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Three hyperimmune egg-based formulations rich in immunoglobulin Y (IgY) were orally administered (daily, for up to 90 days) to C57BL/6 mice that were not microbially challenged. The serum levels of 32 cytokines were quantified every 30 days. Histopathology, hematology, and serum biochemistry investigations were also performed. As a sign of increased immune activity, lymphohistiocytic infiltrates were detected in the digestive tract and the liver after 30, 60, and 90 days of treatment. These infiltrates were also present in the lungs after 30 and 60 days, but not at 90 days. Blood analysis indicated systemic inflammation after 30 days of treatment: increases in pro-inflammatory cytokines, glycemia, total serum proteins, ALT, and ALP. After 60 and 90 days of treatment, the analyzed blood parameters showed mixed signs of both increased and decreased inflammation. The increased cytokines, which varied with formulation and time of exposure, indicated a combination of mostly Th17- and Th2-type immune responses. As the mice were healthy and housed in standardized sanitary conditions, and were not microbially challenged, the data were consistent with an interaction of IgY with the gut-associated lymphoid tissue as the main mechanism of action. This interaction generated a local immune response, which subsequently induced a systemic response. [ABSTRACT FROM AUTHOR]

• In vivo-evaluated 5-ASA-HbNPs as a colon-specific prodrug for treatment of experimental colitis. • HbNPs conjugation is an efficient way to increase the therapeutic effect and to reduce the adverse effects of 5-ASA. • HbNPs acted as not only a pro-moiety but also a therapeutically active agent. • Mucoadhesive property of this colonic nano-delivery system contributed to the treatment of IBD. The oral formulation design for colon-specific drug delivery brings some therapeutic benefits in the ulcerative colitis treatment. We recently reported the specific delivery of hemoglobin nanoparticles-conjugating 5-aminosalicylic acid (5-ASA-HbNPs) to the inflamed site. In the current study, the therapeutic effect of the 5-ASA-HbNPs formulation was confirmed in vivo. This evaluation of 5-ASA-HbNPs not only shows longer colonic retention time due to adhesive properties, also provides full support for it as compared with free 5-ASA. It was considered as a suitable bio-adhesive nanoparticle with mucoadhesive property to pass through the mucus layer and accumulate into the mucosa. In UC model mice, a two-fold decrease in the disease activity indexes and colon weight/length ratios was significantly observed in the group treated with 5-ASA-HbNPs. This group received one percent of the standard dosage of 5-ASA (50 μg/kg), while, a similar result was observed for a significant amount of free 5-ASA (5 mg/kg). Furthermore, microscopic images of histological sections of the extracted colons demonstrated that the 5-ASA-HbNPs and 5-ASA groups displayed instances of inflammatory damage within the colon. However, in comparison to the colitis group, the extent of this damage was relatively moderate, suggesting 5-ASA-HbNPs improved therapeutic efficacy with the lower dosage form. [Display omitted] [ABSTRACT FROM AUTHOR]

The gut microbiota is closely associated with human health, and alterations in gut microbiota can influence various physiological and pathological activities in the human body. Therefore, microbiota regulation has become an important strategy in current disease treatment, albeit facing numerous challenges. Nanomaterials, owing to their excellent protective properties, drug release capabilities, targeting abilities, and good biocompatibility, have been widely developed and utilized in pharmaceuticals and dietary fields. In recent years, significant progress has been made in research on utilizing nanomaterials to assist in regulating gut microbiota for disease intervention. This review explores the latest advancements in the application of nanomaterials for microbiota regulation and offers insights into the future development of nanomaterials in modulating gut microbiota. [ABSTRACT FROM AUTHOR]

Turmeric (Curcuma longa L.), a spice and food coloring agent in food preparation, contains a carotenoid pigment called curcumin. Curcumin has attracted extensive research interest owing to its health benefits, ranging from neuroprotection to chemoprevention and antioxidation. It also exhibits anti-cancer effects due to its capacity to inhibit cancer cell proliferation and stimulate apoptosis. However, the health-promoting effects of curcumin are limited by its poor aqueous solubility and low oral bioavailability. This article presents an overview of the latest understanding of the biological effects of curcumin and its use as a food additive in the development of functional food products. [ABSTRACT FROM AUTHOR]

[Display omitted] Remarkable progress has been made in tumour immunotherapy in recent decades. However, the clinical outcomes of therapeutic interventions remain unpredictable, largely because of inefficient immune responses. To address this challenge and optimise immune stimulation, we present a novel administration route for enhancing the bioavailability of immunotherapeutic drugs. Our approach involves the development of an oral tumour vaccine utilising virus-like particles derived from the Hepatitis B virus core (HBc) antigen. The external surfaces of these particles are engineered to display the model tumour antigen OVA, whereas the interiors are loaded with cytosine phosphoguanosine oligodeoxynucleotide (CpG ODN), resulting in a construct called CpG@OVAHBc with enhanced antigenicity and immune response. For oral delivery, CpG@OVAHBc is encapsulated in a crosslinked dextran hydrogel called CpG@OVAHBc@Dex. The external hydrogel shield safeguards the biomimetic virus particles from degradation by gastric acid and proteases. Upon exposure to intestinal flora, the hydrogel disintegrates, releasing CpG@OVAHBc at the intestinal mucosal site. Owing to its virus-like structure, CpG@OVAHBc exhibits enhanced adhesion to the mucosal surface, facilitating uptake by microfold cells (M cells) and subsequent transmission to antigen-presenting cells. The enzyme-triggered release of this oral hydrogel ensures the integrity of the tumour vaccine within the digestive tract, allowing targeted release and significantly improving bioavailability. Beyond its efficacy, this oral hydrogel vaccine streamlines drug administration, alleviates patient discomfort, and enhances treatment compliance without the need for specialised injection methods. Consequently, our approach expands the horizons of vaccine development in the field of oral drug administration. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus is a prevalent metabolic disease, posing a considerable threat to public health. Oligonucleotide drugs have proven to be a promising field of therapy for the diseases. In this study, we reported that a herbal small RNA (sRNA), JGL‐sRNA‐h7 (B34735529, F1439.L002444.A11), could exhibit potent hypoglycemic effects by targeting glucose‐6‐phosphatase. Oral administration of sphingosine (d18:1)‐JGL‐sRNA‐h7 bencaosomes ameliorated hyperglycemia and diabetic kidney injury better than metformin in db/db mice. Furthermore, glucose tolerance was also improved in sphingosine (d18:1)‐JGL‐sRNA‐h7 bencaosomes‐treated beagle dogs. Our study indicates that JGL‐sRNA‐h7 could be a promising hypoglycemic oligonucleotide drug. [ABSTRACT FROM AUTHOR]

The current research aimed at assessing the effects of different levels of Thymol on blood, feeding and survival factors in Oncorhinchus mykiss against Yersinia ruckeri. In this order, three experimental treatments including control (fed with commercial food), first treatment (commercial food with 0.5 percent Thymol) and second treatment (commercial food with one percent Thymol) were used with three replications for each treatment within a factorial analysis for completely randomized design. Then, fish were fed for seven weeks using associated diets. The result showed that different levels of Thymol had no significant effect on survival rate of Oncorhinchus mykiss (P>0.05). Regarding blood indices before the challenge, we found that the 0.5 percent Thymol had no significant effect, however, the one percent Thymol treatment showed significant difference (P<0.05) which caused an increase in the amount of hemoglobin and the concentration of intraglobulin hemoglobin. Measuring blood indices after the challenge, however, showed no significant different. The comparison of growth indices among different Thymol treatments showed that the 0.5 percent Thymol had significant effect on final weight, weight gain, special growth rate, protein yield ratio and food conversion factor compared to the control and one percent Thymol treatments. The result from current study showed that Thymol stimulates growth and improves nutritional conditions in fish, especially rainbow trout. [ABSTRACT FROM AUTHOR]

Radiation-induced intestinal injury is the most common side effect during radiotherapy of abdominal or pelvic solid tumors, significantly impacting patients' quality of life and even resulting in poor prognosis. Until now, oral application of conventional formulations for intestinal radioprotection remains challenging with no preferred method available to mitigate radiation toxicity in small intestine. Our previous study revealed that nanomaterials derived from spore coat of probiotics exhibit superior anti-inflammatory effect and even prevent the progression of cancer. The aim of this work is to determine the radioprotective effect of spore coat (denoted as spore ghosts, SGs) from three clinically approved probiotics (B.coagulans, B.subtilis and B.licheniformis). All the three SGs exhibit outstanding reactive oxygen species (ROS) scavenging ability and excellent anti-inflammatory effect. Moreover, these SGs can reverse the balance of intestinal flora by inhibiting harmful bacteria and increasing the abundance of Lactobacillus. Consequently, administration of SGs significantly reduce radiation-induced intestinal injury by alleviating diarrhea, preventing X-ray induced apoptosis of small intestinal epithelial cells and promoting restoration of barrier integrity in a prophylactic study. Notably, SGs markedly improve weight gain and survival of mice received total abdominal X-ray radiation. This work may provide promising radioprotectants for efficiently attenuating radiation-induced gastrointestinal syndrome and promote the development of new intestinal predilection. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma is one of the most common malignant tumors in the world with complex etiology, high tumor heterogeneity, and low efficacy of treatment. The establishment of an animal model that is close to the clinical situation of hepatocellular carcinoma and can be successfully modeled many times is of great significance to the study of the pathogenesis, diagnosis and treatment of hepatocellular carcinoma. We used Diethylnitrosamine (DEN) to induce hepatocellular carcinoma in rodents and compared four models of DEN-induced hepatocellular carcinoma. Group C (Control): rats were fed a standard laboratory rat diet and freely drank normal water. Group P (Peritoneal injection): rats were administered an IP injection (50 mg/kg/week) between 5 and 23 weeks after birth. Ten microliter of DEN solution would be injected per g of rat. Group O (DEN-Fed group): rats were allowed unrestricted access to water contaminated with 0.01 % DEN between the ages of 7 and 15 weeks. 0.2 mL of DEN drinking water was consumed per gram of rat. Group P+O (Combined peritoneal injection and Oral feeding): rats were administered an IP injection (50 mg/kg) at weeks 3 and 5 post-birth, and they freely drank water contaminated with 0.012 % DEN between weeks 7 and 14 post-birth. We used an ultrasound scan, biochemical testing, haematoxylin, and eosin staining, Masson staining, Wolf scarlet staining, Ki67, CD34, a-SMA, CD8, and CD68 staining to compare between groups. Liver dissection and ultrasound scan showed that compared to other groups, the liver of Group P+O was darker in color, with more grey-white cancer nodules and larger localized tumors, and the structure of the tumors was slightly disorganized, with the elastography hardness of the middle lobe and the right lobe was slightly increased. The alanine aminotransferase and total bilirubin of Group P+O were higher than those of Group O but lower than those of Group P. Haematoxylin and eosin staining showed that the tumors of Group P+O were large, with large tumor cords and pseudo-glandular, the degree of differentiation was medium and surrounded by more fatty lesions. We conclude that combined DEN treatment is more effective, stable, and has the advantage of multiple modalities, leading to faster tumor formation. [ABSTRACT FROM AUTHOR]

Aeromonas hydrophila is one of the major freshwater fish pathogens. In the current study, a cocktail of D6 and CF7 phages was given orally to Labeo rohita to assess phage survival in fish organs as well as to determine the therapeutic efficacy of phage treatment against fish mortality caused by A. hydrophila. In the phage-coated feed, prepared by simple spraying method, phage counts were quite stable for up to 2 months with a decline of ≤ 0.23 log10 and ≤ 1.66 log10 PFU/g feed during 4 oC and room temperature storage. Throughout the experimental period of 7 days, both phages could be detected in the gut of fish fed with phage-coated feed. Besides, both CF7 and D6 phages were also detected in fish kidneys indicating the ability of both the phage to cross the intestinal barrier. During challenge studies with LD50 dose of A. hydrophila, phage cocktail doses of 1 × 106 – 1 × 108 PFU/g feed prevented the mortality in L. rohita with relative percentage survival (RPS) of 8.7–65.2. When challenged with LD90 dose of A. hydrophila, an RPS value of 28.6 was obtained at a phage cocktail dose of 1 × 108 PFU/g feed. The RPS data showed that orally-fed phage cocktail protected the fish against the mortality caused by A. hydrophila in a dose-dependent manner. Simple practical approaches for phage cocktail development, medicated feed preparation and oral administration along with phage survival and protection data make the current study useful for farmer-level application. [ABSTRACT FROM AUTHOR]

In recent years, increasing interest has been accorded to polyester-based polymer microstructures, driven by their promising potential as advanced drug delivery systems. This study presents the preparation and characterization of new polymeric microparticles based on poly(ethylene brassylate-co-squaric acid) loaded with norfloxacin, a broad-spectrum antibiotic. Polymacrolactone was synthesised in mild conditions through the emulsion polymerization of bio-based and renewable monomers, ethylene brassylate, and squaric acid. The microparticles were obtained using the precipitation technique and subsequently subjected to comprehensive characterization. The impact of the copolymer/drug ratio on various properties of the new system was systematically evaluated, confirming the structure of the copolymer and the encapsulation of norfloxacin. The microspheres are approximately spherical and predominantly homogeneously distributed. The average hydrodynamic diameter of the microparticles falls between 400 and 2000 nm, a decrease that is observed with the increase in norfloxacin content. All samples showed good encapsulation efficiency and drug loading capacity, with the highest values obtained for microparticles synthesised using an equal ratio of copolymer and drug. In vitro drug release results disclose that norfloxacin molecules are released in a sustained biphasic manner for up to 24 h. Antimicrobial activity was also studied, with samples showing very good activity against E. coli and moderate activity against S. aureus and E. faecalis. In addition, HDFA human fibroblast cell cultures demonstrated the cytocompatibility of the microparticles. [ABSTRACT FROM AUTHOR]

Adequate bowel preparation is a prerequisite for colonoscopy, and chronic constipation (CC) is one of the important influencing factors. In recent years, scholars have paid more and more attention to bowel preparation for CC. In this article, the selection of intestinal detergents before colonoscopy for CC was summarized according to literature review. The effectiveness and safety of each protocol were assessed to provide reference for clinical practice, improve the quality of bowel preparation for CC and deliver timely tertiary prevention for colorectal cancer. [ABSTRACT FROM AUTHOR]

Macromolecules are fragile when orally administered. An intestinal villi‐inspired metal–organic frameworks (MOFs)‐based smart pill with multiple advantages is developed to offer a salubrious solution for oral delivery of enzymes. In the pill, MOFs accommodate enzymes as carriers exhibit excellent in vitro and in vivo catalytic activities with good oral biosafety, displaying supreme protection from degradation or inhibition in simulated gastrointestinal tract and high tolerance in simulated gastric acid and intestinal fluid. Moreover, the bioinspired pill possesses the morphology of the small intestinal villi obtained via an in situ moulding strategy for enhancing biocatalysis, which is attributed to the increase of surface area. Collaboratively, the adhesive layer renders increased smart pill in vivo retention, which is verified in pigs, providing a clinically translational and versatile platform for long‐term oral macromolecule delivery. [ABSTRACT FROM AUTHOR]

The perception regarding lactate has changed over the past decades, and some of its physiological roles have gradually been revealed. However, the effects of exogenous lactate on skeletal muscle synthesis remain unclear. This study aimed to confirm the effects of a 5‐week lactate administration and post‐exercise lactate administration on skeletal muscle synthesis. Thirty‐two Institute of Cancer Research mice were randomly assigned to non‐trained + placebo, non‐trained + lactate, trained + placebo, and trained + lactate groups. Furthermore, 3 g/kg of lactate or an equivalent volume of saline was immediately administered after exercise training (maximum oxygen uptake: 70%). Lactate administration and/or exercise training was performed 5 days/week for 5 weeks. After the experimental period, it was observed that lactate administration tended to elevate skeletal muscle weight, increased protein kinase B (p < 0.05) and mammalian target of rapamycin (p < 0.05) mRNA levels, and decreased muscle ring‐finger protein‐1 expression (p < 0.05). Lactate administration after exercise training significantly enhanced plantaris muscle weight; however, it had no additional effects on most signaling factors. This study demonstrated that a 5‐week lactate administration could stimulate skeletal muscle synthesis, and lactate administration after exercise training may provide additional effects, such as increasing skeletal muscle. [ABSTRACT FROM AUTHOR]

Carvacryl acetate (CA) is a monoterpene obtained from carvacrol, which exhibits anti-inflammatory activity. However, its low solubility in aqueous media limits its application and bioavailability. Herein, we aimed to develop a carvacryl acetate nanoemulsion (CANE) and assess its anti-inflammatory potential in preclinical trials. The optimized nanoemulsion was produced by ultrasound, and stability parameters were characterized for 90 days using dynamic light scattering after hydrophilic–lipophilic balance (HLB) assessment. To evaluate anti-inflammatory activity, a complete Freund's adjuvant-induced inflammation model was established. Paw edema was measured, and local interleukin (IL)-1β levels were quantified using ELISA. Toxicity was assessed based on behavioral changes and biochemical assays. The optimized nanoemulsion contained 3% CA, 9% surfactants (HLB 9), and 88% water and exhibited good stability over 90 days, with no signs of toxicity. The release study revealed that CANE followed zero-order kinetics. Dose–response curves for CA were generated for intraperitoneal and oral administration, demonstrating anti-inflammatory effects by both routes; however, efficacy was lower when administered orally. Furthermore, CANE showed improved anti-inflammatory activity when compared with free oil, particularly when administered orally. Moreover, daily treatment with CANE did not induce behavioral or biochemical alterations. Overall, these findings indicate that nanoemulsification can enhance the anti-inflammatory properties of CA by oral administration. [ABSTRACT FROM AUTHOR]

Oxidative stress is common in several human and veterinary conditions and it is associated to alteration of the glutathione peroxidase (GPx) level. GPx is an enzyme present in erythrocytes, kidney, and liver and it has a role in protecting against oxidative damage. In this randomised double-blinded control trial on healthy dogs, we present findings indicating that the administration for a total of 35 days of a supplement containing S-acetyl-glutathione (SAG) alongside other antioxidant natural ingredients, leads to an increase in the GPx level. Furthermore, the supplement positively changes liver blood parameters, even in healthy dogs. These preliminary results hold promise for conducting new studies using the same supplement on dogs affected by liver conditions, thereby confirming its antioxidant effects and the potential improvement of altered blood parameters. Oxidative stress characterises several conditions in dogs and the use of antioxidants can improve their health. The administration of a new supplement containing S-acetyl-glutathione (SAG) together with other antioxidant natural ingredients, increased the level of glutathione peroxidase (GPx). No adverse events were reported after the supplement administration. [ABSTRACT FROM AUTHOR]

Gefitinib (GEF) is a clinical medication for the treatment of lung cancer targeting the epidermal growth factor receptor (EGFR). However, its efficacy is remarkably limited by low solubility and dissolution rates. In this study, two cocrystals of GEF with co-formers were successfully synthesized using the recrystallization method characterized via Powder X-ray Diffraction, Fourier Transform Infrared Spectroscopy, and 2D Nuclear Overhauser Effect Spectroscopy. The solubility and dissolution rates of cocrystals were found to be two times higher than those of free GEF. In vitro cytotoxicity studies revealed that the cocrystals enhanced the inhibition of cell proliferation and apoptosis in A549 and H1299 cells compared to free GEF. In mouse models, GEF@TSBO demonstrated targeted, safe, and effective antitumor activity with only one-dose administration. Mechanistically, the GEF cocrystals were shown to increase the cellular levels of damaged DNA, while potentially downregulating PARP, thereby impairing the DNA repair machinery and leading to an imbalance between DNA damage and restoration. These findings suggest that the cocrystallization of GEF could serve as a promising adjunct to significantly enhance the physicochemical and biopharmaceutical performance for lung cancer treatment, providing a facial strategy to improve GEF anticancer efficiency with high bioavailability that can be orally administrated with only one dose. [ABSTRACT FROM AUTHOR]

Temozolomide (TMZ) is part of the therapeutic armamentarium used in managing pediatric cancers; however, available oral forms (capsules) are not adapted for use in children. Our aim was to assess the dose accuracy and stability of TMZ using capsule contents mixed with food compared with a novel, ready-to-use liquid formulation specifically developed for children (Ped-TMZ, brand name KIZFIZO). Dose accuracy and TMZ stability testing were performed with TMZ capsule contents (90 mg) mixed with food vehicles (apple juice, apple sauce, cream, milk, and mashed potatoes) and compared to an equivalent dose of Ped-TMZ. Acceptance criteria were predefined for TMZ (95.0–105.0%) and its degradation product amino-imidazole-carboxamide (AIC; <1%) content. The delivered dose was significantly higher using Ped-TMZ (96.6 ± 1.2%) and within the predefined criteria for TMZ content, whereas it was systematically under the lower specifications of 95% using capsule-derived preparations with apple juice (91.0 ± 1.5%) and apple sauce (91.6 ± 1.4%), respectively (p < 0.0001). In chemical stability tests, the four food vehicles (apple sauce, cream, milk, mashed potatoes) had a significant effect on TMZ stability (p = 0.0042), and the AIC significantly increased with time in three of the four vehicles (p < 0.0001). Only 1/72 of preparations from capsules met the predefined acceptance criteria, whereas Ped-TMZ showed no TMZ loss, and the AIC remained within specifications. In conclusion, mixing TMZ capsule content with food may result in significant underexposure, possibly even greater in routine practice, as complete food intake by the child is unlikely. [ABSTRACT FROM AUTHOR]

The oral absorption of exenatide, a type 2 diabetes medication, can be increased by employing lipid nanocapsules (LNC). To increase mucus permeability and exenatide intestinal absorption, reverse micelle lipid nanocapsules (RM-LNC) were prepared and their surface was modified with DSPE-PEG-FA. The RM-LNC with surface modification of DSPE-PEG-FA (FA-RM-LNC) were able to target enterocytes and reduce mucus aggregation in the intestine. Furthermore, in vitro absorption at different intestinal sites and flip-flop intestinal loop experiments revealed that LNCs with surface modification significantly increased their absorption efficiency in the small intestine. FA-RM-LNC delivers more drugs into Caco-2 cells via caveolin-, macrophagocytosis-, and lipid raft-mediated endocytosis. Additionally, the enhanced transport capacity of FA-RM-LNC was observed in a study of monolayer transport in Caco-2 cells. The oral administration of exenatide FA-RM-LNC resulted in a prolonged duration of hypoglycemia in diabetic mice and a relative bioavailability (BR) of up to 7.5% in rats. In conclusion, FA-RM-LNC can target enterocytes and has promising potential as a nanocarrier for the oral delivery of peptides. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is a worldwide public health issue with an increasing number of patients annually. However, there is no curative drug for IBD, and the present medication for IBD generally focuses on suppressing hyperactive immune responses, which can only delay disease progression but inevitably induce off-target side effects, including infections and cancers. Herein, late-model orally administered nanotherapeutic micelles (HADLA) were developed based on a conjugate of hyaluronic acid (HA) and dehydrolithocholic acid (DLA), which was simple to achieve and obtained satisfactory therapeutic efficacy in a murine colitis model with a full safety profile. HADLA is capable of targeting inflammatory colon tissues, restoring intestinal barrier function and reducing intestinal epithelial cell death. Moreover, it modulates the adaptive immune system by inhibiting the activation of pathogenic T helper 17 (Th17) cells, and it exhibits more remarkable effects in preventing colitis than DLA alone. Finally, HADLA exhibits a remarkable ability to modulate dysregulated gut microbiomes by increasing beneficial probiotics and decreasing pathogenic bacteria, such as Turicibacter. Compared with the current systemic or subcutaneous administration of biologics, this study opens new avenues in the oral delivery of immune-modulating nanomedicine and introduces DLA as a new medication for IBD treatment. [Display omitted] • Oral delivery of new nanotherapeutic micelles HADLA targets inflammatory colon. • The two carriers, hyaluronic acid and bile acid, are combined together to form HADLA. • HADLA has a unique property of acid-base structural transformation. • HADLA balances the dual behaviors of bile acids for IBD treatment. • HADLA obtains satisfactory therapeutic efficacy in IBD through multiple mechanisms. [ABSTRACT FROM AUTHOR]

Polysaccharide aerogels have emerged as a highly promising technology in the field of oral drug delivery. These nanoporous, ultralight materials, derived from natural polysaccharides such as cellulose, starch, or chitin, have significant potential in colonic drug delivery due to their unique properties. The particular degradability of polysaccharide-based materials by the colonic microbiota makes them attractive to produce systems to load, protect, and release drugs in a controlled manner, with the capability to precisely target the colon. This would allow the local treatment of gastrointestinal pathologies such as colon cancer or inflammatory bowel diseases. Despite their great potential, these applications of polysaccharide aerogels have not been widely explored. This review aims to consolidate the available knowledge on the use of polysaccharides for oral drug delivery and their performance, the production methods for polysaccharide-based aerogels, the drug loading possibilities, and the capacity of these nanostructured systems to target colonic regions. [ABSTRACT FROM AUTHOR]

Possessing the largest surface area of mucosa in the body, the gastrointestinal (GI) tract can easily sufferfrom inflammatory damage under various adverse external exposures, resulting in the occurrence of inflammatory bowel disease (IBD). Excessive reactive oxygen species (ROS) usually lead to local mucosal injury, accelerate the formation of niduses, andamplify the inflammatory and immune response. Antioxidant therapy, therefore, is considered as a potential strategy against IBDs. Herein, a series of novel dihydromyricetin‐based nanoassemblies with excellent antioxidant activities and high dispersion in GI tract as oral preparations are developed for the targeted IBD treatment. By changing raw materials, the current strategy can be well extended to the preparation of other insoluble natural flavonoid compound‐based nanoassemblies. The well‐designed dihydromyricetin‐PEG 1000‐based nanoassemblies (DMY‐1000 NAs) with high stability and great ROS scavenging capacity in the harsh environment of GI tract hold an admirable targeted capability toward the intestinal inflamed lesions. Therefore, these biocompatible DMY‐1000 NAs show promising therapeutic effects for typical IBDs including ulcerative colitis and Crohn's disease in murine models. This study not only provides a new method for constructing antioxidant therapy platforms but also illustrates their prominent therapeutic promise against IBDs. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the impact of oral intake of Hyaluronic Acid (HA) on skin health. Background: HA, an endogenous substance in the human body, plays a key role in skin health. However, its concentration in the skin decreases significantly with age. Previous studies suggested that oral intake of HA can supplement the body's HA level, but did not reveal the effects on different age groups and skin types. Methods: A double‐blind, randomized clinical trial with 129 female participants, covering young and elderly groups and differnet skin types, was conducted to assess the efficacy of orally administered HA on skin health. Results: Oral administration of HA significantly promoted skin hydration after 2‐8 weeks among both young and elderly groups. Skin tone improvement was observed after 4‐8 weeks, while an increase in epidermal thickness was noted after 12 weeks. Conclusion: This study provides direct evidence supporting the clinical efficacy of oral intake of HA in promoting skin health. [ABSTRACT FROM AUTHOR]

A drug delivery system (DDS) is a useful technology that efficiently delivers a target drug to a patient's specific diseased tissue with minimal side effects. DDS is a convergence of several areas of study, comprising pharmacy, medicine, biotechnology, and chemistry fields. In the traditional pharmacological concept, developing drugs for disease treatment has been the primary research field of pharmacology. The significance of DDS in delivering drugs with optimal formulation to target areas to increase bioavailability and minimize side effects has been recently highlighted. In addition, since the burst release found in various DDS platforms can reduce drug delivery efficiency due to unpredictable drug loss, many recent DDS studies have focused on developing carriers with a sustained release. Among various drug carriers, mesoporous silica DDS (MS-DDS) is applied to various drug administration routes, based on its sustained releases, nanosized porous structures, and excellent solubility for poorly soluble drugs. However, the synthesized MS-DDS has caused complications such as toxicity in the body, long-term accumulation, and poor excretion ability owing to acid treatment-centered manufacturing methods. Therefore, biosilica obtained from diatoms, as a natural MS-DDS, has recently emerged as an alternative to synthesized MS-DDS. This natural silica carrier is an optimal DDS platform because culturing diatoms is easy, and the silica can be separated from diatoms using a simple treatment. In this review, we discuss the manufacturing methods and applications to various disease models based on the advantages of biosilica. [ABSTRACT FROM AUTHOR]

In recent years, numerous studies have discovered the potential of natural compounds extracted from medicinal plants as a promising alternative treatment for ischemic stroke (IS). Oroxylum indicum is among the plants that has been widely proven to contain a beneficial flavonoid compound known as baicalein. However, the therapeutic potential of this compound for IS disease has yet to be demonstrated. In this study, a baicalein-enriched fraction (BEF) was harvested from the leaves of O. indicum and tested on neural stem cells (NSCs) to determine its effects on the cell viability and gene expression prior to an in vivo animal study. NSCs were chosen because they are the primitive brain cells that play important roles in neurogenesis after IS injury. It was found that NSCs treated with BEF at concentration of 3.125 µg/mL for 48 hours showed a significant higher cell proliferation rate. Moreover, these cells expressed high NSC markers (Nestin and SOX2) and genes responsible for antioxidant (SOD2) and angiogenesis (ANGPT1) mechanisms, indicating that the BEF treatment could enhance the progenitor brain cells viability and the expression of cytokines that are beneficial to reduce oxidative stress and reinstate blood flow in an ischemic brain. Subsequently, the in vivo therapeutic effects of BEF for IS disease was tested by administering 50 mg/kg b.wt of BEF to male Sprague Dawley (SD) rats via oral gavage before and after induction of IS. Assessments of neurological impairments were performed using a modified neurological severity score (mNSS) and the quantification of the total infarct volume was evaluated as the endpoint of this study. Results showed that an oral administration of BEF improved the behavioral scoring for motor functions (forelimb flexion and forelimb twisting), contralateral sensory functions (paw-whiskers test), motor coordination, balance functions (beam balance test) and reflex functions (pinna, corneal, startle and tail reflex) within 24-72 h; alternatively, the non-treated rats showed continuously lower scores for all the tests throughout the study, indicating that the BEF-treated rats exhibited a faster recovery rate as compared to the non-treated rats. Such improvements were observed up to two weeks. In addition, histological assessment also revealed a reduction of infarct volume in the BEF-treated rats as compared to the control rats. In summary, the present study demonstrated the potential of BEF extracted from the O. indicum as a supplement to improve preclinical IS models. [ABSTRACT FROM AUTHOR]

Lead (Pb) is a prominent heavy metal emitted by motor vehicle exhausts, factory and mining fumes. Its presence in the atmoshpere can endure for up to seven days, posing a considerable risk of contaminating surrounding food and beverages. Lead enters the body through inhalation and the skin. Lead can also enter the human body via the oral route and accumulate in the body. It causes health problems such as oxidative stress and damage human organs such as the kidneys and liver. This research aims to examine the effect of oral lead exposure on the liver histopathology of Swiss Webster strain mice (Mus musculus). Employing a nonprobability sampling technique, 25 male mice were divided into 5 groups: negative control, K2, K3, K4 and K5. These mice were administered a daily oral dose of 0.5 mL and subsequently euthanized in CO2 chamber the following week for liver dissection. The findings reveal signs of hydropic degeneration characterized by cellular swelling, irregular shapes, and disrupted organelles in groups K2, K3, K4, and K5. In addition, the mean degree of liver damage was observed as 0 for the negative control, 1 for group K2, 1 for group K3, 2 for group K4, and 3 for group K5. In conclsuin, this study confirms that lead exposure can result in dentrimenal liver histopathology changes in mice. [ABSTRACT FROM AUTHOR]

Chondroitin sulfate has been widely administered orally to improve knee osteoarthritis. Chondroitin sulfate also has various biological properties, such as anti-inflammatory, immunomodulatory, anti-oxidative, and antitumor activity. However, chondroitin sulfate absorption in the digestive system and bioavailability remains controversial owing to its large molecular weight. In this study, we aimed to evaluate the absorption of chondroitin sulfate oligosaccharides, depolymerized chondroitin sulfate with low molecular weight, in oral administration to humans. Four types of chondroitin sulfate with varying molecular weight [chondroitin sulfate tetrasaccharide (MW. 980), CSOS-1 (MW. 1,500), CSOS-2 (MW. 2,800), and HMWCS (MW. 70,000)] were orally administered and quantified in plasma and urine. Exogenous chondroitin sulfate in these samples was quantified using a high-performance liquid chromatography system equipped with a fluorescence detector. Quantitative changes of administered chondroitin sulfate tetrasaccharide showed similar patterns in plasma and urine, therefore it was presumed that the amount of exogenous chondroitin sulfate excreted in urine reflects its quantitative profile in blood. Considering urinary exogenous chondroitin sulfate as a parameter of intestinal chondroitin sulfate absorption, urinary contents of orally administered chondroitin sulfate with varying molecular weight were compared. Consequently, the amount of urinary exogenous chondroitin sulfate in 24 h after administration was higher in the chondroitin sulfate oligosaccharides group than that in the high molecular weight chondroitin sulfate group. Additionally, in the molecular weight distribution, urinary exogenous chondroitin sulfate after chondroitin sulfate oligosaccharides administration showed a lower content of chondroitin sulfate oligosaccharides with a higher molecular weight than that observed before administration. In summary, our results demonstrated for the first time that lower molecular weight of chondroitin sulfate is more efficiently absorbed through the digestive tract in human, and the improvement of its bioavailability is expected. [ABSTRACT FROM AUTHOR]

Non‐invasive management of intestinal microvascular injury with hemorrhage under constant biochemical‐mechanical encroachment of luminal contents is a major clinical challenge. Herein, an oral hydrogel microsphere is designed, encapsulating the platelet membrane fragment self‐assembled nanohydrogel fabricated by double‐crosslinking of methacrylated hyaluronic acid and Rebamipide‐loaded dendrimer (Rng@PMS), for self‐localization of hemorrhagic focus and intensive management of intestinal microvascular injury via suppression of inflammation‐mediated tissue injury and reintegration of the damaged mucosal barrier. The results indicate that Rng@PMS effectively adheres to exposed collagen on injured microvasculature and attaches to over 90% of activated macrophages within 10 min, endowing Rng@PMS with a significantly prolonged enteral dwell time (over 24 hours). Importantly, Rng@PMS generated from alginate is designed for oral colon‐targeted delivery to avoid the erosion of gastrointestinal contaminants. In vivo study reveals oral administration of microspheres in murine hematochezia model upregulates the intestinal barrier proteins zonula occludens‐1, Occludin, and muc2, and inhibits infiltration of neutrophils, dendritic cells, and macrophages in hemorrhagic foci, thereby reducing the hematochezia score from 4 to 0.8, and the pathology score from 5.3 to 0.5. Oral microspheres for in situ management of intestinal microvascular injury may be applicable more broadly to noninvasively treat diseases with symptoms of mucosal hemorrhage. [ABSTRACT FROM AUTHOR]

The important pathway toward liver fibrosis is the TGF-β1-induced activation of hepatic stellate cells (HSCs). To discover chemicals to inhibit liver fibrosis, we screened 3000 chemicals using cell array system where human HSCs line LX2 cells are activated with TGF-β1. We discovered 3,7-dimethoxyflavone (3,7-DMF) as a chemical to inhibit TGF-β1-induced activation of HSCs. In the thioacetamide (TAA)-induced mouse liver fibrosis model, 3,7-DMF treatment via intraperitoneal or oral administration prevented liver fibrosis as well as reversed the established fibrosis in the separate experiments. It also reduced liver enzyme elevation, suggesting protective effect on hepatocytes because it has antioxidant effect. Treatment with 3,7-DMF induced antioxidant genes, quenches ROS away, and improved the hepatocyte condition that was impaired by H 2 O 2 as reflected by restoration of HNF-4α and albumin. In the TAA-mouse liver injury model also, TAA significantly increased ROS in the liver which led to decrease of albumin and nuclear expression of HNF-4α, increase of TGF-β1 and hepatocytes death, accumulation of lipid, and extra-nuclear localization of HMGB1. Treatment of 3,7-DMF normalized all these pathologic findings and prevented or resolved liver fibrosis. In conclusion, we discovered 3,7-DMF that inhibits liver fibrosis based on dual actions; antioxidant and inhibitor of TGF-β1-induced activation of HSCs. [Display omitted] • We developed a cell array system to identify new compounds capable of inhibiting liver fibrosis, using the human hepatic stellate cells activated by TGF-β1. • We identified 3,7-DMF as a potential chemical to prevent liver fibrosis after injury. • Daily oral administration of 3,7-DMF effectively resolved established liver fibrosis after injury. • 3,7-DMF protected hepatocytes through two mechanisms: scavenging ROS and decreasing the expression of TGF-β1. • 3,7-DMF had a protective effect on injured liver tissues by restoring hepatocyte functional genes, inhibiting hepatic steatosis, regenerating injured hepatocytes, and inhibiting activated HSCs. [ABSTRACT FROM AUTHOR]

Overexpression of classically activated macrophages (M1) subtypes and assessed reactive oxygen species (ROS) levels are often observed in patients with ulcerative colitis. At present, the treatment system of these two problems has yet to be established. Here, the chemotherapy drug curcumin (CCM) is decorated with Prussian blue analogs in a straightforward and cost‐saving manner. Modified CCM can be released in inflammatory tissue (acidic environment), eventually causing M1 macrophages to transform into M2 macrophages and inhibiting pro‐inflammatory factors. Co(III) and Fe(II) have abundant valence variations, and the lower REDOX potential in CCM‐CoFe PBA enables ROS clearance through multi‐nanomase activity. In addition, CCM‐CoFe PBA effectively alleviated the symptoms of UC mice induced by DSS and inhibited the progression of the disease. Therefore, the present material may be used as a new therapeutic agent for UC. [ABSTRACT FROM AUTHOR]

Introduction/Background Vitiligo is an autoimmune disease characterized by depigmentation of skin due to the progressive loss of melanocytes. The often highly visible and chronic nature of vitiligo as well as its unpredictable disease course have negative psychosocial impacts on most patients, affecting quality of life. Disease pathogenesis is largely regulated by interferon-γ activation of the Janus kinase (JAK) signaling pathway. Povorcitinib is an oral, small-molecule, selective JAK1 inhibitor with potential activity in the treatment of nonsegmental vitiligo. Objectives To evaluate the efficacy and safety of povorcitinib in patients with extensive nonsegmental vitiligo in a phase 2b, dose-ranging study (NCT04818346). Methods Adults with nonsegmental vitiligo affecting ≥0.5% facial and ≥8% total body surface areas were eligible. Patients were randomized 1:1:1:1 to once daily povorcitinib 15/45/75 mg or placebo for 24 weeks; subsequently, patients received povorcitinib 45 or 75 mg for an additional 28 weeks, with a 24-week off-treatment follow-up period. The primary endpoint was the percentage change from baseline in total Vitiligo Area Scoring Index (T-VASI) at Week 24. Other endpoints included percentage of patients achieving ≥50% reduction from baseline in T-VASI (T-VASI50), ≥50%/≥75% reduction in facial VASI (F-VASI50/75), and safety. Results Of 171 randomized patients, 54.4% were female and 66.7% had Fitzpatrick skin types I–III. Median (range) age was 50 (23–74) years and disease duration was 16.4 (0.8–58.9) years. At Week 24, the primary efficacy endpoint, T-VASI percentage change from baseline with povorcitinib (15 mg, –19.1%; 45 mg, –17.8%; 75 mg, –15.7%; least square means povorcitinib vs placebo, P <0.01), was statistically superior to placebo (+2.3%). Percentages of patients achieving F-VASI50 at Week 24 were higher for povorcitinib (16.3%, 34.9%, and 23.8% for 15, 45, and 75 mg, respectively) than placebo (7.0%). Improved repigmentation was seen across treatment groups at Week 52; mean percentage changes from baseline in T-VASI for povorcitinib 15-to-75-mg, 45-mg, 75-mg, and placebo-to-75-mg subgroups were –40.7%, –42.7%, –41.3%, and –18.1%, respectively; F-VASI mean percentage changes from baseline were –63.6%, –63.8%, –64.4%, and –54.8%, respectively. T-VASI50 was achieved by 45.2%, 37.0%, 37.9%, and 15.2%; F-VASI50 by 71.0%, 77.8%, 69.0%, and 63.6%; and F-VASI75 by 48.4%, 55.6%, 58.6%, and 45.5% of patients, respectively. A total of 34 patients entered the follow-up period, with 32 completing Week 76. T-VASI mean percentage changes from baseline to Week 76 were –41.3%, –43.6%, –27.1%, and –34.8%, respectively; F-VASI mean changes were –48.9%, –63.0%, –46.4%, and –73.5%, suggesting durability of response after discontinuation of povorcitinib. Treatment-emergent adverse events (TEAEs) occurred in 89.2% and serious adverse events in 2.4% among patients who received povorcitinib 45 or 75 mg through 52 weeks. The most common TEAEs were COVID-19 (36.1%), blood creatine phosphokinase increased (13.3%), acne (12.0%), fatigue (10.8%), and headache (9.6%). Conclusions Oral povorcitinib was associated with substantial facial and total body repigmentation in patients with extensive nonsegmental vitiligo through 52 weeks of treatment in this phase 2b study. Patients who were off treatment for 24 weeks demonstrated durable response, maintaining their level of response achieved at Week 52. All doses of povorcitinib were generally well tolerated. [ABSTRACT FROM AUTHOR]

Introduction/Background Orismilast is a potent selective phosphodiesterase 4 (PDE4)-B and -D inhibitor, showing significant efficacy in a Phase 2b psoriasis study.1,2 PDE4-B and PDE4-D isoforms are over-expressed in the skin of patients with atopic dermatitis (AD), compared to healthy individuals.3 Enhanced PDE4 activity has also been observed in peripheral blood leukocytes in AD. Orismilast inhibits PDE4-B/D isoforms up to 39 times more potently than apremilast,1 leading to potent suppression of Th1, Th17, and Th2 effector cytokines.1 Objectives To evaluate efficacy and safety of orismilast versus placebo in adults with moderate-to-severe AD. Methods ADESOS is a 16-week, phase 2b, double-blinded, placebo-controlled, dose-finding study assessing efficacy and safety of orismilast in adults with moderate-to-severe AD. Patients were randomized (1:1:1:1) to orismilast 20, 30, 40 mg, or placebo, twice daily. Randomized and dosed patients were included in the Intent-to-Treat Population. Missing data were handled using Multiple Imputation (MI) for the analysis of primary and secondary efficacy endpoints. Results Baseline demographics and disease characteristics were generally balanced across groups for the 233 dosed patients. Significantly more patients achieved IGA0/1 responses at Week 16 in orismilast 20 (n=58), 30 (n=61), and 40 mg (n=59) groups, compared to placebo (n=55) (26.3%, 24.3%, 30.9%, and 9.5%, respectively; all p-values <0.05). All active arms demonstrated a significant ≥4-point reduction in itch NRS at Week 2, compared to placebo (p <0.05). Similarly, Patient Global Impression of Change of "much or very much improved" was significant in active arms compared to placebo at Week 16. Mean percentage changes in EASI at Week 16 were -55.1%, - 52.2%, -61.4%, and -50.4%, in orismilast 20, 30, 40 mg and placebo groups, respectively (p>0,05). Mean EASI at baseline was 23, the least severe reported in Phase 2b/3 studies in moderate-to-severe AD.4 In a subgroup analysis of patients with baseline EASI >21 separation from placebo was increased in the 20 and 40 mg arms, as patients on placebo achieving EASI75 and EASI90 were reduced by 50% and 67%, for the severe population versus the full population. At Week 16, percentages of patients experiencing any Treatment Emergent Adverse Event (TEAE) were orismilast 20 mg, 76%; 30 mg, 79%; 40 mg, 86%; and placebo, 64%. Infection rates were numerically lower in the orismilast groups compared to placebo groups. The most common TEAEs were diarrhea, nausea, and headache, mainly seen within the first month, mostly mild in severity, with few leading to treatment discontinuation. Conclusion Orismilast demonstrated early itch reduction NRS≥4 and statistically significant efficacy versus placebo at Week 16 as measured by IGA0/1. The study was impacted by a high EASI placebo rate; however, in severe patients, the 20 and 40 mg doses separated from placebo for EASI75 and EASI90 measurements, consistent with the overall findings as measured by IGA 0/1, patient-reported efficacy, and objective biomarkers. No new safety signals were identified, and the profile was aligned with the well-established experience from the PDE4 inhibitor class. The most frequent TEAEs were gastrointestinal-related and headache. These data confirm the clinical relevance of high potency PDE4B/D selective inhibition with orismilast, potentially offering a convenient, novel, oral therapy for the treatment of AD and other inflammatory diseases. [ABSTRACT FROM AUTHOR]

Stroke was always a disease that threatened human life and health worldwide. We reported the synthesis of a new type of hyaluronic acid-modified multi-walled carbon nanotube. Then, we produced hydroxysafflor yellow A-hydroxypropyl-β-cyclodextrin phospholipid complex water-in-oil nanoemulsion with hyaluronic acid-modified multi-walled carbon nanotubes and chitosan (HC@HMC) for oral treatment of an ischemic stroke. We measured the intestinal absorption and pharmacokinetics of HC@HMC in rats. We found that the intestinal absorption and the pharmacokinetic behavior of HC@HMC was superior to that of HYA. We measured intracerebral concentrations after oral administration of HC@HMC and found that more HYA crossed the blood–brain barrier (BBB) in mice. Finally, we evaluated the efficacy of HC@HMC in middle cerebral artery occlusion/reperfusion (MCAO/R)-injured mice. In MCAO/R mice, oral administration of HC@HMC demonstrated significant protection against cerebral ischemia-reperfusion injury (CIRI). Furthermore, we found HC@HMC may exert a protective effect on cerebral ischemia-reperfusion injury through the COX2/PGD2/DPs pathway. These results suggest that oral administration of HC@HMC may be a potential therapeutic strategy for the treatment of stroke. [ABSTRACT FROM AUTHOR]

This study aims to prepare a nanodrug system for insulin delivery and controlled release with Poly(lactic acid-glycolic acid) (PLGA) as the shell and polyethylene glycol-chondroitin sulfate as the core to enhance its oral administration bioavailability. The insulin/CS-PLGA nanoparticles (NPs) with an average size of about 150 nm and regular spherical shape were obtained and showed good biocompatibility and relative high drug loading. Insulin can be controlled release according to the environmental pH and retained its original structure. The oral administration of insulin/CS-PLGA NPs showed a relatively higher hypoglycemic effect than that of insulin, indicating the NPs is a potential oral delivery system to enhance insulin bioavailability. [ABSTRACT FROM AUTHOR]

Simple Summary: pH-responsive hydrogel microparticles have great potential as drug delivery systems of anti-cancer drugs. Here, we use microfluidics for the generation of asymmetric microgels as carriers for oral administration of 5-fluorouracil (5-FU) in colorectal cancer. Due to their anisotropic shape, they show increased on-demand loading of the drug. The pH-responsiveness is ensured by the presence of alginate methacrylate within the gel network and represents the key factor for 5-FU release at the targeted location. Empty, asymmetric microgels do not show cytotoxicity even at high concentration, while upon treatment with 5-FU loaded microparticles, the viability of tumor cells notably decreases confirming the efficacy of drug release at certain pH. In the last 20 years, the development of stimuli-responsive drug delivery systems (DDS) has received great attention. Hydrogel microparticles represent one of the candidates with the most potential. However, if the role of the cross-linking method, polymer composition, and concentration on their performance as DDS has been well-studied, still, a lot needs to be explained regarding the effect caused by the morphology. To investigate this, herein, we report the fabrication of PEGDA–ALMA-based microgels with spherical and asymmetric shapes for 5-fluorouracil (5-FU) on-demand loading and in vitro pH-triggered release. Due to anisotropic properties, the asymmetric particles showed an increased drug adsorption and higher pH responsiveness, which in turn led to a higher desorption efficacy at the target pH environment, making them an ideal candidate for oral administration of 5-FU in colorectal cancer. The cytotoxicity of empty spherical microgels was higher than the cytotoxicity of empty asymmetric microgels, suggesting that the gel network's mechanical proprieties of anisotropic particles were a better three-dimensional environment for the vital functions of cells. Upon treatment with drug-loaded microgels, the HeLa cells' viability was lower after incubation with asymmetric particles, confirming a minor release of 5-FU from spherical particles. [ABSTRACT FROM AUTHOR]

Subcutaneous insulin (INS) injection as the main therapy method for diabetes shows adverse effects such as inconvenient use and hypoglycemia. Fortunately, the oral route of administration of insulin possesses more application potential. As one of the most mature drug delivery systems, liposomes exist some disadvantages in the oral administration of proteins or peptides, such as poor stability, low drug load, and limited mucus penetration. Herein, according to the phosphocholine (PC) component of the cell membrane, choline phospholipid with trifluoroethyl modified zwitterionic head (DPFCP) is designed and synthesized for constructing liposomes delivery system loaded with insulin (INS@DPFCP) for oral administration. By comparison with phosphate choline liposomes (INS@DPPC) and unfunctionalized choline phosphate liposomes (INS@DPCP), the physicochemical properties, drug release stability, mucus permeability, biocompatibility, endocytosis, and transport ability of INS@DPFCP are studied. The test results indicate that the particle size of INS@DPFCP is 185 nm, and drug entrapment efficiency is (47. 1±3. 9)%. Compared with INS@DPPC (27. 2%) and INS@DPCP (24. 5%), the amount of mucus aggregation for INS@DPFCP is 17. 15%. Hemolysis and cytotoxicity experiments show that INS@DPFCP gets good biocompatibility. When the mass concentration is as high as 1. 2 mg/mL, the hemolysis rate is 6. 88%, and the cell viability is above 90%. In addition, the endocytosis assay results demonstrate that INS@DPFCP is proved to be higher cellular uptake efficiency of Caco-2 cells, and the drug delivery accumulation reaches 47. 5% in 4 h. INS@DPFCP is expected to play an important role in diabetes treatment, and shows potential application in the field of proteins or peptides oral administration [ABSTRACT FROM AUTHOR]

The oral route is the most widely used and preferable way of drug administration. Several pharmacokinetic processes play a role in the distribution of administered drugs. Therefore, accurate quantification of absorption, distribution, metabolism, excretion, and characterisation of drug kinetics after oral administration is extremely important for developing new human drugs. In vivo methods, such as gamma-scintigraphy, magnetic resonance imaging (MRI), and positron emission tomography (PET), have been used to analyse gastrointestinal tract (GIT) absorption behaviour. This scoping review provides an overview of PET studies that used oral tracer administration. A systematic literature search was performed using PubMed, EMBASE, Scopus, Science Direct, and Web of Science databases. Extensive variation between these studies was seen concerning acquisition protocols, quantification methods, and pharmacokinetic outcome parameters. Studies in humans indicate that it takes 10 to 30 min for the tracer to be in the intestine and about 100 min to reach its maximum concentration in the brain. In rodent studies, different pharmacokinetic parameters for the brain, blood, and GIT were estimated, showing the potential of PET to measure the absorption and distribution of drugs and pharmaceuticals non-invasively. Finally, regarding radiation protection, oral administration has a higher absorbed dose in GIT and, consequently, a higher effective dose. However, with the recent introduction of Long Axial Field of View (LAFOV) PET scanners, it is possible to reduce the administered dose, making oral administration feasible for routine clinical studies. [Display omitted] • This route of administration results in delayed plasma peaks dependent on the tracer, population, fasting, use of anaesthetics, and GIT motility. • The approach can have clinical implications for therapeutic strategies, drug dosages, and the treatment of GIT diseases. [ABSTRACT FROM AUTHOR]

Autoimmune diseases are often accompanied by acute exacerbation. However, the mechanism underlying systemic lupus erythematosus (SLE) flares remains unclear. We investigated whether short-term enteric Toll-like receptor 7 (TLR7) stimulation can exacerbate SLE using B6SKG mice, which spontaneously develop SLE due to a mutation in the zeta‒chain‒associated protein kinase 70 (Zap70) gene. Imiquimod (IMQ) or phosphate-buffered saline (PBS) were orally administered on B6WT and B6SKG mice every other day for 2 weeks. SLE exacerbation was assessed via fluorescent immunohistochemical staining of glomeruli for IgG and C3, hematoxylin and eosin staining of kidneys, and enzyme-linked immunosorbent assay for antinuclear antibody (ANA). Flow cytometry was used to evaluate germinal center B cells (GCBs), plasma cells, follicular helper T cells (Tfhs), regulatory T cells (Tregs), effector T cells (Th1s and Th17s), plasmacytoid dendritic cells (pDCs), conventional dendritic cells (cDCs), and macrophages (Mφs) in spleens. Oral administration of IMQ every other day for 2 weeks resulted in exacerbation of splenomegaly, increased IgG and C3 deposition in glomeruli, and increased ANA production in the B6SKG IMQ (SKG-IMQ) group compared to the B6SKG PBS (SKG-PBS) group; the percentages of GCBs, plasma cells, Tfhs, Th1s, pDCs, and Mφs were also increased in the SKG-IMQ group. Splenomegaly, IgG, and C3 deposition in glomeruli, and the percentages of GCBs, plasma cells, Tfhs, and Th1s were enhanced in SKG-IMQ mice compared with B6SKG mice topically treated with IMQ (SKG-ear-IMQ). Oral TLR7 stimulation in a Zap70 genetic mutation background can cause acute exacerbations of SLE. Key Points • The mechanism of SLE flares is not well understood. • We have created a model that causes short-term SLE exacerbations in mice with a genetic background. • IMQ administered orally causes more SLE in mice than transdermally. [ABSTRACT FROM AUTHOR]

Clostridioides difficile infection (CDI) is one of the most common hospital-acquired infections. Its incidence has increased during the last decade in the community among individuals with no previous risk factors; however, morbidity and mortality are still considered high in elderly patients. Oral Vancomycin and Fidaxomicin are the first lines of treatment for CDI. The systemic bioavailability of oral Vancomycin is thought to be undetectable due to its poor absorption in the gastrointestinal tract; therefore, routine monitoring is not warranted. Only 12 case reports were found in the literature that described adverse reactions associated with oral Vancomycin and its related risk factors. We present a case of a 66-year-old gentleman with severe CDI and acute renal failure who was started on oral Vancomycin upon admission. On day five of treatment, he developed leukocytosis associated with neutrophilia, eosinophilia, and atypical lymphocytes, with no evidence of active infection. Three days later, he developed a pruritic maculopapular rash in more than 50% of his body surface area. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) was ruled out since the patient only had three inclusion criteria for this diagnosis. No clear inciting agent was found. Oral Vancomycin was stopped and supportive treatment was supplied for a presumed Vancomycin-induced allergic reaction. The patient had an excellent response, with complete resolution of the rash and leukocytosis in less than 48 h. By reporting this case, we want to raise awareness among clinicians to remember that, albeit rare, oral Vancomycin can be the cause of adverse drug reactions in patients with severe illnesses. [ABSTRACT FROM AUTHOR]

Protein and peptide drugs are predominantly administered by injection to achieve high bioavailability, but this greatly compromises patient compliance. Oral and transdermal drug delivery with minimal invasiveness and high adherence represent attractive alternatives to injection administration. However, oral and transdermal administration of bioactive proteins must overcome biological barriers, namely the gastrointestinal and skin barriers, respectively. The rapid development of new materials and technologies promises to address these physiological obstacles. This review provides an overview of the latest advances in oral and transdermal protein delivery, including chemical strategies, synthetic nanoparticles, medical microdevices, and biomimetic systems for oral administration, as well as chemical enhancers, physical approaches, and microneedles in transdermal delivery. We also discuss challenges and future perspectives of the field with a focus on innovation and translation. [ABSTRACT FROM AUTHOR]

Protein and peptide drugs are predominantly administered by injection to achieve high bioavailability, but this greatly compromises patient compliance. Oral and transdermal drug delivery with minimal invasiveness and high adherence represent attractive alternatives to injection administration. However, oral and transdermal administration of bioactive proteins must overcome biological barriers, namely the gastrointestinal and skin barriers, respectively. The rapid development of new materials and technologies promises to address these physiological obstacles. This review provides an overview of the latest advances in oral and transdermal protein delivery, including chemical strategies, synthetic nanoparticles, medical microdevices, and biomimetic systems for oral administration, as well as chemical enhancers, physical approaches, and microneedles in transdermal delivery. We also discuss challenges and future perspectives of the field with a focus on innovation and translation. [ABSTRACT FROM AUTHOR]

Insulin is one of the most important drugs in the treatment of diabetes. There is an increasing interest in the oral administration of insulin as it mimics the physiological pathway and potentially reduces the side effects associated with subcutaneous injection. Therefore, insulin-loaded polyelectrolyte complex (PEC) nanoparticles were prepared by the ionic cross-linking method using protamine sulfate as the polycationic and sodium alginate as the anionic polymer. Taguchi experimental design was used for the optimization of nanoparticles by varying the concentration of sodium alginate, the mass ratio of sodium alginate to protamine, and the amount of insulin. The optimized nanoparticle formulation was used for further in vitro characterization. Then, insulin-loaded PEC nanoparticles were placed in hard gelatin capsules and the capsules were enteric-coated by Eudragit L100-55 (PEC-eCAPs). Hypoglycemic effects PEC-eCAPs were determined in vivo by oral administration to diabetic rats. Furthermore, in vivo distribution of PEC nanoparticles was evaluated by fluorescein isothiocyanate (FITC) labelled nanoparticles. The experimental design led to nanoparticles with a size of 194.4 nm and a polydispersity index (PDI) of 0.31. The encapsulation efficiency (EE) was calculated as 95.96%. In vivo studies showed that PEC-eCAPs significantly reduced the blood glucose level of rats at the 8th hour compared to oral insulin solution. It was concluded that PEC nanoparticles loaded into enteric-coated hard gelatin capsules provide a promising delivery system for the oral administration of insulin. [Display omitted] [ABSTRACT FROM AUTHOR]

Small extracellular vesicles (sEVs) have burst into biomedicine as a natural therapeutic alternative for different diseases. Considered nanocarriers of biological origin, various studies have demonstrated the feasibility of their systemic administration, even with repeated doses. However, despite being the preferred route of physicians and patients, little is known about the clinical use of sEVs in oral administration. Different reports show that sEVs can resist the degradative conditions of the gastrointestinal tract after oral administration, accumulating regionally in the intestine, where they are absorbed for systemic biodistribution. Notably, observations demonstrate the efficacy of using sEVs as a nanocarrier system for a therapeutic payload to obtain a desired biological (therapeutic) effect. From another perspective, the information to date indicates that food-derived vesicles (FDVs) could be considered future nutraceutical agents since they contain or even overexpress different nutritional compounds of the foods from which they are derived, with potential effects on human health. In this review, we present and critically analyze the current information on the pharmacokinetics and safety profile of sEVs when administered orally. We also address the molecular and cellular mechanisms that promote intestinal absorption and that command the therapeutic effects that have been observed. Finally, we analyze the potential nutraceutical impact that FDVs would have on human health and how their oral use could be an emerging strategy to balance nutrition in people. [ABSTRACT FROM AUTHOR]

Bloodstream infections (BSIs) due to Gram‐positive organisms have traditionally been treated with prolonged courses of intravenous antimicrobials. However, this dogma is associated with substantial burden to the patient and health care system. Consequently, there is growing interest in the utilization of oral stepdown therapy, defined as the transition of intravenous therapy to an active oral agent, for this indication. This review highlights available literature examining oral stepdown in adult patients with BSI due to commonly encountered Gram‐positive pathogens, including Staphylococcus aureus, Streptococcus spp., and Enterococcus spp. Support for oral stepdown in this setting is primarily derived from observational studies subject to selection bias. Nevertheless, this treatment strategy exhibits promising potential in carefully selected patients as it is consistently associated with reductions in hospital length of stay without jeopardizing clinical cure or survivability. Prospective, randomized trials are needed for validation of oral stepdown in Gram‐positive BSI and to identify the optimal patient population and regimen. [ABSTRACT FROM AUTHOR]

Lipopolysaccharide (LPS), an endotoxin, induces systemic inflammation by injection and is thought to be a causative agent of chronic inflammatory diseases, including type 2 diabetes mellitus (T2DM). However, our previous studies found that oral LPS administration does not exacerbate T2DM conditions in KK/Ay mice, which is the opposite of the response from LPS injection. Therefore, this study aims to confirm that oral LPS administration does not aggravate T2DM and to investigate the possible mechanisms. In this study, KK/Ay mice with T2DM were orally administered LPS (1 mg/kg BW/day) for 8 weeks, and blood glucose parameters before and after oral administration were compared. Abnormal glucose tolerance, insulin resistance progression, and progression of T2DM symptoms were suppressed by oral LPS administration. Furthermore, the expressions of factors involved in insulin signaling, such as insulin receptor, insulin receptor substrate 1, thymoma viral proto-oncogene, and glucose transporter type 4, were upregulated in the adipose tissues of KK/Ay mice, where this effect was observed. For the first time, oral LPS administration induces the expression of adiponectin in adipose tissues, which is involved in the increased expression of these molecules. Briefly, oral LPS administration may prevent T2DM by inducing an increase in the expressions of insulin signaling-related factors based on adiponectin production in adipose tissues. [ABSTRACT FROM AUTHOR]

The use of nanoparticles as drug delivery systems has increased in importance in the last decades. Despite the disadvantages of difficulty swallowing, gastric irritation, low solubility, and poor bioavailability, oral administration stands out as the most widely used route for therapeutic treatments, though it may not always be the most effective route. The effect of the first hepatic pass is one of the primary challenges that drugs must overcome to carry out their therapeutic effect. For these reasons, controlled-release systems based on nanoparticles synthesized from biodegradable natural polymers have been reported to be very efficient in enhancing oral delivery in multiple studies. Chitosan has been shown to have an extensive variability of properties and roles in the pharmaceutical and health fields; of its most important properties are the ability to encapsulate and transport drugs within the body and enhance the drug interaction with the target cells, which improves the efficacy of the encapsulated drugs. The physicochemical properties of chitosan give it the ability to form nanoparticles through multiple mechanisms, which will be addressed in this article. The present review article focuses on highlighting the applications of chitosan nanoparticles for oral drug delivery. [ABSTRACT FROM AUTHOR]

Methotrexate (MTX) by oral taking has been employed as the first‐line medication for various chronic inflammatory diseases treatment, such as Crohn's disease and rheumatoid arthritis (RA). However, the oral administration of MTX has very limited clinical benefits and will be discontinued due to the suboptimal response and severe adverse effects on intestinal mucosa. Herein, a multistage albumin nanomedicine depot (denoted as MAND) is formulated by encapsulating MTX‐loaded human serum albumin nanoparticles (MTX@HSA NPs) into calcium alginate chitosan microcapsules using a gas‐shearing technology. The MANDs can provide protection to MTX@HSA NPs with well‐persisted biologic activity against gastric acid erosion and realize specific boost release of MTX@HSA NPs in the intestinal tract in response to the mild basic circumstance. The MTX@HSA NPs absorbed by intestine can selectively accumulate in inflammation lesion by exploiting the inflammation targeting ability of HSA. In the animal experiments, the MANDs show improved therapeutic efficacy for the treatment of both RA and colitis with minimized intestinal side effects in respect to the free MTX by oral administration. Therefore, this conceived oral MANDs can promote a more clinic popularity and enhanced benefits of MTX for the treatment of chronic inflammatory diseases. [ABSTRACT FROM AUTHOR]

Here, we report on the development of lipid-based nanostructures containing zidovudine (1 mg/mL) and lamivudine (0.5 mg/mL) for oral administration in the pediatric population, eliminating the use of organic solvents, which is in accordance with green chemistry principles. The formulations were obtained by ultrasonication using monoolein (MN) or phytantriol (PN), which presented narrow size distributions with similar mean particle sizes (~150 nm) determined by laser diffraction. The zeta potential and the pH values of the formulations were around −4.0 mV and 6.0, respectively. MN presented a slightly higher incorporation rate compared to PN. Nanoemulsions were obtained when using monoolein, while cubosomes were obtained when using phytantriol, as confirmed by Small-Angle X-ray Scattering. The formulations enabled drug release control and protection against acid degradation. The drug incorporation was effective and the analyses using an electronic tongue indicated a difference in palatability between the nanotechnological samples in comparison with the drug solutions. In conclusion, PN was considered to have the strongest potential as a novel oral formulation for pediatric HIV treatment. [ABSTRACT FROM AUTHOR]

We evaluated the whole-body distribution of orally-administered radioiodine-125 labeled acetaminophen (125I-AP) to estimate gastrointestinal absorption of anionic drugs. 125I-AP was added to human embryonic kidney (HEK)293 and Flp293 cells expressing human organic anion transporting polypeptide (OATP)1B1/3, OATP2B1, organic anion transporter (OAT)1/2/3, or carnitine/organic cation transporter (OCTN)2, with and without bromosulfalein (OATP and multidrug resistance-associated protein (MRP) inhibitor) and probenecid (OAT and MRP inhibitor). The biological distribution in mice was determined by oral administration of 125I-AP with and without bromosulfalein and by intravenous administration of 125I-AP. The uptake of 125I-AP was significantly higher in HEK293/OATP1B1, OATP1B3, OATP2B1, OAT1, and OAT2 cells than that in mock cells. Bromosulfalein and probenecid inhibited OATP- and OAT-mediated uptake, respectively. Moreover, 125I-AP was easily excreted in the urine when administered intravenously. The accumulation of 125I-AP was significantly lower in the blood and urinary bladder of mice receiving oral administration of both 125I-AP and bromosulfalein than those receiving only 125I-AP, but significantly higher in the small intestine due to inhibition of OATPs and/or MRPs. This study indicates that whole-body distribution after oral 125I-AP administration can be used to estimate gastrointestinal absorption in the small intestine via OATPs, OATs, and/or MRPs by measuring radioactivity in the urinary bladder. [ABSTRACT FROM AUTHOR]

(1) Background: Many drugs possess poor bioavailability, and many strategies are available to overcome this issue. In this study, smartFilm technology, i.e., a porous cellulose matrix (paper), in which the active compound can be loaded onto in an amorphous state was utilised for oral administration to improve the solubility and bioactivity of a poorly soluble BSC class IV antibiotic. (2) Methods: Norfloxacin was used as the model drug and loaded into commercially available paper. The resulting norfloxacin-loaded smartFilms were transformed into smartFilm granules via wet granulation and the resulting norfloxacin-loaded smartFilm granules were transformed into norfloxacin-loaded tablets made from paper, i.e., smartFilm tablets. The crystalline state of norfloxacin was investigated, as well as the pharmaceutical properties of the granules and the tablets. The bioactivity of the smartFilm tablets was assessed in vitro and ex vivo to determine the antibacterial activity of norfloxacin. The results were compared to a physical mixture tablet that contained non-loaded paper granules and equal amounts of norfloxacin as a crystalline powder. (3) Results: Norfloxacin-loaded smartFilm granules and norfloxacin-loaded smartFilm tablets contained norfloxacin in an amorphous state, which resulted in an improved and faster release of norfloxacin when compared to the physical mixture tablet. The bioactivity was up to three times higher when compared to the physical mixture tablet. The ex vivo model was demonstrated to be a useful tool that allows for a fast and cost-effective discrimination between "good" and "bad" formulations. It provides realistic physiological conditions and can therefore yield meaningful, additional biopharmaceutical information that cannot be assessed in classical in vitro experiments. (4) Conclusions: smartFilm tablets are a promising, universal, industrially feasible and cost-effective formulation strategy for improved solubility and enhanced bioactivity of poorly soluble drugs. [ABSTRACT FROM AUTHOR]