Identification and structure–activity relationships of ortho-biphenyl carboxamides as potent Smoothened antagonists inhibiting the Hedgehog signaling pathway

Ortho-biphenyl carboxamides, originally prepared as inhibitors of microsomal triglyceride transfer protein (MTP) have been identified as novel inhibitors of the Hedgehog signaling pathway. Structure–activity relationship studies for this class of compounds reduced MTP inhibitory activity and led to low nanomolar Hedgehog inhibitors. Binding assays revealed that the compounds act as antagonists of Smoothened and show cross-reactivity for both the human and mouse receptor.     

2′,5′-Phosphodiesterase Activity Depends Upon the Presence of a 3-Hydroxyl Moiety in the Penultimate Position of the Oligonucleotide Substrate

Abstract

3′-Deoxyadenosine-substituted analogs of 2–5A core 5′-mono-phosphate were examined for their degradation by the 2′-phosphodiesterase of mouse cells, leading to the conclusion that the 2′,5′-phosphodiesterase requires the presence of 3′-hydroxyl moiety in the penultimate nucleotide     

Green tea polyphenol epigallocatechin-3-gallate inhibits advanced glycation end product-induced expression of tumor necrosis factor-α and matrix metalloproteinase-13 in human chondrocytes

Introduction  

The major risk factor for osteoarthritis (OA) is aging, but the mechanisms underlying this risk are only partly understood. Age-related accumulation of advanced glycation end products (AGEs) can activate chondrocytes and induce the production of proinflammatory cytokines and matrix metalloproteinases (MMPs). In the present study, we examined the effect of epigallocatechin-3-gallate (EGCG) on AGE-modified-BSA (AGE-BSA)-induced activation and production of TNFα and MMP-13 in human OA chondrocytes.     

Structures of adnectin/protein complexes reveal an expanded binding footprint

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Highlights? Adnectins interact with targets using multiple binding modes ? Residues outside of the diversified loops can interact with ligand ? Some fixed scaffold residues contribute to the binding energy ? Adnectins can interact with epitopes that may be inaccessible to antibodies     

Mouthparts and stylet penetration of the lac insect Kerria lacca (Kerr) (Hemiptera:Tachardiidae)

Hitherto less known aspects on mouthpart morphology and penetration mechanism of the lac insect Kerria lacca have been explored. Unique details of the mouthparts, i.e. morphology of labium and stylets and salivary sheath have been brought out. The gross morphology of the mouthparts though resembled other plant sucking homopterans; a two-segmented labium with symmetrically distributed six pairs of contact-chemoreceptors on its surface was distinct; the mandibular stylets had serrations on its extreme apical region, while the maxillary stylets had their external surface smooth with parallel longitudinal grooves on their inner surface. Formation of flanges, salivary sheath and penetration pathway observed along with probing and penetration of the stylets intracellularly up to the phloem cells, as illustrated herein, are the addition to the existing knowledge on the structural details of the mouthparts and the feeding behavior thereupon.     

Antibacterial activity traceable to the marine blue green alga Trichodesmium erythraeum in the gastro-intestinal contents of two pelagic fishes

Summary The gastro-intestinal contents inHilsa kanagurta (Blkr.) andRastrelliger kanagurta (Cuv). were found to possess antibacterial activity. This could be traced to heavy accumulation ofTrichodesmium erythraeum in the gut. The bloom ofT. erythraeum started this year (1969) about the middle of February and attained a peak during the second week of March. During this period it was found that about 60 to 70 per cent of the fish catches in the inshore waters consistedH. kanagurta andR. kanagurta. Analysis of gut contents of six specimens of each of these two species showed thatT. erythraeum constituted 80 to 90 per cent of the contents. It has been reported previously by the author thatT. erythraeum maintained in cultures in the laboratory and also collected from the sea possesses antibacterial properties. In view of this finding, standard experimental procedures were adopted to determine whether extracts ofT. erythraeum occurring in the gut of the fishes examined also possessed antibacterial activity. It was found thatT. erythraeum collected from the gut ofHilsa andRastrelliger could inhibit both gram-positive and gram-negative bacteria. The gastro-intestinal extract ofHilsa kanagurta andRastrelliger kanagurta collected during nonbloom period ofTrichodesmium showed heavy bacterial and fungal growth. Evidently antibacterial or sterile conditions prevail in the guts of these fishes in a manner similar to what has been observed in polar marine animals by Sieburth (1959 and 1961).     

Rod phosphodiesterase-6 (PDE6) catalytic subunits restore cone function in a mouse model lacking cone PDE6 catalytic subunit

Rod and cone photoreceptor neurons utilize discrete PDE6 enzymes that are crucial for phototransduction. Rod PDE6 is composed of heterodimeric catalytic subunits (αβ), while the catalytic core of cone PDE6 (α') is a homodimer. It is not known if variations between PDE6 subunits preclude rod PDE6 catalytic subunits from coupling to the cone phototransduction pathway. To study this issue, we generated a cone-dominated mouse model lacking cone PDE6 (Nrl(-/-) cpfl1). In this animal model, using several independent experimental approaches, we demonstrated the expression of rod PDE6 (αβ) and the absence of cone PDE6 (α') catalytic subunits. The rod PDE6 enzyme expressed in cone cells is active and contributes to the hydrolysis of cGMP in response to light. In addition, rod PDE6 expressed in cone cells couples to the light signaling pathway to produce S-cone responses. However, S-cone responses and light-dependent cGMP hydrolysis were eliminated when the β-subunit of rod PDE6 was removed (Nrl(-/-) cpfl1 rd). We conclude that either rod or cone PDE6 can effectively couple to the cone phototransduction pathway to mediate visual signaling. Interestingly, we also found that functional PDE6 is required for trafficking of M-opsin to cone outer segments.