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Macrophages are the key effector cells of innate immunity which show two polarized states: M1, classically activated and M2, alternatively activated. Tumor-associated macrophages (TAMs) which usually show M2 polarization, are immunosuppressive cells that enhance tumor metastasis and invasion. Also, enrichment of TAMs is known to be closely associated with poor prognosis of cancer patients. Therefore, TAMs are considered to be promising targets for immunotherapy. Importantly, tumor-derived exosomes emerged as a crucial player in immune regulation which can remodel the tumor microenvironment towards immunosuppressive state. Of note, few studies have shown that exosomes could induce polarization of macrophages towards M2 type in tumor condition, while others showed activation of M1 or mixed phenotype. Considering the role of TAMs in cancer, there is an urgent need to decipher the exosome-mediated cross-talk between tumor cells and macrophages.For this, we used murine model of Dalton’s lymphoma (DL), wherein, firstly, we evaluated increased exosome burden by assessing exosome level in serum as well as in various tissues of tumor-bearing host. Next, proteomic profiling of lymphoma-derived exosomes was done which revealed the presence of immunomodulatory proteins. Of note, these proteins were known to alter the macrophage polarization. In order to assess the effect of these exosomes on macrophages, we performed in vitro study using RAW264.7 cells. In vitro study revealed that frequent uptake of exosomes mediated a morphological change in macrophages which reduced their phagocytic activity. In parallel, exosomes increased reactive oxygen species (ROS) level and inhibited LPS-induced nitric oxide (NO) level in macrophages. Also, exosomes upregulated the expression of arginase-1 (an M2 marker) in macrophages but decreased the LPS-induced nitric oxide synthase 2 (NOS2) (an M1 marker) expression. Moreover, we observed a pro-tumoral cytokine profile in macrophages incubated with exosomes. Our study suggests that exosome load increases in lymphoma-bearing hosts systemically. Importantly, lymphoma-derived exosomes mediate the activation of macrophages towards pro-tumoral M2 type. Our results give an insight into the exosome-mediated tumor and immune cell cross-talk which could serve as an important prospect for targeting in cancer immunotherapy.

Cancer is known to have systemic impact by targeting various organs that ultimately compromises the overall physiology of the host. Several reports have demonstrated the role of neutrophils in cancer wherein the focus has been drawn on the elevated neutrophil count in blood or at tumor loci. However, their role in mediating systemic effects during cancer progression has not been deciphered so far. Therefore, it is worthwhile to explore whether and how neutrophils contribute to systemic deterioration in cancer. To discern their systemic role, we evaluated neutrophil count and function at different stages of tumor growth in Dalton's Lymphoma mice model. Notably, our results displayed a gradual increase in Ly6G

Apoptosis, a major hallmark of cancer cells, regulates cellular fate and homeostasis. BCL-2 (B-cell CLL/Lymphoma 2) protein family is popularly known to mediate the intrinsic mode of apoptosis, of which MCL-1 is a crucial member. Myeloid cell leukemia 1 (MCL-1) is an anti-apoptotic oncoprotein and one of the most investigated members of the BCL-2 family. It is commonly known to be genetically altered, aberrantly overexpressed, and primarily associated with drug resistance in various human cancers. Recent advancements in the development of selective MCL-1 inhibitors and evaluating their effectiveness in cancer treatment establish its popularity as a molecular target. The overall aim is the selective induction of apoptosis in cancer cells by using a single or combination of BCL-2 family inhibitors. Delineating the precise molecular mechanisms associated with MCL-1-mediated cancer progression will certainly improve the efficacy of clinical interventions aimed at MCL-1 and hence patient survival. This review is structured to highlight the structural characteristics of MCL-1, its specific interactions with NOXA, MCL-1-regulatory microRNAs, and at the same time focus on the emerging therapeutic strategies targeting our protein of interest (MCL-1), alone or in combination with other treatments.

Cervical cancer is one of the leading causes of women's mortality in developing countries. The prevalence of cervical cancer is higher in developing countries like India and continents like Africa. Hyper-methylation of tumor suppressor genes through human papillomavirus (HPV) infection is known to be one of the major causes of cervical cancer. The promoter hypermethylation of the cell adhesion molecule 1 (CADM1) and suppressor of cytokine signalling (SOCS1) genes due to DNMT1 overexpression leads to their epigenetic silencing followed by gene repression causing cervical cancer. In silico study on the inhibition effect of capsaicin on DNMT1 was simulated by different servers. The binding energy was observed to be -7.8 kcal/mol. In vitro studies on the effect of capsaicin on aberrant methylation of CADM1 and SOCS1 were performed on the adenocarcinoma cervical cancer cell line, HeLa. The IC

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the pandemic in the year 2020, leading to disruption of the healthcare system with a great impact on socio-economy worldwide. Owing to this, an accelerated development of safe and efficient vaccines is required to fight against this virus. In this line, various vaccine development platforms have been exploited globally in order to manage the exponentially increasing rate of infection and mortality. Some vaccines in clinical phase trials have entered into emergency use authorization by few countries while others are in a preclinical stage. The present review summarizes the various platforms of vaccine development and also gives an insight into the vaccination programme initiated in India.

Neutrophils are the key cells of our innate immune system with a primary role in host defense. They rapidly arrive at the site of infection and display a range of effector functions including phagocytosis, degranulation, and NETosis to eliminate the invading pathogens. However, in recent years, studies focusing on neutrophil biology have revealed the highly adaptable nature and versatile functions of these cells which extend beyond host defense. Neutrophils are now referred to as powerful mediators of chronic inflammation. In several chronic inflammatory diseases, their untoward actions, such as immense infiltration, hyper-activation, dysregulation of effector functions, and extended survival, eventually contribute to disease pathogenesis. Therefore, a better understanding of neutrophils and their effector functions in prevalent chronic diseases will not only shed light on their role in disease pathogenesis but will also reveal them as novel therapeutic targets.We performed a computer-based online search using the databases, PubMed.gov and Clinical trials.gov for published research and review articles.This review provides an assessment of neutrophils and their crucial involvement in various chronic inflammatory disorders ranging from respiratory, neurodegenerative, autoimmune, and cardiovascular diseases. In addition, we also discuss the therapeutic approach for targeting neutrophils in disease settings that will pave the way forward for future research.

Development of novel medical countermeasures (MCMs) against acute radiation syndrome (ARS) and the associated lethality involves protection from and/or mitigation of radiation-induced hematopoietic injury, a critical clinical component of ARS. We earlier identified the molecule 7,8-diacetoxy-4-methylthiocoumarin (DAMTC) as a potent mitigator of hematopoietic injury and mortality in C57BL/6 mice when administered 24 h following total body irradiation (TBI). In the present study, we investigated mechanisms and functional relevance of immune modulation by DAMTC during the mitigation of hematopoietic injury.C57BL/6 mice were subjected to TBI doses of 3 and 7.6Gy; administered DAMTC intra-peritoneally 24 h post TBI. Isolation, characterization, intra-cellular cytokine analysis of myeloid cells from bone marrow and spleen accompanied by flow cytometric determination and characterization of B-lymphocytes, serum isolation from peripheral blood and cytokine analysis.Results showed that DAMTC induced stimulation of pro-inflammatory myeloid subsets in the bone marrow and spleen of TBI mice. Further, it promoted a favorable transition from Th2 to Th1 immunity, triggered humoral immunity, and activated an intricately balanced inflammatory response that appear to contribute to immune-modulation.Thus, the present study shows that immune-modulation maybe one of the contributing factors for the mitigation of hematopoietic injury by DAMTC and underscores its efficacy as a potent mitigator of hematopoietic injury that merits to be developed further as a novel MCM to combat H-ARS.

Background: LATS1 (Large Tumor Suppressor, isoform 1) is a gene that forms a complex with the cyclin-dependent kinase, CDK1, and regulates cell cycle progression. Genetic modifications lead to a loss in the activity of LATS1 gene. OSCC is the most commonly emerging cancer caused by genetic as well as epigenetic changes. Epigenetics changes vary from one population to another because these are influenced by dietary factors and environmental factors. Tobacco chewing and smoking has been reported as major risk factors in OSCC. No report was found in the previous literature showing promoter hypermethylation of LATS1 gene. Methods: A total of 50 OSCC patients and 20 normal individuals were recruited in this study. Blood samples (50) from OSCC patients and blood samples (20) from healthy individuals as controls were used in the present study. Isolation of genomic DNA was carried out from blood using the standard phenol-chloroform extraction. Further Isolated DNA was modified with sodium bisulfite using the agarose bead method and finally, the methylation studies of LATS1 gene were carried out using Methylation-Specific PCR (MSP-PCR). Results: 19 out of 50 patients (38.0%) were found to be methylated for LATS1 gene.; a statistically significant result was obtained (p -value= < 0.05) with an odds ratio of 0.37 in cases compared to controls. The status of methylation of LATS1 genes was also found to be statistically significantly associated with smokers and tobacco chewers (p-value = < 0.05). The methylation of LATS1 gene showed a significant risk of developing OSCC in patients. Conclusion: These results suggest that the LATS1 gene may provide a better alternative as a diagnostic biomarker. This is the first report on the promoter hypermethylation of LATS1 gene in OSCC patients among the North Indian population.

Several studies have confirmed the involvement of cancer stem cells (CSC) in tumour progression, metastasis, drug resistance and cancer relapse. SATB2 (special AT‐rich binding protein‐2) acts as a transcriptional co‐factor and modulates chromatin architecture to regulate gene expression. The purpose of this review was to discuss the pathophysiological roles of SATB2 and assess whether it could be used as a therapeutic target for cancer. SATB2 modulated the expression of those genes which regulated pluripotency and self‐renewal. Overexpression of SATB2 gene in normal epithelial cells was shown to induce transformation, as a result transformed cells gained CSC’s characteristics by expressing stem cell markers and pluripotency maintaining factors, suggesting its role as an oncogene. In addition, SATB2 induced epithelial‐mesenchymal transition (EMT) and metastasis. Interestingly, the expression of SATB2 was positively correlated with the activation of β‐catenin/TCF‐LEF pathway. Furthermore, SATB2 silencing inhibited EMT and their positive regulators, and tumour growth, and suppressed the expression of stem cell markers, pluripotency maintaining factors, cell cycle and cell survival genes, and TCF/LEF targets. Based on the cancer genome atlas (TCGA) expression data and published papers, SATB2 alone or in combination with other proteins could be used a diagnostic biomarker for cancer. Although there is no pharmacological inhibitor of SATB2, studies using genetic approaches suggest that SATB2 could be a potential target for cancer treatment and prevention.

Despite improved screening and surveillance guidelines, significant race/ethnicity‐specific disparities in hepatocellular carcinoma (HCC) continue to exist and disproportionately affect minority and disadvantaged populations. This trend indicates that social determinants, genetic, and environmental factors are driving the epidemic at the population level. Race and geography had independent associations with risk of mortality among patients with HCC. The present review discusses the risk factors and issues related to disparities in HCC. The underlying etiologies for these disparities are complex and multifactorial. Some of the risk factors for developing HCC include hepatitis B (HBV) and hepatitis C (HCV) viral infection, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, smoking and alcohol consumption. In addition, population genetics; socioeconomic and health care access; treatment and prevention differences; and genetic, behavioral, and biological influences can contribute to HCC. Acculturation of ethnic minorities, insurance status, and access to health care may further contribute to the observed disparities in HCC. By increasing awareness, better modalities for screening and surveillance, improving access to health care, and adapting targeted preventive and therapeutic interventions, disparities in HCC outcomes can be reduced or eliminated., Population genetics, socioeconomic and health care access, treatment and prevention differences, dietary composition, and genetic, behavioral and biological influences can contribute to hepatocellular carcinoma (HCC). Acculturation of ethnic minorities, insurance status and access to healthcare may further contribute to the observed disparities in HCC. By increasing awareness and better modalities for screening and surveillance, targeted preventive and therapeutic interventions for reducing disparities can be successfully improved.

The incidence of obesity and type 2 diabetes (T2DM) in the Western world has increased dramatically during the recent decades. According to the American Cancer Society, pancreatic cancer (PC) is the fourth leading cause of cancer‐related death in the United States. The relationship among obesity, T2DM and PC is complex. Due to increase in obesity, diabetes, alcohol consumption and sedentary lifestyle, the mortality due to PC is expected to rise significantly by year 2040. The underlying mechanisms by which diabetes and obesity contribute to pancreatic tumorigenesis are not well understood. Furthermore, metabolism and microenvironment within the pancreas can also modulate pancreatic carcinogenesis. The risk of PC on a population level may be reduced by modifiable lifestyle risk factors. In this review, the interactions of diabetes and obesity to PC development were summarized, and novel strategies for the prevention and treatment of diabetes and PC were discussed.

Total-body exposure to ionizing radiation (TBI) results in life-threatening acute radiation syndrome (ARS), which encompasses hematopoietic and gastrointestinal (GI) injuries and results in dose-dependent morbidity and mortality. Management of ARS warrants the deployment of effective medical countermeasure agents (MCM) that protect against and/or mitigate lethal radiation injury. The polyphenolic acetate (PA) 7,8-diacetoxy-4-methylthiocoumarin (DAMTC) has been identified as a potential MCM against ARS by virtue of it mitigating the lethal effects of TBI in C57BL/6 mice. Herein, we describe current evidence, including mechanistic aspects, for the use of PAs as MCMs against ARS and provide perspectives for their further development as approved drugs for the mitigation of ARS.

Cancer has emerged as a systemic disease which targets various organs thus challenging the overall physiology of the host. Recently, we have shown that hyperactive neutrophils infiltrate various organs of tumor bearing host and contribute to gradual systemic deterioration. Therefore, taming neutrophils via potent immunomodulators could be an appropriate therapeutic approach in regulating systemic damage. Tinospora cordifolia (TC), an Ayurvedic panacea, is known for its immense medicinal values in traditional literature and recent reports have also documented its immunomodulatory potential. However, whether TC can regulate neutrophils to exert its therapeutic effectiveness has not been deciphered so far.For the in vivo study, we utilized murine model of Dalton's Lymphoma (DL). T. cordifolia extract (TCE) treatment was scheduled at early, mid and advanced stages of tumor growth at a dose of 400 mg/kg b.w for 30 consecutive days. Effect of TCE on neutrophil infiltration was examined by immunostaining. Neutrophil elastase (NE) level in serum, ascitic fluid and various tissues was monitored by ELISA. Further, qPCR was performed to assess transcripts levels of NE, myeloperoxidase (MPO), metalloproteinases (MMP-8, MMP-9) and cathepsin G (CSTG) in various tissues. ROS level in tissue was assessed by DHE staining and organ function was assessed by histology post TCE treatment.Our findings showed that TC treatment significantly reduced neutrophil count in peripheral blood and their infiltration in vital organs of tumor-bearing host. Further, it ameliorated neutrophil hyperactivation by down regulating the expression of its key cargoes including NE, MPO, MMP-8, MMP-9 and CSTG at early and mid stage of tumor growth. In addition, TC treatment prevented histopathological alterations and restored the normal serum enzyme levels at different stages of tumor growth. Importantly, TC treatment also showed significant reduction in tumor burden which was accompanied by a remarkable increase in survival of the tumor-bearing mice.We conclude that T. cordifolia could limit systemic damage via regulating neutrophil infiltration and hyperactivation which can further lead to cancer control at both prophylactic and therapeutic level.

Cancer has emerged as a systemic disease which targets various organs thus challenging the overall physiology of the host. Recently, we have shown that hyperactive neutrophils infiltrate various organs of tumor bearing host and contribute significantly to gradual systemic deterioration. Therefore, taming neutrophils via potent immunomodulators could be an appropriate therapeutic approach in regulating systemic damage. Tinospora cordifolia (TC), an Ayurvedic panacea, is known for its immense medicinal values in traditional literature and recent reports have also documented its strong immunomodulatory potential. However, whether TC can regulate neutrophils to exert its therapeutic effectiveness has not been deciphered so far. To discern this, we utilized murine model of Dalton’s Lymphoma (DL) wherein, we have earlier reported heightened infiltration of neutrophils and their hyperactivation. Our findings showed that TC treatment significantly reduced neutrophil count in peripheral blood and their infiltration in vital organs of tumor bearing host. Further, it ameliorated neutrophil hyperactivation by down regulating the expression of its key cargoes including neutrophil elastase (NE), myeloperoxidase (MPO), MMP-8, MMP-9 and cathepsin G (CSTG) at early and mid stage of tumor growth. In addition, TC treatment prevented histopathological alterations and restored the normal serum enzyme levels at different stages of tumor growth. Importantly, TC treatment also showed significant reduction in tumor burden which was accompanied by a remarkable increase in survival of the tumor-bearing mice. We conclude that Tinospora cordifolia could limit systemic damage via regulating neutrophil infiltration and hyperactivation which can further lead to cancer control at both prophylactic and therapeutic level.

Abstract: Exosomes are nanocarriers that mediate intercellular communication crucial for normal physiological functions. However, exponentially emerging reports have correlated their dysregulated release with various pathologies, including cancer. In cancer, from stromal remodeling to metastasis, where tumor cells bypass the immune surveillance and show drug resistivity, it has been established to be mediated via tumor-derived exosomes. Owing to their role in cancer pathogenicity, exosomebased strategies offer enormous potential in treatment regimens. These strategies include the use of exosomes as a drug carrier or as an immunotherapeutic agent, which requires advanced nanotechnologies for exosome isolation and characterization. In contrast, pharmacological inhibition of exosome machinery surpasses the requisites of nanotechnology and thus emerges as an essential prospect in cancer therapeutics. In this line, researchers are currently trying to dissect the molecular pathways to reveal the involvement of key regulatory proteins that facilitate the release of tumor-derived exosomes. Subsequently, screening of various molecules in targeting these proteins, with eventual abatement of exosome-induced cancer pathogenicity, is being done. However, their clinical translation requires more extensive studies. Here, we comprehensively review the molecular mechanisms regulating exosome release in cancer. Moreover, we provide insight into the key findings that highlight the effect of various drugs as exosome blockers, which will add to the route of drug development in cancer management.

Huntington’s disease (HD) is a late-onset; progressive, dominantly inherited neurological disorder marked by an abnormal expansion of polyglutamine (poly Q) repeats in Huntingtin (HTT) protein. The pathological effects of mutant Huntingtin (mHTT) are not restricted to the nervous system but systemic abnormalities including immune dysregulation have been evidenced in clinical and experimental settings of HD. Indeed, mutant huntingtin (mHTT) is ubiquitously expressed and could induce cellular toxicity by directly acting on immune cells. However, it is still unclear if selective expression ofmHTT exon1 in neurons could induce immune responses and hemocyte function. In the present study, we intended to monitor perturbations in the hemocytes population and their physiological functions in Drosophila, caused by pan-neuronal expression of mHTT protein. We found that pan-neuronal expression of mHtt significantly alters crystal cells and plasmatocyte count in larvae and adults with disease progression. Interestingly, plasmatocytes isolated from diseased conditions exhibit a gradual decline in phagocytic activity ex vivo at progressive stages of the disease as compared to age-matched control groups. We also observed an increased production of reactive oxygen species (ROS) in plasmatocytes at advanced stages of the disease. In addition, diseased flies displayed elevated reactive oxygen species (ROS) in circulating plasmatocytes at the larval stage and in sessile plasmatocytes of hematopoietic pockets at of disease. All the parameters were monitored progressively, targeting the circulation at larvae stage and hematopoietic pockets in adults at different disease stages, and many alterations were documented in the early stage itself. These findings strongly implicate that neuronal expression of mHtt alone is sufficient to induce non-cell-autonomous immune dysregulation in vivo. Based on these findings, we propose that further insight into the mechanisms through which neuronal expression of mHtt might be inflicting the innate immune responses would facilitate therapeutic inventions aimed at amelioration of HD pathology and improving the quality of life of the patients.

Various studies have addressed the role of neutrophils in cancer wherein the focus has been drawn on the elevated neutrophil count in blood or at tumor loci. However, cancer has a systemic impact which targets various organs thus challenging the overall physiology of the host. So, it is worthwhile to explore whether and how neutrophils contribute to systemic deterioration in cancer. To discern the systemic role of neutrophils, we monitored their number and function at different stages of tumor growth in Dalton’s lymphoma mice model. Notably, we observed a gradual increase in neutrophil count in blood and their infiltration in vital organs of tumor bearing mice. In parallel, we observed damaged histoarchitecture with significant alterations in biochemical parameters that aggravated with tumor progression. We next examined systemic impact of neutrophil by assessing neutrophil elastase, myeloperoxidase, and matrix metalloproteinases (MMP-8 and MMP-9) wherein we found their upregulated expression and activity in tumor condition. Taken together, our results demonstrate high infiltration and hyperactivation of neutrophils which possibly account for gradual systemic deterioration during cancer progression. Our findings thus implicate neutrophils as a potential therapeutic target that may help to reduce the overall fatality rate of cancer.

br /Large Tumor Suppressor (LATS2) gene are Tumor Suppressor gene, linked with epigenetic modifications. LATS2 promoter hypermethylation is an important epigenetic silencing mechanism leading to cancer. Cancer is the most common, vicious and dangerously increasing diseases of the world today, associated with high morbidity and mortality. Oral cancers (OC) are the blazing universal dilemma and is the sixth most frequent cancer observed in Indian population. Tobacco consumption is the main cause of the increase in OSCC. The association between LATS2 in the pathogenesis of cancers propose that their combination might be studied as a possible molecular marker for particular subgroups of patients. Therefore, the present study tried to investigate whether LATS2 promoter methylation was associated with oral squamous cell carcinoma (OSCC) in North Indian subjects. DNA methylation quantitative studies of LATS2 Tumor Suppressor genes were performed by methylation-specific polymerase chain reaction (MSP). 38 out of 70 patients (55 %) were found to be methylated for LATS2 gene, a statistically significant result was obtained (p-value0.005) for LATS2 genes. The results suggest that epigenetic changes may be related to the down-regulation of LATS2 expression. It can be concluded that LATS2 gene plays a significant role in the diagnosis of cancer and provide a better alternative as a diagnostic biomarker. Our data infer that a low LATS2 expression due to methylation may contribute to the cancer progression and could be useful for the diagnosis of OSCC. Therefore, investigation of promoter methylation in such genes may provide a biomarker which may prove to be useful in early detection of Oral Cancer.br /Keywords: Oral squamous cell carcinoma (OSCC), Epigenetic changes, LATS2 gene, Promoter Hypermethylation, Methylation-Specific PCR (MSP), Biomarkersbr /Abbreviations: OSCC- Oral Squamous Cell Carcinoma; DNA- Deoxyribonucleic acid; LATS-Large Tumor Suppressor (gene); MSP-Methylation-Specific Polymerase Chain Reaction.

The current investigation was intended to elucidate the molecular mechanism of α‐Mangostin in the regulation of pancreatic cancer stem cell (CSC) characteristics. Here, we demonstrate that α‐Mangostin inhibited cell proliferation in pancreatic CSCs and cancer cell lines while it showed no effect on human pancreatic normal ductal epithelial cells. Also, α‐Mangostin inhibited colony formation and induced apoptosis in these cells. Further, α‐Mangostin inhibited the self‐renewal capacity of CSCs isolated from human primary tumours and KrasG12D mice. Furthermore, α‐Mangostin inhibited the invasive and metastatic ability of pancreatic CSCs by suppressing the epithelial‐to‐mesenchymal transition (EMT) via up‐regulation of E‐cadherin and down‐regulation of mesenchymal phenotype by inhibiting N‐cadherin, Snail and Slug expression. Interestingly, the pluripotency maintaining factors and CSC markers were inhibited by α‐Mangostin thus suggesting that α‐Mangostin can target CSCs to inhibit pancreatic cancer effectively. Gli signalling plays a crucial role in the self‐renewal and pluripotency of CSCs. α‐Mangostin inhibited the Gli transcription and the expression of Gli target genes (Nanog, Oct4, c‐Myc, Sox‐2 and KLF4) in CSCs. Using ChIP assay, we demonstrated that Nanog could directly bind to promoters of Cdk2, Cdk6, FGF4, c‐Myc and α‐Mangostin inhibited Nanog binding to these promoters. Conversely, the inhibitory effects of the α‐Mangostin on CSC proliferation and Gli or Nanog transcription and their targets were abrogated by either enforced activation of sonic hedgehog (Shh) or by the overexpression of Nanog. Taken together, our studies suggest that α‐Mangostin may act as Gli inhibitor and establishes the pre‐clinical significance of α‐Mangostin for the prevention and treatment of pancreatic cancer.

Objectives Oxidative stress and antioxidants are involved in all aspects of cervical cancer. The present study evaluated serum levels of oxidative stress and antioxidant biomarkers in cervical cancer patients and healthy controls. Moreover, the effect of Concurrent chemoradiotherapy (CCRT) on these biomarkers and their association with treatment outcome was investigated. Design This study included ninety-seven cervical cancer patients and thirty controls. Three oxidative stress parameters (8-hydroxy-2-deoxyguanosine, Protein Carbonyl, and Malondialdehyde) and four antioxidant parameters (Superoxide Dismutase, Catalase, Glutathione Peroxidase, and Total Antioxidant Status) were measured. The analysis was conducted using repeated measures ANOVA for comparing among the phases (before, during, and follow-up) of treatment. The control group was compared using the Dunnet test. Logistic regression analysis was also conducted between oxidative stress and antioxidant parameters to study their association. Results Significant rises in oxidative damage markers were observed in cervical cancer patients of all stages, compared to controls. There was a further increase in oxidative stress markers during CCRT among complete responders. However, among non-responders, the oxidative stress biomarkers like Protein Carbonyl and Malondialdehyde were unaltered during CCRT. Simultaneously, there was a significant decrease in antioxidant parameters in cervical cancer patients of all stages compared to controls. During CCRT, antioxidant levels continuously depleted among complete responders. Nevertheless, in non-responders, antioxidant parameters like Superoxide Dismutase and Total Antioxidant Status were consistent. The oxidative stress markers and antioxidant parameters normalized among complete responders at six months follow up. While in non-responders, the normalization of these parameters was not observed. Conclusion Our results indicate that increased oxidative stress and diminished antioxidants among patients were associated with carcinoma cervix. Induced oxidative stress and decreased antioxidant parameters during CCRT among the complete responders show the treatment's efficacy. Oxidant-antioxidant profile merits investigation as markers of diagnosis, treatment response, survival, and recurrence in extensive prospective studies.

Blood serum samples from 63 cervical cancer patients and 30 controls were collected at three different phases of the treatment (i.e. before, during, and at follow up). The spectra of serum samples from control as well as patients were classified into different groups using principal component analysis (PCA) and linear discriminant analysis (LDA) based on different phases of treatment using R software. The spectra of blood serum samples have shown the distinct changes and differences compared with each other in the profile of various biochemical parameters. The sensitivity (92.5%) and specificity (85%) were observed maximum between control and cervical cancer patients (before treatment). Between different phases of treatment, the sensitivity and specificity were less but, all accuracies of detection and classification reached above 50%. This method can be considered as a screening method for detection and treatment monitoring.

Neurodegeneration, the slow and progressive loss of neurons in the central nervous system has become a major challenge to public health worldwide particularly with elderly people. Until recently, the brain and immune system were studied exclusively, independent of each other representing two distinct systems. Recent studies ensue crosstalk between these two systems to maintain homeostasis. Though the progressive loss of specific neuronal subsets is a hallmark of neurodegenerative disease, emerging evidences indicate that immune response also plays a critical role in disease progression. Due to conservation of mechanisms that govern neural development and innate immune activation in flies and humans, and availability of powerful genetic tools, the fruit fly Drosophila melanogaster is one of the best model organisms to investigate the immune response in neurodegenerative disease. Owing to significant homology between human and Drosophila immune system and recent reports on interplay between immune system and neurodegenerative disease progression, the main focus of the review is to develop a comprehensive understanding of how neuro-immune interactions contribute to neurodegeneration using Drosophila as a model system.

Sirtuins are a family of deacetylases (Class III histone deacetylases) with evolutionarily conserved functions in cellular metabolism and chromatin regulation. Out of the seven human Sirtuins, the function of Sirt2 is the least understood. The purpose of the present study was to investigate the role of Sir2A, a homolog of human Sirt2 in Dictyostelium discoideum (Dd), a lower eukaryote. We created both overexpressing and deletion strains of Ddsir2A to analyse its functions. We observed sir2A mRNA expression throughout development and the transcript was present in the prespore/spore region of multicellular structures developed. They show a preference towards prestalk/stalk pathway when co-developed with wildtype cells during chimera formation. Deletion strain showed a multi-tipped phenotype, decrease in cell proliferation and inhibition of autophagy. In conclusion, our results show low cAMP levels, reduced cell-adhesion, weak cell migration and impaired autophagy to be responsible for the phenotype shown by the null cells. This study provides new insights into the functions of Ddsir2A.

Calreticulin (CRT), initially identified as a ubiquitous calcium-binding protein in the endoplasmic reticulum, has emerged as a multifunctional protein with roles in calcium homeostasis, molecular chaperoning and cell adhesion. Emerging evidence suggests its involvement in tumorigenesis facilitating proliferation, migration, and adhesion. CRT translocated to the cell surface (ecto-CRT) serves as a phagocytic signal for immunogenic cell death (ICD) mediated through dendritic cells (DCs) and cytotoxic T-cell activation thereby making tumors susceptible to immunotherapy-based anti-cancer strategies. CRT is now regarded as one of the most potent danger-associated molecular patterns (DAMPs) with the ecto-CRT triggering restoration of homeostasis by immune stimulation. A recently identified novel transacetylase activity of CRT adds a new dimension to its multi-faceted involvement in cancer by virtue of polyphenolic acetates (PA): CRT transacetylase (CRTase) system which results in hyperacetylation of target proteins, thereby mimicking the effects of Histone deacetylase inhibitors (HDACi). Since protein acetylation is one of the crucial post-translational modifications (PTMs) influencing the epigenetic regulation and signal transduction, CRT can be a potential target for developing anticancer therapeutics and preventive strategies by employing pharmacologically compatible semi-synthetic acetyl donors like polyphenolic acetates and other agents.

Recent techniques available for the detection of cervical cancer (CC) are highly invasive and costly, which makes it a rate-limiting step toward early diagnosis of this fatal disease. Evaluation of circulating cell-free DNA (ccfDNA) through liquid biopsy is a minimally invasive and cost-effective method that may serve as a unique tumor marker for early detection, treatment monitoring, the status of residual disease, and distant tumor metastasis in CC patients.In this study, initially, ccfDNA was measured in serum samples from 11 histopathologically proven cervix carcinoma patients and 8 controls. On successful screening, it was further extended to 2 more patients with a series of serum samples extracted at 3 different phases of the concurrent chemoradiotherapy (i.e., before, during, and after 6 months of follow-up).Agarose gel electrophoresis profile for ccfDNA of CC patients showed that of 11 patients, 4 patients had a comparatively higher tumor burden (ccfDNA) than the other 7 patients. Notably, during concurrent chemoradiotherapy, ccfDNA load disappeared and, after 6 months of follow-up, appeared back due to distant metastasis.Hence, we propose that this method could be an affordable and reliable way to diagnose/screen CC.

Sonic hedgehog pathway is highly activated in pancreatic cancer stem cells (CSC) which play crucial roles in cancer initiation, progression and metastasis. However, the molecular mechanisms by which sanguinarine regulates pancreatic CSC characteristics is not well understood. The objectives of this study were to examine the molecular mechanisms by which sanguinarine regulates pancreatic CSC characteristics. Sanguinarine inhibited cell proliferation and colony formation and induced apoptosis through oxidative damage. Sanguinarine inhibited self-renewal capacity of pancreatic CSCs isolated from human and KrasG12D mice. Furthermore, sanguinarine suppressed epithelial-mesenchymal transition (EMT) by up-regulating E-cadherin and inhibiting N-cadherin. Significant decrease in expression level of Snail, Slug and Zeb1 corroborated the suppression of EMT in sanguinarine treated pancreatic CSCS. The ability of sanguinarine to inhibit pluripotency maintaining factors and CSC markers suggest that sanguinarine can be an effective agent for inhibiting pancreatic cancer growth and development by targeting CSCs. Furthermore, sanguinarine inhibited Shh-Gli pathway leading to modulation of Gli target genes in pancreatic CSCs. Chromatin immunoprecipitation assay demonstrated that Nanog directly binds to promoters of Cdk2, Cdk6, FGF4, c-Myc and Oct4, and sanguinarine inhibits the binding of Nanog with these genes, suggesting the direct involvement of Nanog in cell cycle, pluripotency and self-renewal. To further investigate the role of Shh-Gli-Nanog pathway, we regulated Shh signaling either by Shh protein or Nanog overexpression. Enforced activation of Shh or overexpression of Nanog counteracted the inhibitory effects of sanguinarine on pancreatic CSC proliferation, suggesting the actions of sanguinarine are mediated, at least in part, through Shh-Gli-Nanog pathway. Our studies suggest that sanguinarine can be used for the treatment and/or prevention of pancreatic cancer by targeting CSCs.

A chiral electrochemical sensor was developed via an electro-generated molecularly imprinted polymer-based ultrathin film using l -ascorbic acid as a template and its biological proficiency was analyzed. The performance of the chiral selective sensor in serum was evaluated by conducting a comparative study of electrochemical response of l -ascorbic acid imprinted polyaniline ferrocene sulfonic acid pencil graphite electrode in aqueous and serum samples employing cyclic voltammetry (CV), differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS). The sensor shows similar electrochemical response in aqueous and serum solutions of l -ascorbic acid of equal concentrations even at considerably high serum proportion in solutions. This shows its excellent ability to counter multifold interference in extraordinary complex biological medium (serum) and hence validates its worth in clinical applications. Surface morphologies are characterized through scanning electron microscopy of the chiral sensor (before and after de-doping of l -ascorbic acid) and compared with bare and non-imprinted electrode. Electrochemical impedance spectroscopy technique is used for the molecularly imprinted electrodes to quantitatively measure l -ascorbic acid with a detection limit of 1 μM. Finally, the proposed sensor offers excellent prospects in biomedical fields for simple, fast and cost effective chiral quantification of ascorbic acid in serum samples.

Mycobacterium tuberculosis (MTB), an intracellular pathogen, still represents a major global health challenge. A number of mycobacterial macromolecules have been shown to target biological processes within host macrophages; however, the exact mechanism for the majority of these host pathogen interactions is still poorly understood. Moreover, the lipid metabolic pathway is one of the most important physiologic pathways that plays a vital role in the survival and infection of Mycobacterium tuberculosis. In present study, we investigated the effect of rLipQ from Mycobacterium tuberculosis H37Rv on macrophage functions in vitro.Our results demonstrate that rLipQ significantly lowers the expression level of pro-inflammatory cytokines (TNF-αIFN-γ) and augments the level of anti inflammatory cytokines such as IL-4IL-10as compared to LPS stimulated macrophages. An up-regulation of anti-inflammatory and down-regulation of pro-inflammatory cytokines levels in rLipQ pretreated macrophages implies immuno-modulatory functions in TB patients. Interestingly, rLipQ also inhibited the expression of iNOS, TLR-2 and transcription factor NF-kB in LPS stimulated macrophages whereas the expression of TLR-4 remains unchanged. The inhibition in the expression of these signaling molecules has been correlated to the inhibition of NO production in macrophages. Taken together, these studies demonstrate that rLipQ is a novel lipase that is highly immunogenic and may play an important role in the virulence and pathogenesis of M. tuberculosis infection, by altering the balance of cytokines, which might help to assess prognosis and contribute to a better understanding against host-pathogen interactions.

Autophagy is a major catabolic process in eukaryotes that helps to degrade and recycle macromolecules and organelles. Recent findings show inhibition of nutrient or growth-related signaling pathways or anti-aging pathways mediates lifespan extensions via autophagy. In the present communication, we have emphasized on the lower eukaryotic model organism Dictyostelium discoideum to study longevity and compared it to other model organisms, which uses autophagy as a major mechanism for increasing lifespan. We observed that both genetic and pharmacological manipulations on the nutrient-signaling pathway increased autophagy-mediated cell survival.

Radiation-induced intestinal injury (RIII) constitutes a crucial clinical element of acute radiation syndrome with life-threatening implications posing challenges in devising effective medical countermeasures. Herein, we report the potential of 7, 8-diacetoxy-4-methylthiocoumarin (DAMTC) to mitigate RIII following total-body irradiation (TBI) in C57BL/6 mice and underlying mechanisms. Administration of DAMTC 24 hours post TBI facilitated structural reconstitution and restoration of functional absorption linked to alleviation of radiation-induced apoptotic death of intestinal crypt progenitor/stem (ICPS) and villus stromal cells through induction of Bcl-2 family-mediated anti-apoptotic signalling. Reduction in TBI-induced DNA damage accumulation coupled with inhibition of cell cycle arrest through stimulation of anti-p53- and anti-p21-dependent synergistic signalling protected ICPS cells from radiation injury. Enhanced proliferation of crypt stem cells, induction of anti-oxidant defence, subjugation of TBI-induced lipid peroxidation and phenotypic polarization of intestinal macrophages to anti-inflammatory M2 class underlie amelioration of RIII. Stimulation of multiple mitigative signalling processes by DAMTC appeared to be associated with enhanced protein acetylation, an important regulator of cellular responses to radiation damage. Our findings establish the mitigative potential of DAMTC against RIII by hyper-acetylation-mediated epigenetic regulation, which triggers axes of anti-apoptotic and pro-survival pathways, enabling proliferation and maintenance of ICPS cells leading to epithelial regeneration.

Sirtuins are a family of deacetylases (Class III histone deacetylases) with evolutionarily conserved functions in cellular metabolism and chromatin regulation. Out of the seven human Sirtuins, the function of Sirt2 is the least understood. The purpose of the present study was to investigate the role of Sir2A, a homolog of human Sirt2 in Dictyostelium discoideum (Dd), a lower eukaryote. We created both overexpressing and deletion strains of Ddsir2A to analyse its functions. We observed sir2A mRNA expression throughout development and the transcript was present in the prespore/spore region of multicellular structures developed. They show a preference towards prestalk/stalk pathway when co-developed with wildtype cells during chimera formation. Deletion strain showed a multi-tipped phenotype, decrease in cell proliferation and inhibition of autophagy. In conclusion, our results show low cAMP levels, reduced cell-adhesion, weak cell migration and impaired autophagy to be responsible for the phenotype shown by the null cells. This study provides new insights into the functions of Ddsir2A.

Trans‑3,4',5‑trihydroxystilbene (resveratrol) is a naturally occurring polyphenolic phytoalexin with marked anticancer activities, and is mainly found in grapes, berries and peanuts. However, due to a low bioavailability, it has not progressed to clinical practice for cancer treatment. Therefore, the aims of the present study were to examine the anticancer activities of the resveratrol derivative, triacetyl resveratrol (TCRV), in pancreatic cancer cells. Apoptosis was measured by fluorescence‑activated cell sorting and terminal deoxynucleotidyl transferase (TdT)‑mediated dUTP nick‑end labeling assays. Gene expression was measured by reverse transcription‑quantitative polymerase chain reaction. TCRV inhibited colony formation and induced apoptosis through caspase‑3 activation in human pancreatic cancer AsPC‑1 and PANC‑1 cells, whereas it exerted no effect on human pancreatic normal ductal epithelial cells (HPNE). TCRV inhibited epithelial‑mesenchymal transition (EMT) by upregulating the expression of E‑cadherin and suppressing the expression of N‑cadherin and the transcription factors, Snail, Slug and Zeb1. TCRV inhibited Zeb1 3'UTR‑luciferase activity through the upregulation of microRNA (miR)‑200 family members. The inhibitory effects of TCRV on pancreatic cancer cell migration and invasion were counteracted by anti‑miR‑200 family members. The inhibitory effects of TCRV on EMT and the induction of apoptosis were exerted through the suppression of the sonic hedgehog (Shh) pathway, and through the modulation of cyclin D1 and Bcl‑2 expression. The hyperactivation of the Shh pathway by either Shh protein or Gli1 overexpression abrogated the biological effects of TCRV. Taken together, the results of this study demonstrate that TCRV inhibits pancreatic cancer growth and EMT by targeting the Shh pathway and its downstream signaling mediators. TCRV inhibited EMT through the upregulation of miR‑200 family members. Since TCRV effectively inhibited the growth of human pancreatic cancer cells by modulating the Shh pathway, without affecting the growth of HPNE cells, our findings suggest the possible use of TCRV as a promising candidate for the treatment and/or prevention of pancreatic cancer.

Since PI3K/Akt/mTOR and sonic hedgehog (SHH) signaling pathways are highly activated in glioblastoma-initiating cells (GICs), we examined the effects of inhibiting these pathways on GIC characteristics and tumor growth in mice. NVP-LDE-225 (inhibitor of Smoothened) inhibited the expression of Gli1, Gli2, Smoothened, Patched1, and Patched2, and induced the expression of SuFu, whereas NVP-BEZ-235 (dual inhibitor of PI3K and mTOR) inhibited the expression of p-PI3K, p-Akt, p-mTOR, and p-p70S6K. NVP-LDE-225 co-operated with NVP-BEZ-235 in inhibiting the self-renewal capacity of GICs, expression of pluripotency maintaining factors (Nanog, c-Myc, Oct4, and Sox2), Musashi1, cyclin D1, and Bcl-2, and transcription and expression of Gli, and in inducing the expression of cleaved caspase-3, cleaved PARP and Bim. Additionally, NVP-LDE-225 co-operated with NVP-BEZ-235 in inhibiting epithelial-mesenchymal transition. Finally, the combination of NVP-LDE-225 and NVP-BEZ-235 was superior in inhibiting tumor growth, regulating the expression of pluripotency promoting factors, stem cell markers, cell cycle, and cell proliferation, and modulating EMT compared to single agent alone. In conclusion, the combined inhibition of PI3K/Akt/mTOR and SHH pathways was superior to single pathway inhibition in suppressing glioblastoma growth by targeting GICs.

The hallmarks of carcinogenesis are characterized by alterations in the expression of multiple genes that occur via genetic and epigenetic alterations, leading to genome rearrangements and instability. The reversible process of epigenetic regulation, which includes changes in DNA methylation, histone modifications, and alteration in microRNA (miRNA) expression that alter phenotype without any change in the DNA sequence, is recognized as a key mechanism in cancer cell metabolism. Recent advancements in the rapidly evolving field of cancer epigenetics have shown the anticarcinogenic potential of natural compounds targeting epigenetic mechanism as a common molecular approach for cancer treatment. This review summarizes the potential of natural chemopreventive agents to reverse cancer-related epigenetic aberrations by regulating the activity of histone deacetylases, histone acetyltransferases, DNA methyltransferase I, and miRNAs. Furthermore, there is impetus for determining novel and effective chemopreventive strategies, either alone or in combination with other anticancer agents that exhibit similar properties, for improving the therapeutic aspects of cancer.

Anticancer drugs are now frequently being combined with dietary phytochemicals/nutraceuticals in an effort to enhance their antitumor efficacy while lowering their toxic effects. This forced the research to shift toward traditional medical practices with some advancement, that is, the use of nutraceuticals such as catechins. Catechins and their gallate esters are a class of polyphenolic compounds that has recently attracted a great deal of attention because of its beneficial effect on human health. They are functionally versatile and regulate a number of biological pathways to deal with various physiological or pathophysiological pathways. Catechins are mostly known for their potent antioxidants activity; however, depending on the doses, they may also show prooxidant effects. Reports on green tea catechin-mediated modulation of several key cellular functions associated with strong chemoprotective and chemosensitizing properties have been often ascribed to both anti- and prooxidant activities. Catechins hit multiple targets in cancer therapy and are also found to be useful in managing multidrug-resistant tumors. Catechins have been shown to suppress several key pathways linked to oncogenesis, including those involved in cell survival, proliferation, and invasion, along with angiogenesis. They are also helpful against disorders involving lipid and glucose metabolism such as type 2 diabetes and obesity and could also alleviate the risk of cardiovascular diseases. The beneficial effects of catechins especially EGCG have been reported from in vitro and in vivo studies in model organisms and from some pilot studies in preclinical and clinical trials. Catechins, potent antioxidants with biological activity relevant to the prevention and treatment of cancer, are actively being tried in combination with many chemotherapeutic drugs in order to increase the efficacy of the chemotherapeutic drugs and to ameliorate the drug-associated side effects.