The Global Distribution and Burden of Dengue and Japanese Encephalitis Co-Infection in Acute Encephalitis Syndrome

Dengue is widespread throughout the tropics globally in more than hundred countries and coincides with various climatic factors for co-infection with other flaviviral infections of the central nervous system (CNS). Dengue and Japanese encephalitis virus co-infection are highly prevalent, with diagnosis dilemma including significant mortality and morbidity in Southeast Asia. Both dengue and Japanese encephalitis transmissions intensify during the rainy season, during which the vector population increases. CNS involvement during dengue and Japanese encephalitis co-infection-associated acute encephalitis syndrome (AES) is still poorly understood, and therefore, there is a desperate need to understand the etiology, therapeutics, clinical management, and prevention of these tropically neglected diseases. AES can be differentiated from other etiologies of encephalopathy through considering its essential features: sudden onset of fever, cerebrospinal fluid (CSF) comprising inflammatory cells, magnetic resonance imaging (MRI)-based confirmation, and presence of pathogen or pathogen-specific antibodies. Complementary and alternative medicine is progressively being used globally and can be effective for the overall management of this co-infection

In vitro cytotoxicity and catalytic evaluation of dioxidovanadium(V) complexes in an azohydrazone ligand environment

Three new anionic dioxidovanadium(V) complexes (HNEt3)[VO2(L)1–3] (1–3) of tridentate binegative aroylhydrazone ligands containing the azobenzene moiety were synthesized and structurally characterized. The aroylhydrazone ligands (H2L1–3) were derived from the condensation of 5-(arylazo) salicylaldehyde derivatives with the corresponding aroyl hydrazides. All the synthesized ligands and metal complexes were successfully characterized by several physicochemical techniques, namely, elemental analysis, electrospray ionization mass spectrometry, spectroscopic methods (IR, UV-vis and NMR), and cyclic voltammetry. Single-crystal X-ray diffraction crystallography of 1–3 revealed five-coordinate geometry, where the ligand coordinates to the metal centre in a binegative tridentate O, N, O coordinating anion and two oxido-O atoms, resulting in distortion towards the square pyramidal structure. The complexes were further evaluated for their in vitro cytotoxicity against HeLa and HT-29 cancer cell lines. All the complexes manifested a cytotoxic potential that was found to be comparable with that of clinically referred drugs, while complex 3 proved to be the most cytotoxic among the three complexes for both cell lines, which may be due to the synergistic effect of the naphthyl substituent in the azohydrazone ligand environment coordinated to the vanadium metal. The synthesized complexes 1–3 were probed as catalysts for the oxidative bromination of thymol and styrene as a functional mimic of vanadium haloperoxidases (VHPOs). All the reactions provided high percentages of conversion (>90%) with a high turnover frequency (TOF) in the presence of the catalysts 1–3. In particular, for the oxidative bromination of thymol, the percentage of conversion and TOF were in the ranges of 98–99% and 5380–7173 (h−1), respectively. Besides, 3 bearing the naphthyl substituent showed the highest TOF among all the complexes for the oxidative bromination of both thymol and styrene

Pathogenesis and Host Immune Response during Japanese Encephalitis Virus Infection

Japanese Encephalitis Virus (JEV) is a mosquito borne flavivirus infection. Transmission of JEV starts with the infected mosquito bite where human dermis layer act as the primary site of infection. Once JEV makes its entry into blood, it infects monocytes wherein the viral replication peaks up without any cell death and results in production of TNF-α. One of the most characteristics pathogenesis of JEV is the breaching of blood brain barrier (BBB). JEV propagation occurs in neurons that results in neuronal cell death as well as dissemination of virus into astrocytes and microglia leading to overexpression of proinflammatory cytokines. JEV infection results in host cells mediated secretion of various types of cytokines including type-1 IFN along with TNF-α and IFN-γ. Molecule like nitrous oxide (NO) exhibits antiviral activities against JEV infection and helps in inhibiting the viral replication by blocking protein synthesis and viral RNA and also in virus infected cells clearance. In addition, the antibody can also acts an opsonizing agent in order to facilitate the phagocytosis of viral particles, which is mediated by Fc or C3 receptor. This chapter focuses on the crucial mechanism of JEV induced pathogenesis including neuropathogenesis viral clearance mechanisms and immune escape strategies

Evaluation of FOXM1 inhibitor (FDI-6) as a potential therapeutic molecule for small cell lung cancer

Lung cancer is the leading cause of cancer deaths accounting for about 22% of all cancer related cases in both males and females. Lung cancers are broadly grouped into two types mainly small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) with SCLC accounting for about 15% of all lung cancer cases. SCLC is different from NSCLC because in most cases it originates centrally in the bronchi and is frequently seen in smokers. SCLC is aggressive and one of the most malignant forms of tumor characterized by uncontrolled rapid growth of certain cells in the lungs. SCLC displays poor prognosis because of early-stage metastasis, acquisition of chemoresistance, and has a high rate of recurrence. One of major drivers of chemoresistance is the transcription factor Forkhead box protein M1 (FOXM1) that is responsible for modulating cell cycle proliferation, maintenance of genomic stability, DNA damage response, and cell differentiation in numerous tumor entities. In order to explore properties of SCLC cancer cell lines, human non-bone metastatic SBC3, bone metastatic SBC5, H1688, and murine (RPM) cells were treated with a FOXM1 inhibitor known as FDI-6. As a transcription factor FOXMI binds sequence-specific motifs on DNA through its DNA-binding domain activating proliferation and differentiation-associated genes. Anomalous overexpression of FOXMI is a crucial characteristic in oncogenesis and the development of SCLC. FDI-6 is a novel small molecule inhibitor of FOXM1, and it works by binding directly to FOXM1 protein, to displace FOXM1 from genomic targets in SCLC cells prompting concomitant translational downregulation. Functional assays performed confirm that FDI-6 is a viable FOXMI inhibitor showing therapeutic efficacies in SCLC.https://digitalcommons.unmc.edu/surp2021/1044/thumbnail.jp

Liquid Biopsies to Occult Brain Metastasis

Brain metastasis (BrM) is a major problem associated with cancer-related mortality, and currently, no specific biomarkers are available in clinical settings for early detection. Liquid biopsy is widely accepted as a non-invasive method for diagnosing cancer and other diseases. We have reviewed the evidence that shows how the molecular alterations are involved in BrM, majorly from breast cancer (BC), lung cancer (LC), and melanoma, with an inception in how they can be employed for biomarker development. We discussed genetic and epigenetic changes that influence cancer cells to breach the blood-brain barrier (BBB) and help to establish metastatic lesions in the uniquely distinct brain microenvironment. Keeping abreast with the recent breakthroughs in the context of various biomolecules detections and identifications, the circulating tumor cells (CTC), cell-free nucleotides, non-coding RNAs, secretory proteins, and metabolites can be pursued in human body fluids such as blood, serum, cerebrospinal fluid (CSF), and urine to obtain potential candidates for biomarker development. The liquid biopsy-based biomarkers can overlay with current imaging techniques to amplify the signal viable for improving the early detection and treatments of occult BrM

Trends in Molecular Aspects and Therapeutic Applications of Drug Repurposing for Infectious Diseases

The pharmaceutical industry has undergone a severe economic crunch in antibiotic discovery research due to evolving bacterial resistance along with enormous time and money that gets consumed in de novo drug design and discovery strategies. Nevertheless, drug repurposing has evolved as an economically safer and excellent alternative strategy to identify approved drugs for new therapeutic indications. Virtual high throughput screening (vHTS) and phenotype-based high throughput screening (HTS) of approved molecules play a crucial role in identifying, developing, and repurposing old drug molecules into anti-infective agents either alone or in synergistic combination with antibiotic therapy. This chapter briefly explains the process of drug repurposing/repositioning in comparison to de novo methods utilizing vHTS and HTS technologies along with ‘omics- and poly-pharmacology-based drug repurposing strategies in the identification and development of anti-microbial agents. This chapter also gives an insightful survey of the intellectual property landscape on drug repurposing. Further, the challenges and applications of drug repurposing strategies in the discovery of anti-infective drugs are exemplified. The future perspectives of drug repurposing in the context of anti-infective agents are also discussed

Blocking c-MET/ERBB1 Axis Prevents Brain Metastasis in ERBB2+ Breast Cancer

Brain metastasis (BrM) remains a significant cause of cancer-related mortality in epidermal growth factor receptor 2-positive (ERBB2+) breast cancer (BC) patients. We proposed here that a combination treatment of irreversible tyrosine kinase inhibitor neratinib (NER) and the c-MET inhibitor cabozantinib (CBZ) could prevent brain metastasis. To address this, we first tested the combination treatment of NER and CBZ in the brain-seeking ERBB2+ cell lines SKBrM3 and JIMT-1-BR3, and in ERBB2+ organoids that expressed the c-MET/ERBB1 axis. Next, we developed and characterized an orthotopic mouse model of spontaneous BrM and evaluated the therapeutic effect of CBZ and NER in vivo. The combination treatment of NER and CBZ significantly inhibited proliferation and migration in ERBB2+ cell lines and reduced the organoid growth in vitro. Mechanistically, the combination treatment of NER and CBZ substantially inhibited ERK activation downstream of the c-MET/ERBB1 axis. Orthotopically implanted SKBrM3+ cells formed primary tumor in the mammary fat pad and spontaneously metastasized to the brain and other distant organs. Combination treatment with NER and CBZ inhibited primary tumor growth and predominantly prevented BrM. In conclusion, the orthotopic model of spontaneous BrM is clinically relevant, and the combination therapy of NER and CBZ might be a useful approach to prevent BrM in BC

Mechanism and kinetics of chlorpyrifos co-metabolism by using environment restoring microbes isolated from rhizosphere of horticultural crops under subtropics

The indiscriminate use of organophosphate insecticide chlorpyrifos in agricultural crops causes significant soil and water pollution and poses a serious threat to the global community. In this study, a microbial consortium ERM C-1 containing bacterial strains Pseudomonas putida T7, Pseudomonas aeruginosa M2, Klebsiella pneumoniae M6, and a fungal strain Aspergillus terreus TF1 was developed for the effective degradation of chlorpyrifos. Results revealed that microbial strains were not only utilizing chlorpyrifos (500 mg L–1) but also coupled with plant growth-promoting characteristics and laccase production. PGP traits, that is, IAA (35.53, 45.53, 25.19, and 25.53 μg mL–1), HCN (19.85, 17.85, 12.18, and 9.85 μg mL–1), and ammonium (14.73, 16.73, 8.05, and 10.87 μg mL–1) production, and potassium (49.53, 66.72, 46.14, and 52.72 μg mL–1), phosphate (52.37, 63.89, 33.33, and 71.89 μg mL–1), and zinc (29.75, 49.75, 49.12, and 57.75 μg mL–1) solubilization tests were positive for microbial strains T7, M2, M6, and TF1, respectively. The laccase activity by ERM C-1 was estimated as 37.53, 57.16, and 87.57 enzyme U mL–1 after 5, 10, and 15 days of incubation, respectively. Chlorpyrifos degradation was associated with ERM C-1 and laccase activity, and the degree of enzyme activity was higher in the consortium than in individual strains. The biodegradation study with developed consortium ERM C-1 showed a decreased chlorpyrifos concentration from the 7th day of incubation (65.77% degradation) followed by complete disappearance (100% degradation) after the 30th day of incubation in the MS medium. First-order degradation kinetics with a linear model revealed a high k –day value and low t1/2 value in ERM C-1. The results of HPLC and GC-MS analysis proved that consortium ERM C-1 was capable of completely removing chlorpyrifos by co-metabolism mechanism

GDF15 Promotes Prostate Cancer Bone Metastasis and Colonization Through Osteoblastic CCL2 and RANKL Activation

Bone metastases occur in patients with advanced-stage prostate cancer (PCa). The cell-cell interaction between PCa and the bone microenvironment forms a vicious cycle that modulates the bone microenvironment, increases bone deformities, and drives tumor growth in the bone. However, the molecular mechanisms of PCa-mediated modulation of the bone microenvironment are complex and remain poorly defined. Here, we evaluated growth differentiation factor-15 (GDF15) function using in vivo preclinical PCa-bone metastasis mouse models and an in vitro bone cell coculture system. Our results suggest that PCa-secreted GDF15 promotes bone metastases and induces bone microarchitectural alterations in a preclinical xenograft model. Mechanistic studies revealed that GDF15 increases osteoblast function and facilitates the growth of PCa in bone by activating osteoclastogenesis through osteoblastic production of CCL2 and RANKL and recruitment of osteomacs. Altogether, our findings demonstrate the critical role of GDF15 in the modulation of the bone microenvironment and subsequent development of PCa bone metastasis