Rajesh Dabur

Natural products – antifungal agents derived from plants

A new spectrum of human fungal infections is increasing due to increased cancer, AIDS, and immunocompromised patients. The increased use of antifungal agents also resulted in the development of resistance to the present drugs. It makes necessary to discover new classes of antifungal compounds to cure fungal infections. Plants are rich source of bioactive secondary metabolites of wide variety such as tannins, terpenoids, saponins, alkaloids, flavonoids, and other compounds, reported to have in vitro antifungal properties. Since the plant kingdom provides a useful source of lead compounds of novel structure, a wide-scale investigation of species from the tropics has been considered. Therefore, the research on natural products and compounds derived from natural products has accelerated in recent years due to their importance in drug discovery. A series of molecules with antifungal activity against different strains of fungus have been found in plants, which are of great importance to humans. These molecules may be used directly or considered as a precursor for developing better molecules. This review attempts to summarize the current status of important antifungal compounds from plants.

Skeletal muscle atrophy: Potential therapeutic agents and their mechanisms of action

Over the last two decades, new insights into the etiology of skeletal muscle wasting/atrophy under diverse clinical settings including denervation, AIDS, cancer, diabetes, and chronic heart failure have been reported in the literature. However, the treatment of skeletal muscle wasting remains an unresolved challenge to this day. About nineteen potential drugs that can regulate loss of muscle mass have been reported in the literature. This paper reviews the mechanisms of action of all these drugs by broadly classifying them into six different categories. Mechanistic data of these drugs illustrate that they regulate skeletal muscle loss either by down-regulating myostatin, cyclooxygenase2, pro-inflammatory cytokines mediated catabolic wasting or by up-regulating cyclic AMP, peroxisome proliferator-activated receptor gamma coactivator-1α, growth hormone/insulin-like growth factor1, phosphatidylinositide 3-kinases/protein kinase B(Akt) mediated anabolic pathways. So far, five major proteolytic systems that regulate loss of muscle mass have been identified, but the majority of these drugs control only two or three proteolytic systems. In addition to their beneficial effect on restoring the muscle loss, many of these drugs show some level of toxicity and unwanted side effects such as dizziness, hypertension, and constipation. Therefore, further research is needed to understand and develop treatment strategies for muscle wasting. For successful management of skeletal muscle wasting either therapeutic agent which regulates all five known proteolytic systems or new molecular targets/proteolytic systems must be identified.

Investigations toward new lead compounds from medicinally important plants

Extensive phytochemical investigations on 30 Piper species growing in India and other medicinal plants have revealed the presence of a large number of novel compounds belonging to different classes. The antiviral activity of several lignans and neolignans belonging to different structural types has been evaluated against six different viral strains. Further, the effects of ethanol, chloroform, and hexane extracts of Piper longum and Piper galiatum on TNF-α induced expression of intercellular adhesion molecule-1 (ICAM-1) on human umbilical vein endothelial cells have been studied, a novel aromatic ester was isolated from the most active extract of P. longum. A potential antifungal compound having implications in treating aspergillosis was isolated from an important Indian medicinal plant, Datura metel.

In vitro and in vivo antimicrobial activities of seeds of Caesalpinia bonduc (Lin.) Roxb.

AIM OF THE STUDY Caesalpinia bonduc (Lin.) Roxb. is a known drug in Ayurveda to treat various diseases specifically tumors, cysts and cystic fibrosis (CF). The aim of this study was to assess in vitro as well as in vivo antimicrobial activity of Caesalpinia bonduc seeds. MATERIALS AND METHODS The in vitro antimicrobial activities of seed coat and seed kernel extracts were investigated by microbroth dilution assay. In vivo activities of hydro-alcoholic extracts were investigated in rat models of chronic Pseudomonas aeruginosa pneumonia mimicking that in patients with cystic fibrosis. RESULTS Various extracts of plant seeds exhibited in vitro antimicrobial activities in a range of 22-350 microg/ml. The extracts also showed activity against methicillin resistant (MR) Staphylococcus aureus and ampicillin resistant (AR) Pseudomonas aeruginosa as in the sensitive strains. In rat model of chronic Pseudomonas aeruginosa pneumonia, hydro-alcoholic extracts of Caesalpinia bonduc seed kernel (CBSK) and Caesalpinia bonduc seed coat (CBSC) were injected subcutaneously in the test groups of animals. The control groups were treated with cortisone and saline. Two weeks after challenge with Pseudomonas aeruginosa, the CBSK treated animals showed a significant bacterial clearance from the lungs (P<0.04) and less severe incidence of lung abscess (P<0.05). CONCLUSION Results showed that Caesalpinia bonduc may have the potential to be promising natural medicine, with other forms of treatments, for CF patients with chronic Pseudomonas aeruginosa lung infections.

Quantitative analysis of catechins in Saraca asoca and correlation with antimicrobial activity

Herbal medicines are highly complex and have unknown mechanisms in diseases treatment. Saraca asoca (Roxb.), De. Wild has been recommended to treat gynecological disorders and used in several commercial polyherbal formulations. In present study, efforts have been made to explore antimicrobial activity and its co-relation with the distributions of catechins in the organs of S. asoca using targeted MS/MS. Eight extracts (cold and hot water) from four different organs of S. asoca and two drugs were prepared and antimicrobial activity was assessed by microbroth dilution assay. Quantitative and qualitative analysis of catechins in crude extracts was done by using targeted and auto-MS/MS and correlated with antimicrobial activity. (+)-Catechin and (+)-epicatechin and their biosynthesis related compound were found to be up-regulated in regenerated bark and leaves extracts. (−)-Epigallocatechin was found to be significantly higher in bark water extract as compared to others but showed low antimicrobial activity. Result showed down-regulation of (−)-epigallocatechin and up-regulation of (+)-catechin and (+)-epicatechin in the regenerated bark and leaves of S. asoca. It might be the contributing factor in the antimicrobial activity of regenerated bark and leaves of the plant. The concentration of (+)-epicatechin in processed drugs (Ashokarishta) from Baidyanath was found to be seven times higher than that of Dabur Pvt. Ltd., but no antimicrobial activity was observed, indicating the variations among the plant based drugs. This will be helpful in rational use of S. asoca parts. Furthermore, the analytical method developed is sensitive, repeatable and reliable; therefore, it is suitable for quality control of herbal drugs.

Efficacy and risk profile of anti-diabetic therapies: Conventional vs traditional drugs—A mechanistic revisit to understand their mode of action

An increasing array of anti-diabetic drugs are available today, yet Type-2 diabetes mellitus (T2DM) - remains a life threatening disease, causing high mortality and morbidity in developing and developed countries. As of now, no effective therapy is available for the complete eradication/cure of diabetes and its associated complications. Therefore, it is time to re-think and revisit molecular pathways and targets of each existing drug in order to identify multiple targets from different signaling pathways that may be manipulated simultaneously to treat or manage T2DM effectively. Bearing this goal in mind, the article reviews the mechanisms of action of available anti-diabetic drugs with in-depth mechanistic analysis of each therapy. The conventional and herbal strategies are analysed and compared for their benefits and the associated possible side effects. This critical information is necessary not only for the development of better, novel and potent anti-diabetic therapy in future but also for best possible combinational therapies and strategies with the available drugs.

T lymphocyte subset profile and serum alpha-1-antitrypsin in pathogenesis of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is an inflammatory disorder characterized by the presence of non‐fully reversible airflow limitation. The study was undertaken to investigate the involvement of alpha‐1‐antitrypsin (α1AT) and T lymphocyte subsets in the pathogenesis of COPD. Blood samples of 50 subjects, including 25 healthy volunteers and 25 patients with COPD, were analysed. Serum trypsin inhibitory capacity (STIC) was determined by enzymatic assay. CD4+ and CD8+ T lymphocytes were enumerated in heparinized blood using a fluorescence activated cell sorter counter. The STIC in COPD patients was found to be decreased significantly than in controls (P < 0·01). In COPD patients with lower expression levels of α1AT, a highly significant decrease in the number of CD4+ T lymphocytes (P < 0·0009) and CD4/CD8 ratio was observed compared with control subjects (P < 0·008). The mean ± standard error of CD8+ lymphocytes was found to be little different (only marginally decreased) in COPD patients compared to healthy controls; however, an alteration in the individual count of CD8+ lymphocytes cells was observed in COPD patients. Using linear regression analysis, a negative correlation was observed between STIC and CD4+ lymphocytes and CD8+ lymphocytes (r = −0·40, P < 0·04; r = −0·42, P < 0·03, respectively) in COPD patients. An alteration in α1AT and T lymphocyte subsets in COPD patients suggested that interplay of these factors may be responsible for the progression of COPD.

Combination Therapy: The Propitious Rationale for Drug Development

Therapeutic options for many infections are extremely limited and at crisis point. We run the risk of entering a second pre-antibiotic era. There had been no miracle drug for the patients infected by resistant microbial pathogens. Most of the very few new drugs under development have problems with their toxicity, or pharmacokinetics and pharmacodynamics. We are already decades behind in the discovery, characterization and development of new antimicrobials. In that scenario, we could not imagine surviving without newer and effective antimicrobial agents. Bacteria have been the champions of evolution and are still evolving continuously, where they pose serious challenges for humans. Along with the crisis of evolving resistance, the condition is made worst by the meager drug pipeline for new antimicrobials. Despite ongoing efforts only 2 new antibiotics (Telavancin in 2009 and Ceftaroline fosamil in 2010) have been approved since 2009 pipeline status report of Infectious Disease Society of America (IDSA). Recent approval of new combination based antiviral drugs such as Stribild (combination of four drugs for HIV treatment) and Menhibrix (combination vaccine to prevent meningococcal disease and Haemophilus influenzae type b in children) proves that combination therapy is still the most promising approach to combat the ever evolving pathogens. Combination therapy involves the drug repurposing and regrouping of the existing antimicrobial agents to provide a synergistic approach for management of infectious diseases. This review article is an effort to highlight the challenges in new drug development and potential of combination drug therapy to deal with them.

Nontargeted Identification of the Phenolic and Other Compounds of Saraca asoca by High Performance Liquid Chromatography-Positive Electrospray Ionization and Quadrupole Time-of-Flight Mass Spectrometry

High performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometer was used for separation and identification of phenolic and other compounds in the water extracts of Saraca asoca (Roxb.), De. Wilde. The aim of the study was to identify and evaluate the distribution of phenolic compounds in the different parts of the plant. The identity of compounds was established through the comparison with standards and characteristic base peaks as well as other daughter ions. In crude extracts, 34 catechin derivatives, 34 flavonoids, and 17 other compounds were identified. Interestingly, further analysis of compounds showed plant part specific unique pattern of metabolites; that is, regenerated bark is observed to be the best source for catechin/catechin derivative while flowers were found to be the source for wide variety of flavonoids. Moreover, these plant part specific compounds can be used as biomarkers for the identification of plant material or herbal drugs. Overall, the present study provides for the first time a comprehensive analysis of the phenolic components of this herb which may be helpful not only to understand their usage but also to contribute to quality control as well.

Investigations on anti-Aspergillus properties of bacterial products.

Aims:  To investigate the anti‐Aspergillus properties of bacterial products.