Transdermal delivery of resveratrol loaded solid lipid nanoparticle as a microneedle patch: a novel approach for the treatment of Parkinson's disease.

Parkinson's disease (PD), affecting millions of people worldwide and expected to impact 10 million by 2030, manifests a spectrum of motor and non-motor symptoms linked to the decline of dopaminergic neurons. Current therapies manage PD symptoms but lack efficacy in slowing disease progression, emphasizing the urgency for more effective treatments. Resveratrol (RSV), recognized for its neuroprotective and antioxidative properties, encounters challenges in clinical use for PD due to limited bioavailability. Researchers have investigated lipid-based nanoformulations, specifically solid lipid nanoparticles (SLNs), to enhance RSV stability. Oral drug delivery via SLNs faces obstacles, prompting exploration into transdermal delivery using SLNs integrated with microneedles (MNs) for improved patient compliance. In this study, an RSV-loaded SLNs (RSV -SLNs) incorporated into the MN patch was developed for transdermal RSV delivery to improve its stability and patient compliance. Characterization studies demonstrated favorable physical properties of SLNs with a sustained drug release profile of 78.36 ± 0.74%. The developed MNs exhibited mechanical robustness and skin penetration capabilities. Ex vivo permeation studies displayed substantial drug permeation of 68.39 ± 1.4% through the skin. In an in vivo pharmacokinetic study, the RSV-SLNs delivered through MNs exhibited a significant increase in Cmax, Tmax, and AUC0 - t values, alongside a reduced elimination rate in blood plasma in contrast to the administration of pure RSV via MNs. Moreover, an in vivo study showcased enhanced behavioral functioning and increased brain antioxidant levels in the treated animals. In-vivo skin irritation study revealed no signs of irritation till 24 h which permits long-term MNs application. Histopathological analysis showed notable changes in the brain regions of the rat, specifically the striatum and substantia nigra, after the completion of the treatment. Based on these findings, the development of an RSV-SLN loaded MNs (RSVSNLMP) patch presents a novel approach, with the potential to enhance the drug's efficiency, patient compliance, and therapeutic outcomes for PD, offering a promising avenue for advanced PD therapy.

How do Photoswitchable Lipids Influence the Intercalation of Anticancer Drug in Lipid Membrane? Investigation using Molecular Dynamics Simulation.

Photoswitchable lipids, particularly azobenzene-derivatized phosphatidylcholine (azoPC) lipids, offer a unique mechanism for reversible modification of membrane properties upon exposure to ultraviolet (UV) radiation. Through all-atom molecular dynamics simulations, we explore how UV irradiation-induced trans-to-cis photoisomerization(TCPI) of AzoPC lipid influences the structure and dynamics of a lipid membrane, composed of dipalmitoylphosphatidylcholine (DPPC) and cholesterol with similar composition to that of the DOXIL®.  Structural and dynamical analyses of two states of the membrane, 'dark' state (containing cis-azoPC lipid) and 'bright' state (containing 85% cis-azoPC and 15% trans-azoPC lipids) reveal that the TCPI reduces membrane packing density and increases diffusivity of lipids. We have demonstrated an enhanced intercalation of doxorubicine (DOX), an anticancer drug, in the 'bright' state of the membrane compared to that in 'dark' state. This study - elucidating the complex interplay between lipid composition, photoswitching, and lipid-drug interactions - contribute to the design of lipid-based systems for targeted drug delivery and biomedical applications.

Targeted lipidomics uncovers oxylipin perturbations and potential circulation biomarkers in Bietti's crystalline dystrophy.

PURPOSE: Abnormalities in lipid metabolism have been proposed in Bietti's crystalline dystrophy (BCD). We aim to characterize the lipid profiles in a case-control study. METHODS: All participants were genetically confirmed by CYP4V2 gene sequencing and underwent chorioretinopathy evaluation by calculating the percentages of AF atrophy (PAFA). Fasting blood samples of BCD patients and controls were collected, and plasma was analyzed for routine lipid profiles. Targeted lipidomic evaluation includes long chain polyunsaturated fatty acids (LCPUFA) and associated eicosanoid metabolites. RESULTS: Routine lipids profiles showed elevated plasma levels of triglyceride (P = 0.043) and low-density lipoprotein cholesterol (P = 0.024) in BCD patients. Lipidomic analysis showed significantly decreased levels of ω-3 LCPUFA including docosahexaenoic acid (DHA, 22:6, P = 0.00068) and eicosapentaenoic acid (EPA, 20:5, P = 0.0016), as well as ω-6 LCPUFA arachidonic acid (ARA, 20:4, P < 0.0001) in BCD patients. Eicosanoid metabolites, either derived from ω-3 and/ or ω-6 LCPUFAs via cyclooxygenase (COX) or lipoxygenase (LOX) pathways, including 5-HEPE, 12-HEPE, 13-HDHA, 15-HETE, 12-HETE, 5-HETE, 6k-PGF1a, PGE2, PGJ2, and TXB2, exhibited significant differences (P < 0.0001) between BCD patients and controls. Genotypes of CYP4V2, specifically the biallelic null mutations, were observed to correlate with more remarkably reduced levels of oxylipins, involving major LOX pathway metabolites including 5-HETE, 5-HEPE, 12-HEPE and LTB4. CONCLUSIONS: BCD patients demonstrated significant decreases in plasma levels of ω-3 and ω-6 LCPUFA (DHA, EPA, and ARA), as well as their downstream metabolites via the COX and LOX pathways, suggesting that these might be implicated in BCD pathogenesis and could serve as biomarkers and therapeutic targets of the disease. KEY MESSAGES: What is known BCD is a vision-threatening hereditary disease the causative gene of which is CYP4V2. Abnormalities in lipid metabolism have been proposed and demonstrated previously in BCD studies. The detailed pathogenesis remains unclear and controversial. What is new We observed prominent lipidomic alterations in the circulation when compared with age, gender, and bodymass index (BMI)-matched healthy controls. BCD patients demonstrated significant decreases in plasma levels of ω-3 and ω-6 LCPUFA (DHA, EPA, and ARA). Remarkable changes were observed in the downstream metabolites of the LCPUFA via the COX and LOX pathways. Genotypes of CYP4V2, specifically the biallelic null mutations, were observed to correlate with more remarkably reduced levels of oxylipins, involving major LOX pathway metabolites.

Demystifying the potential of lipid-based nanocarriers in targeting brain malignancies.

Drug targeting for brain malignancies is restricted due to the presence of the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB), which act as barriers between the blood and brain parenchyma. Certainly, the limited therapeutic options for brain malignancies have made notable progress with enhanced biological understanding and innovative approaches, such as targeted therapies and immunotherapies. These advancements significantly contribute to improving patient prognoses and represent a promising shift in the landscape of brain malignancy treatments. A more comprehensive understanding of the histology and pathogenesis of brain malignancies is urgently needed. Continued research focused on unraveling the intricacies of brain malignancy biology holds the key to developing innovative and tailored therapies that can improve patient outcomes. Lipid nanocarriers are highly effective drug delivery systems that significantly improve their solubility, bioavailability, and stability while also minimizing unwanted side effects. Surface-modified lipid nanocarriers (liposomes, niosomes, solid lipid nanoparticles, nanostructured lipid carriers, lipid nanocapsules, lipid-polymer hybrid nanocarriers, lipoproteins, and lipoplexes) are employed to improve BBB penetration and uptake through various mechanisms. This systematic review illuminates and covers various topics related to brain malignancies. It explores the different methods of drug delivery used in treating brain malignancies and delves into the benefits, limitations, and types of brain-targeted lipid-based nanocarriers. Additionally, this review discusses ongoing clinical trials and patents related to brain malignancy therapies and provides a glance into future perspectives for treating this condition.

Clinical serum lipidomic profiling revealed potential lipid biomarkers for early diabetic retinopathy.

Diabetic retinopathy (DR) is a serious complication of diabetes featuring abnormal lipid metabolism. However, the specific lipid molecules associated with onset and progression remain unclear. We used a broad-targeted lipidomics approach to assess the lipid changes that occur before the proliferative retinopathy stage and to identify novel lipid biomarkers to distinguish between patients without DR (NDR) and with non-proliferative DR (NPDR). Targeted lipomics analysis was carried out on serum samples from patients with type I diabetes, including 20 NDRs and 20 NPDRs. The results showed that compared with the NDR group, 102 lipids in the NPDR group showed specific expressions. Four lipid metabolites including TAG58:2-FA18:1 were obtained using the Least Absolute Shrink And Selection Operator (LASSO) and Support Vector Machine Recursive Feature Elimination (SVM-RFE) methods. The four-lipid combination diagnostic models showed good predictive ability in both the discovery and validation sets, and were able to distinguish between NDR patients and NPDR patients. The identified lipid markers significantly improved diagnostic accuracy within the NPDR group. Our findings help to better understand the complexity and individual differences of DR lipid metabolism.

Exploring selection signatures in the divergence and evolution of lipid droplet (LD) associated genes in major oilseed crops.

BACKGROUND: Oil bodies or lipid droplets (LDs) in the cytosol are the subcellular storage compartments of seeds and the sites of lipid metabolism providing energy to the germinating seeds. Major LD-associated proteins are lipoxygenases, phospholipaseD, oleosins, TAG-lipases, steroleosins, caleosins and SEIPINs; involved in facilitating germination and enhancing peroxidation resulting in off-flavours. However, how natural selection is balancing contradictory processes in lipid-rich seeds remains evasive. The present study was aimed at the prediction of selection signatures among orthologous clades in major oilseeds and the correlation of selection effect with gene expression. RESULTS: The LD-associated genes from the major oil-bearing crops were analyzed to predict natural selection signatures in phylogenetically close-knit ortholog clusters to understand adaptive evolution. Positive selection was the major force driving the evolution and diversification of orthologs in a lineage-specific manner. Significant positive selection effects were found in 94 genes particularly in oleosin and TAG-lipases, purifying with excess of non-synonymous substitution in 44 genes while 35 genes were neutral to selection effects. No significant selection impact was noticed in Brassicaceae as against LOX genes of oil palm. A heavy load of deleterious mutations affecting selection signatures was detected in T-lineage oleosins and LOX genes of Arachis hypogaea. The T-lineage oleosin genes were involved in mainly anther, tapetum and anther wall morphogenesis. In Ricinus communis and Sesamum indicum > 85% of PLD genes were under selection whereas selection pressures were low in Brassica juncea and Helianthus annuus. Steroleosin, caleosin and SEIPINs with large roles in lipid droplet organization expressed mostly in seeds and were under considerable positive selection pressures. Expression divergence was evident among paralogs and homeologs with one gene attaining functional superiority compared to the other. The LOX gene Glyma.13g347500 associated with off-flavor was not expressed during germination, rather its paralog Glyma.13g347600 showed expression in Glycine max. PLD-α genes were expressed on all the tissues except the seed,δ genes in seed and meristem while ß and γ genes expressed in the leaf. CONCLUSIONS: The genes involved in seed germination and lipid metabolism were under strong positive selection, although species differences were discernable. The present study identifies suitable candidate genes enhancing seed oil content and germination wherein directional selection can become more fruitful.

Evaluation of the ability of insulin resistance and lipid-related indices to predict the presence of NAFLD in obese adolescents.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has become an important health issue in adolescents. Although several parameters and indices have been investigated for the evaluation of NAFLD in adults, these indices are limited in adolescents. In this study, body mass index, waist circumference, triponderal mass index, HbA1c, homeostatic model assessment insulin resistance (HOMA-IR), triglyceride/high-density lipoprotein (Tg/HDL), the lipid accumulation product (LAP) index, the triglyceride-glucose (TyG) index and the aminotransferase (AT) index were examined together, and their diagnostic values in the clinical treatment of NAFLD were compared. MATERIALS AND METHODS: Seventynine adolescents (10-19 years old) with obesity who were admitted to a pediatric clinic between January and August 2022 and who were diagnosed with exogenous obesity without any comorbidities were included in the study. The presence of NAFLD was evaluated by liver magnetic resonance imaging. The laboratory findings were obtained retrospectively from system records. Parameters were compared between the NAFLD (+) and NAFLD (-) groups. Logistic regression analysis was used to determine the most effective factors for NAFLD treatment. Receiver operating characteristic (ROC) analysis was performed with significant indices. Sex, HOMA-IR, TyG and AT indices were evaluated together with multivariate analysis to design a diagnostic scale. RESULTS: HbA1c, HOMA-IR, AT indices and TyG indices were greater in the NAFLD (+) group (P = 0.012; P = 0.001; P = 0.012; P = 0.002, respectively). There was a positive correlation between liver fat percentage and HOMA-IR, the TyG index, the AT index, and Tg/HDL. According to the regression analysis, male sex and elevated HOMA-IR were determined to be significant risk factors for the presence of NAFLD. A probability scale with 4 parameters [sex, HOMA-IR, the TyG index, and alanine aminotransferase (ALT)] was designed with 82.5% specificity and 80% sensitivity. CONCLUSION: Evaluation of the HOMA-IR and TyG indices, especially in high-risk patients, will support the diagnosis of NAFLD via ultrasonography. A probability scale with ALT, HOMA-IR, TyG, and sex data with a diagnostic accuracy of 80% may aid in the diagnosis of NAFLD in adolescents with obesity.

Disturbed intracellular folate homeostasis impairs autophagic flux and increases hepatocytic lipid accumulation.

BACKGROUND: Metabolic associated fatty liver disease (MAFLD), a prevalent liver disorder affecting one-third of the global population, encompasses a spectrum ranging from fatty liver to severe hepatic steatosis. Both genetic and lifestyle factors, particularly diet and nutrition, contribute to its etiology. Folate deficiency, a frequently encountered type of malnutrition, has been associated with the pathogenesis of MAFLD and shown to impact lipid deposition. However, the underlying mechanisms of this relationship remain incompletely understood. We investigated the impact of disturbed folate-mediated one-carbon metabolism (OCM) on hepatic lipid metabolism both in vitro using human hepatoma cells and in vivo using transgenic fluorescent zebrafish displaying extent-, stage-, and duration-controllable folate deficiency upon induction. RESULTS: Disturbed folate-mediated one-carbon metabolism, either by inducing folate deficiency or adding anti-folate drug, compromises autophagy and causes lipid accumulation in liver cells. Disturbed folate status down-regulates cathepsin L, a key enzyme involved in autophagy, through inhibiting mTOR signaling. Interfered mitochondrial biology, including mitochondria relocation and increased fusion-fission dynamics, also occurs in folate-deficient hepatocytes. Folate supplementation effectively mitigated the impaired autophagy and lipid accumulation caused by the inhibition of cathepsin L activity, even when the inhibition was not directly related to folate deficiency. CONCLUSIONS: Disruption of folate-mediated OCM diminishes cathepsin L expression and impedes autophagy via mTOR signaling, leading to lipid accumulation within hepatocytes. These findings underscore the crucial role of folate in modulating autophagic processes and regulating lipid metabolism in the liver.

The mutual lipid-mediated effect of the transmembrane domain of SARS-CoV-2 E-protein and glycyrrhizin nicotinate derivatives on the localization in the lipid bilayer.

Glycyrrhizinic acid (GA) is one of the active substances in licorice root. It exhibits antiviral activity against various enveloped viruses, for example, SARS-CoV-2. GA derivatives are promising biologically active compounds from perspective of developing broad-spectrum antiviral agents. Given that GA nicotinate derivatives (Glycyvir) demonstrate activity against various DNA- and RNA-viruses, a search for a possible mechanism of action of these compounds is required. In the present paper, the interaction of Glycyvir with the transmembrane domain of the SARS-CoV-2 E-protein (ETM) in a model lipid membrane was investigated by NMR spectroscopy and molecular dynamics simulation. The lipid-mediated influence on localization of the SARS-CoV-2 E-protein by Glycyvir was observed. The presence of Glycyvir leads to deeper immersion of the ETM in lipid bilayer. Taking into account that E-protein plays a significant role in virus production and takes part in virion assembly and budding, the data on the effect of potential antiviral agents on ETM localization and structure in the lipid environment may provide a basis for further studies of potential coronavirus E-protein inhibitors.

Assessment of metabolomic variations among individuals returning to plain areas after exposure to high altitudes: a metabolomic analysis of human plasma samples with high-altitude de-acclimatization syndrome.

Background: High altitude de-acclimatization (HADA) is gradually becoming a public health concern as millions of individuals of different occupations migrate to high-altitude areas for work due to economic growth in plateau areas. HADA affects people who return to lower elevations after exposure to high altitudes. It causes significant physiological and functional changes that can negatively impact health and even endanger life. However, uncertainties persist about the detailed mechanisms underlying HADA. Methods: We established a population cohort of individuals with HADA and assessed variations in metabolite composition. Plasm samples of four groups, including subjects staying at plain (P) and high altitude (H) as well as subjects suffering from HADA syndrome with almost no reaction (r3) and mild-to-moderate reaction (R3) after returning to plain from high altitude, were collected and analyzed by Liquid Chromatography-Mass Spectrometry metabolomic. Multivariate statistical analyses were used to explore significant differences and potential clinical prospect of metabolites. Result: Although significantly different on current HADAS diagnostic symptom score, there were no differences in 17 usual clinical indices between r3 and R3. Further multivariate analyses showed isolated clustering distribution of the metabolites among the four groups, suggesting significant differences in their metabolic characteristics. Through K-means clustering analysis, we identified 235 metabolites that exhibited patterns of abundance change consistent with phenotype of HADA syndrome. Pathway enrichment analysis indicated a high influence of polyunsaturated fatty acids under high-altitude conditions. We compared the metabolites between R3 and r3 and found 107 metabolites with differential abundance involved in lipid metabolism and oxidation, suggesting their potential role in the regulation of oxidative stress homeostasis. Among them, four metabolites might play a key role in the occurrence of HADA, including 11-beta-hydroxyandrosterone-3-glucuronide, 5-methoxyindoleacetate, 9,10-epoxyoctadecenoic acid, and PysoPC (20:5). Conclusion: We observed the dynamic variation in the metabolic process of HADA. Levels of four metabolites, which might be provoking HADA mediated through lipid metabolism and oxidation, were expected to be explore prospective indices for HADA. Additionally, metabolomics was more efficient in identifying environmental risk factors than clinical examination when dramatic metabolic disturbances underlying the difference in symptoms were detected, providing new insights into the molecular mechanisms of HADAS.

Multiple Acyl-CoA Dehydrogenase Deficiency: Phenotypic and Genetic Features of a Malaysian Cohort.

BACKGROUND AND PURPOSE: Multiple acyl-CoA dehydrogenase deficiency (MADD) is an inherited disorder of fatty acid oxidation that causes lipid storage myopathy (LSM). This is the first report on MADD that describes the phenotypic and genetic features of a Malaysian cohort. METHODS: Among the >2,500 patients in a local muscle biopsy database, patients with LSM were identified and their genomic DNA were extracted from muscle samples and peripheral blood. All 13 exons of the electron-transfer flavoprotein dehydrogenase gene (ETFDH) were subsequently sequenced. Fifty controls were included to determine the prevalence of identified mutations in the normal population. RESULTS: Fourteen (82%) of the 17 LSM patients had MADD with ETFDH mutations. Twelve (86%) were Chinese and two were Malay sisters. Other unrelated patients reported that they had no relevant family history. Nine (64%) were females. The median age at onset was 18.5 years (interquartile range=16-37 years). All 14 demonstrated proximal limb weakness, elevated serum creatine kinase levels, and myopathic changes in electromyography. Three patients experienced a metabolic crisis at their presentation. Sanger sequencing of ETFDH revealed nine different variants/mutations, one of which was novel: c.998A>G (p.Y333C) in exon 9. Notably, 12 (86%) patients, including the 2 Malay sisters, carried a common c.250G>A (p.A84T) variant, consistent with the hotspot mutation reported in southern China. All of the patients responded well to riboflavin therapy. CONCLUSIONS: Most of our Malaysian cohort with LSM had late-onset, riboflavin-responsive MADD with ETFDH mutations, and they demonstrated phenotypic and genetic features similar to those of cases reported in southern China. Furthermore, we report a novel ETFDH mutation and possibly the first ever MADD patients of Malay descent.

Chlorogenic acid alleviates renal fibrosis by reducing lipid accumulation in diabetic kidney disease through suppressing the Notch1 and Stat3 signaling pathway.

AIMS: Abnormal renal lipid metabolism causes renal lipid deposition, which leads to the development of renal fibrosis in diabetic kidney disease (DKD). The aim of this study was to investigate the effect and mechanism of chlorogenic acid (CA) on reducing renal lipid accumulation and improving DKD renal fibrosis. METHODS: This study evaluated the effects of CA on renal fibrosis, lipid deposition and lipid metabolism by constructing in vitro and in vivo models of DKD, and detected the improvement of Notch1 and Stat3 signaling pathways. Molecular docking was used to predict the binding between CA and the extracellular domain NRR1 of Notch1 protein. RESULTS: In vitro studies have shown that CA decreased the expression of Fibronectin, α-smooth muscle actin (α-SMA), p-smad3/smad3, alleviated lipid deposition, promoted the expression of carnitine palmitoyl transferase 1 A (CPT1A), and inhibited the expression of cholesterol regulatory element binding protein 1c (SREBP1c). The expression of Notch1, Cleaved Notch1, Hes1, and p-stat3/stat3 were inhibited. These results suggested that CA might reduce intercellular lipid deposition in human kidney cells (HK2) by inhibiting Notch1 and stat3 signaling pathways, thereby improving fibrosis. Further, in vivo studies demonstrated that CA improved renal fibrosis and renal lipid deposition in DKD mice by inhibiting Notch1 and stat3 signaling pathways. Finally, molecular docking experiments showed that the binding energy of CA and NRR1 was -6.6 kcal/mol, which preliminarily predicted the possible action of CA on Notch1 extracellular domain NRR1. CONCLUSION: CA reduces renal lipid accumulation and improves DKD renal fibrosis by inhibiting Notch1 and stat3 signaling pathways.

Cucurbitacin B targets STAT3 to induce ferroptosis in non-small cell lung cancer.

Cucurbitacin B (CuB) is a compound found in plants like Cucurbitaceae that has shown promise in fighting cancer, particularly in lung cancer. However, the specific impact of CuB on ferroptosis and how it works in lung cancer cells has not been fully understood. Our research has discovered that CuB can effectively slow down the growth of non-small cell lung cancer (NSCLC) cells. Even in small amounts, it was able to inhibit the growth of various NSCLC cell lines. This inhibitory effect was reversed when ferroptosis inhibitors DFO, Lip-1 and Fer-1 were introduced. CuB was found to increase the levels of reactive oxygen species (ROS), lipid ROS, MDA, and ferrous ions within H358 lung cancer cells, leading to a decrease in GSH, mitochondrial membrane potential (MMP) and changes in ferroptosis-related proteins in a dose-dependent manner. These findings were also confirmed in A549 lung cancer cells. In A549 cells, different concentrations of CuB induced the accumulation of intracellular lipid ROS, ferrous ions and changes in ferroptosis-related indicators in a concentration-dependent manner. Meanwhile, the cytotoxic effect induced by CuB in A549 cells was counteracted by ferroptosis inhibitors DFO and Fer-1. Through network pharmacology, we identified potential targets related to ferroptosis in NSCLC cells treated with CuB, with STAT3 targets showing high scores. Further experiments using molecular docking and cell thermal shift assay (CETSA) revealed that CuB interacts with the STAT3 protein. Western blot and immunofluorescence staining demonstrated that CuB inhibits the phosphorylation of STAT3 (P-STAT3) in H358 cells. Silencing STAT3 enhanced CuB-induced accumulation of lipid ROS and iron ions, as well as the expression of ferroptosis-related proteins. On the other hand, overexpression of STAT3 reversed the effects of CuB-induced ferroptosis. The results indicate that CuB has the capability to suppress STAT3 activation, resulting in ferroptosis, and could be a promising treatment choice for NSCLC.

A Critical Review of Short Antimicrobial Peptides from Scorpion Venoms, Their Physicochemical Attributes, and Potential for the Development of New Drugs.

Scorpion venoms have proven to be excellent sources of antimicrobial agents. However, although many of them have been functionally characterized, they remain underutilized as pharmacological agents, despite their evident therapeutic potential. In this review, we discuss the physicochemical properties of short scorpion venom antimicrobial peptides (ssAMPs). Being generally short (13-25 aa) and amidated, their proven antimicrobial activity is generally explained by parameters such as their net charge, the hydrophobic moment, or the degree of helicity. However, for a complete understanding of their biological activities, also considering the properties of the target membranes is of great relevance. Here, with an extensive analysis of the physicochemical, structural, and thermodynamic parameters associated with these biomolecules, we propose a theoretical framework for the rational design of new antimicrobial drugs. Through a comparison of these physicochemical properties with the bioactivity of ssAMPs in pathogenic bacteria such as Staphylococcus aureus or Acinetobacter baumannii, it is evident that in addition to the net charge, the hydrophobic moment, electrostatic energy, or intrinsic flexibility are determining parameters to understand their performance. Although the correlation between these parameters is very complex, the consensus of our analysis suggests that there is a delicate balance between them and that modifying one affects the rest. Understanding the contribution of lipid composition to their bioactivities is also underestimated, which suggests that for each peptide, there is a physiological context to consider for the rational design of new drugs.

Multifunctional Nanosystem for Dual Anti-Inflammatory and Antibacterial Photodynamic Therapy in Infectious Diabetic Wounds.

Infectious diabetic wounds present a substantial challenge, characterized by inflammation, infection, and delayed wound healing, leading to elevated morbidity and mortality rates. In this work, we developed a multifunctional lipid nanoemulsion containing quercetin, chlorine e6, and rosemary oil (QCRLNEs) for dual anti-inflammatory and antibacterial photodynamic therapy (APDT) for treating infectious diabetic wounds. The QCRLNEs exhibited spherical morphology with a size of 51 nm with enhanced encapsulation efficiency, skin permeation, and localized delivery at the infected wound site. QCRLNEs with NIR irradiation have shown excellent wound closure and antimicrobial properties in vitro, mitigating the nonselective cytotoxic behavior of PDT. Also, excellent biocompatibility and anti-inflammatory and wound healing responses were observed in zebrafish models. The infected wound healing properties in S. aureus-infected diabetic rat models indicated re-epithelization and collagen deposition with no signs of inflammation. This multifaceted approach using QCRLNEs with NIR irradiation holds great promise for effectively combating oxidative stress and bacterial infections commonly associated with infected diabetic wounds, facilitating enhanced wound healing and improved clinical outcomes.

The Diagnosis of Allergy to Lipid Transfer Proteins.

PURPOSE OF REVIEW: To provide an update on the diagnosis of non-specific Lipid Transfer Protein (nsLTP) allergy. RECENT FINDINGS: More publications report the presence of nsLTP allergy in Northern European countries and nsLTP sensitisation in children. Individuals are more likely to have severe reactions if there is recognition of increasing numbers of LTP components. Diagnosis is problematic; not all those with nsLTP allergy will have a positive test to a peach extract containing Pru p 3, the peach nsLTP. Sensitisation to nsLTP is being reported in more countries, including to the nsLTP in Cannabis Sativa in North America. Meals containing multiple nsLTP foods are more likely to be involved in co-factor reactions. Component-resolved diagnostics are superior to skin prick tests, to determine sensitisation to the individual nsLTP allergens causing symptoms and, in the future, the Basophil Activation test may best discriminate between sensitization and clinical allergy.

Causal impact of statins on susceptibility to osteoarthritis: insights from a two-sample Mendelian randomization analysis.

BACKGROUND: Osteoarthritis is a widely prevalent cause of pain and disability among older adults. It is an incurable condition, and most treatments are aimed at alleviating symptoms. AIM: This study aimed to investigate the impact of statins on osteoarthritis by using a two-sample Mendelian randomization approach, using genetic variants associated with statin use as instrumental variables. METHOD: Information on single nucleotide polymorphisms associated with statin medication was obtained from the FinnGen study, and data on osteoarthritis were sourced from the UK Biobank. The inverse variance weighted method was used as the primary analytical approach for the Mendelian randomization analysis. Sensitivity analyses were conducted to evaluate horizontal pleiotropy and heterogeneity. To examine the genetic relationship between statins and osteoarthritis, linkage disequilibrium score regression-based estimates were used. RESULTS: Mendelian randomization analysis indicated a positive effect of statin use on the treatment of osteoarthritis (odds ratio 0.951, 95% confidence interval 0.914-0.99, p < 0.05). This conclusion was supported by various Mendelian randomization methods. Sensitivity analyses revealed no significant directional pleiotropy or influential single nucleotide polymorphisms that could compromise the overall causal inference. Linkage disequilibrium score regression-based estimates suggested a modest genetic correlation between statin use and osteoarthritis (Rg = 0.098, Se = 0.034, p < 0.05), thus reinforcing the robustness of the Mendelian randomization analysis. CONCLUSION: Statins reduce the risk of osteoarthritis, aligning with the results of observational studies. Further research is essential to validate these results and explore the underlying mechanisms in detail.

Functionalized solid lipid nanoparticles combining docetaxel and erlotinib synergize the anticancer efficacy against triple-negative breast cancer.

The goal of the study was to fabricate folic acid functionalized docetaxel (DOC)/erlotinib (ERL)-loaded solid lipid nanoparticles (SLNs) to synergistically increase the anticancer activity against triple-negative breast cancer. DOC/ERL-SLNs were prepared by the high shear homogenization - ultrasound dispersion method (0.1 % w/v for DOC, and 0.3 %w/v for ERL) and optimized using Plackett Burman Design (PBD) followed by Box Behnken Design (BBD). The optimized SLNs demonstrated particle size < 200 nm, PDI < 0.35, and negative zeta potential with entrapment and loading efficiency of ∼80 and ∼4 %, respectively. The SLNs and folic acid functionalized SLNs (FA-SLNs) showed sustained release for both drugs, followed by Higuchi and Korsemeyer-Peppas drug release models, respectively. Further, the in vitro pH-stat lipolysis model demonstrated an approximately 3-fold increase in the bioaccessibility of drugs from SLNs compared to suspension. The TEM images revealed the spherical morphology of the SLNs. DOC/ERL loaded SLNs showed dose- and time-dependent cytotoxicity and exhibited a synergism at a molar ratio of 1:3 in TNBC with a combination index of 0.35 and 0.37, respectively. FA-DOC/ERL-SLNs showed enhanced anticancer activity as evidenced by MMP and ROS assay and further inhibited the colony-forming ability and the migration capacity of TNBC cells. Conclusively, the study has shown that SLNs are encouraging systems to improve the pharmaceutical attributes of poorly bioavailable drugs.

Effects of high-intensity intermittent exercise on glucose and lipid metabolism in type 2 diabetes patients: a systematic review and meta-analysis.

Objective: To evaluate the effects of high-intensity interval training (HIIT) on glycolipid metabolism among type 2 diabetes patients. Methods: HIIT is consistent with an exercise program (65%-90%VO2max or 75%-95% HRmax; exercise cycle≥2 weeks; frequency ≥ 2 times/week). A meta-analysis was conducted utilizing the random effects model to synthesize the data. Results: A total of 22 RCT studies with 1034 diabetic patients were included. Compared to moderate-intensity aerobic exercise or conventional controls, HIIT yields noteworthy effects on FBG (MD: -0.55; 95% CI: -0.85- -0.25, Hedges' g =0.98), 2h-PG (MD: -0.36; 95% CI: -0.57- -0.14, Hedges' g =1.05), FINS (MD: -0.41; 95% CI: -0.79- -0.03, Hedges' g =1.07), HbA1c (MD: -0.60; 95% CI: -0.84- -0.36, Hedges' g =2.69), TC (MD: -0.58; 95% CI: -0.80- -0.36, Hedges' g =2.36), TG (MD: -0.50; 95% CI: -0.86- -0.14, Hedges' g =1.50), HDL (MD: 0.62; 95% CI: 0.29-0.95, Hedges' g =1.19) and LDL (MD: -0.31; 95% CI: -0.56- -0.08, Hedges' g =0.91), all of the above p<0.01. Conclusions: HIIT has been shown to improve glucose and lipid metabolism in patients with type 2 diabetes, especially in HbA1c, TC, TG, and HDL. For patients between the ages of 40 and 60 with less than 5 years of disease, exercise programs of moderate to longer duration or moderate to high intensity will produce more favorable results.

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.