HIV proteins target host hub proteins for transient binding interactions. The presence of viral proteins in the infected cell results in out-competition of host proteins in their interaction with hub ...proteins, drastically affecting cell physiology. Functional genomics and interactome datasets can be used to quantify the sequence hotspots on the HIV proteome mediating interactions with host hub proteins. In this study, we used the HIV and human interactome databases to identify HIV targeted host hub proteins and their host binding partners (H2). We developed a high throughput computational procedure utilizing motif discovery algorithms on sets of protein sequences, including sequences of HIV and H2 proteins. We identified as HIV sequence hotspots those linear motifs that are highly conserved on HIV sequences and at the same time have a statistically enriched presence on the sequences of H2 proteins. The HIV protein motifs discovered in this study are expressed by subsets of H2 host proteins potentially outcompeted by HIV proteins. A large subset of these motifs is involved in cleavage, nuclear localization, phosphorylation, and transcription factor binding events. Many such motifs are clustered on an HIV sequence in the form of hotspots. The sequential positions of these hotspots are consistent with the curated literature on phenotype altering residue mutations, as well as with existing binding site data. The hotspot map produced in this study is the first global portrayal of HIV motifs involved in altering the host protein network at highly connected hub nodes.
The interaction of advanced glycation end products (AGEs) and their receptor (RAGE) plays a central role in diabetic nephropathy. We screened DNA aptamers directed against RAGE (RAGE-aptamers) in ...vitro and examined the effects on the development and progression of diabetic nephropathy in streptozotocin-induced diabetic rats. RAGE-aptamer bound to RAGE with a
of 5.68 nmol/L and resultantly blocked the binding of AGEs to RAGE. When diabetic rats received continuous intraperitoneal injection of RAGE-aptamer from week 7 to 11 of diabetes, the increases in renal NADPH oxidase activity, oxidative stress generation, AGE, RAGE, inflammatory and fibrotic gene and protein levels, macrophage and extracellular matrix accumulation, and albuminuria were significantly suppressed, which were associated with improvement of podocyte damage. Two-week infusion of RAGE-aptamer just after the induction of diabetes also inhibited the AGE-RAGE-oxidative stress system and MCP-1 levels in the kidneys of 8-week-old diabetic rats and simultaneously ameliorated podocyte injury and albuminuria. Moreover, RAGE-aptamer significantly suppressed the AGE-induced oxidative stress generation and inflammatory and fibrotic reactions in human cultured mesangial cells. The findings suggest that continuous infusion of RAGE-aptamer could attenuate the development and progression of experimental diabetic nephropathy by blocking the AGE-RAGE axis.
Natural products represents an important source of new lead compounds in drug discovery research. Several drugs currently used as therapeutic agents have been developed from natural sources; plant ...sources are specifically important. In the past few decades, pharmaceutical companies demonstrated insignificant attention towards natural product drug discovery, mainly due to its intrinsic complexity. Recently, technological advancements greatly helped to address the challenges and resulted in the revived scientific interest in drug discovery from natural sources. This review provides a comprehensive overview of various approaches used in the selection, authentication, extraction/isolation, biological screening, and analogue development through the application of modern drug-development principles of plant-based natural products. Main focus is given to the bioactivity-guided fractionation approach along with associated challenges and major advancements. A brief outline of historical development in natural product drug discovery and a snapshot of the prominent natural drugs developed in the last few decades are also presented. The researcher's opinions indicated that an integrated interdisciplinary approach utilizing technological advances is necessary for the successful development of natural products. These involve the application of efficient selection method, well-designed extraction/isolation procedure, advanced structure elucidation techniques, and bioassays with a high-throughput capacity to establish druggability and patentability of phyto-compounds. A number of modern approaches including molecular modeling, virtual screening, natural product library, and database mining are being used for improving natural product drug discovery research. Renewed scientific interest and recent research trends in natural product drug discovery clearly indicated that natural products will play important role in the future development of new therapeutic drugs and it is also anticipated that efficient application of new approaches will further improve the drug discovery campaign.
Fruit and vegetable processing industry is one of the relevant generators of food by-products, which display limited commercial exploitation entailing economic and environmental problems. However, ...these by-products present a considerable amount of dietary fiber as well as bioactive compounds with important biological activities such as antioxidant and antimicrobial properties. Therefore, the international scientific community has considered the incorporation of their extracts or powders to preserve or fortify food products an area of interest, mainly because nowadays consumers demand the production of safer and health-promoting foods. In the present review, several statistical and other relevant data concerning the increasing generation of fruit and vegetable by-products (FVB) are critically analyzed and presented. Next, a special focus is given to the chemical characterization and bioactivities (namely antioxidant and antimicrobial properties) of several FVB. Lastly, an in-depth review with recent studies (briefly compiled) about the incorporation of fruit and vegetable processing wastes in animal, dairy, beverages, and bakery products, among others is provided.
Natural products and their structural analogues have historically made a major contribution to pharmacotherapy, especially for cancer and infectious diseases. Nevertheless, natural products also ...present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization, which contributed to a decline in their pursuit by the pharmaceutical industry from the 1990s onwards. In recent years, several technological and scientific developments - including improved analytical tools, genome mining and engineering strategies, and microbial culturing advances - are addressing such challenges and opening up new opportunities. Consequently, interest in natural products as drug leads is being revitalized, particularly for tackling antimicrobial resistance. Here, we summarize recent technological developments that are enabling natural product-based drug discovery, highlight selected applications and discuss key opportunities.
The activities linked to the fishing sector generate substantial quantities of by-products, which are often discarded or used as low-value ingredients in animal feed. However, these marine ...by-products are a prominent potential good source of bioactive compounds, with important functional properties that can be isolated or up-concentrated, giving them an added value in higher end markets, as for instance nutraceuticals and cosmetics. This valorization of fish by-products has been boosted by the increasing awareness of consumers regarding the relationship between diet and health, demanding new fish products with enhanced nutritional and functional properties. To obtain fish by-product-derived biocompounds with good, functional and acceptable organoleptic properties, the selection of appropriate extraction methods for each bioactive ingredient is of the outmost importance. In this regard, over the last years, innovative alternative technologies of intensification, such as ultrasound-assisted extraction (UAE) and supercritical fluid extraction (SFE), have become an alternative to the conventional methods in the isolation of valuable compounds from fish and shellfish by-products. Innovative green technologies present great advantages to traditional methods, preserving and even enhancing the quality and the extraction efficiency, as well as minimizing functional properties' losses of the bioactive compounds extracted from marine by-products. Besides their biological activities, bioactive compounds obtained by innovative alternative technologies can enhance several technological properties of food matrices, enabling their use as ingredients in novel foods. This review is focusing on analyzing the principles and the use of UAE and SFE as emerging technologies to valorize seafoods and their by-products.
The growing interest in producing healthier animal products with a higher ratio of polyunsaturated to saturated fatty acids, is associated with an increase in lipoperoxidation. For this reason, it is ...essential to attenuate oxidative deterioration in the derived products. Natural antioxidants such as polyphenols represent a good candidate in this respect. The first part of the review highlights the occurrence, bioavailability, and the role of polyphenols in food-producing animals that, especially in intensive systems, are exposed to stressful situations in which oxidation plays a crucial role. The second part offers an overview of the effects of polyphenols either supplemented to the diet of monogastric and ruminants or added directly to meat and dairy products on the physicochemical and sensorial properties of the product. From this review emerges that polyphenols play an important, though not always clear, role in the quality of meat and meat products, milk and dairy products. It cannot be ruled out that different compounds or amounts of polyphenols may lead to different results. However, the inclusion of agro-industrial by-products rich in polyphenols, in animal feed, represents an innovative and alternative source of antioxidants as well as being useful in reducing environmental and economic impact.
The formation of advanced glycation end products (AGEs) in foods is accelerated with heat treatment, particularly within foods that are cooked at high temperatures for long periods of time using dry ...heat. The modern processed diet is replete with AGEs, and excessive AGE consumption is thought to be associated with a number of negative health effects. Many dietary AGEs have high molecular weight and are not absorbed in the intestine, and instead pass through to the colon, where they are available for metabolism by the colonic bacteria. Recent studies have been conducted to explore the effects of AGEs on the composition of the gut microbiota as well as the production of beneficial microbial metabolites, in particular, short-chain fatty acids. However, there is conflicting evidence regarding the impact of dietary AGEs on gut microbiota reshaping, which may be due, in part, to the formation of alternate compounds during the thermal treatment of foods. This review summarises the current evidence regarding dietary sources of AGEs, their gastrointestinal absorption and role in gut microbiota reshaping, provides a brief overview of the health implications of dietary AGEs and highlights knowledge gaps and avenues for future study.
Antisense Piwi-interacting RNAs (piRNAs) guide silencing of established transposons during germline development, and sense piRNAs drive ping-pong amplification of the antisense pool, but how the ...germline responds to genome invasion is not understood. The KoRV-A gammaretrovirus infects the soma and germline and is sweeping through wild koalas by a combination of horizontal and vertical transfer, allowing direct analysis of retroviral invasion of the germline genome. Gammaretroviruses produce spliced Env mRNAs and unspliced transcripts encoding Gag, Pol, and the viral genome, but KoRV-A piRNAs are almost exclusively derived from unspliced genomic transcripts and are strongly sense-strand biased. Significantly, selective piRNA processing of unspliced proviral transcripts is conserved from insects to placental mammals. We speculate that bypassed splicing generates a conserved molecular pattern that directs proviral genomic transcripts to the piRNA biogenesis machinery and that this “innate” piRNA response suppresses transposition until antisense piRNAs are produced, establishing sequence-specific adaptive immunity.
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•KoRV-A and three endogenous retroviruses are active in the koala genome•Unspliced KoRV-A proviral transcripts are preferentially processed into piRNAs•piRNA production from unspliced transposon transcripts is deeply conserved
KoRV-A retroviral invasion of the koala germline provides insights into an “innate” genome immune response.
Backround: Laboratory and human studies raise concerns about endocrine disruption and asthma from exposure to chemicals in consumer products. Limited labeling or testing information is available to ...evaluate products as exposure sources. Objectives: We analytically quantified endocrine disruptors and asthma-related chemicals in a range of cosmetics, personal care products, cleaners, sunscreens, and vinyl products. We also evaluated whether product labels provide information that can be used to select products without these chemicals. Methods: We selected 213 commercial products representing 50 product types. We tested 42 composited samples of high-market-share products, and we tested 43 alternative products identified using criteria expected to minimize target compounds. Analytes included parabens, phthalates, bisphenol A (BPA), triclosan, ethanolamines, alkylphenols, fragrances, glycol ethers, cyclosiloxanes, and ultraviolet (UV) filters. Results: We detected 55 compounds, indicating a wide range of exposures from common products. Vinyl products contained > 10% bis(2-ethylhexyl) phthalate (DEHP) and could be an important source of DEHP in homes. In other products, the highest concentrations and numbers of detects were in the fragranced products (e.g., perfume, air fresheners, and dryer sheets) and in sunscreens. Some products that did not contain the well-known endocrine-disrupting phthalates contained other less-studied phthalates (dicyclohexyl phthalate, diisononyl phthalate, and di-n-propyl phthalate; also endocrine-disrupting compounds), suggesting a substitution. Many detected chemicals were not listed on product labels. Conclusions: Common products contain complex mixtures of EDCs and asthma-related compounds. Toxicological studies of these mixtures are needed to understand their biological activity. Regarding epidemiology, our findings raise concern about potential confounding from co-occurring chemicals and misclassification due to variability in product composition. Consumers should be able to avoid some target chemicals—synthetic fragrances, BPA, and regulated active ingredients— using purchasing criteria. More complete product labeling would enable consumers to avoid the rest of the target chemicals.
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