Computational and Experimental Approaches Towards Understanding the Role of ATG8 in Autophagy: A Therapeutic Paradigm in Leishmaniasis.

In the realm of parasitology, autophagy has emerged as a critical focal point, particularly in combating Leishmaniasis. Central to this endeavour is the recognition of the protein ATG8 as pivotal for the survival and infectivity of the parasitic organism Leishmania major, thereby making it a potential target for therapeutic intervention. Consequently, there is a pressing need to delve into the structural characteristics of ATG8 to facilitate the design of effective drugs. In this study, our efforts centered on the purification of ATG8 from Leishmania major, which enabled novel insights into its structural features through meticulous spectroscopic analysis. We aimed to comprehensively assess the stability and behaviour of ATG8 in the presence of various denaturants, including urea, guanidinium chloride, and SDS-based chemicals. Methodically, our approach included secondary structural analysis utilizing CD spectroscopy, which not only validated but also augmented computationally predicted structures of ATG8 reported in previous investigations. Remarkably, our findings unveiled that the purified ATG8 protein retained its folded conformation, exhibiting the anticipated secondary structure. Moreover, our exploration extended to the influence of lipids on ATG8 stability, yielding intriguing revelations. We uncovered a nuanced perspective suggesting that targeting both the lipid composition of Leishmania major and ATG8 could offer a promising strategy for future therapeutic approaches in combating leishmaniasis. Collectively, our study underscores the importance of understanding the structural intricacies of ATG8 in driving advancements towards the development of targeted therapies against Leishmaniasis, thereby providing a foundation for future investigations in this field.

A Lipid-Structured Model of Atherosclerosis with Macrophage Proliferation.

Atherosclerotic plaques are fatty deposits that form in the walls of major arteries and are one of the major causes of heart attacks and strokes. Macrophages are the main immune cells in plaques and macrophage dynamics influence whether plaques grow or regress. Macrophage proliferation is a key process in atherosclerosis, particularly in the development of mid-stage plaques, but very few mathematical models include proliferation. In this paper we reframe the lipid-structured model of Ford et al. (J Theor Biol 479:48-63, 2019. https://doi.org/10.1016/j.jtbi.2019.07.003 ) to account for macrophage proliferation. Proliferation is modelled as a non-local decrease in the lipid structural variable. Steady state analysis indicates that proliferation assists in reducing eventual necrotic core lipid content and spreads the lipid load of the macrophage population amongst the cells. The contribution of plaque macrophages from proliferation relative to recruitment from the bloodstream is also examined. The model suggests that a more proliferative plaque differs from an equivalent (defined as having the same lipid content and cell numbers) recruitment-dominant plaque in the way lipid is distributed amongst the macrophages. The macrophage lipid distribution of an equivalent proliferation-dominant plaque is less skewed and exhibits a local maximum near the endogenous lipid content.

Pharmacokinetics and Histotoxic Profile of a Novel Azithromycin-Loaded Lipid-Based Nanoformulation.

Azithromycin traditional formulations possesses poor oral bioavailability which necessitates development of new formulation with enhanced bioavailability of the drug. The objective of current research was to explore the kinetics and safety profile of the newly developed azithromycin lipid-based nanoformulation (AZM-NF). In the in-vitro study of kinetics profiling, azithromycin (AZM) release was assessed using dialysis membrane enclosing equal quantity of either AZM-NF, oral suspension of azithromycin commercial product (AZM-CP), or azithromycin pure drug (AZM-PD) in simulated intestinal fluid. The ex-vivo study was performed using rabbit intestinal segments in physiological salts solution in a tissue bath. The in-vivo study was investigated by oral administration of AZM to rabbits while taking blood samples at predetermined time-intervals, followed by HPLC analysis. The toxicity study was conducted in rats to observe histopathological changes in rat's internal organs. In the in-vitro study, maximum release was 95.38 ± 4.58% for AZM-NF, 72.79 ± 8.85% for AZM-CP, and 46.13 ± 8.19% for AZM-PD (p < 0.0001). The ex-vivo investigation revealed maximum permeation of 85.68 ± 5.87 for AZM-NF and 64.88 ± 5.87% for AZM-CP (p < 0.001). The in-vivo kinetics showed Cmax 0.738 ± 0.038, and 0.599 ± 0.082 µg/ml with Tmax of 4 and 2 h for AZM-NF and AZM-CP respectively (p < 0.01). Histopathological examination revealed compromised myocardial fibers integrity by AZM-CP only, liver and kidney showed mild aberrations by both formulations, with no remarkable changes in the rest of studied organs. The results showed that AZM-NF exhibited significantly enhanced bioavailability with comparative safer profile to AZM-CP investigated.

Food availability aligns with contrasting demographics in populations of an at-risk songbird.

Golden-winged Warblers (Vermivora chrysoptera) have become rare across much of their historic breeding range and response to conservation efforts is variable. Evidence from several recent studies suggests that breeding output is a primary driver explaining responses to conservation and it is hypothesized that differences in food availability may be driving breeding output disparity between two subpopulations of the warbler's Appalachian breeding range. Herein, we studied two subpopulations: central Pennsylvania ("central subpopulation"), where breeding productivity is relatively low, and eastern Pennsylvania ("eastern subpopulation"), where breeding productivity is relatively high. To test the food-availability hypothesis in this system, we measured density of caterpillars, plasma lipid metabolites (triglycerides [TRIG; fat deposition] and glycerol [GLYC; fat breakdown]), body mass of adults males, and acquired body mass data for fledglings at 38 sites managed for nesting habitat. Consistent with our prediction, leaf-roller caterpillar density, the group upon which Golden-winged Warblers specialize, was 45× lower in the central subpopulation than the eastern subpopulation. TRIG concentrations were highest within the eastern subpopulation during breeding grounds arrival. The change in TRIG concentrations from the breeding-grounds-arrival stage to the nestling-rearing stage was subpopulation dependent: TRIG decreased in the eastern subpopulation and was constant in the central subpopulation, resulting in similar concentrations during the nestling-rearing stage. Furthermore, GLYC concentrations were higher in the eastern subpopulation, which suggests greater energy demands in this region. Despite this, adult male warblers in the eastern subpopulation maintained a higher average body mass. Finally, fledgling body mass was 16% greater in the eastern subpopulation than the central subpopulation before and after fledging. Collectively, our results suggest that poor breeding success of Golden-winged Warblers in the central subpopulation could be driven by lower availability of primary prey during the breeding season (leaf-roller caterpillars), and this, in turn, limits their response to conservation efforts.

Effect of dates on blood glucose and lipid profile among patients with type 2 diabetes.

Poor fruit and vegetable consumption is one of the 10 major risk factors for mortality. There is a misconception regarding the consumption of dates among patients with diabetes. This manuscript assessed the effects of date consumption on fasting and postprandial blood glucose, glycated hemoglobin, total cholesterol, triglycerides, low-density lipoproteins, high-density lipoproteins, and microbial markers. Four literature databases were searched for relevant articles. Of the 595 studies retrieved, 24 assessed the effects of dates on glycemic control and lipids. Overall, the evidence suggests that dates have a lowering effect on blood glucose. Dates reduce total cholesterol and triglyceride levels and increase high-density lipoprotein levels. Dates also promote the abundance of beneficial gut microbiota. Therefore, patients with diabetes and dyslipidemia can consume dates to reduce their blood glucose, cholesterol, and triglycerides.

Comparative Effects of Target-Controlled Infusion of Propofol Versus Spinal and Thiopental-Sevoflurane Anesthesia on Lipid Peroxidation in Elective Cesarean Section: A Prospective, Open-Label Study.

BACKGROUND: During pregnancy, physiological changes can increase oxidative stress (OS) in both mothers and fetuses. The use of anesthesia for cesarean sections (CSs) could exacerbate this stress due to its impact on the ischemia-reperfusion effect. Our study aimed to explore the effects of target-controlled infusion of propofol on OS during CSs, and to compare these effects with those of spinal and thiopental-sevoflurane anesthesia. METHODS: The study included ninety parturients undergoing elective CS, allocated into three groups: Group S (spinal) (n = 30), Group P (propofol) (n = 30), and Group TS (thiopental-sevoflurane) (n = 30). Venous blood samples were taken from mothers at three time points, before, during, and after surgery, and one sample was taken from the umbilical vein after delivery. Blood samples were analyzed with the thiobarbituric acid reactive substances (TBARS) assay and blood gas analysis. A statistical comparison between groups was obtained by one-way analysis of variance (ANOVA) and the Wilcoxon test where appropriate. RESULTS: Levels of TBARS after the induction of anesthesia were lower in all groups compared to values preoperatively. In Group P, TBARS levels started to decrease in the first five minutes after the induction (1.90 ± 0.47; P < 0.001) and had significantly lower values compared to Group S (2.22 ± 0.21) and Group TS (2.40 ± 0.20). Two hours after surgery, TBARS values were the lowest in Group P (1.76 ± 0.15, P<0.001), compared to Group S (2.18 ± 0.24) and Group TS (2.41 ± 0.21). TBARS value in umbilical venous blood was significantly lower in Group P (1.56 ± 0.16, P < 0.001) compared to Group S (2.18 ± 0.17) and Group TS (2.09 ± 0.09). Umbilical cord venous blood gas values (pH, PCO2, HCO3, lactates, and base excess (BE)) were not different between the groups, except for PO2, which was significantly lower in Group S (20.5 ± 5.0; P < 0.001) compared to Group P (36.5 ± 19.2) and Group TS (33.5 ± 10.1). CONCLUSION: Target-controlled infusion of propofol anesthesia could be advantageous for parturients with compromised oxidative status, especially those undergoing emergency CSs when general anesthesia is required.

A Patent Analysis on Nano Drug Delivery Systems.

BACKGROUND: A nano drug delivery system is an effective tool for drug delivery and controlled release, which is used for a variety of medical applications. In recent decades, nano drug delivery systems have been significantly developed with the emergence of new nanomaterials and nanotechnologies. OBJECTIVE: This article aimed to provide insight into the technological development of nano drug delivery systems through patent analysis. METHODS: 3708 patent documents were used for patent analysis after retrieval from the Incopat patent database. RESULTS: The number of patents on nano drug delivery systems has shown a rapid growth trend in the past two decades. At present, China and the United States have obvious contributions to the number of patents. According to the patent data, the nanomaterials used in nano drug delivery system are mainly inorganic nanomaterials, lipid-based nanomaterials, and macromolecules. In recent years, the highly cited patents (≥14) for nano drug delivery systems mainly involve lipid-based nanomaterials, indicating that their technology is mature and widely used. The inorganic nanomaterials in drug delivery have received increasing attention, and the number of related patents has increased significantly after 2016. The number of highly cited patents in the United States is 250, which is much higher than in other countries. CONCLUSION: Even after decades of development, nano drug delivery systems remain a hot topic for researchers. The significant increase in patents since 2016 can be attributed to the large number of new patents from China. However, according to the proportion of highly cited patents in total, China's patented technologies in nano drug delivery systems are not advanced enough compared to developed countries, including the United States, Canada, Germany, and France. In the future, research on emerging nanomaterials for nano drug delivery systems, such as inorganic nanomaterials, may focus on developing new materials and optimising their properties. The lipid-based and polymer- based nanomaterials can be continuously improved for the development of new nanomedicines.

Polar Lipids Supplementation Enhances Basal Excitatory Synaptic Transmission in Primary Cortical Neuron.

SCOPE: Polar lipids, such as gangliosides and phospholipids, are fundamental structural components that play critical roles in the development and maturation of neurons in the brain. Recent evidence has demonstrated that dietary intakes of polar lipids in early life are associated with improved cognitive outcomes during infancy and adolescence. However, the specific mechanisms through which these lipids impact cognition remain unclear. METHODS AND RESULTS: This study examines the direct physiological impact of polar lipid supplementation, in the form of buttermilk powder, on primary cortical neuron growth and maturation. The changes are measured with postsynaptic current response recordings, immunohistochemical examination of functional synapse localization and numbers, and the biochemical quantification of receptors responsible for neuronal synaptic neurotransmission. Chronic exposure to polar lipids increases primary mouse cortical neuron basal excitatory synapse response strength attributed to enhanced dendritic complexity and an altered expression of the excitatory α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit 2 (GluR2). CONCLUSION: The present finding suggests that dietary polar lipids improve human cognition through an enhancement of neuronal maturation and/or function.

Physiologic medium renders human iPSC-derived macrophages permissive for M. tuberculosis by rewiring organelle function and metabolism.

In vitro studies are crucial for our understanding of the human macrophage immune functions. However, traditional in vitro culture media poorly reflect the metabolic composition of blood, potentially affecting the outcomes of these studies. Here, we analyzed the impact of a physiological medium on human induced pluripotent stem cell (iPSC)-derived macrophages (iPSDM) function. Macrophages cultured in a human plasma-like medium (HPLM) were more permissive to Mycobacterium tuberculosis (Mtb) replication and showed decreased lipid metabolism with increased metabolic polarization. Functionally, we discovered that HPLM-differentiated macrophages showed different metabolic organelle content and activity. Specifically, HPLM-differentiated macrophages displayed reduced lipid droplet and peroxisome content, increased lysosomal proteolytic activity, and increased mitochondrial activity and dynamics. Inhibiting or inducing lipid droplet formation revealed that lipid droplet content is a key factor influencing macrophage permissiveness to Mtb. These findings underscore the importance of using physiologically relevant media in vitro for accurately studying human macrophage function. IMPORTANCE: This work compellingly demonstrates that the choice of culture medium significantly influences M. tuberculosis replication outcomes, thus emphasizing the importance of employing physiologically relevant media for accurate in vitro host-pathogen interaction studies. We anticipate that our work will set a precedent for future research with clinical relevance, particularly in evaluating antibiotic efficacy and resistance in cellulo.

BECC-engineered live-attenuated Shigella vaccine candidates display reduced endotoxicity with robust immunogenicity in mice.

Shigella spp. infection contributes significantly to the global disease burden, primarily affecting young children in developing countries. Currently, there are no FDA-approved vaccines against Shigella, and the prevalence of antibiotic resistance is increasing, making therapeutic options limited. Live-attenuated vaccine strains WRSs2 (S. sonnei) and WRSf2G12 (S. flexneri 2a) are highly immunogenic, making them promising vaccine candidates, but possess an inflammatory lipid A structure on their lipopolysaccharide (LPS; also known as endotoxin). Here, we utilized bacterial enzymatic combinatorial chemistry (BECC) to ectopically express lipid A modifying enzymes in WRSs2 and WRSf2G12, as well as their respective wild-type strains, generating targeted lipid A modifications across the Shigella backgrounds. Dephosphorylation of lipid A, rather than deacylation, reduced LPS-induced TLR4 signaling in vitro and dampened endotoxic effects in vivo. These BECC-modified vaccine strains retained the phenotypic traits of their parental strains, such as invasion of epithelial cells and immunogenicity in mice without adverse endotoxicity. Overall, our observations suggest that BECC-engineered live attenuated vaccines are a promising approach to safe and effective Shigella vaccines.

The Role of Alpha-Synuclein in Synucleinopathy: Impact on Lipid Regulation at Mitochondria-ER Membranes.

The protein alpha-synuclein (αSyn) plays a critical role in the pathogenesis of synucleinopathy, which includes Parkinson's disease and multiple system atrophy, and mounting evidence suggests that lipid dyshomeostasis is a critical phenotype in these neurodegenerative conditions. Previously, we identified that αSyn localizes to mitochondria-associated endoplasmic reticulum membranes (MAMs), temporary functional domains containing proteins that regulate lipid metabolism, including the de novo synthesis of phosphatidylserine. In the present study, we have analyzed the lipid composition of postmortem human samples, focusing on the substantia nigra pars compacta of Parkinson's disease and controls, as well as three less affected brain regions of Parkinson's donors. To further assess synucleinopathy-related lipidome alterations, similar analyses were performed on the striatum of multiple system atrophy cases. Our data show region-and disease-specific changes in the levels of lipid species. Specifically, our data revealed alterations in the levels of specific phosphatidylserine species in brain areas most affected in Parkinson's disease. Some of these alterations, albeit to a lesser degree, are also observed multiples system atrophy. Using induced pluripotent stem cell-derived neurons, we show that αSyn contributes to regulating phosphatidylserine metabolism at MAM domains, and that αSyn dosage parallels the perturbation in phosphatidylserine levels. Our results support the notion that αSyn pathophysiology is linked to the dysregulation of lipid homeostasis, which may contribute to the vulnerability of specific brain regions in synucleinopathy. These findings have significant therapeutic implications.

The N-glycosylation defect in Lec5 and Lec9 CHO cells is caused by absence of the DHRSX gene.

Glycosylation-deficient Chinese hamster ovary (CHO) cell lines have been instrumental in the discovery of N-glycosylation machinery. Yet, the molecular causes of the glycosylation defects in the Lec5 and Lec9 mutants have been elusive, even though for both cell lines a defect in dolichol formation from polyprenol was previously established. We recently found that dolichol synthesis from polyprenol occurs in three steps consisting of the conversion of polyprenol to polyprenal by DHRSX, the reduction of polyprenal to dolichal by SRD5A3 and the reduction of dolichal to dolichol, again by DHRSX. This led us to investigate defective dolichol synthesis in Lec5 and Lec9 cells. Both cell lines showed increased levels of polyprenol and its derivatives, concomitant with decreased levels of dolichol and derivatives, but no change in polyprenal levels, suggesting DHRSX deficiency. Accordingly, N-glycan synthesis and changes in polyisoprenoid levels were corrected by complementation with human DHRSX but not with SRD5A3. Furthermore, the typical polyprenol dehydrogenase and dolichal reductase activities of DHRSX were absent in membrane preparations derived from Lec5 and Lec9 cells, while the reduction of polyprenal to dolichal, catalyzed by SRD5A3, was unaffected. Long-read whole genome sequencing of Lec5 and Lec9 cells did not reveal mutations in the ORF of SRD5A3, but the genomic region containing DHRSX was absent. Lastly, we established the sequence of Chinese hamster DHRSX and validated that this protein has similar kinetic properties to the human enzyme. Our work therefore identifies the basis of the dolichol synthesis defect in CHO Lec5 and Lec9 cells.

Interrelationship among substrate utilization, metabolic productions, and housekeeping-related gene expression levels in Mortierella alpine CBS 754.68.

The impacts of Magnesium oxide nanoparticles (MgONPs) on the expression of 10 potential housekeeping genes of Mortierella alpine were assayed. Actin emerged as the good candidate when Mortierella alpine entered the death phase subsequent to the growth phase while Dihydropteridine reductase and 28 s were identified as suitable candidates when Mortierella alpine remained in the growth phase.

Spatiotemporal fate of nanocarriers-embedded dissolving microneedles: the impact of needle dissolving rate.

OBJECTIVE: Dissolving microneedles (DMNs) have shown great potential for transdermal drug delivery due to their excellent skin-penetrating ability and combination with nanocarriers (NCs) can realize targeted drug delivery. The objective of this study was to investigate the impact of microneedle dissolving rate on the in vivo fate of NC-loaded DMNs, which would facilitate the clinical translation of such systems. METHODS: Solid lipid nanoparticles (SLNs) were selected as the model NC for loading in DMNs, which were labeled by P4 probes with aggregation-quenching properties. Sodium hyaluronate acid (HA) and chitosan (CS), with different aqueous dissolving rates, were chosen as model tip materials. The effects of needle dissolving rate on the in vivo fate of NC-loaded DMNs was investigated by tracking the distribution of fluorescence signals after transdermal exposure. RESULTS: P4 SLNs achieved a deeper diffusion depth of 180 µm in DMN-HA with a faster dissolution rate, while the diffusion depth in DMN-CS with a slower dissolution rate was lower (140 µm). The in vivo experiments demonstrated that P4 SLNs had a T1/2 value of 12.14 h in DMN-HA, whilst a longer retention time was found in DMN-CS, with a T1/2 of 13.12 h. CONCLUSIONS: This study confirmed that the in vivo diffusion rate of NC-loaded DMNs was determined by the dissolving rate of DMNs materials and provided valuable guidance for the design and development of NC-loaded DMNs in the future.

The processed Euphorbia lathyris L. alleviates the inflammatory injury via regulating LXRα/ABCA1 expression and TLR4 positioning to lipid rafts.

Euphorbia lathyris L. (EL) is a traditional poisonous herbal medicine used to treat dropsy, ascites, amenorrhea, anuria and constipation. Processing to reduce toxicity of EL is essential for its safe and effective application. However, there is little known regarding the molecular mechanism of reducing toxicity after EL processing. This research aimed to screen the differential markers for EL and PEL, explore the differential mechanisms of inflammatory injury induced by EL and processed EL (PEL) to expound the mechanism of alleviating toxicity after EL processing. The results showed that 15 potential biomarkers, mainly belonging to diterpenoids, were screened to distinguish EL from PEL. EL promoted the expressions of TLR4, NLRP3, NF-κB p65, IL-1ß and TNF-α, increased lipid rafts abundance and promoted TLR4 positioning to lipid rafts. Meanwhile, EL decreased LXRα and ABCA1 expression, and reduced cholesterol efflux. In contrast to EL, the effects of PEL on these indicators were markedly weakened. In addition, Euphorbia factors L1, L2, and L3 affected LXRα, ABCA1, TLR4, NLRP3, NF-κB p65, TNF-α and IL-1ß expression, influenced cholesterol efflux and lipid rafts abundance, and interfered with the colocalization of TLR4 and lipid rafts. The inflammatory injury caused by processed EL was significantly weaker than that caused by crude EL, and reduction of Euphorbia factors L1, L2, and L3 as well as attenuation of inflammatory injury participated in processing-based detoxification of EL. Our results provide valuable insights into the attenuated mechanism of EL processing and will guide future research on the processing mechanism of toxic traditional Chinese medicine.

The cytoplasmic tail of myelin protein zero induces morphological changes in lipid membranes.

The major myelin protein expressed by the peripheral nervous system Schwann cells is protein zero (P0), which represents 50% of the total protein content in myelin. This 30-kDa integral membrane protein consists of an immunoglobulin (Ig)-like domain, a transmembrane helix, and a 69-residue C-terminal cytoplasmic tail (P0ct). The basic residues in P0ct contribute to the tight packing of myelin lipid bilayers, and alterations in the tail affect how P0 functions as an adhesion molecule necessary for the stability of compact myelin. Several neurodegenerative neuropathies are related to P0, including the more common Charcot-Marie-Tooth disease (CMT) and Dejerine-Sottas syndrome (DSS) as well as rare cases of motor and sensory polyneuropathy. We found that high P0ct concentrations affected the membrane properties of bicelles and induced a lamellar-to-inverted hexagonal phase transition, which caused bicelles to fuse into long, protein-containing filament-like structures. These structures likely reflect the formation of semicrystalline lipid domains with potential relevance for myelination. Not only is P0ct important for stacking lipid membranes, but time-lapse fluorescence microscopy also shows that it might affect membrane properties during myelination. We further describe recombinant production and low-resolution structural characterization of full-length human P0. Our findings shed light on P0ct effects on membrane properties, and with the successful purification of full-length P0, we have new tools to study the role of P0 in myelin formation and maintenance in vitro.

Benzoate glycosides from Gentiana scabra Bge. and their lipid-lowering activity.

Seven undescribed benzoate glycosides (1-7) and five known ones (8-12) were isolated from the rhizomes of Gentiana scabra Bge. Their structures were characterized by comprehensive NMR and MS spectroscopic data analysis. The lipid-lowering effects of these compounds were evaluated by measuring the triglyceride (TG) contents and intracellular lipid droplets (LDs) in oleic acid (OA)-treated HepG2 cells. The results showed that compounds 1, 5, 7, and 11 significantly reduced the TG content at 20 µM, and the Bodipy staining displayed that OA enhanced the levels of LDs in the cell, while these compounds reversed the lipid accumulation caused by OA. These findings provide a basis for further development and utilization of G. scabra as a natural source of potential lipid-lowering agents.

Vitamins and fatty acids against chemotherapy-induced intestinal mucositis.

Chemotherapy has allowed an increase in cancer survivorship, but it causes important adverse effects. Mucositis affecting the gastrointestinal tract is one of the main problems acutely caused by many antineoplastic drugs, such as 5-fluorouracil or methotrexate. Mucositis may cause pain, diarrhea, anorexia, weight loss, systemic infections and even death. This narrative review focuses on intestinal mucositis and the role that some nutraceuticals, namely vitamins (both lipid- and water-soluble) as well as fatty acids (FAs) and lipid-based products, can have in it. In preclinical (cell cultures, animal models) and/or human studies, vitamins A, D, E, B2, B9 and C, omega-3 long-chain FAs (eicosapentaenoic, docosahexaenoic, conjugated linoleic acid), short-chain FAs (mainly butyrate), medium-chain FAs (capric acid), and different lipid-based products (emu oil, extra-virgin olive oil, lipid replacement therapy), enriched in beneficial FAs and natural antioxidants, were shown to exert beneficial effects (both preventative and palliative) against chemotherapy-induced intestinal mucositis. Although the exact mechanisms of action involved in these effects are not yet well known, our review highlights the interest of investigating on diet and nutrition to implement scientifically robust strategies to improve protection of cancer patients against chemotherapy-induced adverse effects.

Proteomic and lipidomic analysis of the mechanism underlying astragaloside IV in mitigating ferroptosis through hypoxia-inducible factor 1α/heme oxygenase 1 pathway in renal tubular epithelial cells in diabetic kidney disease.

ETHNOPHARMACOLOGICAL RELEVANCE: The limitations of modern medicine in mitigating the pathological process of diabetic kidney disease (DKD) necessitate novel, precise, and effective prevention and treatment methods. Huangqi, the root of Astragalus membranaceus Fisch. ex Bunge has been used in traditional Chinese medicine for various kidney ailments. Astragaloside IV (AS-IV), the primary pharmacologically active compound in A. membranaceus, is involved in lipid metabolism regulation; however, its potential in ameliorating renal damage in DKD remains unexplored. AIM OF THE STUDY: To elucidate the specific mechanism by which AS-IV moderates DKD progression. MATERIALS AND METHODS: A murine model of DKD and high glucose-induced HK-2 cells were treated with AS-IV. Furthermore, multiomics analysis, molecular docking, and molecular dynamics simulations were performed to elucidate the mechanism of action of AS-IV in DKD, which was validated using molecular biological methods. RESULTS: AS-IV regulated glucose and lipid metabolism in DKD, thereby mitigating lipid deposition in the kidneys. Proteomic analysis identified 12 proteins associated with lipid metabolism regulated by AS-IV in the DKD renal tissue. Additionally, lipid metabolomic analysis revealed that AS-IV upregulated and downregulated 4 beneficial and 79 harmful lipid metabolites, respectively. Multiomics analysis further indicated a positive correlation between the top-ranked differential protein heme oxygenase (HMOX)1 and the levels of various harmful lipid metabolites and a negative correlation with the levels of beneficial lipid metabolites. Furthermore, enrichment of both ferroptosis and hypoxia-inducible factor (HIF)-1 signaling pathways during the AS-IV treatment of DKD was observed using proteomic analysis. Validation results showed that AS-IV effectively reduced ferroptosis in DKD-affected renal tubular epithelial cells by inhibiting HIF-1α/HMOX1 pathway activity, upregulating glutathione peroxidase-4 and ferritin heavy chain-1 expression, and downregulating acyl-CoA synthetase long-chain family member-4 and transferrin receptor-1 expression. Our findings demonstrate the potential of AS-IV in mitigating DKD pathology by downregulating the HIF-1α/HMOX1 signaling pathway, thereby averting ferroptosis in renal tubular epithelial cells. CONCLUSIONS: AS-IV is a promising treatment strategy for DKD via the inhibition of ferroptosis in renal tubular epithelial cells. The findings of this study may help facilitate the development of novel therapeutic strategies.