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Oral administration is the most simple, noninvasive, convenient treatment. With the increasing demands on the targeted drug delivery, the traditional oral treatment now is facing some challenges: 1) biologics how to implement the oral treatment and ensure the bioavailability is not lower than the subcutaneous injections; 2) How to achieve targeted therapy of some drugs in the gastrointestinal tract? Based on these two issues, drug delivery microrobots have shown great application prospect in oral drug delivery due to their characteristics of flexible locomotion or driven ability. Therefore, this paper summarizes various drug delivery microrobots developed in recent years and divides them into four categories according to different driving modes: magnetic-controlled drug delivery microrobots, anchored drug delivery microrobots, self-propelled drug delivery microrobots and biohybrid drug delivery microrobots. As oral drug delivery microrobots involve disciplines such as materials science, mechanical engineering, medicine, and control systems, this paper begins by introducing the gastrointestinal barriers that oral drug delivery must overcome. Subsequently, it provides an overview of typical materials involved in the design process of oral drug delivery microrobots. To enhance readers' understanding of the working principles and design process of oral drug delivery microrobots, we present a guideline for designing such microrobots. Furthermore, the current development status of various types of oral drug delivery microrobots is reviewed, summarizing their respective advantages and limitations. Finally, considering the significant concerns regarding safety and clinical translation, we discuss the challenges and prospections of clinical translation for various oral drug delivery microrobots presented in this paper, providing corresponding suggestions for addressing some existing challenges.

Abstract Staphylococcal Enterotoxin C2 (SEC2), a classical superantigen, is an antitumor immunotherapy agent. However, the injectable formulation of SEC2 limits its clinical application. Here, it is reported that oral administration of SEC2 activates the intestinal immune system and benefits intestinal health in a mouse model. These results indicate that intact SEC2 is detected in the stomach, intestine, and serum after oral administration. Continuous oral administration of SEC2 activates immune cells in gut‐associated lymphoid tissues, promoting extensive differentiation and proliferation of CD4+ and CD8+ T cells and CD19+ B cells, leading to increased production of cytokines and secretory immunoglobulin A. SEC2 also enhances intestinal barrier function, as demonstrated by an increased villus length/crypt depth ratio and elevated expression of mucins and tight junction proteins. Additionally, SEC2 indirectly influenced gut microbiota, reinforcing potential probiotics and short‐chain fatty acid synthesis. Enhanced differentiation of T and B cells in the spleen, coupled with elevated serum interleukin‐2 levels, suggests systemic immune enhancement following oral administration of SEC2. These findings provide a scientific basis for the development of SEC2 as an oral immunostimulant for immune enhancement and anti‐tumor immunotherapy.

Abstract The objective was to evaluate the effect of oral administration of strontium (Sr) on the regeneration of a critical bone defect. Twenty Wistar rats were divided into two groups, assessed at 15 and 60 days postoperatively: GSr - oral administration of Sr; and CG - without oral administration of Sr. At 15 and 60 days, blood was collected to measure Sr and calcium (Ca), and the calvaria was removed for histomorphological and histomorphometric analyses. Sr+2 plasmatic concentrations were higher in GSr than in CG. The dosage of Ca+2 showed a small increase in the CG about the GSr. In all evaluated groups, new bone formation was restricted to the edges of the defect, and the residual area was filled with fibrous connective tissue. The oral administration of Sr associated with HA microspheres substituted by the metal, in a concentration of 23 mol%, did not affect the formation of the osteoid matrix.

Oral delivery of an inexpensive COVID-19 (coronavirus disease 2019) vaccine could dramatically improve immunization rates, especially in low- and middle-income countries. Previously, we described a potential universal COVID-19 vaccine, rLVS ΔcapB/MN, comprising a replicating bacterial vector, LVS (live vaccine strain) ΔcapB, expressing the highly conserved SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) membrane and nucleocapsid (N) proteins, which, when administered intradermally or intranasally, protects hamsters from severe COVID-19-like disease after high-dose SARS-CoV-2 respiratory challenge. Here, we show that oral administration of the vaccine also protects against high-dose SARS-CoV-2 respiratory challenge; its protection is comparable to that of intradermal, intranasal, or subcutaneous administration. Hamsters were protected against severe weight loss and lung pathology and had reduced oropharyngeal and lung virus titers. Protection against weight loss and histopathology by the vaccine, which in mice induces splenic and lung cell interferon gamma in response to N protein stimulation, was correlated in hamsters with pre-challenge serum anti-N TH1-biased IgG (IgG2/3). Thus, rLVS ΔcapB/MN has potential as an oral universal COVID-19 vaccine. IMPORTANCE The COVID-19 pandemic continues to rage into its fourth year worldwide. To protect the world's population most effectively from severe disease, hospitalization, and death, a vaccine is needed that is resistant to rapidly emerging viral variants of the causative agent SARS-CoV-2, inexpensive to manufacture, store, and transport, and easy to administer. Ideally, such a vaccine would be capable of oral administration, especially in resource-poor countries of the world where there are shortages of needles, syringes and trained personnel to administer injectable vaccines. Here, we show that oral administration of a bacterium-vectored vaccine meeting all these criteria protects naturally susceptible Syrian hamsters from severe COVID-19-like disease, including severe weight loss and lung pathology, after high-dose SARS-CoV-2 respiratory challenge. As the vaccine is based upon inducing immunity to highly conserved SARS-CoV-2 membrane and nucleocapsid proteins, as opposed to the rapidly mutating Spike protein, it should remain resistant to newly emerging SARS-CoV-2 variants.

Acetyl tributyl citrate (ATBC) and acetyl triethyl citrate (ATEC) are widely used as plasticizers, but their metabolites as exposure biomarkers for biomonitoring, as well as approximate human metabolic pathways, are not well understood. This study addresses this knowledge gap by conducting suspect screening to propose specific metabolites in human urine as potential biomarkers of exposure and explore their kinetic profiles. Ten volunteers were administered deuterium labeled ATBC (ATBC-d3) and seven received ATEC or deuterium labeled ATEC (ATEC-d3), with urine samples collected over 48 h post-administration. Employing ultra-performance liquid chromatography coupled to quadrupole-time-of-flight mass spectrometry (UPLC-qTOF/MS), six metabolites of ATBC were consistently detected, including (OH)3-ATBC-d3, ADBC-d3, OH-ADBC-d3, DBC, OH-DBC, and OH-DBA. For ATEC, four metabolites were identified: ADEC-d3, AMEC-d3, OH-ADEC-d3, and DEC. Based on their high detection frequency, relative response, and specificity to their parent compounds, ADBC-d3 and OH-ADBC-d3 were identified as promising candidate biomarkers for ATBC exposure, while ADEC-d3 emerged as a suitable biomarker for ATEC. Estimated urinary elimination half-lives ranged from 1.0 to 9.9 h for ATBC metabolites and 1.6 to 3.0 h for ATEC metabolites. One-compartment kinetic modeling provided preliminary insights into metabolite kinetics. This research advances the understanding of ATBC and ATEC metabolism in humans, providing a foundation for future exposure assessments and toxicological studies. The identified biomarkers and preliminary metabolic profiles offer valuable starting points for biomonitoring and risk assessment of these alternative plasticizers.

Abstract 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.

Introduction. The development and registration of antiviral drugs is an urgent task. Flavonoids, in particular, luteolin-7-glycoside (cinaroside, luteolin-7-O-glycoside) demonstrate high broad-spectrum antiviral activity in vitro, and the industrial regulations for the production of luteolin-7-glycoside from the leaves of holly willow have already been developed at the VILAR. One of the problems with the introduction of flavonoids into medical practice is their low bioavailability and intensive biotransformation. Existing publications provide contradictory data on the pharmacokinetics of luteolin-7-glycoside, and therefore our own research was conducted.Aim. To develop a methodology for the quantitative analysis of luteolin-7-glycoside and its metabolites in blood plasma and to test it on laboratory animals.Materials and methods. Animal experiments were carried out in accordance with the requirements of the "Guidelines for conducting preclinical studies of medicines". To develop a method of analysis and further clarify the time intervals of blood sampling, time points were analyzed: 30, 60 minutes, 2, 4, 8, 24 hours after administration of the test substance. Tubes with citrate blood of laboratory animals were centrifuged at 2000 rpm for 10 minutes. The plasma was placed in an Eppendorf-type test tube, frozen and stored at –20 °C until chromatographic analysis was performed. Blood plasma sample preparation was carried out by precipitation with methyl alcohol, the supernatant was chromatographically separated on a column Luna® 5 µm C18 column 100 Å 250 × 4.6 mm in a gradient mode in a water-acetonitrile system and a modifier – 0.2 % formic acid. The metabolites were identified by high-performance liquid chromatography with mass spectrometric detection. To do this, the spectral characteristics of the peaks that appeared on the chromatograms of blood plasma samples after oral administration of luteolin-7-glycoside were interpreted. The concentration of the analyzed substances was assessed by the internal standard method, which was rutin. To determine the concentration of luteolin, a standardized luteolin substance was used as a standard sample, the concentration of the remaining metabolites was estimated in terms of luteolin.Results and discussion. It was found that after oral administration of luteolin-7-glycoside in starch paste to laboratory animals, native luteolin-7-glycoside was not detected in blood plasma. The main metabolites were luteolin-diglucuronide and luteolin-glucuronide, their maximum plasma concentrations are about three times higher than luteolin and methyllyuteolin-diglucuronide. The results are compared with data from other studies.Conclusion. The absence of native luteolin-7-glycoside in blood plasma after oral administration makes it necessary to seriously reconsider the relevance of the conclusions obtained during studies of its activity in vitro. However, in the presence of antiviral activity in vivo, there is an urgent need for further research to establish the real mechanisms of action of this medicinal substance.

This paper summarized the Nursing of a patient with post-stroke constipation of Qi-deficiency type treated by Baliao acupoints moxibustion and acupuncture combined with oral administration of Yiqi Runchang decoction. A comprehensive assessment of nursing risk was carried out before treatment. Traditional Chinese Medicine external treatment such as moxibustion and acupuncture at Baliao acupoints were performed to improve the recovery of intestinal function. The patient received oral administration of Yiqi Runchang decoction to regulate the body constitution. In addition, a prescription of drinking habits was administrated to promote defecation, and other interventions such as dietary guidance, exercise and emotion care were carried out to relieve the symptoms of Qi-deficiency syndromes. (本文总结灸八髎穴联合内服益气润肠中药汤剂治疗1例中风后气虚便秘患者的护理体会。在完善护理评估的基础上, 遵医嘱给予八髎穴艾灸、针灸等中医外治疗法, 以增强肠道蠕动, 缓解便秘; 给予益气润肠中药汤剂内服, 从根本上调理; 同时基于子午流注理论, 为患者开具饮水处方, 以软化粪便, 促进胃肠蠕动, 利于排便; 结合患者的疾病特点予以饮食调护、运动疗法和情志护理。经过10 d中医内服外用联合治疗以及辨证施护, 患者气虚便秘症状得到有效改善。)

Abstract Interferon α (IFNα) and interferon γ (IFNγ) play pivotal roles in mediating crucial biological functions, including antiviral activity and immune regulation. However, the efficacy of monomeric IFN is limited, and its administration relies solely on injection. To address this issue, we successfully expressed and purified a recombinant porcine IFNα and IFNγ fusion protein (rPoIFNα/γ). Furthermore, we developed a pH-triggered humic acid hydrogel delivery system that effectively protects rPoIFNα/γ from gastric acid degradation, enhancing its oral bioavailability. Neither the humic acid hydrogel nor rPoIFNα/γ exhibited cytotoxic effects on porcine kidney-15 (PK-15) cells in vitro. The replication of vesicular stomatitis virus and pseudorabies virus (PRV) was effectively inhibited by rPoIFNα/γ, resulting in an antiviral activity of approximately 104 U/mL. Scanning electron microscopy revealed that the humic acid hydrogel had a loose and porous honeycomb structure. The IFNα/γ@PAMgel hydrogel effectively adsorbed rPoIFNα/γ, as confirmed by Fourier transform infrared spectroscopy analysis, demonstrating a favourable IFN-loading capacity. In vitro experiments revealed that IFNα/γ@PAMgel swelled and released IFNα/γ rapidly at pH 7.4 but not at pH 1.2. The oral administration of IFNα/γ@PAMgel in mice enhanced the proliferation and differentiation of CD4+ and CD8+ cells. Additionally, mice infected with PRV and treated with IFNα/γ@PAMgel presented increased transcription levels of interferon-stimulated genes in the serum, reduced mortality rates, lower viral loads in various tissues, and decreased levels of organ damage. In conclusion, this study demonstrates that orally administered IFNα/γ@PAMgel has antiviral and immunomodulatory effects, highlighting its potential as a therapeutic agent against PRV infection.

Abstract Background Astragali radix (AR) is one of the most widely used traditional Chinese herbal medicines. It exhibits diverse biological activities, including immunomodulatory and anti-inflammatory properties; however, some of its activities have only been demonstrated in vitro. Objective To examine the effects of orally administered AR extract on immune cells and the intestine under physiological conditions, which bridges the gap between previously observed in vitro outcomes and in vivo results. Methods AR extract was prepared by hot water extraction. Three separate animal experiments were conducted to isolate macrophages, splenocytes, and the small intestine epithelium. For the macrophage preparation experiment, an intraperitoneal injection of sterile thioglycolate was administered. The mice received oral AR extract at doses of 0.1, 0.5, or 2.5 g/kg for ten days. At the end of each experiment, cells or tissues were isolated. A portion of macrophages and splenocytes were analyzed for the phenotypic changes. The remaining cells were cultured and stimulated with lipopolysaccharide (LPS) or mitogen ex vivo to assess activation status, proliferation, and cytokine production. Samples of the intestine were subjected to real-time RT-PCR. Results Peritoneal macrophages from AR-treated mice exhibited increased expression of scavenger receptors, including SRA and CD36. Stimulation of these macrophages ex vivo with LPS selectively modulated the inflammatory response, including reduced expression of the costimulatory molecules CD40 and CD86, which are important for T cell responses, without affecting TNF-α and IL-6 production. Splenocytes from AR-treated mice exhibited a dose-dependent increase in CD4 and CD8 T cells; however, stimulation with mitogen decreased T cell proliferation and reduced IFN-γ production, which is essential for macrophage activation. An analysis of the small intestinal epithelium revealed an attenuated antimicrobial response, including reduced IgA content in the lumen and decreased expression of mucin-2 and polymeric Ig receptor genes. Conclusion The response of immune cells following oral treatment with AR extract did not replicate the previously documented in vitro findings. Immune cells and intestinal epithelium from mice administered oral AR extract exhibited a selective anti-inflammatory phenotype. The overall findings indicate that the systemic effects after oral administration of AR extract include reduced sensitivity to inflammatory insults.

Abstract Ulcerative colitis (UC) belongs to chronic inflammatory disease with a relapsing characterization. Conventional oral drugs of UC are restricted in clinical by premature degradation in the gastrointestinal tract, modest efficacy, and adverse effects. CX5461 can treat autoimmune disease, immunological rejection, and vascular inflammation. However, low solubility, intravenous administration, and non-inflammatory targeting limited its clinical application. Herein, this work aims to develop Sophora Flavescens-derived exosomes-like nanovesicles carrying CX5461 (SFELNVs@CX5461) for efficient CX5461 oral delivery for UC therapy. We identified SFELNVs as nano-diameter (80 nm) with negative zeta potential (-32mV). Cellular uptake has shown that SFELNVs were targeted uptake by macrophages, thus increasing drug concentration. Additionally, oral SFELNVs@CX5461 exhibited good safety and stability, as well as inflammation-targeting ability in the gastrointestinal tract of dextran sodium sulfate (DSS)-induced colitis mice. In vivo, oral administration of SFELNVs and CX5461 could relieve mice colitis. More importantly, combined SFELNVs and CX5461 alleviated mice colitis by inhibiting pro-inflammatory factors (TNF-α, IL-1β, and IL-6) expression and promoting M2 macrophage polarization. Furthermore, SFELNVs promoted M2 polarization by miR4371c using miRNA sequencing. Our results suggest that SFELNVs@CX5461 represents a novel orally therapeutic drug that can ameliorate colitis, and a promising targeting strategy for safe UC therapy.

Abstract The oral administration of antioxidants may suppress UV-B-induced skin damage. HITHION YH-15, the extract of Torula yeast (Cyberlindnera jadinii), is rich in cysteine-containing peptides such as reduced and oxidized glutathione (GSH and GSSG), γ-glutamylcysteine (γ-Glu-Cys), and cysteinylglycine (Cys-Gly). These four constituents are termed cysteine peptides. In this study, we investigated the protective effects of cysteine peptides against UV-B in a randomized, placebo-controlled, double-blind, parallel-group study. A total of 90 healthy males and females aged 30–59 years were enrolled and randomized into two groups of 45 individuals each (cysteine peptides (48 mg/day) and placebo). Changes in UV-B-induced erythema and pigmentation were compared between groups after 5 weeks of test food intake. The minimal erythema dose (MED) significantly increased (*p = 0.019) in the cysteine peptides group compared to that in the placebo group, indicating suppression of UV-B-induced erythema. ΔL* value significantly increased (***p

Background. Global anthropogenic environmental pollution, intensification of production, daily physical, emotional and psychogenic stress on humans, as well as the working environment provoke a variety of diseases, fatigue, and cognitive impairment, etc. This may be attributed to a reduced nonspecific resistance of the health system and the development of stressful conditions. Therefore, one of the focal points of preventive toxicology is the development of agents with adaptogenic properties that would prevent the occurrence of harmful effects under the influence of stressors. The aim of the present study was to examine the effect of 2,6-dimethylpyridine N-oxide on cognitive functions and emotional status of rats following its long-term oral administration. Materials and Methods. The plant growth regulator (PGR) Ivin (2,6-dimethylpyridine N-oxide, 99.9%) was chosen for the study. Adaptogen Eleutherococcus was used as a reference agent. The study was conducted on Wistar Hannover rats divided into 2 cohorts. Each cohort included the following groups: 1 – intact animals, 2 – control (distilled water), 3 and 4 – Ivin at doses of 13.0 and 0.013 mg/kg (1/100 and 1/100000 LD50), respectively, 5 – Eleutherococcus at a dose of 50 mg/kg. Exposure period – 28 days, oral route of administration. The state of the central nervous system was assessed by behavioural reactions in the Morris Water Maze and the Elevated Plus Maze. Results. Ivin at doses of 13 and 0.013 mg/kg increased the ability to learn and to form short- and long-term memory in rats, as evidenced by a decrease in the average time of platform location in the Morris Water Maze test. Ivin at a dose of 0.013 mg/kg significantly increased the number of rearings in closed arms of the Elevated Plus Maze, indicating its anxiolytic effect. The anti-anxiety effect of Ivin needs to be confirmed by additional studies in the Open Field and/or Hole-board tests. The effectiveness of Ivin in terms of the studied parameters was similar or exceeded those of the known adaptogen Eleutherococcus.