Leishmania donovani Modulates Macrophage Lipidome During Infection.

Obligate intracellular protozoan parasite, Leishmania donovani, causative agent of visceral leishmaniasis, led to impaired macrophage functions. It is well documented that many of these changes were induced by parasite-mediated reduction in macrophage cholesterol content. Leishmania-mediated alteration in the other lipids has not been explored in detail yet. Here, we found that the expression of key cholesterol biosynthetic genes and total cellular cholesterol were reduced during L. donovani infection. Further, we have also identified that this reduction in the cholesterol led to increased membrane fluidity and inhibition of antigen-presenting potential of macrophages. In addition to this, we studied the relative changes in different lipids in THP-1-derived macrophages during L. donovani infection through liquid chromatography-mass spectrometry. We found that Sphingomyelin (16:0) and ceramide (20:1, 26:0 and 26:1) were significantly reduced in infected macrophages. We further observed that the majority of different sub-classes of phospholipids were downregulated significantly. Overall ratio of phosphatidylcholine versus phosphotidylethanolamine was decreased which indicated the compensatory mechanism of cell in response to cholesterol reduction. The observed Leishmania-mediated alteration in macrophage-lipidome provided the novel insights into mechanism of host-pathogen interactions.

Mechanistic Insight into the Autophagic and Apoptotic Activity of Kaempferol on Liver Cancer Cells.

Background: The accumulation of poorly folded protein in the endoplasmic reticulum (ER) promotes ER stress and contributes to the pathogenesis of hepatocellular carcinoma (HCC). Current therapies have various adverse effects, therefore, laying the need for an alternative approach. Kaempferol (KP), a naturally occurring flavonoid, possesses potent anti-proliferative properties against various cancer cells. Nevertheless, its involvement in HCC remains relatively unexplored, particularly regarding its influence on apoptosis and autophagy pathways. Methods: The effect of KP on cell viability, and motility of Hep3B cells was evaluated by MTT, and scratch assay, respectively. Hoechst staining and FACS analysis were done to check the effect of KP on apoptosis and cell cycle progression. qRTPCR was used to evaluate the expression of several apoptosis and autophagy-related genes. KP was docked with several ER stress-related proteins involved in HCC to gain further insights into molecular mechanisms. The results of docking studies were validated with MD simulation and in vitro studies. Results: Treatment with KP at different time intervals showed dose- and time-dependent growth inhibition of liver cancer cells. KP decreased motility and arrested the cell cycle at the G0/G1 phase in Hep3B cells. Additionally, in the context of HCC, the relationship between KP, apoptosis, and autophagy is significant. It induced apoptosis and autophagy in Hep3B cells by downregulating the expression of Bcl-2 and upregulated Bax and Bid, Caspase-3, Beclin-1, and LC3. KP showed a better binding affinity with Nrf2, PERK, and IRE1α among all selected proteins. Further, it reversed the protective effect of 4-PBA (ER Stress inhibitor) by inducing apoptosis and autophagy in Hep3B cells. Conclusion: The study suggested KP as a potential chemopreventive agent for managing HCC by effectively inducing apoptosis and autophagy in Hep3B cells.

Stealing survival: Iron acquisition strategies of Mycobacteriumtuberculosis.

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), faces iron scarcity within the host due to immune defenses. This review explores the importance of iron for Mtb and its strategies to overcome iron restriction. We discuss how the host limits iron as an innate immune response and how Mtb utilizes various iron acquisition systems, particularly the siderophore-mediated pathway. The review illustrates the structure and biosynthesis of mycobactin, a key siderophore in Mtb, and the regulation of its production. We explore the potential of targeting siderophore biosynthesis and uptake as a novel therapeutic approach for TB. Finally, we summarize current knowledge on Mtb's iron acquisition and highlight promising directions for future research to exploit this pathway for developing new TB interventions.

Deciphering drug discovery and microbial pathogenesis research in tuberculosis during the two decades of postgenomic era using entity mining approach.

We examined literature on Mycobacterium tuberculosis (Mtb) subsequent to its genome release, spanning years 1999-2020. We employed scientometric mapping, entity mining, visualization techniques, and PubMed and PubTator databases. Most popular keywords, most active research groups, and growth in quantity of publications were determined. By gathering annotations from the PubTator, we determined direction of research in the areas of drug hypersensitivity, drug resistance (AMR), and drug-related side effects. Additionally, we examined the patterns in research on Mtb metabolism and various forms of tuberculosis, including skin, brain, pulmonary, extrapulmonary, and latent tuberculosis. We discovered that 2011 had the highest annual growth rate of publications, at 19.94%. The USA leads the world in publications with 18,038, followed by China with 14,441, and India with 12,158 publications. Studies on isoniazid and rifampicin resistance showed an enormous increase. Non-tuberculous mycobacteria also been the subject of more research in effort to better understand Mtb physiology and as model organisms. Researchers also looked at co-infections like leprosy, hepatitis, plasmodium, HIV, and other opportunistic infections. Host perspectives like immune response, hypoxia, and reactive oxygen species, as well as comorbidities like arthritis, cancer, diabetes, and kidney disease etc. were also looked at. Symptomatic aspects like fever, coughing, and weight loss were also investigated. Vitamin D has gained popularity as a supplement during illness recovery, however, the interest of researchers declined off late. We delineated dominant researchers, journals, institutions, and leading nations globally, which is crucial for aligning ongoing and evolving landscape of TB research efforts. Recognising the dominant patterns offers important information about the areas of focus for current research, allowing biomedical scientists, clinicians, and organizations to strategically coordinate their efforts with the changing priorities in the field of tuberculosis research.

Targeting caspase pathway by novel N-Me aziridine derivatives for hepatocellular carcinoma drug discovery.

Azaheterocycles are three-membered rings, known as aziridines, that occur naturally and have pharmaceutical applications.These compounds are present as several secondary metabolites produced by plants and microorganisms.Recent studies have demonstrated the effectiveness of aziridine derivatives (N-H/N-Me) as anticancer agents.We synthesized 18 compounds containing an N-Me enone aziridine group, the chemistry of which has been previously published. However, these compounds have drug-likeness properties; therefore, we aimed to demonstrate their drug-like properties using in silico and in vitro investigations.The molecular structures of the compounds were optimized using density functional theory (DFT). The ADMET parameters of the derivatives were calculated using SwissADME and PreADMET. Additionally, these derivatives were evaluated for their ability to bind to caspase-3 and caspase-9 and then subjected to molecular docking. The lead chemical AY128 maintained stable complexes with target proteins during molecular dynamics simulations, as evidenced by the root mean square deviation (RMSD) and root mean square fluctuation (RMSF) parameters. In vitro cytotoxicity and ELISA tests showed that the novel aziridine derivatives, especially AY128, had strong anticancer activity against HepG2 hepatocellular carcinoma cells.Our study suggests that AY128 may be a potential drug candidate for hepatocellular carcinoma through the caspase-3 and caspase-9-dependent apoptotic pathways.Communicated by Ramaswamy H. Sarma.

Discovery of SDS-347 as a specific peptide competitive inhibitor of G9a with promising anti-cancer potential.

BACKGROUND: G9a is a histone H3K9 methyltransferase enzyme found highly upregulated in many cancers. H3 binds to the rigid I-SET domain and the cofactor, S-adenosyl methionine, binds to the flexible post-SET domain of G9a. Inhibition of G9a is known to inhibit the growth of cancer cell-lines. METHODS: Recombinant G9a and H3 were used to develop radioisotope-based inhibitor screening assay. The identified inhibitor was evaluated for isoform selectivity. The mode of enzymatic inhibition was studied by enzymatic assays and bioinformatics. Anti-proliferative activity of the inhibitor was studied in cancer cell lines by utilizing MTT assay. The mechanism of cell death was studied by western blotting and microscopy. RESULTS: We developed a robust G9a inhibitor screening assay that led to the discovery of SDS-347 as a potent G9a inhibitor with IC50 of 3.06 µM. It was shown to reduce the levels of H3K9me2 in cell-based assay. The inhibitor was found to be peptide competitive and highly specific as it did not show any significant inhibition of other histone methyltransferases and DNA methyltransferase. Docking studies showed that SDS-347 could form direct bonding interaction with Asp1088 of the peptide-binding site. SDS-347 showed anti-proliferative effect against various cancer cell lines especially the K562 cells. Our data suggested that SDS-347 mediated antiproliferative action via ROS generation, induction of autophagy and apoptosis. CONCLUSION: Overall, the findings of the current study include development of a new G9a inhibitor screening assay and identification of SDS-347, as a novel, peptide competitive and highly specific G9a inhibitor with promising anticancer potential.

Differential gene expression analysis of RAGE-S100A6 complex for target selection and the design of novel inhibitors for anticancer drug discovery.

Receptor for advanced glycation end products (RAGE), a member of the immunoglobulin family, interactions with its ligands trigger downstream signaling and induce an inflammatory response linked to diabetes, inflammation, carcinogenesis, cardiovascular disease, and a variety of other human disorders. The interaction of RAGE and S100A6 has been associated with a variety of malignancies. For the control of RAGE-related illnesses, there is a great demand for more specialized drug options. To identify the most effective target for combating human malignancies associated with RAGE-S100A6 complex, we conducted single and differential gene expression analyses of S100A6 and RAGE, comparing normal and malignant tissues. Further, a structure-based virtual screening was conducted using the ZINC15 database. The chosen compounds were then subjected to a molecular docking investigation on the RAGE active site region, recognized by the various cancer-related RAGE ligands. An optimized RAGE structure was screened against a library of drug-like molecules. The screening results suggested that three promising compounds were presented as the top acceptable drug-like molecules with a high binding affinity at the RAGE V-domain catalytic region. We depicted that these compounds may be potential RAGE inhibitors and could be used to produce a successful medication against human cancer and other RAGE-related diseases based on their various assorted parameters, binding energy, hydrogen bonding, ADMET characteristics, etc. MD simulation on a time scale of 50 ns was used to test the stability of the RAGE-inhibitor complexes. Therefore, targeting RAGE and its ligands using these drug-like molecules may be an effective therapeutic approach.

Identification of a stretch of four discontinuous amino acids involved in regulating kinase activity of IGF1R.

IGF1R is pursued as a therapeutic target because of its abnormal expression in various cancers. Recently, we reported the presence of a putative allosteric inhibitor binding pocket in IGF1R that could be exploited for developing novel anti-cancer agents. In this study, we examined the role of nine highly conserved residues surrounding this binding pocket, with the aim of screening compound libraries in order to develop small-molecule allosteric inhibitors of IGF1R. We generated GFP fusion constructs of these mutants to analyze their impact on subcellular localization, kinase activity and downstream signaling of IGF1R. K1055H and E1056G were seen to completely abrogate the kinase activity of IGF1R, whereas R1064K and L1065A were seen to significantly reduce IGF1R kinase activity. During molecular dynamics analysis, various structural and conformational changes were observed in different conserved regions of mutant proteins, particularly in the activation loop, compromising the kinase activity of IGF1R. These results show that a stretch of four discontinuous residues within this newly identified binding pocket is critical for the kinase activity and structural integrity of IGF1R. This article has an associated First Person interview with the first author of the paper.

A review on enzyme complexes of electron transport chain from Mycobacterium tuberculosis as promising drug targets.

Energy metabolism is a universal process occurring in all life forms. In Mycobacterium tuberculosis (Mtb), energy production is carried out in two possible ways, oxidative phosphorylation (OxPhos) and substrate-level phosphorylation. Mtb is an obligate aerobic bacterium, making it dependent on OxPhos for ATP synthesis and growth. Mtb inhabits varied micro-niches during the infection cycle, outside and within the host cells, which alters its primary metabolic pathways during the pathogenesis. In this review, we discuss cellular respiration in the context of the mechanism and structural importance of the proteins and enzyme complexes involved. These protein-protein complexes have been proven to be essential for Mtb virulence as they aid the bacteria's survival during aerobic and hypoxic conditions. ATP synthase, a crucial component of the electron transport chain, has been in the limelight, as a prominent drug target against tuberculosis. Likewise, in this review, we have explored other protein-protein complexes of the OxPhos pathway, their functional essentiality, and their mechanism in Mtb's diverse lifecycle. The review summarises crucial target proteins and reported inhibitors of the electron transport chain pathway of Mtb.

Simple sequence repeat insertion induced stability and potential 'gain of function' in the proteins of extremophilic bacteria.

Here, we analysed the genomic evolution in extremophilic bacteria using long simple sequence repeats (SSRs). Frequencies of occurrence, relative abundance (RA) and relative density (RD) of long SSRs were analysed in the genomes of extremophilic bacteria. Thermus aquaticus had the most RA and RD of long SSRs in its coding sequences (110.6 and 1408.3), followed by Rhodoferax antarcticus (77.0 and 1187.4). A positive correlation was observed between G + C content and the RA-RD of long SSRs. Geobacillus kaustophilus, Geobacillus thermoleovorans, Halothermothrix orenii, R. antarcticus, and T. aquaticus preferred trinucleotide repeats within their genomes, whereas others preferred a higher number of tetranucleotide repeats. Gene enrichment showed the presence of these long SSRs in metabolic enzyme encoding genes related to stress tolerance. To analyse the functional implications of SSR insertions, three-dimensional protein structure modelling of SSR containing diguanylate cyclase (DGC) gene encoding protein was carried out. Removal of SSR sequence led to an inappropriate folding and instability of the modelled protein structure.

RAGE Inhibitors for Targeted Therapy of Cancer: A Comprehensive Review.

The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin family that is overexpressed in several cancers. RAGE is highly expressed in the lung, and its expression increases proportionally at the site of inflammation. This receptor can bind a variety of ligands, including advanced glycation end products, high mobility group box 1, S100 proteins, adhesion molecules, complement components, advanced lipoxidation end products, lipopolysaccharides, and other molecules that mediate cellular responses related to acute and chronic inflammation. RAGE serves as an important node for the initiation and stimulation of cell stress and growth signaling mechanisms that promote carcinogenesis, tumor propagation, and metastatic potential. In this review, we discuss different aspects of RAGE and its prominent ligands implicated in cancer pathogenesis and describe current findings that provide insights into the significant role played by RAGE in cancer. Cancer development can be hindered by inhibiting the interaction of RAGE with its ligands, and this could provide an effective strategy for cancer treatment.

p38 Mitogen-activated protein kinase modulates cisplatin resistance in Head and Neck Squamous Cell Carcinoma cells.

OBJECTIVE: This study aims to investigate the role of p38 Mitogen-activated protein kinase (MAPK) in imparting cisplatin resistance in head and neck squamous cell carcinoma (HNSCC) cells. DESIGN: Laboratory generated cisplatin resistant HNSCC cells were treated with p38 inhibitor and were subjected to increasing dosage of cisplatin. Western blot, immunohistochemistry and RT PCR analysis were performed to investigate expression level of p-p38 and Cancer stem cell (CSC) markers in cisplatin resistant HNSCC cells with or without p38 inhibitor. Chemoresistance, wound healing capacity and Spheroids formation capacity were assessed following p38 inhibition in cisplatin resistant HNSCC cell lines. In addition, alkaline comet assay and γ-H2AX immunostaining were performed to evaluate the DNA damage response and repair abilities in cisplatin resistant HNSCC cells after p38 inhibition. RESULTS: It was observed that following p38 inhibition, cisplatin resistant HNSCC cells exhibited significant reduction in expression of CSC markers, ß-catenin, reduced migration potential and sphere forming ability along with increased apoptotic index demonstrating there was increased sensitivity towards Cisplatin. Molecular docking study identified several interface amino acid residues between p-p38 with CSC markers (Klf4 and CD44). p38 inhibited cisplatin resistant HNSCC cells also exhibited increased DNA damage as measured by Comet assay and γ-H2AX foci formation index. There was significant decrease in DNA repair as confirmed by reduced ERRC1 expression. CONCLUSIONS: Our study demonstrated that p38 MAPK inhibition can be a targeted approach to overcome resistance in HNSCC thereby escalating the effectiveness of chemotherapy in HNSCC.

Analyzing structural differences between insulin receptor (IR) and IGF1R for designing small molecule allosteric inhibitors of IGF1R as novel anti-cancer agents.

IR and insulin-like growth factor-1 receptor (IGF-1R) share high degree of sequence and structural similarity that hinders the development of anticancer drugs targeting IGF1R, which is dysregulated in many cancers. Although IR and IGF1R mediate their activities through similar signalling pathways, yet they show different physiological effects. The exact molecular mechanism(s) how IR and IGF1R exert their distinct functions remain largely unknown. Here, we performed in silico analysis and generated GFP-fusion proteins of wild type IR and its K1079R mutant to analyze their subcellular localization, cytoplasmic and nuclear activities in comparison to IGF1R and its K1055R mutant. We showed that, like K1055R mutation in IGF1R, K1079R mutation does not impede the subcellular localization and nuclear activities of IR. Although K1079R mutation significantly decreases the kinase activity of IR but not as much as K1055R mutation, which was seen to drastically reduce the kinase activity of IGF1R. Moreover, K1079 residue in IR is seen to be sitting in a pocket which is different than the allosteric inhibitor binding pocket present in its homologue (IGF1R). This is for the first time such a study has been conducted to identify structural differences between these receptors that could be exploited for designing small molecule allosteric inhibitor(s) of IGF1R as novel anti-cancer drugs.

Design of an inhibitor of Helicobacter pylori cholesteryl-α-glucoside transferase critical for bacterial colonization.

BACKGROUND: Fifty percent of the world's population surves as a host for Helicobacter pylori, gastric cancer causing bacteria, that colonizes the gastric region of digestive tract. It has a remarkable capacity to infect the host stomach for the entire lifetime despite an activated host immune response. METHODS: In this study, we have performed the virtual screening analysis of protein-inhibitor binding between the glycosyl transferase enzymes of Helicobacter pylori (CapJ or HP0421) and a corresponding library of inhibitors in the known substrate-binding pockets. We have docked our library of ligands consisting of cholesterol backbone with CapJ protein and identified several ligands' interacting amino acid residues present in active site pocket(s) of the protein. RESULTS: In most of the cases, the ligands showed an interaction with the residues of the same pocket of the enzyme. Top three (03) hits were filtered out from the whole data set, which might act as potent inhibitors of the enzyme-substrate reaction. CONCLUSIONS: This study describes a new possibility by which colonization of H. pylori can be limited. The reported evidence suggests that comprehensive knowledge and wet laboratory validation of these inhibitors are needed in order to develop them as lead molecules.

Phenanthridine derivatives as promising new anticancer agents: synthesis, biological evaluation and binding studies.

Aim: Phenanthridines are an essential class of nitrogenous heterocycles with extensive applications in medicinal chemistry. The development of efficient and eco-friendly methods for the preparation of chirally pure dihydropyrrolo[1,2-f]phenanthridines (5a-h), and their in vitro evaluation and modeling studies as potential anticancer, antioxidant and DNA cleavage agents is reported. Methodology & results: Compounds 5a-h were prepared through a facile one-pot synthesis and characterized by infrared, high resolution mass spectrometry, 1H and 13C nuclear magnetic resonance. The molecules were subjected to virtual screening and docking analysis against selected human molecular targets. Compound 5g displayed good binding properties as well as significant anticancer and DNA cleavage activity. Conclusion: Compound 5g has been identified as a potential lead candidate for further testing against additional cancer cell lines and animal models in future.

Role of telomeric RAP1 in radiation sensitivity modulation and its interaction with CSC marker KLF4 in colorectal cancer.

Aims: Radiotherapy is predominantly used as one of the treatment modalities to treat local tumor in colorectal cancer (CRC). Hindrance in disease treatment can be attributed to radio-tolerance of cancer stem cells (CSCs) subsistence in the tumor. Understanding the radio-resistant property of CSCs might help in the accomplishment of targeted radiotherapy treatment and increased disease-free survival. Telomeric RAP1 contributes in modulation of various transcription factors leading to aberrant cell proliferation and tumor cell migration. Therefore, we investigated the role of RAP1 in maintaining resistance phenotype and acquired stemness in radio-resistant cells.Main methods: Characterization of HCT116 derived radio-resistant cell (HCT116RR) was performed by cell survival and DNA damage profiling. RAP1 silenced cells were investigated for DNA damage and expression of CSC markers through western blotting and Real-time PCR post-irradiation. Molecular docking and co-immunoprecipitation study were performed to investigate RAP1 and KLF4 interaction followed by RAP1 protein status profiling in CRC patient.Key findings: We established radio-resistant cells, which showed tolerance to radiotherapy and elevated expression of CSC markers along with RAP1. RAP1 silencing showed enhanced DNA damage and reduced expression of CSC markers post-irradiation. We observed strong physical interaction between RAP1 and KLF4 protein. Furthermore, higher RAP1 expression was observed in the tumor of CRC patients. Dataset analysis also revealed that high expression of RAP1 expression is associated with poor prognosis.Significance: We conclude that higher expression of RAP1 implicates its possible role in promoting radio-resistance in CRC cells by modulating DNA damage and CSC phenotype.

Inhibition of CD44 sensitizes cisplatin-resistance and affects Wnt/ß-catenin signaling in HNSCC cells.

CD44 is one of the key cancer stem-like cell (CSC) marker and may have a potential role in tumorigenesis. In this study, we investigated the role of CD44 in prognosis of HNSCC patients, its possible crosstalk with Wnt/ß-catenin signaling and modulating cisplatin resistance. We observed increased expression of CD44 in the cut margin of recurrent HNSCC patients were associated with poor prognosis. We observed that inhibition of CD44 by using 1,2,3,4 tetrahydroisoquinoline (THIQ) modulates the expression of Wnt/ ß-catenin signaling proteins and further silencing of ß-catenin also decreases the expression of CD44. This led us to investigate the possible protein-protein interaction between CD44 and ß-catenin. Co-immunoprecipitation study illustrated possible interaction between CD44 and ß-catenin which was further confirmed by molecular docking and molecular dynamic (MD) simulation studies. Molecular docking study revealed that one interface amino acid residue Glu642 of ß -catenin interacts with Lys92 of CD44 which was also present for 20% of simulation time. Furthermore, we observed that inhibition of CD44 chemosensitizes cisplatin-resistant HNSCC cells towards cisplatin. In conclusion, this study investigated the possible role of CD44 along with Wnt/ ß-catenin signaling and their possible therapeutic role to abrogate cisplatin resistance.

Attenuation of neuroblastoma cell growth by nisin is mediated by modulation of phase behavior and enhanced cell membrane fluidity.

Antimicrobial peptides have been attracting significant attention as potential anti-cancer therapeutic agents in recent times. Yet most antimicrobial peptides seem to possess cytotoxic effects on non-cancerous cells. Nisin, an antimicrobial peptide and FDA approved food preservative, has recently been found to induce selective apoptotic cell death and reduced cell proliferation in different cancer cell lines. However, the mechanism of nisin interaction with cancer cell membranes remains unexplored. Using potentiometric dye-based fluorescence and monolayer surface pressure-area isotherms we find that nisin interaction enhances the fluidity and reduces the dipole potential of a neuroblastoma cell membrane model. The quantified compressibility modulus suggests that the changes in fluidity are predominantly driven by the nisin interaction with the non-raft like regions. However, the measured positive Gibbs free energy of mixing and enthalpy hints that nisin, owing to its unfavorable mixing with cholesterol, might significantly disrupt the raft-like domains.

Biodegradation of di­n­butyl phthalate by psychrotolerant Sphingobium yanoikuyae strain P4 and protein structural analysis of carboxylesterase involved in the pathway.

A priority pollutant Phthalate Esters (PAEs) are widely used as plasticizers and are responsible mainly for carcinogenicity and endocrine disruption in human. For the bioremediation of PAEs, a psychrotolerant Sphingobium yanoikuyae strain P4, capable of utilizing many phthalates di­methyl phthalate (DMP), di­ethyl phthalate (DEP), di­n­butyl phthalate (DBP), di­isobutyl phthalate (DIBP), butyl benzyl phthalate (BBP), and few Polycyclic Aromatic Hydrocarbons as the sole source of carbon and energy was isolated from Palampur, Kangra, Himachal Pradesh, India. 100% utilization of DBP (1 g L-1) by the strain was observed within 24 h of incubation at 28 °C. Interestingly the strain also degraded DBP completely at 20 °C and 15 °C within 36 h and 60 h, respectively. Esterase involved in DBP degradation was found to be inducible in nature and intracellular. Comparative sequence analysis of carboxylesterase enzyme sequences revealed conserved motifs: G-X-S-X-G and -HGG- which were the characteristic peptide motifs reported in different esterases. Structural analysis showed that the enzyme belongs to serine hydrolase superfamily, which has an α/ß hydrolase fold. Interaction and binding of DBP to a catalytic Ser184 residue in the esterase enzyme were also analysed. In conclusion, carboxylesterase possess the required active site which may be involved in the catabolism of DBP.

The role of p38 MAPK pathway in p53 compromised state and telomere mediated DNA damage response.

There is an intricate balance of DNA damage response and repair which determines the homeostasis of human genome function. p53 protein is widely known for its role in cell cycle regulation and tumor suppressor activity. In case of several cancers where function of p53 gene gets compromised either by mutation or partial inactivation, the role of p53 in response to DNA damage needs to be supplemented by another molecule or pathway. Due to sedentary lifestyle and exposure to genotoxic agents, genome is predisposed to chronic stress, which ultimately leads to unrepaired or background DNA damage. p38 MAPK signaling pathway is strongly activated in response to various environmental and cellular stresses. DNA damage response and the repair options have crucial links with chromosomal integrity. Telomere that regulates integrity of genome is protected by a six member shielding unit called shelterin complex which communicates with other pathways for functionality of telomeres. There are evidences that p38 gets activated through ATM in response to DNA damage. Dysfunctional telomere leads to activation of ATM which subsequently activates p38 suggesting a crosstalk between p38, ATM and shelterin complex. This review focuses on activation of p38 in response to genotoxic stress induced DNA damage in p53 mutated or compromised state and its possible cross talk with telomere shelterin proteins. Thus p38 may act as an important target to treat various diseases and in majority of cancers in p53 mutated state.