Exploring the Potential of Natural Products as FoxO1 Inhibitors: an In Silico Approach.

FoxO1, a member of the Forkhead transcription factor family subgroup O (FoxO), is expressed in a range of cell types and is crucial for various pathophysiological processes, such as apoptosis and inflammation. While FoxO1's roles in multiple diseases have been recognized, the target has remained largely unexplored due to the absence of cost-effective and efficient inhibitors. Therefore, there is a need for natural FoxO1 inhibitors with minimal adverse effects. In this study, docking, MMGBSA, and ADMET analyses were performed to identify natural compounds that exhibit strong binding affinity to FoxO1. The top candidates were then subjected to molecular dynamics (MD) simulations. A natural product library was screened for interaction with FoxO1 (PDB ID- 3CO6) using the Glide module of the Schrödinger suite. In silico ADMET profiling was conducted using SwissADME and pkCSM web servers. Binding free energies of the selected compounds were assessed with the Prime-MMGBSA module, while the dynamics of the top hits were analyzed using the Desmond module of the Schrödinger suite. Several natural products demonstrated high docking scores with FoxO1, indicating their potential as FoxO1 inhibitors. Specifically, the docking scores of neochlorogenic acid and fraxin were both below -6.0. These compounds also exhibit favorable drug-like properties, and a 25 ns MD study revealed a stable interaction between fraxin and FoxO1. Our findings highlight the potential of various natural products, particularly fraxin, as effective FoxO1 inhibitors with strong binding affinity, dynamic stability, and suitable ADMET profiles.

Repurposing FDA-approved drugs as NLRP3 inhibitors against inflammatory diseases: machine learning and molecular simulation approaches.

Activation of NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3) has been associated with multiple chronic pathologies, including diabetes, atherosclerosis, and rheumatoid arthritis. Moreover, histone deacetylases (HDACs), specifically HDAC6 is required for the NLRP3 inflammasome to assemble and activate. Thus, NLRP3 serves as an attractive target for the development of novel therapeutic approaches. Several companies are now attempting to develop specific modulators of the NLRP3 inflammasome, but only a handful of small molecules of NLRP3 inflammasome inhibitors, such as MCC950 and Tranilast, are currently available for clinical use. However, their use is limited due to severe side effects and short half-lives. Thus, the repurposing of FDA-approved drugs with NLRP3 inhibitory activity is needed. The present study was aimed at repurposing preexisting drugs that might act as safe and effective NLRP3 inhibitors. A library of 2,697 FDA-approved drugs was screened for binding with NLRP3 (PDB: 7ALV) using Glide (Schrödinger). The top seven FDA-approved drugs with potential binding affinities were selected based on docking scores and subjected to ADMET profiling using pkCSM and SwissADME. The binding of the ADMET-favorable FDA-approved drugs to NLRP3 was validated using MMGBSA (Prime) and Molecular Dynamics (Desmond) in the Schrödinger suite. ADMET profiling revealed that of the seven best docking drugs, empagliflozin and citicoline had good drug-likeness properties. Moreover, MMGBSA analysis and molecular dynamics demonstrated that empagliflozin and citicoline exhibited stable ligand-NLRP3 interactions in the presence of solvents. This study sheds light on the ability of various FDA-approved drugs to act as NLRP3 inhibitors.Communicated by Ramaswamy H. Sarma.

State-of-the-art progress on tamarind seed polysaccharide (Tamarindus indica) and its diverse potential applications, a review with insight.

Tamarind seed polysaccharide (TSP) is a biocompatible, non-ionic polymer with antioxidant properties. Its uses include drug delivery, food industry, and wastewater treatment. TSP has various hydroxy functional groups, one of the most favorable sites for graft copolymerization of different monomers. Hence, various chemical methods for TSP modification were developed to satisfy increasing industrial demand. Of particular interest in scientific community are the methods of graft copolymerization because of their ability to alter the physicochemical properties of TSP, including pH sensitivity and the swelling index, leading to improvements in the adsorption efficiency of hazardous heavy metals and dyes from wastewater effluents. Moreover, in recent years, TSP has been used for controlled drug delivery applications due to its unique advantages of high viscosity, broad pH tolerance, non-carcinogenicity, mucoadhesive properties, biocompatibility, and high drug entrapment capacity. In light of the plethora of literature on the topic, a comprehensive review of TSP-based graft copolymers and unmodified and modified TSP important applications is necessary. Therefore, this review comprehensively highlights several synthetic strategies for TSP-grafted copolymers and discusses unmodified and modified TSP potential applications, including cutting-edge pharmaceutical, environmental applications, etc. In brief, its many advantages make TSP-based polysaccharide a promising material for applications in various industries.

Revealing the Substrate Constraint Effect on the Thermodynamic Behaviour of the Pd-H through Capacitive-Based Hydrogen-Sorption Measurement.

Mechanical constraints imposed on the Pd-H system can induce significant strain upon hydrogenation-induced expansion, potentially leading to changes in the thermodynamic behavior, such as the phase-transition pressure. However, the investigation of the constraint effect is often tricky due to the lack of simple experimental techniques for measuring hydrogenation-induced expansion. In this study, a capacitive-based measurement system is developed to monitor hydrogenation-induced areal expansion, which allows us to control and evaluate the magnitude of the substrate constraint. By using the measurement technique, the influence of substrate constraint intensity on the thermodynamic behavior of the Pd-H system is investigated. Through experiments with different constraint intensities, it is found that the diffefrence in the constraint intensity minimally affects the phase-transition pressure when the Pd-H system allows the release of constraint stress through plastic deformation. These experiments can improve the understanding of the substrate constraint behaviours of Pd-H systems allowing plastic deformation while demonstrating the potential of capacitive-based measurement systems to study the mechanical-thermodynamic coupling of M-H systems.

Engineering a self-healing grafted chitosan-sodium alginate based hydrogel with potential keratinocyte cell migration property and inhibitory effect against fluconazole resistance Candida albicans biofilm.

Biofilms developed by microorganisms cause an extremely severe clinical problem that leads to drug failure. Bioactive polymeric hydrogels display potential for controlling the formation of microorganism-based biofilms, but their rapid biodegradability in these biofilm sites is still a major challenge. To overcome this, chitosan (CS), a natural functional biomaterial, has been used because of its effective penetrability in the cell wall of microorganisms; however, its fast biodegradability has restricted its further use. Hence, in this study, to improve the stability of CS and increase its penetration retention inside a biofilm, grafted CS was prepared and then crosslinked with sodium alginate (SA) to synthesize CS-poly(MA-co-AA)SA hydrogel via a free radical grafting method, therefore enhancing its antibiofilm efficiency against biofilms. The prepared hydrogel demonstrated excellent effectiveness against (≥90 % inhibition) biofilms of Candida albicans. Additionally, in vitro and in vivo safety assays established that the prepared hydrogel can be used in a biofilm microenvironment and might reduce drug resistance burden owing to its long-term antibiofilm effect and improved CS stability at the biofilm site. Furthermore, in vitro wound healing outcomes of hydrogel indicated its potential application for chronic wound treatment. This research opens a new advanced strategy for biofilm-associated infection treatment, including wound treatment.

Soft-capsule formulation of a re-esterified triglyceride omega-3 employing self-emulsifying technology and bioavailability evaluation in healthy volunteers.

Despite the superior clinical efficacy of the re-esterified triglyceride (rTG) form compared to the ethylester form, few studies have been conducted on improving the bioavailability of the rTG form of omega-3 oil. The aim of study was to evaluate the effect of self emulsifying formulation on the improvement of bioavailability of rTG form of omega-3 oil. To develop a re-esterified triglyceride (rTG) soft capsule, an rTG-loaded self-emulsifying delivery system (SEDS) was designed using coconut oil, polysorbate 80, and lecithin. Candidate formulations were designed from a phase-diagram study and optimal SEDS formulations containing 85% of high omega-3 (ω-3) oils were screened from the evaluation of droplet size distribution, measurement of oil floating area and emulsion turbidity. The selected, optimized rTG SEDS formulation was filled into a soft capsule (NOVASEDS) and applied to a sequence-randomized, double-blind, single-dose, and two-way crossover clinical study (n = 44), and the the bioavailability of NOVASEDS was compared with that of a 'raw' rTG capsule (rTG OMEGA3) as control. The droplet size (D50) formed from the candidate formulations was approximately 30-45 µm, and the optimal formulation showed a unimodal particle distribution with the smallest oil floating area and small changes in turbidity after 24 h. Cmax and AUC from 0 to 24 h for NOVASEDS, calculated from docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and as the sum of DHA and EPA, were significantly higher (P < 0.05) than corresponding values for rTG OMEGA3. In conclusion, NOVASEDS formulated by SEDS technology enabled the manufacture of a high rTG payload soft capsule with improved bioavailability in human subjects.

Functionalized Lipid Nanocarriers for Simultaneous Delivery of Docetaxel and Tariquidar to Chemoresistant Cancer Cells.

The simultaneous drug delivery efficiency of a co-loaded single-carrier system of docetaxel (DTX)- and tariquidar (TRQ)-loaded nanostructured lipid carrier (NLC) functionalized with PEG and RIPL peptide (PRN) (D^T-PRN) was compared with that of a physically mixed dual-carrier system of DTX-loaded PRN (D-PRN) and TRQ-loaded PRN (T-PRN) to overcome DTX mono-administration-induced multidrug resistance. NLC samples were prepared using the solvent emulsification evaporation technique and showed homogeneous spherical morphology, with nano-sized dispersion (<220 nm) and zeta potential values of -15 to -7 mV. DTX and/or TRQ was successfully encapsulated in NLC samples (>95% encapsulation efficiency and 73-78 µg/mg drug loading). In vitro cytotoxicity was concentration-dependent; D^T-PRN exhibited the highest MDR reversal efficiency, with the lowest combination index value, and increased the cytotoxicity and apoptosis in MCF7/ADR cells by inducing cell-cycle arrest in the G2/M phase. A competitive cellular uptake assay using fluorescent probes showed that, compared to the dual nanocarrier system, the single nanocarrier system exhibited better intracellular delivery efficiency of multiple probes to target cells. In the MCF7/ADR-xenografted mouse models, simultaneous DTX and TRQ delivery using D^T-PRN significantly suppressed tumor growth as compared to other treatments. A single co-loaded system for PRN-based co-delivery of DTX/TRQ (1:1, w/w) constitutes a promising therapeutic strategy for drug-resistant breast cancer cells.

EGF, a veteran of wound healing: highlights on its mode of action, clinical applications with focus on wound treatment, and recent drug delivery strategies.

Epidermal growth factor (EGF) has been used in wound management and regenerative medicine since the late 1980s. It has been widely utilized for a long time and still is because of its excellent tolerability and efficacy. EGF has many applications in tissue engineering, cancer therapy, lung diseases, gastric ulcers, and wound healing. Nevertheless, its in vivo and during storage stability is a primary concern. This review focuses on the topical use of EGF, especially in chronic wound healing, the emerging use of biomaterials to deliver it, and future research possibilities. To successfully deliver EGF to wounds, a delivery system that is proteolytically resistant and stable over the long term is required. Biomaterials are an area of interest for the development of such systems. These systems may be used in non-healing wounds such as diabetic foot ulcers, pressure ulcers, and burns. In these pathologies, EGF can reduce the risk of amputation of the lower extremities, as it accelerates the wound healing process. Furthermore, appropriate delivery system would also stabilize and control the EGF release profile in a wound. Several in vitro and in vivo studies have already proven the efficacy of such systems in the above-mentioned types of wounds. Moreover, several formulations such as ointments and intralesional injections are already available on the market. However, these products are still problematic in terms of inadequate diffusion of EGF, low bioavailability storage conditions, and shelf-life. This review discusses the nano formulations comprising biomaterials infused with EGF which could be a promising delivery system for chronic wound healing in the future.

Assessment of hydrophobic-ion paired insulin incorporated SMEDDS for the treatment of diabetes mellitus.

To overcome the low oral bioavailability of insulin, we hypothesized that the insulin-hydrophobic ion pairing (HIP) complex incorporated self-microemulsifying drug delivery system (SMEDDS) would be beneficial. In the present study, an oral insulin delivery system was developed and estimated using the HIP technique and SMEDDS. Further insulin-HIP complexes were characterized using various spectroscopical techniques. Additionally, insulin-HIP complexes were subjected to analysis of complexes' conformational stability in the real physiological solution using computational approaches. On the other hand, in vitro, and in vivo studies were carried out to investigate the permeability and hypoglycemic effect. Subsequently, in an in vitro non-everted gut sac study, the apparent permeability coefficient (Papp) was approximately 8-fold higher in the colon than in the jejunum, and the HIP-incorporated SMEDDS showed an approximately 3-fold higher Papp value than the insulin solution. The hypoglycemic effect after in situ colon instillation, the HIP complex between insulin and sodium docusate-incorporated SMEDDS showed a pharmacological availability of 2.52 ± 0.33 % compared to the subcutaneously administered insulin solution. Thus, based on these outcomes, it can be concluded that the selection of appropriate counterions is important in developing HIP-incorporated SMEDDS, wherein this system shows promise as a tool for oral peptide delivery systems.

Enhanced oral absorption of insulin: hydrophobic ion pairing and a self-microemulsifying drug delivery system using a D-optimal mixture design.

The lipophilicity of a peptide drug can be considerably increased by hydrophobic ion pairing with amphiphilic counterions for successful incorporation into lipid-based formulations. Herein, to enhance the oral absorption of insulin (INS), a self-microemulsifying drug delivery system (SMEDDS) formulation was developed. Prior to optimization, INS was complexed with sodium n-octadecyl sulfate (SOS) to increase the loading into the SMEDDS. The INS-SOS complex was characterized via scanning electron microscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, and its dissociation behavior. The SMEDDS was optimized using a D-optimal mixture design with three independent variables including Capmul MCM (X1, 9.31%), Labrasol (X2, 49.77%), and Tetraglycol (X3, 40.92%) and three response variables including droplet size (Y1, 115.2 nm), INS stability (Y2, 46.75%), and INS leakage (Y3, 17.67%). The desirability function was 0.766, indicating excellent agreement between the predicted and experimental values. The stability of INS-SOS against gastrointestinal enzymes was noticeably improved in the SMEDDS, and the majority of INS remained in oil droplets during release. Following oral administration in diabetic rats, the optimized SMEDDS resulted in pharmacological availabilities of 3.23% (50 IU/kg) and 2.13% (100 IU/kg). Thus, the optimized SMEDDS is a good candidate for the practical development of oral delivery of peptide drugs such as INS.

Design of Montelukast Nanocrystalline Suspension for Parenteral Prolonged Delivery.

Background: Montelukast (MTK), a representative leukotriene receptor antagonist, is currently being investigated as a potential candidate for treating Alzheimer's disease. For potent and effective dosing in elderly patients, a parenteral prolonged delivery system is favored, with improved medication adherence with reduced dosage frequency. Purpose: This study aimed to design a nanocrystalline suspension (NS)-based MTK prolonged delivery system and evaluate its pharmacokinetics profile and local tolerability following subcutaneous administration. Methods: To decelerate the dissolution rate, the amorphous MTK raw material was transformed into a crystalline state using a solvent-mediated transformation method and subsequently formulated into NS using a bead-milling technique. The MTK NSs were characterized by morphology, particle size, crystallinity, and in vitro dissolution profiles. The pharmacokinetic profile and local tolerability at the injection site following subcutaneous injection of MTK suspension were evaluated in rats. Results: Microscopic and physical characterization revealed that the amorphous MTK powder was lucratively transformed into a crystalline form in acidic media (pH 4). MTK crystalline suspensions with different diameters (200 nm, 500 nm, and 3 µm) were uniformly prepared using bead-milling technology, employing polysorbate 80 as suspending agent. Prepared crystalline suspensions exhibited analogous crystallinity (melting point, 150°C) and size-dependent in vitro dissolution profiles. MTK NSs with particle sizes of 200 nm and 500 nm provided a protracted pharmacokinetic profile for up to 4 weeks in rats, with a higher maximum drug concentration in plasma than the 3 µm-sized injectable suspensions. Histopathological examination revealed that MTK NS caused chronic granulomatous inflammation at the injection site, which resolved after 4 weeks. Conclusion: The MTK parenteral NS delivery system is expected to be a valuable tool for treating Alzheimer's disease with extended dose intervals.

Optimized self-microemulsifying drug delivery system improves the oral bioavailability and brain delivery of coenzyme Q10.

Our study aimed to develop a self-microemulsifying drug delivery system for the poorly aqueous-soluble drug Coenzyme Q10, to improve the dissolution and the oral bioavailability. Excipients were selected based on their Coenzyme Q10 solubility, and their concentrations were set for the optimization of the microemulsion by using a D-optimal mixture design to achieve a minimum droplet size and a maximum solubility of Coenzyme Q10 within 15 min. The optimized formulation was composed of an oil (omega-3; 38.55%), a co-surfactant (Lauroglycol® 90; 31.42%), and a surfactant (Gelucire® 44/14; 30%) and exhibited a mean droplet size of 237.6 ± 5.8 nm and a drug solubilization (at 15 min) of 16 ± 2.48%. The drug dissolution of the optimized formulation conducted over 8 h in phosphate buffer medium (pH 6.8) was significantly higher when compared to that of the Coenzyme Q10 suspension. A pharmacokinetic study in rats revealed a 4.5-fold and a 4.1-fold increase in the area under curve and the peak plasma concentration values generated by the optimized formulation respectively, as compared to the Coenzyme Q10 suspension. A Coenzyme Q10 brain distribution study revealed a higher Coenzyme Q10 distribution in the brains of rats treated with the optimized formulation than the Coenzyme Q10 suspension. Coenzyme Q10-loaded self microemulsifying drug delivery system was successfully formulated and optimized by a response surface methodology based on a D-optimal mixture design and could be used as a delivery vehicle for the enhancement of the oral bioavailability and brain distribution of poorly soluble drugs such as Coenzyme Q10.

Recent progresses in exosome-based systems for targeted drug delivery to the brain.

Despite the multiple ongoing and novel initiatives for developing brain-targeted drug delivery systems, insurmountable obstacles remain. A perfect drug delivery device that can bypass the brain-blood barrier and boost therapeutic efficacy is urgently needed for clinical applications. Exosomes hold unrivaled benefits as a drug delivery vehicle for treating brain diseases due to their endogenous and innate attributes. Unique properties, such as the ability to penetrate physical barriers, biocompatibility, innate targeting features, ability to leverage natural intracellular trafficking pathways, favored tumor homing, and stability, make exosomes suitable for brain-targeted drug delivery. Herein, we provide an overview of recent exosome-based drug delivery nanoplatforms and discuss how these inherent vesicles can be used to deliver therapeutic agents to the brain to cure neurodegenerative diseases, brain tumors, and other brain disorders. Moreover, we review the current roadblocks associated with exosomes and other brain-targeted drug delivery systems and discuss future directions for achieving successful therapy outcomes.

lncRNAs UC.145 and PRKG1-AS1 Determine the Functional Output of DKK1 in Regulating the Wnt Signaling Pathway in Gastric Cancer.

DKK1 inhibits the canonical Wnt signaling pathway that is known to be involved in various cancers. However, whether DKK1 acts as an oncogene or tumor suppressor gene remains controversial. Furthermore, the DKK1-regulating mechanism in gastric cancer has not yet been defined. The aim of this study was to explore whether the ultraconserved region UC.145 regulates epigenetic changes in DKK1 expression in gastric cancer. Microarray analysis revealed that UC.145 exhibited the highest binding affinity to EZH2, a histone methyltransferase. The effects of UC.145 inactivation were assessed in gastric cancer cell lines using siRNA. The results indicated that UC.145 triggers DKK1 methylation via interaction with EZH2 and is involved in the canonical Wnt signaling pathway. Additionally, interaction between UC.145 and another long non-coding RNA adjacent to DKK1, PRKG1-AS1, induced a synergistic effect on Wnt signaling. The regulation of these three genes was closely associated with patient overall survival. Inactivation of UC.145 induced apoptosis and inhibited the growth and migratory, invasive, and colony-forming abilities of gastric cancer cells. The study findings provide insights into Wnt signaling in gastric cancer and support UC.145 as a potential novel predictive biomarker for the disease.

Enhanced dissolution and bioavailability of revaprazan using self-nanoemulsifying drug delivery system.

A self-nanoemulsifying drug delivery system (SNEDDS) was developed to enhance the dissolution and oral bioavailability (BA) of revaprazan (RVP). Various SNEDDSs containing 200 mg of RVP were formulated using Capmul MCM, Tween 80, and Brij L4, and they were characterized according to their size, polydispersity index, and dissolution behavior. Dissolution rates of all SNEDDS formulations significantly (p < 0.05) improved with the formation of nanoemulsion with monodispersity. Formulation D resulted in RVP dissolution exceeding 70% at 2 h. Compared to raw RVP, SNEDDS exhibited a 4.8- to 7.4-fold improved effective permeability coefficient (Peff) throughout the intestine in the in situ single pass intestinal permeability study and a 5.1-fold increased oral BA in the in vivo oral absorption assessment in rats. To evaluate the degree of lymphatic uptake, cycloheximide (CYC), a chylomicron flowing blocker, was pretreated prior to the experiment. This pretreatment barely affected the absorption of raw RVP; however, it greatly influenced the absorption of SNEDDS, resulting in an approximately 40% reduction in both the Peff value and oral BA representing lymphatic transport. Thus, we suggest that the SNEDDS formulation is a good candidate for improving oral absorption of RVP through enhanced lymphatic uptake.

Examination of Effective Buccal Absorption of Salmon Calcitonin Using Cell-Penetrating Peptide-Conjugated Liposomal Drug Delivery System.

INTRODUCTION: The buccal route has been considered an attractive alternative delivery route for injectable formulations. Cell-penetrating peptides (CPPs) are gaining increased attention for their cellular uptake and tissue permeation effects. This study was aimed to evaluate the in vitro and ex vivo permeation-enhancing effect of penetratin-conjugated liposomes for salmon calcitonin (sCT) in TR146 human buccal cells and porcine buccal tissues. METHODS: Penetratin was conjugated to phospholipids through a maleimide-thiol reaction. Liposomes were prepared and sCT was encapsulated using a thin-film hydration method. Physical properties such as particle size, zeta potential, encapsulation efficiency, and morphological images via transmission electron microscopy were obtained. Cellular uptake studies were conducted using flow cytometry (FACS) and confocal laser scanning microscopy (CLSM). A cell permeation study was performed using a Transwell® assay, and permeation through porcine buccal tissue was evaluated. The amount of sCT permeated was quantified using an ELISA kit and was optically observed using CLSM. RESULTS: The particle size of penetratin-conjugated liposomes was approximately 123.0 nm, their zeta potential was +29.6 mV, and their calcitonin encapsulation efficiency was 18.0%. In the cellular uptake study using FACS and CLSM, stronger fluorescence was observed in penetratin-conjugated liposomes compared with the solution containing free sCT and control liposomes. Likewise, the amount of sCT permeated from penetratin-conjugated liposomes was higher than that from the free sCT solution and control liposomes by 5.8-fold across TR146 cells and 91.5-fold across porcine buccal tissues. CONCLUSION: Penetratin-conjugated liposomes are considered a good drug delivery strategy for sCT via the buccal route.

Enhancing solubility and bioavailability of coenzyme Q10: formulation of solid dispersions using Soluplus® as a carrier.

Improving the aqueous solubility of poorly soluble compounds have been a major issue in the pharmaceutical industry. In the present study, binary amorphous solid dispersions (SDs) of Coenzyme Q10 (CoQ10), a biopharmaceutics classification system (BCS) II compound and Soluplus® were prepared to enhance the solubility and pharmacokinetic properties compared to crystalline CoQ10. SDs were prepared with different ratios of CoQ10 and Soluplus® (1:3, 1:5, and 1:7) using spray drying technology, and the physicochemical properties of the SDs were evaluated. X-ray powder diffraction, differential scanning calorimetry, and scanning electron microscopy suggested the conversion of the crystalline form of CoQ10 to a binary amorphous system in the SDs. Fourier transform infrared spectroscopy revealed no potential interactions between CoQ10 and Soluplus®. The solubility of the optimal SD formulation (SD 1:7) was approximately 9000-fold higher than that of crystalline CoQ10, and the increment was Soluplus® concentration dependent. As a result, optimized SD 1:7 also showed significantly enhanced dissolution rate where maximum drug release was observed within 30 min in two different dissolution media. Moreover, in contrast to crystalline CoQ10, CoQ10 SDs showed improved pharmacokinetic parameters. Thus, the SD 1:7 formulation is expected to improve biopharmaceutical properties and therapeutic efficacy of CoQ10.

Exertional heat stroke with reversible severe cerebral edema.

Severe cerebral edema associated with exertional heat stroke is a major cause of death or disability. However, few studies on severe cerebral edema resulting from heat stroke have reported neuroradiological findings. Moreover, all the patients in these previous reports either died or remained severely disabled. Here, we report a case of exertional heat stroke with severe cerebral edema that probably developed or worsened due to delayed body temperature normalization. In contrast to previous reports, the patient showed complete clinical and neuroradiological recovery. This rare case suggests that severe cerebral edema could be reversed through meticulous supportive management. Moreover, it confirms the importance of rapid and effective cooling in heat stroke treatment.

Bile acid transporter-mediated oral absorption of insulin via hydrophobic ion-pairing approach.

Despite many ongoing and innovative approaches, there are still formidable challenges in the clinical translation of oral peptide drugs into marketable products due to their low absorption and poor bioavailability. Herein, a novel nanocarrier platform was developed that employs a hydrophobic ion-pairing (HIP) of model peptide (insulin) and the anionic bile salt (sodium glycodeoxycholate, SGDC), and markedly improves intestinal absorption via the bile acid pathway. The developed HIP-nanocomplexes (C1 and C2) were optimized, characterized, and in vitro and in vivo evaluation were performed to assess oral efficacy of these system. The optimal molar ratios of C1 and C2-nanocomplexes were 30:1 and 6:1 (SGDC:insulin), respectively. Compared to the insulin solution, the C1 and C2 nanocomplexes significantly enhanced the permeation of insulin across the Caco-2 cell monolayers, with 6.36- and 4.05-fold increases in apparent permeability, respectively. Uptake mechanism studies were conducted using different endocytosis inhibitors and apical sodium-dependent bile acid transporter (ASBT)-transfected MDCK cells, which demonstrated the involvement of the energy-dependent ASBT-mediated active transport. Furthermore, the intrajejunal administration of C1 and C2 resulted in their pharmacological availabilities (PA) being 6.44% and 0.10%, respectively, indicating increased potential for C1, when compared to C2. Similarly, the PA and the relative bioavailability with intrajejunal administration of the C1 were 17.89-fold and 16.82-fold greater than those with intracolonic administration, respectively, confirming better jejunal absorption of C1. Overall, these findings indicate that the HIP-nanocomplexes could be a prominent platform for the effective delivery of peptides with improved intestinal absorption.

Facilitated Buccal Insulin Delivery via Hydrophobic Ion-Pairing Approach: In vitro and ex vivo Evaluation.

BACKGROUND: The clinical use of therapeutic peptides has been limited because of their inefficient delivery approaches and, therefore, inadequate delivery to target sites. Buccal administration of therapeutic peptides offers patients a potential alternative to the current invasive routes of administration. PURPOSE: The aim of the study was to fabricate hydrophobic ion-pairing (HIP)-nanocomplexes (C1 and C2) utilizing anionic bile salts and cationic peptides, and to assess their permeability across TR146 buccal cell layers and porcine buccal tissue. METHODS: C1 and C2-nanocomplexes were fabricated using the HIP approach. In addition, their physiochemical and morphological attributes, in vitro and ex vivo permeability properties, and qualitative and quantitative cellular uptake were evaluated and compared. The localization of C1 and C2-nanocomplexes in porcine buccal tissue was determined using confocal laser scanning microscopy. RESULTS: The C1-nanocomplex was the superior nanocarrier and significantly enhanced the transport of insulin across TR146 cell layers and porcine buccal tissue, exhibiting a 3.00- and 51.76-fold increase in permeability coefficient, respectively, when compared with insulin solution (p < 0.01). C1-nanocomplex was more efficient than C2-nanocomplex at facilitating insulin permeability, with a 2.18- and 27.64-fold increase across TR146 cell layers and porcine buccal tissue, respectively. The C1-nanocomplex demonstrated immense uptake and localization of insulin in TR146 cells and porcine buccal tissue, as evidenced by a highly intense fluorescence in TR146 cells, and a great shift of fluorescence intensity towards the inner region of buccal tissue over time. The increase in fluorescence intensity was observed in the order of C1 > C2 > insulin solution. CONCLUSION: In this study, we highlighted the efficacy of potential nanocarriers in addressing the daunting issues associated with the invasive administration of insulin and indicated a promising strategy for the buccal administration and delivery of this life-saving peptide hormone.