Search Results (12)

The efficient oral delivery of therapeutic proteins and peptides poses a tremendous challenge due to their inherent instability, large molecular size, and susceptibility to enzymatic degradation. Several nanocarrier systems, such as liposomes, solid lipid nanoparticles, and polymeric nanoparticles, have been explored to overcome these problems. Liposomes and other lipid-based nanocarriers show excellent biocompatibility and the ability to encapsulate hydrophobic and hydrophilic drugs; however, they often suffer from poor structural stability, premature leakage of the loaded drugs, and poor encapsulation efficiency for macromolecular peptides and proteins. On the other hand, polymeric nanoparticles are more stable and allow better control over drug release; nevertheless, they usually lack the necessary biocompatibility and cellular uptake efficiency. Recently, lipid-polymer hybrid nanoparticles (LPHNs) have emerged as an advanced solution combining the structural stability of polymers and the biocompatibility and surface functionalities of lipids to enhance the controlled release, stability, and bioavailability of protein and peptide drugs. In this review, an attempt was made to set a clear definition of the LPHNs and extend the concept and area, so to our knowledge, this is the first review that highlights six categories of the LPHNs based on their anatomy. Moreover, this review offers a detailed analysis of LPHN preparation methods, including conventional and nonconventional one-step and two-step processes, nanoprecipitation, microfluidic mixing, and emulsification methods. Moreover, the material attributes and critical process parameters affecting the output of the preparation methods were illustrated with supporting examples to enable researchers to select the suitable preparation method, excipients, and parameters to be manipulated to get the LPHNs with the predetermined quality. The number of reviews focusing on the formulation of peptide/protein pharmaceutics usually focus on a specific drug like insulin. To our knowledge, this is the first review that generally discusses LPHN-based delivery of biopharmaceuticals. by discussing representative examples of previous reports comparing them to a variety of nanocarrier systems to show the potentiality of the LPHNs to deliver peptides and proteins. Moreover, some ideas and suggestions were proposed by the authors to tackle some of the shortcomings highlighted in these studies. By presenting this comprehensive overview of LPHN preparation strategies and critically analyzing literature studies on this topic and pointing out their strong and weak points, this review has shown the gaps and enlightened avenues for future research. Full article

Background/Objectives: Variations of the latrophilin-3 (Lphn3) gene have been associated with attention-deficit hyperactivity disorder (ADHD). To explore the functional influence of this gene, Lphn3 knockout (KO) rats were generated and have thus far demonstrated deficits in ADHD-relevant phenotypes, including working memory, impulsivity, and hyperactivity. However, inattention remains unexplored. Methods: We assessed automatic attention in Lphn3 KO (n = 19) and their control line (wildtype/WT, n = 20) through use of the following auditory event-related potentials (ERPs): P1, N1, P2, and N2. We also extended this exploratory study by comparing these same ERPs in spontaneously hypertensive rats (SHRs, n = 16), the most commonly studied animal model of ADHD, to their control line (Wistar–Kyoto/WKY, n = 20). Electroencephalograms (EEG) were recorded using subdermal needle electrodes at frontocentral sites while freely moving rats were presented with five-tone trains (50 ms tones, 400 ms tone onset asynchronies) with varying short (1 s) and long (5 s) inter-train intervals. Peak amplitudes and latencies were analyzed using GLM-mixed ANOVAs to assess differences across genotypes (KO vs. WTs) and strains (SHRs vs. WKYs). Results: The KOs did not demonstrate any significant differences in peak amplitudes relative to the WT controls, suggesting that the null expression of Lphn3 does not result in the development of inefficiencies in automatic attention. However, the SHRs exhibited significantly reduced peak P1 (and peak-to-peak P1–N1) values relative to the WKYs. These attenuations likely reflect inefficiencies in bottom-up arousal networks that are necessary for efficient automatic processing. Conclusions: Distinct findings between these animal models likely reflect differing alterations in dopamine and noradrenaline neurotransmission that may underlie ADHD-relevant phenotypes. Full article

Cancer is considered as the second leading cause of death worldwide. Chemotherapy, radiotherapy, immunotherapy, and targeted drug delivery are the main treatment options for treating cancers. Chemotherapy drugs are either available for oral or parenteral use. Oral chemotherapy, also known as chemotherapy at home, is more likely to improve patient compliance and convenience. Oral anti-cancer drugs have bioavailability issues associated with lower aqueous solubility, first-pass metabolism, poor intestinal permeability and drug absorption, and degradation of the drug throughout its journey in the gastrointestinal tract. A highly developed carrier system known as lipid polymer hybrid nanoparticles (LPHNs) has been introduced. These nanocarriers enhance drug stability, solubility, and absorption, and reduce first-pass metabolism. Consequently, this will have a positive impact on oral bioavailability enhancement. This article provides an in-depth analysis of LPHNs as a novel drug delivery system for anti-cancer agents. It discusses an overview of the limited bioavailability of anti-cancer drugs, their reasons and consequences, LPHNs based anti-cancer drug delivery, conventional and modern preparation methods as well as their drug loading and entrapment efficiencies. In addition, this article also gives an insight into the mechanistic approach to oral bioavailability enhancement, potential applications in anti-cancer drug delivery, limitations, and future prospects of LPHNs in anti-cancer drug delivery. Full article

The most common trigger of sepsis and septic shock is bacterial lipopolysaccharide (LPS). Endothelial cells are among the first to encounter LPS directly. Generally, their function is closely linked to active endothelial NO Synthase (eNOS), which is significantly reduced under septic conditions. LPS treatment of endothelial cells leads to their activation and apoptosis, resulting in loss of integrity and vascular leakage, a hallmark of septic shock. Hence, therapies that prevent endothelial leakage or restore the endothelial barrier would be invaluable for patients. Adhesion GPCRs (aGPCRs) have been largely overlooked in this context, although particularly one of them, ADGRL2/LPHN2, has been implicated in endothelial barrier function. Our study shows that overexpression of ADGRL2 protects endothelial cells from LPS-induced activation, apoptosis, and impaired migration. Mechanistically, ADGRL2 preserves eNOS activity by shifting its binding from Caveolin-1 to Heat Shock Protein 90. Furthermore, ADGRL2 enhances antioxidative responses by increasing NRF2 activity. Notably, we found that this function may be evolutionarily conserved. In the absence of lat-2, a homolog of ADGRL2 in Caenorhabditis elegans, worms show higher ROS levels and altered stress response gene expression. Additionally, lat-2 mutants have a significantly reduced lifespan, altogether indicating a protective role of ADGRL2 against oxidative stress across species. Full article

Latrophilins (LPHNs), a group of the G-protein–coupled receptor to which a spider venom latrotoxin (LTX) is known to bind, remain largely uncharacterized in neoplastic diseases. In the present study, we aimed to determine the role of LPHNs in the progression of prostate cancer. We assessed the actions of LPHNs, including LPHN1, LPHN2, and LPHN3, in human prostate cancer lines via their ligand (e.g., α-LTX, FLRT3) treatment or shRNA infection, as well as in surgical specimens. In androgen receptor (AR)-positive LNCaP/C4-2/22Rv1 cells, dihydrotestosterone considerably increased the expression levels of LPHNs, while chromatin immunoprecipitation assay revealed the binding of endogenous ARs, including AR-V7, to the promoter region of each LPHN. Treatment with α-LTX or FLRT3 resulted in induction in the cell viability and migration of both AR-positive and AR-negative lines. α-LTX and FLRT3 also enhanced the expression of Bcl-2 and phosphorylated forms of JAK2 and STAT3. Meanwhile, the knockdown of each LPHN showed opposite effects on all of those mediated by ligand treatment. Immunohistochemistry in radical prostatectomy specimens further showed the significantly elevated expression of each LPHN in prostate cancer, compared with adjacent normal-appearing prostate, which was associated with a significantly higher risk of postoperative biochemical recurrence in both univariate and multivariable settings. These findings indicate that LPHNs function as downstream effectors of ARs and promote the growth of androgen-sensitive, castration-resistant, or even AR-negative prostate cancer. Full article

Imaging and genetic studies have characterized biological risk factors contributing to specific reading disability (SRD). The current study aimed to apply this literature to a family of twins discordant for SRD and an older sibling with reading difficulty. Intraclass correlations were used to understand the similarity of imaging phenotypes between pairs. Reading-related genes and brain region phenotypes, including asymmetry indices representing the relative size of left compared to right hemispheric structures, were descriptively examined. SNPs that corresponded between the SRD siblings and not the typically developing (TD) siblings were in genes ZNF385D, LPHN3, CNTNAP2, FGF18, NOP9, CMIP, MYO18B, and RBFOX2. Imaging phenotypes were similar among all sibling pairs for grey matter volume and surface area, but cortical thickness in reading-related regions of interest (ROIs) was more similar among the siblings with SRD, followed by the twins, and then the TD twin and older siblings, suggesting cortical thickness may differentiate risk for this family. The siblings with SRD had more symmetry of cortical thickness in the transverse temporal and superior temporal gyri, while the TD sibling had greater rightward asymmetry. The TD sibling had a greater leftward asymmetry of grey matter volume and cortical surface area in the fusiform, supramarginal, and transverse temporal gyrus. This exploratory study demonstrated that reading-related risk factors appeared to correspond with SRD within this family, suggesting that early examination of biological factors may benefit early identification. Future studies may benefit from the use of polygenic risk scores or machine learning to better understand SRD risk. Full article

Crumbly dough fermentation was applied to produce dried hollow noodles, with Lactobacillus plantarum, Koji and yeast as the main fermenting agents. The cooking, textural and digestive properties of the noodles were studied, followed by the morphological, crystalline and thermal properties of the starch. The results show that, compared to unfermented noodles, the optimal cooking time of Koji pre-fermented noodles (KJHN) decreased from 460 s to 253 s, and they possessed a higher percentage of weakly bound water and degree of gelatinization at the same cooking time. After cooking, KJHN had a softer texture and higher starch digestibility. In addition, the physicochemical properties of the KJHN and Lactobacillus plantarum pre-fermented noodles (LPHN) showed a decrease in pH and amylose content, and an increase in reducing sugars content. The starch extracted from KJHN and LPHN had significant superficial erosion and pore characteristics, and the gelatinization enthalpy, relative crystallinity and short-range order were all increased. These changes in the starch properties and the quality characteristics of noodles resulting from Koji fermentation might provide a reference for the development of easy-to-cook and easy-to-digest noodles. Full article

Cancer progression relies on cellular transition states accompanied by changes in the functionality of adhesion molecules. The gene for adhesion G protein-coupled receptor latrophilin-3 (aGPCR Lphn3 or ADGRL3) is targeted by tumor-specific somatic mutations predominantly affecting the conserved GAIN domain where most aGPCRs are cleaved. However, it is unclear how these GAIN domain-altering mutations impact Lphn3 function. Here, we studied Lphn3 cancer-related mutations as a proxy for revealing unknown GAIN domain functions. We found that while intra-GAIN cleavage efficiency was unaltered, most mutations produced a ligand-specific impairment of Lphn3 intercellular adhesion profile paralleled by an increase in cell-matrix actin-dependent contact structures for cells expressing the select S810L mutation. Aberrant remodeling of the intermediate filament vimentin, which was found to coincide with Lphn3-induced modification of nuclear morphology, had less impact on the nuclei of S810L expressing cells. Notoriously, receptor signaling through G13 protein was deficient for all variants bearing non-homologous amino acid substitutions, including the S810L variant. Analysis of cell migration paradigms revealed a non-cell-autonomous impairment in collective cell migration indistinctly of Lphn3 or its cancer-related variants expression, while cell-autonomous motility was potentiated in the presence of Lphn3, but this effect was abolished in S810L GAIN mutant-expressing cells. These data identify the GAIN domain as an important regulator of Lphn3-dependent cell motility, thus furthering our understanding of cellular and molecular events linking Lphn3 genetic somatic mutations to cancer-relevant pathogenesis mechanisms. Full article

Norfloxacin (NOR), widely employed as an anti-bacterial drug, has poor oral bioavailability. Nano based drug delivery systems are widely used to overcome the existing oral bioavailability challenges. Lipid–Polymer Hybrid Nanoparticles (LPHNs) exhibit the distinctive advantages of both polymeric and liposomes nanoparticles, while excluding some of their disadvantages. In the current study, NOR loaded LPHNs were prepared, and were solid amorphous in nature, followed by in vitro and in vivo evaluation. The optimized process conditions resulted in LPHNs with the acceptable particle size 121.27 nm, Polydispersity Index (PDI) of 0.214 and zeta potential of −32 mv. The addition of a helper lipid, oleic acid, and polymers, ethyl cellulose, substantially increased the encapsulation efficiency (EE%) (65% to 97%). In vitro study showed a sustained drug release profile (75% within 12 h) for NOR LPHNs. The optimized NOR LPHNs showed a significant increase (p < 0.05) in bioavailability compared to the commercial product. From the acute toxicity study, the LD50 value was found to be greater than 1600 mg/kg. The molecular modelling studies substantiated the experimental results with the best combination of polymers and surfactants that produced highly stable LPHNs. Therefore, LPHNs proved to be a promising system for the delivery of NOR, as well as for other antibiotics and hydrophobic drugs. Full article

P-glycoprotein (known as ABCB1 transporter) expression in myeloid blasts of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) leads to the commonly observed multidrug resistance. Overexpression of latrophilin-1 was detected in leukemic cells from AML patients. In a previous study, we showed that ABCB1 overexpression is associated with decreased latrophilin-1 expression in MOLM-13/VCR and SKM-1/VCR AML cell variants derived from MOLM-13 and SKM-1 cells by vincristine selection/adaptation. In the present study, we found that if ABCB1 overexpression occurs in myeloid blasts of newly diagnosed MDS patients, latrophilin-1 expression is attenuated. Latrophilin-1 may initiate TIM-3- and galectin-9-mediated immune escape. We demonstrated changes in the expression of both proteins by comparing ABCB1-positive cell variants (MOLM-13/VCR, SKM-1/VCR) with their ABCB1-negative counterparts. Galectin-9 was present in our cell lines in eight protein isoforms for which we identified the respective transcription variants resulting from alternative splicing, and we verified their structure by sequencing. The isoform profile of galectin-9 was different between ABCB1-positive and ABCB1-negative cell variants. The interaction partner of galectin-9 is CD44, and its expression was altered in the ABCB1-positive variants MOLM-13/VCR and SKM-1/VCR compared to their ABCB1-negative counterparts. Full article

Enoxaparin, an anticoagulant that helps prevent the formation of blood clots, is administered parenterally. Here, we report the development and evaluation of lipid–polymer hybrid nanoparticles (LPHNs) for the oral delivery of enoxaparin. The polymer poloxamer 407 (P407) was incorporated into lipid nanoparticles to form gel cores and ensure high encapsulation efficiency and the controlled release of enoxaparin. In vitro results indicated that 30% of P407 incorporation offered higher encapsulation efficiency and sustained the release of enoxaparin. Laser confocal scanning microscopy (LCSM) images showed that LPHNs could not only significantly improve the accumulation of enoxaparin in intestinal villi but also facilitate enoxaparin transport into the underlayer of intestinal epithelial cells. In vivo pharmacokinetic study results indicated that the oral bioavailability of enoxaparin was markedly increased about 6.8-fold by LPHNs. In addition, its therapeutic efficacy against pulmonary thromboembolism was improved 2.99-fold by LPHNs. Moreover, LPHNs exhibited excellent biocompatibility in the intestine. Overall, the LPHN is a promising delivery carrier to boost the oral absorption of enoxaparin. Full article

Attention Deficit Hyperactivity Disorder (ADHD) is a highly heritable and prevalent neurodevelopmental disorder that frequently persists into adulthood. Strong evidence from genetic studies indicates that single nucleotide polymorphisms (SNPs) harboured in the ADGRL3 (LPHN3), SNAP25, FGF1, DRD4, and SLC6A2 genes are associated with ADHD. We genotyped 26 SNPs harboured in genes previously reported to be associated with ADHD and evaluated their potential association in 386 individuals belonging to 113 nuclear families from a Caribbean community in Barranquilla, Colombia, using family-based association tests. SNPs rs362990-SNAP25 (T allele; p = 2.46 × 10⁻⁴), rs2282794-FGF1 (A allele; p = 1.33 × 10⁻²), rs2122642-ADGRL3 (C allele, p = 3.5 × 10⁻²), and ADGRL3 haplotype CCC (markers rs1565902-rs10001410-rs2122642, OR = 1.74, P_permuted = 0.021) were significantly associated with ADHD. Our results confirm the susceptibility to ADHD conferred by SNAP25, FGF1, and ADGRL3 variants in a community with a significant African American component, and provide evidence supporting the existence of specific patterns of genetic stratification underpinning the susceptibility to ADHD. Knowledge of population genetics is crucial to define risk and predict susceptibility to disease. Full article