol (Alvocidib; L868275; HMR-1275; NSC 649890 of Sanofi-Aventis + NCI) is approved as an orphan drug for treatment of chronic lymphocytic leukemia and is currently undergoing phase II studies as monotherapy and also as in combination regimes with traditional chemotherapy agents. P-276-00 (12) is currently in phase II clinical studies for advanced refractory neoplasms and multiple myeloma. Extensive amount of medicinal chemistry efforts have been reported on these flavoalkaloids. Flavopiridol demonstrated potent and specific in vitro inhibition of variety of cyclindependent kinases with clear block in cell cycle progression at the G1/S and G2/M phases. Preclinical studies demonstrated the capacity of flavopiridol to induce programmed cell death, promote differentiation, inhibit angiogenic processes and modulate transcriptional events. The co-crystallised structure of deschloro-flavopiridol with CDK-2 is available and key interactions in the ATP binding site have been reported. Flavopiridol has also been studied for the treatment of arthritis and atherosclerotic plaque formation. The present review comprises discovery, medicinal chemistry, pharmacology and preclinical/clinical development of flavoalkaloids as CDK inhibitors. © 2012 Bentham Science Publishers.

Bharate S.S.,Indian Institute of Integrative Medicine | Vishwakarma R.A.,Indian Institute of Integrative Medicine
Expert Opinion on Drug Delivery | Year: 2013

Introduction: Preformulation assists scientists in screening lead candidates based on their physicochemical and biopharmaceutical properties. This data is useful for selection of new chemical entities (NCEs) for preclinical efficacy/toxicity studies which is a major section under investigational new drug application. A strong collaboration between discovery and formulation group is essential for selecting right NCEs in order to reduce attrition rate in the late stage development. Areas covered: This article describes the significance of preformulation research in drug discovery and development. Various crucial preformulation parameters with case studies have been discussed. Expert opinion: Physicochemical and biopharmaceutical characterization of NCEs is a decisive parameter during product development. Early prediction of these properties helps in selecting suitable physical form (salt, polymorph, etc.) of the candidate. Based on pharmacokinetic and efficacy/toxicity studies, suitable formulation for Phase I clinical studies can be developed. Overall these activities contribute in streamlining efficacy/toxicology evaluation, allowing pharmacologically effective and developable molecules to reach the clinic and eventually to the market. In this review, the magnitude of understanding preformulation properties of NCEs and their utility in product development has been elaborated with case studies. © 2013 Informa UK, Ltd.

Wadhwa B.,Indian Institute of Integrative Medicine
Anti-Cancer Drugs | Year: 2017

The serine/threonine protein kinase B (PKB), also known as Akt, is one of the multifaceted kinases in the human kinome, existing in three isoforms. PKB plays a vital role in phosphoinositide 3-kinase (PI3K)-mediated oncogenesis in various malignancies and is one of the attractive targets for cancer drug discovery. Recent studies have shown that the functional significance of an individual isoform of PKB is not redundant in cancer. It has been found that PKB isoforms play distinct roles in the regulation of cellular invasion and migration during tumorigenesis. PKB activation plays a central role during epithelial–mesenchymal transition, a cellular program required for the cancer cell invasion and migration. However, the differential behavior of each PKB isoform has been shown in the regulation of epithelial–mesenchymal transition. Recent studies have suggested that PKBα (Akt1) plays a conflicting role in tumorigenesis by acting either as a pro-oncogenic factor by suppressing the apoptotic machinery or by restricting tumor invasion. PKBβ (Akt2) promotes cell migration and invasion and similarly PKBγ (Akt3) has been reported to promote tumor migration. As PKB is known for its pro-oncogenic properties, it needs to be unraveled how three isoforms of PKB compensate during tumor progression. In this review, we attempted to sum up how different isoforms of PKB play a role in cancer progression, metastasis, and drug resistance. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

Rani C.,Indian Institute of Integrative Medicine | Khan I.A.,Indian Institute of Integrative Medicine
European Journal of Pharmaceutical Sciences | Year: 2016

In the past five years, an alarming increase in the number of patients with multidrug resistant tuberculosis (MDR TB) and extensively drug-resistant tuberculosis (XDR TB) has been reported, particularly in Eastern Europe, Asia and Southern Africa. Current situation has challenged the control and treatment of tuberculosis (TB) which sparked an emergent need to find new anti-tubercular agents with different chemical scaffolds and mechanisms of action. A very fruitful way to identify novel anti-tubercular agents is the development of compounds that target the enzymes essentially required for the biosynthesis and assembly of the mycobacterial cell wall. Biosynthesis of uridine diphospho-N-acetylglucosamine (UDP-GlcNAc) represents one such pathway. Enzymes involved in UDP-GlcNAc biosynthesis have been predicted to be essential for Mycobacterium tuberculosis growth in vitro. It is a key precursor molecule of M. tuberculosis cell wall, being situated at the branched point of two essential biosynthetic pathways, namely peptidoglycan and a disaccharide linker, D-N-GlcNAc-1-rhamnose. This article provides a comprehensive overview of the present knowledge on the enzymes catalyzing the particular steps of the pathway in M. tuberculosis, with special emphasis put on N-acetylglucosamine-1-phosphate uridyltransferase (GlmU), a bifunctional enzyme, which catalyzes the last two steps of this pathway. It also gives an insight into the present knowledge about the inhibitors reported against the enzymes, which could be further used as chemical scaffold for the discovery of more potent anti-TB compounds. © 2015 Elsevier B.V. All rights reserved.

Bharate S.S.,P.A. College | Bharate S.B.,Indian Institute of Integrative Medicine
ACS Chemical Neuroscience | Year: 2012

(Figure Presented) ThermoTRPs, a subset of the Transient Receptor Potential (TRP) family of cation channels, have been implicated in sensing temperature. TRPM8 and TRPA1 are both activated by cooling. TRPM8 is activated by innocuous cooling (<30 °C) and contributes to sensing unpleasant cold stimuli or mediating the effects of cold analgesia and is a receptor for menthol and icilin (mint-derived and synthetic cooling compounds, respectively). TRPA1 (Ankyrin family) is activated by noxious cold (<17 °C), icilin, and a variety of pungent compounds. Extensive amount of medicinal chemistry efforts have been published mainly in the form of patent literature on various classes of cooling compounds by various pharmaceutical companies; however, no prior comprehensive review has been published. When expressed in heterologous expression systems, such as Xenopus oocytes or mammalian cell lines, TRPM8 mediated currents are activated by a number of cooling compounds in addition to menthol and icilin. These include synthetic p-menthane carboxamides along with other class of compounds such as aliphatic/alicyclic alcohols/esters/amides, sulphones/sulphoxides/sulphonamides, heterocyclics, keto-enamines/lactams, and phosphine oxides. In the present review, the medicinal chemistry of various cooling compounds as activators of thermoTRPM8 channel will be discussed according to their chemical classes. The potential of these compounds to emerge as therapeutic agents is also discussed. © 2012 American Chemical Society.

Rouf A.,Indian Institute of Integrative Medicine | Taneja S.C.,Indian Institute of Integrative Medicine
Chirality | Year: 2014

Chiral-center enantiomers have been shown to differ significantly in biological activity, pharmacodynamics, pharmacokinetics and toxicity. New developments in the stereoselective organic synthesis have enriched the vast literature of synthetic methodologies applicable to access natural products as well as bioactive molecules. These compounds also include new drugs, drug candidates and reagents used to explore biological processes. The article reviews the synthesis of optically pure drugs, biologically active intermediates and amino alcohols by using different methods. © 2013 Wiley Periodicals, Inc.

Kaul M.K.,Indian Institute of Integrative Medicine
Indian Journal of Traditional Knowledge | Year: 2010

Emerging trends of underutilization of high altitude medicinal plants by Indian phytopharmaceutical industry suggest that therapeutic potential of these species has been exploited to a very less extent despite availability of rich traditional knowledge and also greater possibilities of offering novel bioactive compounds. According to a recent estimate only 20% high altitude medicinal plants available in Indian subcontinent (predominantly herbs) are used in drug trade. In India, we often wake to our own therapeutic wisdom only after recognition comes from the west. High altitude herbal medicines offer therapeutics for many disorders like memory loss, osteoporosis, immune and age-related problems, etc. particularly the ones for which no modern medicines are available. Of late, these plants are also reported to offer satisfactory therapies for deadly diseases like AIDS and cancer. As high altitude plants are growing under stressful situations and exposed to high UV radiations, they are reported to have immense potential in biological radioprotection. An attempt has been made to highlight the promise that these stress-tolerant plants hold in alleviating human and veterinary ailments with less side effects. Studies on the characteristics of ethnopharmacological resources in high altitude Northwest Himalayan region revealing use of 154 botanicals in home remedy patterns of 55 common ailments as well as integration of food and medicine in several traditional herbal therapies are discussed and included in the text.

Bharate S.B.,Indian Institute of Integrative Medicine | Sawant S.D.,Indian Institute of Integrative Medicine | Singh P.P.,Indian Institute of Integrative Medicine | Vishwakarma R.A.,Indian Institute of Integrative Medicine
Chemical Reviews | Year: 2013

The ocean occupies three-fourths of the Earth's surface and hosts approximately 80% of all living species. In fact, some areas of the sea such as coral reefs possess a biodiversity density greater than that of tropical rainforests. A recent census of marine life by 2700 scientists from more than 80 countries assessed the diversity, distribution, and abundance of marine life and reported over 6000 potentially novel species. Molecules with potential biomedical applications include alkaloids, terpenoids, steroids, polypeptides, polyethers, macrolides, and polysaccharides. Marine organisms produce secondary metabolites that are structurally distinct from those produced by terrestrial organisms, due to the unique biosynthetic milieu, and unusual functional groups such as isocyanate, isonitrile, dichloroimine, and halogenated functionalities that are predominantly found in marine metabolites.

Johri R.K.,Indian Institute of Integrative Medicine
Pharmacognosy Reviews | Year: 2011

Cuminum cyminum and Carum carvi are the sources of cumin and caraway seeds respectively, which have been used since antiquity for the treatment of various indications in traditional healing systems in wide geographical areas. Cumin and caraway seeds are rich sources of essential oils and have been actively researched for their chemical composition and biological activities. In recent times (especially during the last 3 years) considerable progress has been made regarding validation of their acclaimed medicinal attributes by extensive experimental studies. In this attempt many novel bioactivities have been revealed. This review highlights the significance of cumin and caraway as potential source of diverse natural products and their medicinal applications.

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