Spectrum of microRNAs and their target genes in cancer: intervention in diagnosis and therapy.

Till date, several groups have studied the mechanism of microRNA (miRNA) biogenesis, processing, stability, silencing, and their dysregulation in cancer. The miRNA coding genes recurrently go through abnormal amplification, deletion, transcription, and epigenetic regulation in cancer. Some miRNAs function as tumor promoters while few others are tumor suppressors based on the transcriptional regulation of target genes. A review of miRNAs and their target genes in a wide range of cancers is attempted in this article, which may help in the development of new diagnostic tools and intervention therapies. The contribution of miRNAs for drug sensitivity or resistance in cancer therapy and opportunities of miRNAs in cancer prognosis or diagnosis and therapy is also presented in detail.

Biocompatible silver nanoparticles reduced from Anethum graveolens leaf extract augments the antileishmanial efficacy of miltefosine.

Despite the existence of chemotherapy, there is no effective cure for leishmaniasis. In the light of recommended therapeutic regimen is attributed for toxicity and development of clinical resistance, exploration of an efficient method of drug delivery could be one of the option in reducing the dosage and toxicity of drugs. This work is aimed in such fashion to study the enhanced antileishmanial activity of miltefosine with silver-nanoparticles (AgNPs) synthesized by using Anethum graveolens (dill) leaf extract as reducing agent. AgNPs were synthesized in a single step process and characterized by UV-visible, X-ray diffraction (XRD), Fourier transform infra-red spectroscopy (FTIR) to understand the crystal structure and functional groups on their surface. TEM analysis showed that the synthesized AgNPs are of an average size of 35 nm. By performing MTT assay, we found that, AgNPs (between 20 and 100 µM) are biocompatible in nature through pertaining >80% viability of macrophages. Furthermore, AgNPs alone (50 µM) have not shown antileishmanial effect on promastigote stage of Leishmania parasite but in combination with miltefosine (12.5 µM and 25 µM), it magnifies the leishmanicidal effect of miltefosine by ∼2-folds (i.e. AgNPs cut down the IC50 of miltefosine about to half). Scanning electron microscopic (SEM) observation for morphological aberration and genomic DNA fragmentation in promastigotes confirmed the enhanced effect of meltefosine in combination with AgNPs (50 µM AgNPs plus 12.5 µM miltefosine). Similarly, this combination has likely shown a slight augmentation (p = 0.057) of miltefosine (2.5 µM) leishmanicidal efficacy on amastigote stage of the parasite in infected human macrophages by reducing their intracellular growth.

Mangiferin, A Naturally Occurring Glucosylxanthone, Induces Apoptosis in Caco-2 Cells In Vitro and Exerts Protective Effects on Acetic Acid-Induced Ulcerative Colitis in Mice through the Regulation of NLRP3.

Inflammatory bowel diseases (IBD), an inflammatory disease, include Crohn's disease and ulcerative colitis. Dysregulated autoimmune response to gut dysbiosis is mainly involved in the pathogenesis of IBD and is triggered by various inciting environmental factors. With its rising prevalence in every continent, IBD has evolved into a global disease, which is on the rise, affecting people of all ages. There is a growing incidence of IBD in the elderly population, as evidenced by epidemiological data. IBD is characterized by an inflammatory process that requires a lifelong treatment. The main challenge in IBD management is the adverse side effects associated with almost all of the currently available drugs. Hence, there is a search for drugs with more efficacy and fewer side effects. Natural products with great structural diversity and ease of modification chemically are being explored, as they were shown to control IBD by safely suppressing pro-inflammatory pathways. The present study aims at understanding the role of mangiferin, a COX-2 inhibitor isolated from tubers of Pueraria tuberosa in the treatment of IBD and colon cancer, in vitro on the Caco-2 human colon cancer cell line and in vivo in the acetic acid-induced IBD mouse model. In the acetic acid-induced colitis model, it prevented the decrease in length of the colon, mucosal erosion, and cellular infiltration in a dose-dependent manner. The expression levels of various pro-inflammatory markers like COX-2, IL1ß, TNF-α, INF-γ, IL-6, NLRP3, and caspase-1 were downregulated in an acetic acid-induced mouse model on treatment with mangiferin in a dose dependent manner. Mangiferin also showed anticancer effects on Caco-2 cells by increasing the expression of Fas ligand, Fas receptor, FADD, caspase-8, and caspase-3 proteins, whereas Bid and Bcl-2 proteins showed decreased expression. These data suggest that mangiferin, an inhibitor of COX, induces apoptosis in colon cancer cells in vitro and protects mice from acetic acid-induced colitis in vivo.

Endocytosis of LXRs: Signaling in liver and disease.

Nuclear receptors are among one of the major transcriptional factors that induces gene regulation in the nucleus. Liver X receptor (LXR) is a transcription factor which regulates essential lipid homeostasis in the body including fatty acid, cholesterol and phospholipid synthesis. Liver X receptor-retinoid X receptor (LXR-RXR) heterodimer is activated by either of the ligand binding on LXR or RXR. The promoter region of the gene which is targeted by LXR is bound to the response element of LXR. The activators bind to the heterodimer once the corepressor is dissociated. The cellular process such as endocytosis aids in intracellular trafficking and endosomal formation in transportation of molecules for essential signaling within the cell. LXR isotypes play a crucial role in maintaining lipid homeostasis by regulating the level of cholesterol. In the liver, the deficiency of LXRα can alter the normal physiological conditions depicting the symptoms of various cardiovascular and liver diseases. LXR can degrade low density lipoprotein receptors (LDLR) by the signaling of LXR-IDOL through endocytic trafficking in lipoprotein uptake. Various gene expressions associated with cholesterol level and lipid synthesis are regulated by LXR transcription factor. With its known diversified ligand binding, LXR is capable of regulating expression of various specific genes responsible for the progression of autoimmune diseases. The agonists and antagonists of LXR stand to be an important factor in transcription of the ABC family, essential for high density lipoprotein (HDL) formation. Endocytosis and signaling mechanism of the LXR family is broad and complex despite their involvement in cellular growth and proliferation. Here in this chapter, we aimed to emphasize the master regulation of LXR activation, regulators, and their implications in various metabolic activities especially in lipid homeostasis. Furthermore, we also briefed the significant role of LXR endocytosis in T cell immune regulation and a variety of human diseases including cardiovascular and neuroadaptive.

Histone deacetylase (HDACs) inhibitors: Clinical applications.

Histone Deacetylases (HDACs) deacetylate lysine residues in histone and non-histone proteins. HDACs have been implicated in several diseases, including cancer, neurodegeneration, and cardiovascular disease. HDACs play an essential role in gene transcription, cell survival, growth, and proliferation, with histone hypoacetylation as one of the critical downstream signatures. HDAC inhibitors (HDACi) regulate gene expression epigenetically by restoring acetylation levels. Contrarily, only few HDACi have received FDA approval, and the majority are presently undergoing clinical trials to ascertain their effectiveness in the prevention and treatment of disease. In this book chapter, we give a detailed list of HDAC classes, and their functions in advancing diseases like cancer, cardiovascular, and neurodegeneration. Furthermore we touch upon novel and promising HDACi therapy approaches in the relevance of the current clinical scenario.

Advances in aggregation induced emission (AIE) materials in biosensing and imaging of bacteria.

With their ubiquitous nature, bacteria have had a significant impact on human health and evolution. Though as commensals residing in/on our bodies several bacterial communities support our health in many ways, bacteria remain one of the major causes of infectious diseases that plague the human world. Adding to this, emergence of antibiotic resistant strains limited the use of available antibiotics. The current available techniques to prevent and control such infections remain insufficient. This has been proven during one of greatest pandemic of our generation, COVID-19. It has been observed that bacterial coinfections were predominantly observed in COVID-19 patients, despite antibiotic treatment. Such higher rates of coinfections in critical patients even after antibiotic treatment is a matter of concern. Owing to many reasons across the world drug resistance in bacteria is posing a major problem i. According to Center for Disease control (CDC) antibiotic report threats (AR), 2019 more than 2.8 million antibiotic resistant cases were reported, and more than 35,000 were dead among them in USA alone. In both normal and pandemic conditions, failure of identifying infectious agent has played a major role. This strongly prompts the need to improve upon the existing techniques to not just effective identification of an unknown bacterium, but also to discriminate normal Vs drug resistant strains. New techniques based on Aggregation Induced Emission (AIE) are not only simple and rapid but also have high accuracy to visualize infection and differentiate many strains of bacteria based on biomolecular variations which has been discussed in this chapter.

Introduction to aggregation induced emission (AIE) materials.

Idea of introducing aggregation-induced emission (AIE) fundamentally altered the scientific community's perception of classical photophysical processes. Many exciting new possibilities have been coming into light due to the emergence of AIE, such as ability of rapid detection and in analyzing variety of bioactive substances required to monitor the complexed biological processes. This also became a handy tool in elucidating the essential physiological and pathological behaviors of organisms. AIE luminogens (AIEgens) are luminous substances that are either weakly or non-emissive in organic solvents or hydrophobic environment alone, but it gives strong emissive when aggregated along with transforming polarities upon aggregation. Owing to the their outstanding advantages such as rapid turn on/off of high brightness emission, big Stokes shift, excellent photostability, and strong biocompatibility AIEgens have become first choice among bio-inspired probes in biomedicine. In the view of providing basic information on AIE, this chapter give a brief overview of aggregation-caused quenching (ACQ) phenomenon, approaches to transform ACQ to AIE phenomenon, photo-physics of AIE phenomenon, followed by known and reportedly novel AIE active molecules and their biomedical applications.

Assessing Differential Binding of Aggregation-Induced Emission-Based Luminogens to Host Interacting Surface Proteins of SARS-CoV-2 and Influenza Virus-An in silico Approach.

Early detection of asymptomatic cases through mass screening is essential to constrain the coronavirus disease 2019 (COVID-19) transmission. However, the existing diagnostic strategies are either resource-intensive, time-consuming, or less sensitive, which limits their use in the development of rapid mass screening strategies. There is a clear pressing need for simple, fast, sensitive, and economical diagnostic strategy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) screening even in resource-limited settings. In the current work, we assessed the in silico feasibility of directly labeling virus surface proteins using fluorogenic molecules with aggregation-induced emission (AIE) property. Here, we present the results for binding of two such AIE probes, phosphonic acid derivative of tetraphenyl ethylene (TPE-P) and sulfonic acid derivative of tetraphenyl ethylene (TPE-S), to SARS-CoV-2 spike protein based on in silico docking studies. Our results show that both TPE-P and TPE-S bind to angiotensin converting enzyme 2 (ACE2)-binding, and N-terminal domains of SARS-CoV-2 spike protein. Molecular dynamic simulations have revealed specific nature of these interactions. We also show that TPE-P and TPE-S bind to hemagglutinin protein of influenza virus, but the interaction strength was found to be different. This difference in interaction strength may affect the emission spectrum of aforementioned AIE probes. Together, these results form a basis for the development of AIE-based diagnostics for differential detection of SARS-CoV-2 and influenza viruses. We believe that these in silico predictions certainly aid in differentially labeling of the both viruses toward the development of rapid detection by AIE probes.

Role of Biosynthesized Ag-NPs Using Aspergillus niger (MK503444.1) in Antimicrobial, Anti-Cancer and Anti-Angiogenic Activities.

Green synthesis of nanoparticles is regarded as a safe and non-toxic process over conventional synthesis. Owing to the medicinal value of biologically derived biomolecules and utilizing them in synergy with nanoscience to offer more accurate therapeutic options to various diseases is an emerging field. One such study we present here with highlights of the synthesis and efficacy of biogenic silver nanoparticles produced from the extract of Aspergillus niger SAP2211 (accession number: MK503444.1) as an antimicrobial, anti-cancerous and anti-angiogenic agent. The synthesized Ag-NPs were characterized following UV-vis, FTIR, XRD, SEM and TEM, and were found to possess bactericidal activity against the selected pathogenic microbes, such as Staphylococcus aureus, Escherichia coli, and Salmonella typhi. Further, we evaluated cytotoxicity effect of this biogenic Ag-NPs using MMT assay on normal cardio myoblast (H9C2) and cancerous human cervical carcinoma (HeLa) cells. Doxorubicin used as positive control. This Ag-NPs have shown trivial cytotoxicity at the IC50 concentration on normal cells (IC50 = 47.17 µg/ml) over the cancer cells (IC50 = 8.609 µg/ml) with nearly 7 fold difference, indicating it as a selective anti-cancerous agent in contrast to standard drug doxorubicin (IC50 = 6.338 µg/ml). Further in-vitro assessment of wound healing capability by scratch wound healing assay, invasion by transwell matrigel invasion assay, and apoptosis via DAPI and annexin V-FITC assays were studied in HeLa cells. Synthesized biogenic Ag-NPs have shown to be anti-angiogenic in nature, which was established by in-vivo chick chorioallantois membrane assay. Overall, in vitro studies revealed that biogenic Ag-NPs positively inhibited migration, invasion, and induced apoptosis, and in-vivo CAM assay revealed that intercapillary network was reduced and the angiogenesis was inhibited.

Pharmacophore modeling and virtual screening for designing potential 5-lipoxygenase inhibitors.

Inhibitors of the 5-Lipoxygenase (5-LOX) pathway have a therapeutic potential in a variety of inflammatory disorders such as asthma. In this study, chemical feature based pharmacophore models of inhibitors of 5-LOX have been developed with the aid of HipHop and HypoGen modules within Catalyst program package. The best quantitative pharmacophore model, Hypo1, which has the highest correlation coefficient (0.97), consists of two hydrogen-bond acceptors, one hydrophobic feature and one ring aromatic feature. Hypo1 was further validated by test set and cross validation method. The application of the model shows great success in predicting the activities of 65 known 5-LOX inhibitors in our test set with a correlation coefficient of 0.85 with a cross validation of 95% confidence level, proving that the model is reliable in identifying structurally diverse compounds for inhibitory activity against 5-LOX. Furthermore, Hypo1 was used as a 3D query for screening Maybridge and NCI databases within catalyst and also drug like compounds obtained from Enamine Ltd, which follow Lipinski's rule of five. The hit compounds were subsequently subjected to filtering by docking and visualization, to identify the potential lead molecules. Finally 5 potential lead compounds, identified in the above process, were evaluated for their inhibitory activities. These studies resulted in the identification of two compounds with potent inhibition of 5-LOX activity with IC(50) of 14 microM and 35 microM, respectively. These studies thus validate the pharmacophore model generated and suggest the usefulness of the model in screening of various small molecule libraries and identification of potential lead compounds for 5-LOX inhibition.

Gold-Silver Bimetallic Nanoparticles Reduced with Herbal Leaf Extracts Induce ROS-Mediated Death in Both Promastigote and Amastigote Stages of Leishmania donovani.

Resistance to antileishmanial drugs such as sodium stibogluconate (SSG), amphotericin B (Amp-B), and miltefosine is on the rise, and alternate strategies for effective treatment have gained importance in recent years. Although nanoparticle (NP)-based composite drugs that have emerged recently have been found to be effective, the associated toxicity limits their usage. Bimetallic NPs produced through reduction with medicinal plant extracts are proposed to overcome the toxicity of the NPs. In the present study, three types of gold-silver bimetallic nanoparticles (Au-Ag BNPs) were synthesized through a single-step reduction process using fenugreek, coriander, and soybean leaf extracts. All of the three types of BNPs exhibited high antileishmanial effects against promastigotes with half-inhibitory concentration (IC50) values in the range of 0.03-0.035 µg/mL. The IC50 values of the BNPs are much lower compared to those of miltefosine (IC50 = 10 µg/mL). The synthesized BNPs induced the reactive oxygen species (ROS)-mediated apoptosis-like death in the promastigotes and could potentiate the antileishmanial activity of macrophages. The intracellular amastigotes were reduced by 31-46% in macrophages. The biogenic BNPs synthesized in this study and their potent antileishmanial activity provide further impetus to the ongoing quest for novel drugs to effectively manage leishmaniasis.

The Role of Pi, Glutamine and the Essential Amino Acids in Modulating the Metabolism in Diabetes and Cancer.

PURPOSE: Re-examine the current metabolic models. METHODS: Review of literature and gene networks. RESULTS: Insulin activates Pi uptake, glutamine metabolism to stabilise lipid membranes. Tissue turnover maintains the metabolic health. Current model of intermediary metabolism (IM) suggests glucose is the source of energy, and anaplerotic entry of fatty acids and amino acids into mitochondria increases the oxidative capacity of the TCA cycle to produce the energy (ATP). The reduced cofactors, NADH and FADH2, have different roles in regulating the oxidation of nutrients, membrane potentials and biosynthesis. Trans-hydrogenation of NADH to NADPH activates the biosynthesis. FADH2 sustains the membrane potential during the cell transformations. Glycolytic enzymes assume the non-canonical moonlighting functions, enter the nucleus to remodel the genetic programmes to affect the tissue turnover for efficient use of nutrients. Glycosylation of the CD98 (4F2HC) stabilises the nutrient transporters and regulates the entry of cysteine, glutamine and BCAA into the cells. A reciprocal relationship between the leucine and glutamine entry into cells regulates the cholesterol and fatty acid synthesis and homeostasis in cells. Insulin promotes the Pi transport from the blood to tissues, activates the mitochondrial respiratory activity, and glutamine metabolism, which activates the synthesis of cholesterol and the de novo fatty acids for reorganising and stabilising the lipid membranes for nutrient transport and signal transduction in response to fluctuations in the microenvironmental cues. Fatty acids provide the lipid metabolites, activate the second messengers and protein kinases. Insulin resistance suppresses the lipid raft formation and the mitotic slippage activates the fibrosis and slow death pathways.

Cytokines: Key Determinants of Resistance or Disease Progression in Visceral Leishmaniasis: Opportunities for Novel Diagnostics and Immunotherapy.

Leishmaniasis is a parasitic disease of humans, highly prevalent in parts of the tropics, subtropics, and southern Europe. The disease mainly occurs in three different clinical forms namely cutaneous, mucocutaneous, and visceral leishmaniasis (VL). The VL affects several internal organs and is the deadliest form of the disease. Epidemiology and clinical manifestations of VL are variable based on the vector, parasite (e.g., species, strains, and antigen diversity), host (e.g., genetic background, nutrition, diversity in antigen presentation and immunity) and the environment (e.g., temperature, humidity, and hygiene). Chemotherapy of VL is limited to a few drugs which is expensive and associated with profound toxicity, and could become ineffective due to the parasites developing resistance. Till date, there are no licensed vaccines for humans against leishmaniasis. Recently, immunotherapy has become an attractive strategy as it is cost-effective, causes limited side-effects and do not suffer from the downside of pathogens developing resistance. Among various immunotherapeutic approaches, cytokines (produced by helper T-lymphocytes) based immunotherapy has received great attention especially for drug refractive cases of human VL. Therefore, a comprehensive knowledge on the molecular interactions of immune cells or components and on cytokines interplay in the host defense or pathogenesis is important to determine appropriate immunotherapies for leishmaniasis. Here, we summarized the current understanding of a wide-spectrum of cytokines and their interaction with immune cells that determine the clinical outcome of leishmaniasis. We have also highlighted opportunities for the development of novel diagnostics and intervention therapies for VL.

Emergence of Leptin in Infection and Immunity: Scope and Challenges in Vaccines Formulation.

Deficiency of leptin (ob/ob) and/or desensitization of leptin signaling (db/db) and elevated expression of suppressor of cytokine signaling-3 (SOCS3) reported in obesity are also reported in a variety of pathologies including hypertriglyceridemia, insulin resistance, and malnutrition as the risk factors in host defense system. Viral infections cause the elevated SOCS3 expression, which inhibits leptin signaling. It results in immunosuppression by T-regulatory cells (Tregs). The host immunity becomes incompetent to manage pathogens' attack and invasion, which results in the accelerated infections and diminished vaccine-specific antibody response. Leptin was successfully used as mucosal vaccine adjuvant against Rhodococcus equi. Leptin induced the antibody response to Helicobacter pylori vaccination in mice. An integral leptin signaling in mucosal gut epithelial cells offered resistance against Clostridium difficile and Entameoba histolytica infections. We present in this review, the intervention of leptin in lethal diseases caused by microbial infections and propose the possible scope and challenges of leptin as an adjuvant tool in the development of effective vaccines.

Synthesis, Characterization, and Biodistribution of Quantum Dot-Celecoxib Conjugate in Mouse Paw Edema Model.

Increased risk of cardiovascular side effects has been reported with many of the drugs in the market, including nonsteroidal anti-inflammatory drugs (NSAIDs). Hence, it is critical to thoroughly evaluate the biodistribution and pharmacokinetic properties of the drugs. Presently nanotechnology in combination with noninvasive imaging techniques such as magnetic resonance imaging (MRI), computed axial tomography (CAT), and positron emission tomography (PET) provides a better estimate of the spatio-temporal distribution of therapeutic molecules. Optical imaging using quantum dot- (QD-) tagged biological macromolecules is emerging as a fast, economical, sensitive, and safer alternative for theranostic purposes. In the present study, we report the nanoconjugates of mercaptopropionic acid- (MPA-) capped CdTe quantum dots (QDs) and Celecoxib for bio-imaging in carrageenan-induced mouse paw edema model of inflammation. QD-Celecoxib conjugates were characterized by fluorescence, FT-IR, NMR, and zeta-potential studies. In vivo imaging of QD-Celecoxib conjugates showed clear localization in the inflamed tissue of mouse paw within 3 h, with a gradual increase reaching a maximum and a later decline. This decrease of fluorescence in the paw region is followed by an increase in urinary bladder region, suggesting the possible excretion of QD-drug conjugates from mice within 24 h.

Spectroscopic characterization, antioxidant and antitumour studies of novel bromo substituted thiosemicarbazone and its copper(II), nickel(II) and palladium(II) complexes.

A new, slightly distorted octahedral complex of copper(II), square planar complexes of nickel(II) and palladium(II) with 2,4'-dibromoacetophenone thiosemicarbazone (DBAPTSC) are synthesized. The ligand and the complexes are characterized by FT-IR, FT-Raman, powder X-ray diffraction studies. The IR and Raman data are correlated for the presence of the functional groups which specifically helped in the confirmation of the compounds. In addition, the free ligand is unambiguously characterized by (1)H and (13)C NMR spectroscopy while the copper(II) complex is characterized by electron paramagnetic resonance spectroscopy (EPR). The g values for the same are found to be 2.246 (g1), 2.012 (g2) and 2.005 (g3) which suggested rhombic distortions. The HOMO-LUMO band gap calculations for these compounds are found to be in between 0.5 and 4.0 eV and these compounds are identified as semiconducting materials. The synthesized ligand and its copper(II), nickel(II) and palladium(II) complexes are subjected to antitumour activity against the HepG2 human hepatoblastoma cell lines. Among all the compounds, nickel(II) complex is found to exert better antitumour activity with 57.6% of cytotoxicity.

Halo-substituted thiosemicarbazones and their copper(II), nickel(II) complexes: detailed spectroscopic characterization and study of antitumour activity against HepG2 human hepatoblastoma cells.

Copper(II) and nickel(II) complexes of two different halogen substituted thiosemicarbazone ligands were synthesized. The ligands 3,4-difluoroacetophenone thiosemicarbazone (1) and 2-bromo-4'-chloroacetophenone thiosemicarbazone (2) were characterized and confirmed spectroscopically by FT-IR, FT-Raman, UV-vis and fluorescence spectral analysis, while the respective copper(II) complexes [Cu(C9H9N3F2S)2Cl2] (1a), [Cu(C9H9N3ClBrS)2Cl2] (2a) and nickel(II) complexes [Ni(C9H9N3F2S)2] (1b), [Ni(C9H9N3ClBrS)2] (2b) were characterized by FT-IR, UV-vis and electron paramagnetic spectroscopy (EPR). The EPR spectra of the Cu(II) complexes provided the rhombic octahedral and axial symmetry of the complexes 1a and 2a respectively. For the complex 1a, the g values calculated as g1=2.1228, g2=2.0706 and g3=2.001 between 2900 and 3300 G. While for the complex 2a, a set of two resonance absorptions were observed. The synthesized compounds were tested for antitumor activity and showed that the ability to kill liver cancer cells significantly. Out of all the synthesized compounds, copper(II) complexes 1a and 2a showed high cytotoxic effect on liver cancer cells with 67.51% and 42.77% of cytotoxicity respectively at 100 µM.