Sri Krishna Jayadev Magani

Abstract: Background Salidroside is a glucoside of tyrosol found mostly in the roots of Rhodiola spp. It exhibits diverse biological and pharmacological properties. In the last decade, enormous research is conducted to explore the medicinal properties of salidroside; this research reported many activities like anti-cancer, anti-oxidant, anti-aging, anti-diabetic, anti-depressant, anti-hyperlipidemic, anti-inflammatory, immunomodulatory, etc. Objective: Despite its multiple pharmacological effects, a comprehensive review detailing its metabolism and therapeutic activities is still missing. This review aims to provide an overview of the metabolism of salidroside, its role in alleviating different metabolic disorders, diseases and its molecular interaction with the target molecules in different conditions. This review mostly concentrates on the metabolism, biological activities and molecular pathways related to various pharmacological activities of salidroside. Conclusion Salidroside is produced by a three-step pathway in the plants with tyrosol as an intermediate molecule. The molecule is biotransformed into many metabolites through phase I and II pathways. These metabolites, together with a certain amount of salidroside may be responsible for various pharmacological functions. The salidroside based inhibition of PI3k/AKT, JAK/ STAT, and MEK/ERK pathways and activation of apoptosis and autophagy are the major reasons for its anti-cancer activity. AMPK pathway modulation plays a significant role in its anti-diabetic activity. The neuroprotective activity was linked with decreased oxidative stress and increased antioxidant enzymes, Nrf2/HO-1 pathways, decreased inflammation through suppression of NF-κB pathway and PI3K/AKT pathways. These scientific findings will pave the way to clinically translate the use of salidroside as a multi-functional drug for various diseases and disorders in the near future.

Abstract: Ferrocene-based compounds have recently gained widespread importance in cancer treatment becuase of their lower toxicity and cost-effective synthesis. However, ferrocene-based compounds do not exist in nature. Moreover, the synthesis of thianes containing ferrocene is quite rare. In the recent past, our group has reported iodine catalyzed synthesis of ferrocenated benzothiazole and β-ketooxothioacetal by the thermal reaction of ferrocenated β-chlorocinnamaldehyde with 2-aminothiophenol and 2-mercaptoethanol respectively.The molecular structure of both the compounds is quite interesting due to the presence of ferrocene which makes them highly important from an anticancer point of view. In this script, the synergistic effect of ferrocene and thiol has been observed in ferrocene functionalized thiols (Fenton reagents) for tumour growth suppression. The anticancer properties of both the compounds separately as well as in combination show a significant anticancer effect on cancer cell lines HCT116 (Colon), A549 (lung cancer), and MCF7 (Breast cancer). Both compounds and their combinations reflect cell death by generating ROS and depolarization of mitochondrial membrane potential. Gene expression profiling and protein expression studies of apoptosis-related genes (cleaved caspase 9, cleaved caspase 3, cleaved PARP and Bcl-2) were also evaluated. Results indicated that ferrocenated benzothiozole and β-ketooxothioacetal induced apoptosis through oxidative stress-mediated activation of intrinsic apoptosis pathway by generating intracellular ROS, loss of MMP, and alteration of expression of genes related to apoptosis. In addition, the anti-metastatic activity of benzothiozole and β-ketooxothioacetal was seen by wound healing assay showing anti-migratory properties. The properties like anti metastatic activity, cytotoxicity and showing synergistic effect when used in combination make benzothiozole and β-ketooxothioacetal potent platforms for the development of new anticancer agents. Benzothiazole and β-ketooxothioacetal can replace existing organometallic compounds with rare metals like platinum, due to their higher stability, lower cost, and lower toxicity.

Abstract: Tropical Calcific Pancreatitis (TCP) is a neglected juvenile form of chronic non-alcoholic pancreatitis. Cathepsin B (CTSB), a lysosomal protease involved in the cellular degradation process, has recently been studied as a potential candidate gene in the pathogenesis of TCP. According to the Cathepsin B hypothesis, mutated CTSB can lead to premature intracellular activation of trypsinogen, a key regulatory mechanism in pancreatitis. So far, CTSB mutations have been studied in pancreatitis and neurodegenerative disorders, but little is known about the structural and functional effect of variants in CTSB. In this study, we investigated the effect of single nucleotide variants (SNVs) specifically associated with TCP, using molecular dynamics and simulation algorithms. There were two non-synonymous variants (L26V and S53G) of CTSB, located in the propeptide region. We tried to predict the effect of these variants on structure and function using multiple algorithms: SIFT, Polyphen2, PANTHER, SDM sever, i-Mutant2.0 suite, mCSM algorithm, and Vadar. Further, using databases like miRdbSNP, PolymiRTS, and miRNASNP, two SNPs in the 3'UTR region were predicted to affect the miRNA binding sites. Structural mutated models of nsSNP mutants (L26V and S53G) were prepared by MODELLER v9.15 and evaluated using TM-Align, Verify 3D, ProSA and Ramachandran plot. The 3D mutated structures were simulated using GROMACS 5.0 to predict the impact of these SNPs on protein stability. The results from in silico analysis and molecular dynamics simulations suggested that these variants in the propeptide region of Cathepsin B could lead to structural and functional changes in the protein and thus could be pathogenic. Hence, the structural and functional analysis results have given interim conclusions that these variants can have a deleterious effect in TCP pathogenesis, either uniquely or in combination with other mutations. Thus, it could be extrapolated that Cathepsin B gene can be screened in samples from all TCP patients in future, to decipher the distribution of variants in patients.

Abstract: Cancer is the second major cause of deaths next to noncommunicable diseases worldwide. The major treatment regimens followed to counter this disease include surgical resection, radiation therapy, and chemotherapy. These treatment regimens can be employed individually or in combinations. The heterogeneity in gastrointestinal (GI) cancers and development of resistance to chemotherapeutics agents and the secondary complication due to their toxic activity in normal cells lead to the research for discovery of novel therapeutics. With increasing knowledge of the aberrant signaling pathways in cancers, the novel approach to avoid the toxic effect of the chemotherapeutic drugs in normal cells was to look for targeted therapeutics. Targeted therapies include the use of either monoclonal antibodies against receptors or extracellular molecules present on cancer cells or using inhibitor molecules that target aberrant pathways in cancers. This chapter mostly focusses on discussing the role of protein kinase inhibitors a class of small molecule inhibitors in cancers with their functional significance and limitations.

Abstract: Triggered by the resounding success of cisplatin, the past decades have seen tremendous efforts to produce clinically beneficial analogues. The recent achievement of oxaliplatin for the treatment of colon cancer should, however, not belie the imbalance between a plethora of investigated complexes and a very small number of clinically approved platinum drugs. Strategies opening up new avenues are increasingly being sought using complexes of metals other than platinum such as ruthenium or gallium. Based on the chemical differences between these metals, the spectrum of molecular mechanisms of action and potential indications can be broadened substantially. Other approaches focus on complexes with tumour-targeting properties, thereby maximizing the impact on cancer cells and minimizing the problem of adverse side effects, and complexes with biologically active ligands.

Abstract: Colorectal cancer (CRC) is often diagnosed at an advanced stage when tumor cell dissemination has taken place. Chemo- and targeted therapies provide only a limited increase of overall survival for these patients. The major reason for clinical outcome finds its origin in therapy resistance. Escape mechanisms to both chemo- and targeted therapy remain the main culprits. Here, we evaluate major resistant mechanisms and elaborate on potential new therapies. Amongst promising therapies is α-amanitin antibody-drug conjugate targeting hemizygous p53 loss. It becomes clear that a dynamic interaction with the tumor microenvironment exists and that this dictates therapeutic outcome. In addition, CRC displays a limited response to checkpoint inhibitors, as only a minority of patients with microsatellite instable high tumors is susceptible. In this review, we highlight new developments with clinical potentials to augment responses to checkpoint inhibitors.

Abstract: Three rationally designed glucose-platinum conjugates (Glc-Pts) were synthesized and their biological activities evaluated. The Glc-Pts, 1-3, exhibit high levels of cytotoxicity toward a panel of cancer cells. The subcellular target and cellular uptake mechanism of the Glc-Pts were elucidated. For uptake into cells, Glc-Pt 1 exploits both glucose and organic cation transporters, both widely overexpressed in cancer. Compound 1 preferentially accumulates in and annihilates cancer, compared to normal epithelial, cells in vitro.

Abstract: Ferrocene-based compounds have recently gained widespread importance in cancer treatment becuase of their lower toxicity and cost-effective synthesis. However, ferrocene-based compounds do not exist in nature. Moreover, the synthesis of thianes containing ferrocene is quite rare. In the recent past, our group has reported iodine catalyzed synthesis of ferrocenated benzothiazole and β-ketooxothioacetal by the thermal reaction of ferrocenated β-chlorocinnamaldehyde with 2-aminothiophenol and 2-mercaptoethanol respectively.The molecular structure of both the compounds is quite interesting due to the presence of ferrocene which makes them highly important from an anticancer point of view. In this script, the synergistic effect of ferrocene and thiol has been observed in ferrocene functionalized thiols (Fenton reagents) for tumour growth suppression. The anticancer properties of both the compounds separately as well as in combination show a significant anticancer effect on cancer cell lines HCT116 (Colon), A549 (lung cancer), and MCF7 (Breast cancer). Both compounds and their combinations reflect cell death by generating ROS and depolarization of mitochondrial membrane potential. Gene expression profiling and protein expression studies of apoptosis-related genes (cleaved caspase 9, cleaved caspase 3, cleaved PARP and Bcl-2) were also evaluated. Results indicated that ferrocenated benzothiozole and β-ketooxothioacetal induced apoptosis through oxidative stress-mediated activation of intrinsic apoptosis pathway by generating intracellular ROS, loss of MMP, and alteration of expression of genes related to apoptosis. In addition, the anti-metastatic activity of benzothiozole and β-ketooxothioacetal was seen by wound healing assay showing anti-migratory properties. The properties like anti metastatic activity, cytotoxicity and showing synergistic effect when used in combination make benzothiozole and β-ketooxothioacetal potent platforms for the development of new anticancer agents. Benzothiazole and β-ketooxothioacetal can replace existing organometallic compounds with rare metals like platinum, due to their higher stability, lower cost, and lower toxicity.

Abstract: Our earlier experimental and computational report produced evidence on the antiviral nature of the compound seselin purified from the leaf extracts of Aegle marmelos against Bombyx mori Nuclear Polyhedrosis Virus (BmNPV). In the pandemic situation of COVID-19 caused by the SARS-COV-2 virus, an in silico effort to evaluate the potentiality of the seselin was made to test its efficacy against multiple targets of SARS-COV-2 such as spike protein S2, COVID-19 main protease and free enzyme of the SARS-CoV-2 (2019-nCoV) main protease. The ligand seselin showed the best interaction with receptors, spike protein S2, COVID-19 main protease and free enzyme of the SARS-CoV-2 (2019-nCoV) main protease with a binding energy of -6.3 kcal/mol, -6.9 kcal/mol and -6.7 kcal/mol, respectively. Docking analysis with three different receptors identified that all the computationally predicted lowest energy complexes were stabilized by intermolecular hydrogen bonds and stacking interactions. The amino acid residues involved in interactions were ASP1184, GLU1182, ARG1185 and SER943 for spike protein, SER1003, ALA958 and THR961 for COVID-19 main protease, and for SARS-CoV-2 (2019-nCoV) main protease, it was THR111, GLN110 and THR292. The MD simulation and MM/PBSA analysis showed that the compound seselin could effectively bind with the target receptors. The outcome of pharmacokinetic analysis suggested that the compound had favourable drugability properties. The results suggested that the seselin had inhibitory potential over multiple SARS-COV-2 targets and hold a high potential to work effectively as a novel drug for COVID-19 if evaluated in experimental setups in the foreseeable future. Communicated by Ramaswamy H. Sarma.