Targeted recruitment of immune effector cells for rapid eradication of influenza virus infections.

Despite much research, considerable data suggest that influenza virus remains a serious health problem because i) the effectiveness of current vaccines ranges only from 19% to 60%, ii) available therapies remain ineffective in advanced stages of disease, iii) death rates vary between 25,000 and 72,000/year in the United States, and iv) avian influenza strains are now being transmitted to dairy cattle that in turn are infecting humans. To address these concerns, we have developed zanDR, a bispecific small molecule that binds and inhibits viral neuraminidase expressed on both free virus and virus-infected cells and recruits naturally occurring anti-rhamnose and anti-dinitrophenyl (DNP) antibodies with rhamnose and DNP haptens. Because the neuraminidase inhibition replicates the chemotherapeutic mechanism of zanamivir and oseltamivir, while rhamnose and DNP recruit endogenous antibodies much like an anti-influenza vaccine, zanDR reproduces most of the functions of current methods of protection against influenza virus infections.

Ketomimetic Nutrients Trigger a Dual Metabolic Defense in Breast Cancer Cells.

While the triggers for the metastatic transformation of breast cancer (BC) cells remain unknown, recent evidence suggests that intrinsic cellular metabolism could be a crucial driver of migratory disposition and chemoresistance. Aiming to decode the molecular mechanisms involved in BC cell metabolic maneuvering, we study how a ketomimetic (ketone body rich, low glucose) medium affects Doxorubicin (DOX) susceptibility and invasive disposition of BC cells. We quantified glycocalyx sialylation and found an inverse correlation with DOX-induced cytotoxicity and DOX internalization.

Assessing the impact of extracellular matrix fiber orientation on breast cancer cellular metabolism.

The extracellular matrix (ECM) is a dynamic and complex microenvironment that modulates cell behavior and cell fate. Changes in ECM composition and architecture have been correlated with development, differentiation, and disease progression in various pathologies, including breast cancer [1]. Studies have shown that aligned fibers drive a pro-metastatic microenvironment, promoting the transformation of mammary epithelial cells into invasive ductal carcinoma via the epithelial-to-mesenchymal transition (EMT) [2].

Receptor-interacting protein kinase 2 (RIPK2) stabilizes c-Myc and is a therapeutic target in prostate cancer metastasis.

Despite progress in prostate cancer (PC) therapeutics, distant metastasis remains a major cause of morbidity and mortality from PC. Thus, there is growing recognition that preventing or delaying PC metastasis holds great potential for substantially improving patient outcomes. Here we show receptor-interacting protein kinase 2 (RIPK2) is a clinically actionable target for inhibiting PC metastasis.

Novel α-tocopherol-ferrocene conjugates for the specific delivery of transgenes in liver cancer cells under high serum conditions.

The delivery of therapeutic genes to a specific organ has drawn significant research attention. Among the pool of various delivery vectors, cationic liposomes (non-viral) are potential candidates for delivering therapeutic genes due to their low immunogenic response. Here, we have developed novel ferrocene-conjugated cationic tocopheryl aggregates as non-viral vectors.

Reciprocal deregulation of NKX3.1 and AURKA axis in castration-resistant prostate cancer and NEPC models.

Background: NKX3.1, a prostate-specific tumor suppressor, is either genomically lost or its protein levels are severely downregulated, which are invariably associated with poor prognosis in prostate cancer (PCa). Nevertheless, a clear disconnect exists between its mRNA and protein levels, indicating that its post-translational regulation may be critical in maintaining its protein levels.

LIMK2-NKX3.1 Engagement Promotes Castration-Resistant Prostate Cancer.

NKX3.1's downregulation is strongly associated with prostate cancer (PCa) initiation, progression, and CRPC development. Nevertheless, a clear disagreement exists between NKX3.

Antibody-Conjugated Vitamin E-Derived Liposomes for Targeted Gene Transfer.

Construction of a vitamin E-based liposomal biomaterial and its ability to deliver therapeutic genes selectively across liver cancer cells are demonstrated herein. In humans, liver regulates the levels of α-tocopherol, i.e.

Phosphorylation-dependent regulation of SPOP by LIMK2 promotes castration-resistant prostate cancer.

Background: SPOP, an E3 ubiquitin ligase adaptor, can act either as a tumour suppressor or a tumour promoter. In prostate cancer (PCa), it inhibits tumorigenesis by degrading several oncogenic substrates. SPOP is the most altered gene in PCa (~15%), which renders it ineffective, promoting cancer.

Molecular Interplay between AURKA and SPOP Dictates CRPC Pathogenesis via Androgen Receptor.

SPOP, an adaptor protein for E3 ubiquitin ligase can function as a tumor-suppressor or a tumor-enhancer. In castration-resistant prostate cancer (CRPC), it inhibits tumorigenesis by degrading many oncogenic targets, including androgen receptor (AR). Expectedly, SPOP is the most commonly mutated gene in CRPC (15%), which closely correlates with poor prognosis.

Negative cross talk between LIMK2 and PTEN promotes castration resistant prostate cancer pathogenesis in cells and in vivo.

Androgen deprivation therapy (ADT) and androgen receptor (AR) signaling inhibitors are front-line treatments for highly aggressive prostate cancer. However, prolonged inhibition of AR triggers a compensatory activation of PI3K pathway, most often due to the genomic loss of tumor suppressor PTEN, driving progression to the castration-resistant prostate cancer (CRPC) stage, which has very poor prognosis. We uncovered a novel mechanism of PTEN downregulation triggered by LIMK2, which contributes significantly to CRPC pathogenesis.

Specific stabilization of promoter G-Quadruplex DNA by 2,6-disubstituted amidoanthracene-9,10-dione based dimeric distamycin analogues and their selective cancer cell cytotoxicity.

We have designed and synthesized anthraquinone containing compounds which have oligopyrrole side chains of varying lengths. These compounds stabilized the G-quadruplex DNA formed in the promoter regions of c-MYC oncogenes selectively over the duplex DNA. These observations were recorded using UV-vis spectroscopic titrations, fluorescence measurements and circular dichroism (CD) spectral titrations.

New Water-Soluble Oxyamino Chitosans as Biocompatible Vectors for Efficacious Anticancer Therapy via Co-Delivery of Gene and Drug.

Among the many nonviral gene delivery vectors, chitosan, being a polysaccharide of natural origin, has gained special importance. In this report, chitosan (CS) has been solubilized in water by preparing its carboxymethyl derivative, CS(CHCOOH), with an optimum degree of carboxymethylation. This has been further derivatized to get the pyridine-substituted product (py)CS(CHCOOH), where the degree of pyridine substitution (47%) was optimized based on zeta potential measurements.

Tumor Chemosensitization through Oncogene Knockdown Mediated by Unique α-Tocopherylated Cationic Geminis.

Herein, siRNA transfection efficiency of a unique set of α-tocopherylated gemini lipids has been established in vitro and in vivo. High efficacy of oncogene silencing achieved using the biomacromolecular assembly, formed from siRNA complexes of co-liposomes containing an α-tocopherylated gemini lipid, has been utilized for tumor regression via chemosensitization. Delivery studies with the gemini bearing hydroxyethyl headgroup with octamethylene spacer (TH8S) pointed to a higher siRNA transfection efficacy than its analog without hydroxyethyl group (T8S).

Simultaneous sensing of ferritin and apoferritin proteins using an iron-responsive dye and evaluation of physiological parameters associated with serum iron estimation.

An iron-responsive optical probe has been developed for simultaneous sensing of both ferritin and apoferritin proteins at pH 7.4 in water. The compound showed an exclusive response (turn-off signal) towards ferritin among a wide range of proteins even at nanomolar concentration.

Correction: Transfection efficiencies of α-tocopherylated cationic gemini lipids with hydroxyethyl bearing headgroups under high serum conditions.

Correction for 'Transfection efficiencies of α-tocopherylated cationic gemini lipids with hydroxyethyl bearing headgroups under high serum conditions' by Bappa Maiti et al., Org. Biomol.

Transfection efficiencies of α-tocopherylated cationic gemini lipids with hydroxyethyl bearing headgroups under high serum conditions.

Herein, five new α-tocopheryl cationic gemini lipids with hydroxyethyl bearing headgroups (THnS, n = 4, 5, 6, 8, 12) have been synthesized for efficient plasmid DNA (pDNA) delivery into cancer cells. Among these gemini lipid formulations, the lipid with an octamethylene [-(CH)] spacer (TH8S) showed the highest transfection efficiency (TE) that was comparable to that of the commercial standard lipofectamine 2000 (L2K) in terms of luciferase expression in HepG2 (liver hepatocellular carcinoma) cells. The addition of the helper lipid DOPE (1,2-dioleoyl phosphatidyl ethanolamine) with cationic lipids in mixed liposomes further enhanced the TE and the optimized molar ratio was 2 : 1 (DOPE : cationic lipid).

Identification of a flavonoid isolated from plum (Prunus domestica) as a potent inhibitor of Hepatitis C virus entry.

Hepatitis C virus (HCV) infection is a major cause of chronic liver diseases that often requires liver transplantation. The standard therapies are limited by severe side effects, resistance development, high expense and in a substantial proportion of cases, fail to clear the infection which bespeak the need for development of well-tolerated antivirals. Since most of the drug development strategies target the replication stage of viral lifecycle, the identification of entry inhibitors might be crucial especially in case of liver-transplant recipients.

A plant-derived dehydrorotenoid: a new inhibitor of hepatitis C virus entry.

Emergence of drug-resistant viruses, high cost and adverse side-effects associated with the standard therapy against hepatitis C virus (HCV) infection demonstrate the need for development of well tolerated and effective antivirals. We identified and chemically characterised the dehydrorotenoid boeravinone H, isolated from the herb Boerhavia diffusa, as a new inhibitor of HCV entry. The compound significantly inhibits the binding and entry of hepatitis C-like particles (HCV-LPs) in hepatoma cells in vitro with no apparent cytotoxicity.

Enhanced G-Quadruplex DNA Stabilization and Telomerase Inhibition by Novel Fluorescein Derived Salen and Salphen Based Ni(II) and Pd(II) Complexes.

Metal based salen complexes have been considered as an important scaffold toward targeting of DNA structures. In the present work, we have synthesized nickel(II) and palladium(II) salen and salphen complexes by using readily available fluorescein as the backbone to provide an extended aromatic surface. The metal complexes exhibit affinity toward the human telomeric G-quadruplex DNA with promising inhibition of telomerase activity.

Novel Oligopyrrole Carboxamide based Nickel(II) and Palladium(II) Salens, Their Targeting of Human G-Quadruplex DNA, and Selective Cancer Cell Toxicity.

DNA targeting by various metal complexes is a key strategy toward the restriction of cancer cell proliferation. Toward this end, we designed and synthesized novel salen-based Ni(II) and Pd(II) metal complexes with positively charged flanking side chains comprising N-methylpyrrole carboxamides of varying lengths. The compounds showed high specificity toward G-quadruplex DNA over duplex DNA.

New Fe(iii) and Co(ii) salen complexes with pendant distamycins: selective targeting of cancer cells by DNA damage and mitochondrial pathways.

Minor groove binding distamycin like moieties were conjugated with core salens and the corresponding Fe(iii) and Co(ii) complexes were synthesized. Herein, we have shown efficient DNA minor groove binding specificities along with excellent DNA cleavage capacities with metallosalen conjugates. The metal complexes showed toxicity toward various cancer cells over normal cells with high specificity.