Macrocyclic natural products have evolved to fulfil numerous biochemical functions, and their profound pharmacological properties have led to their development as drugs. A macrocycle provides diverse ...functionality and stereochemical complexity in a conformationally pre-organized ring structure. This can result in high affinity and selectivity for protein targets, while preserving sufficient bioavailability to reach intracellular locations. Despite these valuable characteristics, and the proven success of more than 100 marketed macrocycle drugs derived from natural products, this structural class has been poorly explored within drug discovery. This is in part due to concerns about synthetic intractability and non-drug-like properties. This Review describes the growing body of data in favour of macrocyclic therapeutics, and demonstrates that this class of compounds can be both fully drug-like in its properties and readily prepared owing to recent advances in synthetic medicinal chemistry.
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.
The safety and immunogenicity of a vaccine regimen consisting of a 6-plasmid HIV-1 DNA prime (envA, envB, envC, gagB, polB, nefB) boosted by a recombinant adenovirus serotype-5 (rAd5) HIV-1 with ...matching inserts was evaluated in HIV-seronegative participants from South Africa, United States, Latin America and the Caribbean.
480 participants were evenly randomized to receive either: DNA (4 mg i.m. by Biojector) at 0, 1 and 2 months, followed by rAd5 (10(10) PU i.m. by needle/syringe) at 6 months; or placebo. Participants were monitored for reactogenicity and adverse events throughout the 12-month study. Peak and duration of HIV-specific humoral and cellular immune responses were evaluated after the prime and boost.
The vaccine was well tolerated and safe. T-cell responses, detected by interferon-γ (IFN-γ) ELISpot to global potential T-cell epitopes (PTEs) were observed in 70.8% (136/192) of vaccine recipients overall, most frequently to Gag (54.7%) and to Env (54.2%). In U.S. vaccine recipients T-cell responses were less frequent in Ad5 sero-positive versus sero-negative vaccine recipients (62.5% versus 85.7% respectively, p = 0.035). The frequency of HIV-specific CD4+ and CD8+ T-cell responses detected by intracellular cytokine staining were similar (41.8% and 47.2% respectively) and most secreted ≥2 cytokines. The vaccine induced a high frequency (83.7%-94.6%) of binding antibody responses to consensus Group M, and Clades A, B and C gp140 Env oligomers. Antibody responses to Gag were elicited in 46% of vaccine recipients.
The vaccine regimen was well-tolerated and induced polyfunctional CD4+ and CD8+ T-cells and multi-clade anti-Env binding antibodies.
ClinicalTrials.gov NCT00125970.
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.
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.
We study a firm that makes new products in the first period and uses returned cores to make remanufactured products (along with new products) in future periods. The remanufactured product is ...differentiated from the new product, so the firm needs to choose differentiated prices. We analyze the monopoly environment in two-period, multi-period (three, four and five) and infinite planning horizons, and characterize the optimal remanufacturing and pricing strategy for the firm. In the process, we identify remanufacturing savings thresholds that determine the production and pricing strategy for the firm. Among other results, we find—counter to intuition—that in a finite-horizon, multi-period setting, the optimal policy is not necessarily monotone in remanufacturing savings.
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.
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