Branched fatty acids in prodrug nanoassemblies: Molecular gating for governing stability and activation efficiency to amplify therapeutic benefits

Effects of modification modules-adjusted intermolecular forces on docetaxel prodrug Nanoassemblies: From assembly mechanisms to in vivo fate.

Self-assembly prodrugs usually consist of drug modules, activation modules, and assembly modules. The selection of suitable modules to construct prodrug nanoassemblies with self-assembly stability and "intelligent" activation is a challenge. As a common assembly module, oleic acid can provide a driving force and steric hindrance for prodrugs self-assembly. However, the unsaturated double bond of oleic acid is readily oxidized and it affects its chemical stability. Herein, two docetaxel (DTX) prodrugs were designed using disulfide bonds as activation modules and two different fatty acids (isostearic acid and oleic acid) as assembly modules, respectively. Compared with oleic acid, isostearic acid had higher chemical stability. Simultaneously, the terminal propyl structure of isostearic acid compensated for the steric hindrance without a double bond. Overall, this structural deformation improved the self-assembly ability and chemical stability of the prodrug nanoassemblies, thus balancing the effectiveness and safety of the prodrugs. Our findings reveal the importance of the assembly modules and provide a guidance for the rational design of prodrug nanoassemblies.

Rational engineering of cholesterol-modified prodrug nanoassemblies for improving the tumor selectivity and safety of mitoxantrone

7. Management of hypertriglyceridemic patients: B. Dietary management of hypertriglyceridemic patients

Bakery products have gained prominence in modern diets due to their convenience and accessibility, often serving as staple meals across diverse regions. However, the fats used in these products are rich in saturated fatty acids and often comprise trans fatty acids, which are considered as a major biomarker for non-communicable diseases like cardiovascular disorders, obesity and diabetes. Additionally, these fats lack the essential omega-3 fatty acids, which are widely known for their therapeutic benefits. They play a major role in lowering the risk of cardiovascular diseases, cancer and diabetes. Thus, there is need for incorporating these essential fatty acids into bakery fats. Nevertheless, fortifying food products with polyunsaturated fatty acids (PUFAs) poses several challenges due to their high susceptibility to oxidation. This oxidative deterioration leads to not only the formation of undesirable flavors, but also a loss of nutritional value in the final products. This review focuses on the development of healthier trans-fat-free bakery fat enriched with omega-3 fatty acids and its effect on the physicochemical, functional, sensory and nutritional properties of bakery fats and products. Further, the role of various technologies like physical blending, enzymatic interesterification and encapsulation to improve the stability of PUFA-rich bakery fat is discussed, where microencapsulation emerged as a novel and effective technology to enhance the stability and shelf life. By preventing deteriorative changes, microencapsulation ensures that the nutritional, physicochemical and sensory properties of food products remain intact. Novel modification methods like interesterification and microencapsulation used for developing PUFA-rich bakery fats have a potential to address the health risks occurring due to consumption of bakery fat having higher amount of saturated and trans fatty acids. © 2023 Society of Chemical Industry.

In addition to being used in the food and animal feed industry, fish oils have also been used traditionally as dietary supplements. Due to the presence of long-chain n-3 fatty acids, fish oils have therapeutic benefits in the prevention and treatment of cardiovascular, immunological, and arthritic diseases, as well as childhood deficiency diseases such as rickets, because of a high content of vitamin D. However, fish oils are also susceptible to contamination with lipophilic organic chemicals that are now ubiquitous contaminants of marine ecosystems. Many vegetable oils are sources of the shorter chain precursor forms of n-3 fatty acids, and in recent years the specialist dietary supplement market has expanded to include these oils in a variety of different formulations. This paper reports analytical results of selected contaminants, including polychlorinated biphenyls, organochlorine pesticides, and polybrominated diphenyl ethers, for a range of commercially available n-3 fatty acid rich fish and vegetable oil dietary supplements. Using principal component analysis, the values are compared with historic samples to elucidate time trends in contamination profiles. Levels of contaminants are discussed in relation to the nutritional benefits to the consumer of long- and short-chain forms of n-3 fatty acids.

Effects of fish oil in parenteral nutrition

We hypothesized that reduction/loss of very long chain PUFAs (VLC-PUFAs) due to mutations in the ELOngase of very long chain fatty acid-4 (ELOVL4) protein contributes to retinal degeneration in autosomal dominant Stargardt-like macular dystrophy (STGD3) and age-related macular degeneration; hence, increasing VLC-PUFA in the retina of these patients could provide some therapeutic benefits. Thus, we tested the efficiency of elongation of C20-C22 PUFA by the ELOVL4 protein to determine which substrates are the best precursors for biosynthesis of VLC-PUFA. The ELOVL4 protein was expressed in pheochromocytoma cells, while green fluorescent protein-expressing and nontransduced cells served as controls. The cells were treated with 20:5n3, 22:6n3, and 20:4n6, either individually or in equal combinations. Both transduced and control cells internalized and elongated the supplemented FAs to C22-C26 precursors. Only ELOVL4-expressing cells synthesized C28-C38 VLC-PUFA from these precursors. In general, 20:5n3 was more efficiently elongated to VLC-PUFA in the ELOVL4-expressing cells, regardless of whether it was in combination with 22:6n3 or with 20:4n6. In each FA treatment group, C34 and C36 VLC-PUFAs were the predominant VLC-PUFAs in the ELOVL4-expressing cells. In summary, 20:5n3, followed by 20:4n6, seems to be the best precursor for boosting the synthesis of VLC-PUFA by ELOVL4 protein.

A body of translational evidence has implicated dietary deficiency in long-chain omega-3 (LCn-3) fatty acids, including eicosapenaenoic acid (EPA) and docosahexaenoic acid (DHA), in the pathophysiology and potentially etiology of different psychiatric disorders. Case–control studies have consistently observed low erythrocyte (red blood cell) EPA and/or DHA levels in patients with major depressive disorder, bipolar disorder, schizophrenia, and attention deficit hyperactivity disorder. Low erythrocyte EPA + DHA biostatus can be treated with fish oil-based formulations containing preformed EPA + DHA, and extant evidence suggests that fish oil supplementation is safe and well-tolerated and may have therapeutic benefits. These and other data provide a rationale for screening for and treating LCn-3 fatty acid deficiency in patients with psychiatric illness. To this end, we have implemented a pilot program that routinely measures blood fatty acid levels in psychiatric patients entering a residential inpatient clinic. To date over 130 blood samples, primarily from patients with treatment-refractory mood or anxiety disorders, have been collected and analyzed. Our initial results indicate that the majority (75 %) of patients exhibit whole blood EPA + DHA levels at ≤4 percent of total fatty acid composition, a rate that is significantly higher than general population norms (25 %). In a sub-set of cases, corrective treatment with fish oil-based products has resulted in improvements in psychiatric symptoms without notable side effects. In view of the urgent need for improvements in conventional treatment algorithms, these preliminary findings provide important support for expanding this approach in routine psychiatric practice.

Structured triglycerides (STs) containing both medium-chain fatty acids (MCFA) and polyunsaturated fatty acids (PUFA) in the same molecule offer nutritional and therapeutic benefits. The aim of this work was to establish the incorporation of MCFA into fish oil triglycerides (TAGs), while maintaining substantial levels of docosahexaenoic and eicosapentaenoic acids. The effects of different acyl donors (capric acid methyl ester/MeC10 or medium chain triglyceride/TCM) and of the catalyst (chemical or enzymatic) on the fatty acid composition of the reaction product were studied. The fatty acid composition of the fish oil TAG was modified after interesterification to contain MCFA, and it depended on the catalyst and on the substrates. Thermograms obtained by Differential Scanning Calorimetry (DSC) showed that interesterification promoted noteworthy changes in the melting profile of the samples. STs of clinical nutrition interest containing both EPA and DHA obtained from fish oil along with MCFA were successfully produced.

Fatty Acid Requirements in Preterm Infants and Their Role in Health and Disease

Various unicellular algae produce omega-3 (w3) very-long-chain polyunsaturated fatty acids (VLC-PUFA), which are rarely found in higher plants. In this research and other studies from our laboratories, it has been demonstrated that the marine unicellular alga Nannochloropsis (Eustigmatophyceae) can be used as a reliable and high quality source for the w3 VLC-PUFA eicosapentaenoic acid (EPA). This alga is widely used in mariculture systems as the primary component of the artificial food chain in fish larvae production, mainly due to its high EPA content. Furthermore, w3 fatty acids are essential for humans as dietary supplements and may have therapeutic benefits. The goal of this research proposal was to understand the physiological and biochemical mechanisms which regulate the synthesis and accumulation of glycerolipids enriched with w3 VLC-PUFA in Nannochloropsis. The results of our studies demonstrate various aspects of lipid synthesis and its regulation in the alga: 1. Variations in lipid class composition imposed by various environmental conditions were determined with special emphasis on the relative abundance of the molecular species of triacylglycerol (TAG) and monogalactosyl diacylglycerol (MGDG). 2. The relationships between the cellular content of major glycerolipids (TAG and MGDG) and the enzymes involved in their synthesis were studied. The results suggested the importance of UDP-galactose diacylglycerol galactosyl (UDGT) in regulation of the cellular level of MGDG. In a current effort we have purified UDGT several hundredfold from Nannochloropsis. It is our aim to purify this enzyme to near homogeneity and to produce antibodies against this enzyme in order to provide the tools for elucidation of the biochemical mechanisms that regulate this enzyme and carbon allocation into galactolipids. 3. Our in vitro and in vivo labeling studies indicated the possibility that phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are associated with desaturation of the structural lipids, whereas shorter chain saturated fatty acids are more likely to be incorporated into TAG. 4. Isolation of several putative mutants of Nannochloropsis which appear to have different lipid and fatty acid compositions than the wild type; a mutant of a special importance that is devoid of EPA was fully characterized. In addition, we could demonstrate the feasibility of Nannochloropsis biomass production for aquaculture and human health: 1) We demonstrated in semi-industrial scale the feasibility of mass production of Nannochloropsis biomass in collaboration with the algae plant NBT in Eilat; 2) Nutritional studies verified the importance algal w3 fatty acids for the development of rats and demonstrated that Nannochloropsis biomass fed to pregnant and lactating rats can benefit their offspring.

Niger is a minor oilseed crop primarily grown in Ethiopia and India. The oil content in niger seeds ranges from 32% to 47%. Niger oil has several nutritional and therapeutic benefits. Despite these benefits, the crop has been widely neglected by breeders due to its low productivity. Therefore, understanding the extent of genetic variability within the niger germplasm is a prerequisite for selecting superior genotypes and enhancing productivity. The present experiment was conducted at the ICAR‐Indian Institute of Oilseeds Research, Hyderabad, Telangana, during the kharif seasons of 2022 and 2023. The study used an augmented randomized complete block design (ARCBD) with 111 accessions and four checks to assess variability in oil content and fatty acid composition. The analysis of variance showed significant differences among the accessions. Oil content ranged from 26.1% to 44.8%, with the highest oil content recorded in IC260240 (44.8%). Unsaturated fatty acids, such as linoleic and oleic acids, constituted the major portion of fatty acids among the accessions. The presence of a higher amount of unsaturated fatty acids indicates low susceptibility to autoxidation and confers a therapeutic advantage to niger oil. The accessions IC260250 and IC211053 exhibited high levels of linoleic and oleic acid content, respectively. Based on the Euclidean distance matrix method, the accessions were grouped into six hierarchical clusters. Cluster II had the highest number of accessions (34), followed by Cluster IV with nine accessions. The maximum genetic distance was observed between Clusters III and VI. Palmitic and stearic acids showed a significant positive correlation, whereas linolenic acid and oleic acid exhibited a significant negative correlation. No discernible variations were observed in the fatty acid composition among the accessions during the two seasons. The elite accessions identified from this study can be utilized as donors in the niger oil quality improvement program.

Natural products are a vast reservoir of complex and highly structurally diverse chemical compounds which play a key role in the discovery of novel bioactive molecules (lead compounds) with therapeutic benefit, and/or structures that could be used as chemical probes for understanding unknown biological processes. Recent advances in our understanding of intra-/inter-cellular processes and interaction mechanisms has led to the discovery of new biological targets for drug discovery. Moreover, technological advances in extraction and screening as well as for characterisation of natural products and biological targets open new possibilities for natural products in areas of biochemistry and drug discovery. In the present study four emerging biological targets (assays) were used to explore new small molecules which: [1] inhibit the complex formation between CUGn-RNA and MBNL1 which was identified as an important target for the treatment of myotonic dystrophy type 1 (DM1); [2] inhibit the expression of a protein named coronin-1, which was proposed as a new target for the treatment of tuberculosis (TB); [3] promote lymphatic endothelial cell (LEC) growth, which is of relevance in the treatment of lymphedema or chronic skin inflammation; and [4] inhibit thrombin-induced [Ca2+] influx which leads to a reduction in endothelial hyperpermeability, since this was found to be an underlying mechanism of action for the commercialised Crataegus WS 1442 extract which is used as a therapy for mild chronic heart failure (CHF). The first three projects (i.e., DM1, TB and Lymphatic) started with the screening of an extract library; whereas the last project (CHF) focused on Crataegus WS 1442 extract. In each of these projects, an approach known as HPLC-based activity profiling was utilised to track activity and characterise selected natural products that exhibited an interaction with the biological target. In the DM1 project, harmine (from Peganum harmala), 1,2-dihydrotanshinquinone I and methylenetanshinquinone (from Salvia miltiorrhiza), and berberine (from an alkaloid library screening) were identified as the most active compounds in inhibiting CUGn-RNA and MBNL1 complex formation. Accordingly, these hit compounds may have a potential for drug discovery in RNA-mediated diseases. In overall, compounds with planar scaffolds and in particular those containing nitrogen proved to be most active in inhibiting the complex formation and restoring MBNL1 function. In the TB project, two extracts that lead to the inhibition of coronin-1 expression, namely EtOAc extract of Dorstenia contrajerva and MeOH extract of Pancratium littorale, were prioritised for further investigation. A compound isolated from D. contrajerva EtOAc extract, known as dorstenin, only exhibited activity at a very high concentration. Therefore, it is postulated that the activity of D. contrajerva EtOAc extract was in fact due to minor constituents which act in a synergistic manner. Correlation of activity and toxicity data with structural information for alkaloids from P. littorale MeOH extract showed that molecules with secondary amines and/or methylenedioxy groups exhibited higher toxicity, whereas molecules which contained a hemiacetal ring and acetyl groups were more active. These results were found while using GFP assay. However, further analysis on the active alkaloids with western blotting did not confirm coronin-1 inhibition at the protein level. Accordingly, further investigations are needed to understand the interaction mechanisms of these compounds with the biological assay (GFP). In the Lymphatic project, DCM extract of Daphne giraldii was identified as an active extract in inducing LEC growth. Consecutive fractionation and assaying of this extract showed that activity was consistently localised in lipophilic regions of the extract. Further analysis on the active micro-fractions showed that each contained trace amounts of potent bioactive constituents. Various correlative analysis techniques suggested that daphnetoxin and some derivatives thereof were the main contributing factors for the observed activity. In the CHF project, fractions of Crataegus WS 1442 extract were tested in a calcium imaging assay. After further fractionation, one active sub-fraction was obtained that exhibited a strong reduction in endothelial hyperpermeability. The sub-fraction consisted mainly of fatty acids (40%) including stearic and palmitic acids, and triterpenes such as hyptatic acid (50%). However, none of these constituents in a purified state were found to inhibit thrombin-induced calcium influx. Accordingly, it is postulated that the activity of Crataegus WS 1442 extract is possibly induced by either a minor constituent with potent activity, or constituents which act synergistically. Each of these projects was among the first to assess the interaction of natural products with the four emerging biological targets which are highlighted above. Also, considering the lack of effective agents on the market to treat the corresponding diseases, this study made significant contributions to the discovery of new drugs in therapeutically unmet areas, via: (a) providing new hit compounds; (b) identifying constituents of potently active fractions; (c) correlating structural features with bioactivity as well as (d) identifying challenges and providing recommendations for further investigations.

IgA nephropathy (IgAN) is the most prevalent glomerular disease in young adults worldwide, while idiopathic nephrotic syndrome (INS) represents the most frequent manifestation of glomerular disease in childhood. Over the years, studies have speculated about the potential benefits of omega-3 polyunsaturated fatty acids (PUFAs) in improving morbidity in both forms of chronic kidney disease (CKD). The proposed mechanisms of action include reduction of proteinuria and modulation of dyslipidemia. Although in vitro and in vivo experimental studies report the suppressive effect of omega-3 PUFAs on inflammatory pathways linked with the progression of nephropathy, the evidence supporting their beneficial effect in IgAN and INS is still weak. Also, their ability to regulate levels of total cholesterol, low-density lipoprotein-cholesterol (LDL-C), and triglycerides (TG) suggests that they could delay both dyslipidemia-associated nephrotoxicity and atherosclerosis. Most of the clinical trials that were conducted on their therapeutic benefits in IgAN patients reported positive outcomes with low and high doses of omega-3 PUFAs. However, few of the trials noted inconclusive findings, with low-quality evidence suggesting potential improvements in surrogate renal function outcomes. If the beneficial effect of omega-3 PUFAs is predicated on their hypolipidemic action, much higher doses could be used in well-designed randomized-controlled trials (RCTs) to determine if they could produce better renal function outcomes and provide much stronger evidence of their therapeutic benefits in IgAN and INS. However, the current hypothetical mechanisms of action in these forms of CKD also include the effect of omega-3 PUFAs on renal inflammatory pathways and glomerular proteinuria. Perhaps, the unresolved therapeutic efficacy of these fatty acids in IgAN and INS suggests that their exact mechanisms of action are yet to be fully established. In this narrative review, we aim to appraise the current evidence of their potential therapeutic benefits in these diseases.