Targeting Dysregulated Lipid Metabolism in Cancer with Pharmacological Inhibitors.

Metabolic plasticity is recognised as a hallmark of cancer cells, enabling adaptation to microenvironmental changes throughout tumour progression. A dysregulated lipid metabolism plays a pivotal role in promoting oncogenesis. Oncogenic signalling pathways, such as PI3K/AKT/mTOR, JAK/STAT, Hippo, and NF-kB, intersect with the lipid metabolism to drive tumour progression. Furthermore, altered lipid signalling in the tumour microenvironment contributes to immune dysfunction, exacerbating oncogenesis. This review examines the role of lipid metabolism in tumour initiation, invasion, metastasis, and cancer stem cell maintenance. We highlight cybernetic networks in lipid metabolism to uncover avenues for cancer diagnostics, prognostics, and therapeutics.

BRD4 isoforms have distinct roles in tumour progression and metastasis in rhabdomyosarcoma.

BRD4, a bromodomain and extraterminal (BET) protein, is deregulated in multiple cancers and has emerged as a promising drug target. However, the function of the two main BRD4 isoforms (BRD4-L and BRD4-S) has not been analysed in parallel in most cancers. This complicates determining therapeutic efficacy of pan-BET inhibitors. In this study, using functional and transcriptomic analysis, we show that BRD-L and BRD4-S isoforms play distinct roles in fusion negative embryonal rhabdomyosarcoma. BRD4-L has an oncogenic role and inhibits myogenic differentiation, at least in part, by activating myostatin expression. Depletion of BRD4-L in vivo impairs tumour progression but does not impact metastasis. On the other hand, depletion of BRD4-S has no significant impact on tumour growth, but strikingly promotes metastasis in vivo. Interestingly, BRD4-S loss results in the enrichment of BRD4-L and RNA Polymerase II at integrin gene promoters resulting in their activation. In fusion positive alveolar rhabdomyosarcoma, BRD4-L is unrestricted in its oncogenic role, with no evident involvement of BRD4-S. Our work unveils isoform-specific functions of BRD4 in rhabdomyosarcoma.

Association of plasma NRP2 and VEGF-C levels with prostate cancer disease severity.

BACKGROUND: Neuropilin 2 (NRP2) expression in tissue is an independent prognostic factor for aggressive prostate cancer. Since the NRP2 pathway activation is thought to occur in part through secondary resistance, quantification of NRP2 in initial tissue biopsy specimens collected at diagnosis may have limited utility in identifying patients at highest risk for morbidity and mortality. Given that metastatic tissue is only occasionally obtained for analysis, there is a need for development of a plasma biomarker indicative of NRP2 pathway activation to potentially inform prostate cancer prognosis. Therefore, we investigated if plasma levels of NRP2 or vascular endothelial growth factor C (VEGF-C), a known soluble ligand of NRP2, are prognostic for prostate cancer. We hypothesized that plasma NRP2 and VEGF-C would be associated with more advanced disease or relapsed disease. METHODS: NRP2 and VEGF-C levels were quantified by enzyme-linked immunoassay in plasma samples obtained from 145 prostate cancer patients in an opportunistic biobank. These patients were either (1) newly diagnosed (N = 28), (2) in remission (N = 56), or (3) relapsed disease (N = 61). Plasma samples from 15 adult males without known malignancy served as a comparator cohort. Statistical analysis was performed to investigate the association of plasma NRP2/VEGF-C with patient outcomes, adjusting for age, race, prostate-specific antigen (PSA), Gleason score, and tumor stage at diagnosis. RESULTS: Neither NRP2 nor VEGF-C levels were significantly different in cancer patients compared to noncancer controls. We observed no clear association between plasma NRP2 and disease severity. Increased plasma VEGF-C was significantly associated with disease remission and correlated with Stage I/II and intermediate-risk Gleason score. Neither NRP2 nor VEGF-C correlated with PSA level. CONCLUSIONS: Although tissue NRP2 expression correlates with severe disease, this was not observed for plasma NRP2. Plasma NRP2 levels did not correlate with disease severity or relapse. VEGF-C was highest in patients in remission and with less severe disease. Future investigation is needed to identify noninvasive methods to assess tumor NRP2 status.

BRD4 isoforms have distinct roles in tumor progression and metastasis in embryonal rhabdomyosarcoma.

BRD4, a bromodomain and extraterminal (BET) protein, is deregulated in multiple cancers and has emerged as a promising drug target. However, the function of the two main BRD4 isoforms (BRD4-L and BRD4-S) has not been analyzed in parallel in most cancers. This complicates determining therapeutic efficacy of pan-BET inhibitors. In this study, using functional and transcriptomic analysis, we show that BRD-L and BRD4-S isoforms play distinct roles in embryonal rhabdomyosarcoma. BRD4-L has an oncogenic role and inhibits myogenic differentiation, at least in part, by activating myostatin expression. Depletion of BRD4-L in vivo impairs tumor progression but does not impact metastasis. On the other hand, depletion of BRD4-S has no significant impact on tumor growth, but strikingly promotes metastasis in vivo . Interestingly, BRD4-S loss results in the enrichment of BRD4-L and RNA Polymerase II at integrin gene promoters resulting in their activation. Our work unveils isoform-specific functions of BRD4 and demonstrates that BRD4-S functions as a gatekeeper to constrain the full oncogenic potential of BRD4-L.

Understanding the role of Pax5 in development of taxane-resistant neuroendocrine like prostate cancers.

Resistance to the current Androgen Receptor Signaling Inhibitor (ARSI) therapies has led to higher incidences of therapy-induced neuroendocrine-like prostate cancer (t-NEPC). This highly aggressive subtype with predominant small cell-like characteristics is resistant to taxane chemotherapies and has a dismal overall survival. t-NEPCs are mostly treated with platinum-based drugs with a combination of etoposide or taxane and have less selectivity and high systemic toxicity, which often limit their clinical potential. During t-NEPC transformation, adenocarcinomas lose their luminal features and adopt neuro-basal characteristics. Whether the adaptive neuronal characteristics of t-NEPC are responsible for such taxane resistance remains unknown. Pathway analysis from patient gene-expression databases indicates that t-NEPC upregulates various neuronal pathways associated with enhanced cellular networks. To identify transcription factor(s) (TF) that could be important for promoting the gene expression for neuronal characters in t-NEPC, we performed ATAC-Seq, acetylated-histone ChIP-seq, and RNA-seq in our NE-like cell line models and analyzed the promoters of transcriptionally active and significantly enriched neuroendocrine-like (NE-like) cancer-specific genes. Our results indicate that Pax5 could be an important transcription factor for neuronal gene expression and specific to t-NEPC. Pathway analysis revealed that Pax5 expression is involved in axonal guidance, neurotransmitter regulation, and neuronal adhesion, which are critical for strong cellular communications. Further results suggest that depletion of Pax5 disrupts cellular interaction in NE-like cells and reduces surface growth factor receptor activation, thereby, sensitizing them to taxane therapies. Moreover, t-NEPC specific hydroxymethylation of Pax5 promoter CpG islands favors Pbx1 binding to induce Pax5 expression. Based on our study, we concluded that continuous exposure to ARSI therapies leads to epigenetic modifications and Pax5 activation in t-NEPC, which promotes the expression of genes necessary to adopt taxane-resistant NE-like cancer. Thus, targeting the Pax5 axis can be beneficial for reverting their taxane sensitivity.

Epigenetic Small-Molecule Modulators Targeting Metabolic Pathways in Cancer.

Metabolic deregulation is a key factor in cancer progression. Epigenetic changes and metabolic rewiring are intertwined in cancer. Deregulated epigenetic modifiers cause metabolic aberrations by targeting the expression of metabolic enzymes. Conversely, metabolites and cofactors affect the expression and activity of epigenetic regulators. Small molecules are promising therapeutic approaches to target the epigenetic-metabolomic crosstalk in cancer. Here, we focus on the interplay between metabolic rewiring and epigenetic landscape in the context of tumourigenesis and highlight recent advances in the use of small-molecule drug targets for therapy.

An interplay between BRD4 and G9a regulates skeletal myogenesis.

Histone acetylation and methylation are epigenetic modifications that are dynamically regulated by chromatin modifiers to precisely regulate gene expression. However, the interplay by which histone modifications are synchronized to coordinate cellular differentiation is not fully understood. In this study, we demonstrate a relationship between BRD4, a reader of acetylation marks, and G9a, a writer of methylation marks in the regulation of myogenic differentiation. Using loss- and gain-of-function studies, as well as a pharmacological inhibition of its activity, we examined the mechanism by which BRD4 regulates myogenesis. Transcriptomic analysis using RNA sequencing revealed that a number of myogenic differentiation genes are downregulated in Brd4-depleted cells. Interestingly, some of these genes were upregulated upon G9a knockdown, indicating that BRD4 and G9a play opposing roles in the control of myogenic gene expression. Remarkably, the differentiation defect caused by Brd4 knockdown was rescued by inhibition of G9a methyltransferase activity. These findings demonstrate that the absence of BRD4 results in the upregulation of G9a activity and consequently impaired myogenic differentiation. Collectively, our study identifies an interdependence between BRD4 and G9a for the precise control of transcriptional outputs to regulate myogenesis.

Cancer Cachexia: Signaling and Transcriptional Regulation of Muscle Catabolic Genes.

Cancer cachexia (CC) is a multifactorial syndrome characterized by a significant reduction in body weight that is predominantly caused by the loss of skeletal muscle and adipose tissue. Although the ill effects of cachexia are well known, the condition has been largely overlooked, in part due to its complex etiology, heterogeneity in mediators, and the involvement of diverse signaling pathways. For a long time, inflammatory factors have been the focus when developing therapeutics for the treatment of CC. Despite promising pre-clinical results, they have not yet advanced to the clinic. Developing new therapies requires a comprehensive understanding of how deregulated signaling leads to catabolic gene expression that underlies muscle wasting. Here, we review CC-associated signaling pathways and the transcriptional cascade triggered by inflammatory cytokines. Further, we highlight epigenetic factors involved in the transcription of catabolic genes in muscle wasting. We conclude with reflections on the directions that might pave the way for new therapeutic approaches to treat CC.

Crosstalk Between Inflammatory Signaling and Methylation in Cancer.

Inflammation is an intricate immune response against infection and tissue damage. While the initial immune response is important for preventing tumorigenesis, chronic inflammation is implicated in cancer pathogenesis. It has been linked to various stages of tumor development including transformation, proliferation, angiogenesis, and metastasis. Immune cells, through the production of inflammatory mediators such as cytokines, chemokines, transforming growth factors, and adhesion molecules contribute to the survival, growth, and progression of the tumor in its microenvironment. The aberrant expression and secretion of pro-inflammatory and growth factors by the tumor cells result in the recruitment of immune cells, thus creating a mutual crosstalk. The reciprocal signaling between the tumor cells and the immune cells creates and maintains a successful tumor niche. Many inflammatory factors are regulated by epigenetic mechanisms including DNA methylation and histone modifications. In particular, DNA and histone methylation are crucial forms of transcriptional regulation and aberrant methylation has been associated with deregulated gene expression in oncogenesis. Such deregulations have been reported in both solid tumors and hematological malignancies. With technological advancements to study genome-wide epigenetic landscapes, it is now possible to identify molecular mechanisms underlying altered inflammatory profiles in cancer. In this review, we discuss the role of DNA and histone methylation in regulation of inflammatory pathways in human cancers and review the merits and challenges of targeting inflammatory mediators as well as epigenetic regulators in cancer.

Review of the genus Odontomutilla Ashmead, 1899 (Hymenoptera: Mutillidae) of the Indian subcontinent, with description of two new species.

Review of the 12 species and one subspecies of the genus Odontomutilla of the Indian subcontinent is provided. Two new species, O. sairandhriensis Terine, Girish Kumar Lelej, sp. nov., ♀ (Kerala part of Southern Western Ghats) and O. fletcheri Lelej, Terine Girish Kumar, sp. nov. ♀, ♂ (Sri Lanka), and the hitherto unknown male of O. trichocondyla (André, 1894) are described and illustrated. Mutilla indiga Bingham, 1908, ♂ (India: Uttar Pradesh) is transferred from the genus Odontomutilla to Smicromyrme Thomson, 1870 (comb. nov.). Odontomutilla speciosa (Smith, 1855), ♀ is excluded from the Indian subcontinent fauna as misidentified O. spectra (Bingham, 1908). Keys to the 12 species and one subspecies (males and females) of the genus are given.

Transition metal complexes incorporated with photoswitchable azo-based benzimidazole ligands: Photochromic and solvatochromic studies.

Photochromic compounds are well-known for their promising applications in many areas. It attracts remarkable attention because of their potential ability for optical memory media and optical switching devices. Herein, we have synthesized azo-based benzimidazole ligand and their transition metal complexes for photochromic applications in the liquid state. The azo-based benzimidazole ligand exhibits trans-to-cis photoisomerization with highly tunable and excellent π-π* and n-π* band separation of ligand, whereas complexes show light-induced photo-dissociation as well as trans-to-cis photoisomerization of the ligand part. The reverse cis-to-trans isomerization can be driven by without using light or any external stimuli at room temperature by keeping the system in the dark condition.

A novel rhodamine-based optical probe for mercury(II) ion in aqueous medium: A nanomolar detection, wide pH range and real water sample application.

In present work, we designed and synthesized new chemosensor RPy, containing the rhodamine and 2,6-pyridinedicarboxaldehyde functionality, for the selective detection of mercury (II) (Hg2+) ion in aqueous DMSO solvents. The RPy acts as "turn ON" probe for Hg2+ ion with high selectivity and sensitivity over the series of other competing metal ions based on colorimetric and fluorimetric techniques. Due to the incorporation of two rhodamine moieties enhance the chelation sites for mercury binding, which reflects in the lowering of the detection limit up to 26 nM. The Job plot method confirms the 1:2 stoichiometric interactions between the RPy and Hg2+ ion. The formation of the chelation complex between RPy and Hg2+ ion with spirolactam ring opening was thoroughly investigated by absorption, emission, 1H NMR, and mass analysis. The detection of Hg2+ ion by RPy is retained at broad pH range 4-9. Further, the probe RPy is successfully explored to measure the contamination of Hg2+ ion in the real water samples using spike and recovery method.

Discovery of the genus Kudakrumia Krombein, 1979 (Hymenoptera: Mutillidae) in India and description of a new species.

The Oriental genus Kudakrumia Krombein, 1979 is newly reported from India with two species: K. mirabilis Krombein, 1979 (Kerala) and K. rangnekari Girish Kumar Lelej, sp. nov. (Goa, Kerala). A key to the Oriental genera and species of tribe Kudakrumiini is given.

Genotypes of glycoprotein B gene among the Indian symptomatic neonates with congenital CMV infection.

BACKGROUND: Cytomegalovirus [CMV] is a causative agent of congenital infection worldwide and often leads to neurological deficits and hearing loss in newborns. Infants born with symptomatic congenital Cytomegalovirus infection [cCMV] are at significant high risk for developing adverse long-term outcomes. In this study, we look into the sequence variability of surface glycoprotein B [gB] encoding region in newborns with symptomatic CMV infection for the first time in Eastern region of India. METHODS: 576 suspected newborns from seropositive mothers were subjected to the study and ELISA was used to confirm CMV infection. Different genotypes and their subtypes were determined using multiplex nested-PCR. Viral load of different glycoprotein B [gB] genotypes was measured using RT-PCR. Sequencing and phylogenetic analysis was then performed using Bayesian interference. RESULTS: The overall frequency of cCMV infection was 18.4%, where 16.0% neonates were symptomatic. Among the different gB genotypes, gB1 had the highest frequency [23.5%] and gB4 showed the lowest occurrence [5.8%]. 23.5% of symptomatic neonates had mixed genotypes of gB, probably indicating matrenal reinfection with CMV strains in Indian population. Significant genotypic clades [gB1-gB2-gB3-gB5] were grouped closely based on gene sequences, but the gB4 sequence was in the outlier region of the phylogenetic tree indicating the genetic polymorphism. CONCLUSION: This is the first study on cCMV genotyping and its phylogenetic analysis from Eastern Indian neonatal population. The study holds importance in the assessment of cCMV seroprevalence in global perspective. gB protein can be used as a potential therapeutic target against CMV infection.

Ultrafast Conformational Relaxation Dynamics in Anthryl-9-benzothiazole: Dynamic Planarization Driven Delocalization and Protonation-Induced Twisting Dynamics.

Conformational motion in the excited state of fluorophores critically governs their photophysical properties. Unveiling controlling parameters of photoinduced molecular motion in organic dyes is essential for optimization of light-triggered processes. Herein, we present ultrafast dynamics of conformational relaxation controlled photophysical properties of anthryl-9-benzthiazole (AnBT). The title compound is a bichromophore, consists of anthracene (AN) and benzothiazole (BT) units connected by a single bond, and exists in out of plane ground state conformation (dihedral angle of about 65?). Vibronic resolved structured absorption feature of anthracene localized excitation is lost in first excited singlet state displaying large Stokes-shifted fluorescence, characteristics of delocalized state involving both AN and BT unit. Ultrafast transient absorption spectroscopic studies revealed evolution of anthracene-localized Franck?Condon state to a delocalized excited state in a few picosecond time scale depending on solvent viscosity. A planarized motion of AN and BT units is proposed to be involved in excited state relaxation. However, protonation of BT unit is shown to induce significant intramolecular charge transfer facilitated by ultrafast torsional relaxation promoting nonradiative deactivation. Thus, depending upon protonation state, AnBT is shown to undergo either ultrafast planarized motion facilitating delocalized emissive excited state or perpendicular torsion rendering nonemissive twisted intramolecular charge transfer state. Experimental results were corroborated by quantum chemical calculation.

A simple benzimidazole styryl-based colorimetric chemosensor for dual sensing application.

A new colorimetric styryl-benzimidazole based receptor to recognize more than one analyte trans-2-[4'-(dimethylamino)styryl]benzimidazole) (L1) has been synthesized and fully characterized by 13C and 1H NMR, elemental analysis, UV-vis spectroscopy, and HRMS. Investigation of sensing ability of receptor L1 was carried out in presence of multiple anions (Br-, CN-, Cl-, ClO4-, F-, HSO4-, PF6-, NO3-, S2-, OH-, AcO- and H2PO4-) and cations (Cu2+, Cr3+, Al3+, Mg2+, Cd2+, Ni2+, Fe3+, K+, Fe2+, Mn2+, Ag+, Hg2+, Ca2+, Co2+, Pb2+, Na+, and Zn2+) by using UV-vis spectroscopy. Receptor L1 showed colorimetric response towards only for HSO4- ion. Receptor L1-HSO4- interaction confirmed with the help of 1H NMR titration. Among various cations, L1 selectively sense the Cu2+ and Al3+ with the drastic colour change from yellow to green and dark yellow respectively. The stoichiometric binding ratio of L1 with HSO4-, Cu2+, and Al3+ found to be 1:1 by jobs method and HRMS data proved the complex formation between L1 and Cu2+/Al3+ with very low detection limit. In addition to explore practical applicability of L1, paper strips have been made and used to detect HSO4- and Cu2+ ions, respectively, up to 10 ppm level.

Assessment of lead tolerance in gamma exposed Aspergillus niger van Tieghem & Penicillium cyclopium Westling.

Purpose: Present study deals with the role of gamma irradiation in modulating lead (Pb) tolerance of Aspergillus niger van Tieghem. and Penicillium cyclopium Westling. Materials and methods: After being exposed to gamma absorbed doses those fungal strains were subjected to heavy metal uptake efficacies and anti-oxidative study. Fourier Transform Infrared (FTIR) spectra and Scanning Electron Microscopic (SEM) studies were also evaluated. Result: Gamma exposed A. niger & P. cyclopium showed enhanced growth in terms of colony forming unit (CFU) and more Pb uptake efficacies compared to their un-irradiated counterparts. FTIR spectra illustrated the involvement of functional groups in Pb biosorption. SEM photographs revealed the structural deformities in both the fungal strains after being exposed to Pb and gamma. Upregulated anti-oxidative defense system (super oxide dismutase, catalase, total glutathione) in gamma exposed fungal groups are accountable for enhanced Pb tolerance and removal than that of their un-irradiated counterparts. Conclusion: The outcomes of this study exhibit a light towards a new step of heavy metal bioremediation.

A nanomolar detection of mercury(II) ion by a chemodosimetric rhodamine-based sensor in an aqueous medium: Potential applications in real water samples and as paper strips.

A new promising rhodamine based colorimetric and fluorometric chemosensor, RDV has been designed and synthesized for specific detection of Hg2+ ion. It acts as highly selective "turn-on" fluorescent chemosensor for Hg2+ ion without interference from other competitive metal ions in aqueous acetonitrile medium. The drastic color change with addition of Hg2+, from colorless to pink, indicates RDV can acts as "naked-eye" indicator for Hg2+. The Hg2+ promoted selective hydrolysis of appended vinyl ether group in RDV followed by Hg2+ chelated complex formation with concomitant opening of spirolactam ring is the plausible sensing mechanism. The detailed absorption, fluorescence, 1H NMR, 13C NMR and mass spectrometry confirms the proposed sensing mechanism. The limit of detection (LOD) of Hg2+ by RDV is 136 nM indicating the high sensitivity towards Hg2+. The RDV shows consistent spectroscopic response in biological pH range 4-10. In addition to explore practical applicability of RDV, its paper strips have been made and used to detect Hg2+ in pure water solution up to 10 ppm level. Furthermore, the potential application of RDV for the sensing of Hg2+ in real water samples (tap water and drinking waters from different sources) were also monitored and demonstrated.

Protonation-induced ultrafast torsional dynamics in 9-anthrylbenzimidazole: a pH activated molecular rotor.

We report the photophysical properties and excited state dynamics of 9-anthrylbenzimidazole (ANBI) which exhibits protonation-induced molecular rotor properties. In contrast to the highly emissive behavior of neutral ANBI, protonation of the benzimidazole group of ANBI induces efficient nonradiative deactivation by ultrafast torsional motion around the bond connecting the anthracene and benzimidazole units, as revealed by ultrafast transient absorption and fluorescence spectroscopy. Contrary to viscosity-independent fluorescence of neutral dyes, protonated ANBI is shown to display linear variation of emission yield and lifetime with solvent viscosity. The protonation-induced molecular rotor properties in the studied system are shown to be driven by enhanced charge transfer and are corroborated by quantum chemical calculations. Potential application as a microviscosity sensor of acidic regions in a heterogeneous environment by these proton-activated molecular rotor properties of ANBI is discussed.

Unexpected Nonresponsive Behavior of a Flexible Metal-Organic Framework under Conformational Changes of a Photoresponsive Guest Molecule.

In this article, we describe the synthesis, characterization, and optical properties of a photochromic-guest-incorporated metal-organic framework (MOF). The photochromic guest molecule, 2-phenylazopyridine (PAP), was introduced into a pre-synthesized porous crystalline host MOF, [Zn2(1,4-bdc)2(dabco)] n (1). The successful embedment of PAP has been confirmed by elemental analysis, powder X-ray diffraction measurements, IR spectroscopy, etc. The number of PAP molecules per unit cell of host was 1.0, as evidenced by elemental and thermogravimetric analyses of the host-guest composite, 1⊃PAP. The 1⊃PAP composite did not adsorb N2, revealed by the adsorption isotherm of 1⊃PAP, which indicates the pore blockage by the close contact of the host framework with the guest PAP in the trans form. The light-induced trans/cis isomerization with partial reversibility of the guest molecule (PAP) in this hybrid host-guest compound (1⊃PAP) has been investigated by detailed IR spectroscopy and UV-vis spectroscopy. The structural transformation from tetragonal in 1 to orthorhombic in 1⊃PAP exhibits dynamic nature of the framework upon inclusion of guest in the framework, which remarkably becomes nonresponsive with the photoirradiation of guest PAP, retaining its orthorhombic structure in the photoirradiated complex, 1⊃PAP(UV).