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Early weaned piglets suffer from oxidative stress and enteral infection, which usually results in gut microbial dysbiosis, serve diarrhea, and even death. Rice bran oil (RBO), a polyphenol-enriched by-product of rice processing, has been shown to have antioxidant and anti-inflammatory properties both in vivo and in vitro. Here, we ascertained the proper RBO supplementation level, and subsequently determined its effects on lipopolysaccharide (LPS)-induced intestinal dysfunction in weaned piglets. A total of 168 piglets were randomly allocated into four groups of seven replicates (42 piglets each group, (21±1) d of age, body weight (7.60±0.04) kg, and half males and half females) and were given basal diet (Ctrl) or basal diet supplemented with 0.01% (mass fraction) RBO (RBO1), 0.02% RBO (RBO2), or 0.03% RBO (RBO3) for 21 d. Then, seven piglets from the Ctrl and the RBO were treated with LPS (100 μg/kg body weight (BW)) as LPS group and RBO+LPS group, respectively. Meanwhile, seven piglets from the Ctrl were treated with the saline vehicle (Ctrl group). Four hours later, all treated piglets were sacrificed for taking samples of plasma, jejunum tissues, and feces. The results showed that 0.02% was the optimal dose of dietary RBO supplementation based on diarrhea, average daily gain, and average daily feed intake indices in early weaning piglets. Furthermore, RBO protected piglets against LPS-induced jejunal epithelium damage, which was indicated by the increases in villus height, villus height/crypt depth ratio, and Claudin-1 levels, as well as a decreased level of jejunal epithelium apoptosis. RBO also improved the antioxidant ability of LPS-challenged piglets, which was indicated by the elevated concentrations of catalase and superoxide dismutase, and increased total antioxidant capacity, as well as the decreased concentrations of diamine oxidase and malondialdehyde in plasma. Meanwhile, RBO improved the immune function of LPS-challenged weaned piglets, which was indicated by elevated immunoglobulin A (IgA), IgM, β‍‍-defensin-1, and lysozyme levels in the plasma. In addition, RBO supplementation improved the LPS challenge-induced dysbiosis of gut microbiota. Particularly, the indices of antioxidant capacity, intestinal damage, and immunity were significantly associated with the RBO-regulated gut microbiota. These findings suggested that 0.02% RBO is a suitable dose to protect against LPS-induced intestinal damage, oxidative stress, and jejunal microbiota dysbiosis in early weaned piglets.

Early weaning is an effective method for improving the utilization rate of sows in intensive pig farms. However, weaning stress induces diarrhea and intestinal damage in piglets. Berberine (BBR) is known for its anti-diarrhea properties and ellagic acid (EA) is known for its antioxidant properties, however, whether their combination improves diarrhea and intestinal damage in piglets has not been studied, and the mechanism remains unclear. To explore the combined effects in this experiment, a total of 63 weaned piglets (Landrace × Yorkshire) were divided into three groups at 21 days. Piglets in the Ctrl group were treated with a basal diet and 2 mL saline orally, while those in the BE group were treated with a basal diet supplemented with 10 mg/kg (BW) BBR, 10 mg/kg (BW) EA, and 2 mL saline orally. Piglets in the FBE group were treated with a basal diet and 2 mL fecal microbiota suspension from the BE group orally, respectively, for 14 days. Compared with the Ctrl group, dietary supplementation with BE improved growth performance by increasing the average daily gain and average daily food intake and reducing the fecal score in weaned piglets. Dietary supplementation with BE also improved intestinal morphology and cell apoptosis by increasing the ratio of villus height to crypt depth and decreasing the average optical density of apoptotic cells; meanwhile, improvements also involved attenuating oxidative stress and intestinal barrier dysfunction by increasing the total antioxidant capacity, glutathione, and catalase, and upregulating the mRNA expressions of Occludin, Claudin-1, and ZO-1. Interestingly, the oral administration of a fecal microbiota suspension to piglets fed BE had similar effects to those of the BE group. According to 16S rDNA sequencing analysis, dietary supplementation with BE altered the composition of the microbiota, including firmicutes , bacteroidetes , lactobacillus , phascolarctobacterium , and parabacteroides , and increased the metabolites of propionate and butyrate. In addition, Spearman analysis revealed that improvements in growth performance and intestinal damage were significantly correlated with differential bacteria and short-chain fatty acids (SCFAs). In brief, dietary supplementation with BE improved the growth performance and intestinal damage by altering the gut microbiota composition and SCFAs in weaned piglets.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by chronic synovitis and the destruction of bones and joints. Exosomes are nanoscale lipid membrane vesicles originating from multivesicular bodies and are used as a vital means of intercellular communication. Both exosomes and the microbial community are essential in RA pathogenesis. Multiple types of exosomes from different origins have been demonstrated to have effects on various immune cells through distinct mechanisms in RA, which depend on the specific cargo carried by the exosomes. Tens of thousands of microorganisms exist in the human intestinal system. Microorganisms exert various physiological and pathological effects on the host directly or through their metabolites. Gut microbe-derived exosomes are being studied in the field of liver disease; however, information on their role in the context of RA is still limited. Gut microbe-derived exosomes may enhance autoimmunity by altering intestinal permeability and transporting cargo to the extraintestinal system. Therefore, we performed a comprehensive literature review on the latest progress on exosomes in RA and provided an outlook on the potential role of microbe-derived exosomes as emerging players in clinical and translational research on RA. This review aimed to provide a theoretical basis for developing new clinical targets for RA therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhao, Zhang, Meng and Hu.)

This study aimed to explore the relationship between wild birds and the transmission of multidrug-resistant strains. Klebsiella pneumoniae was isolated from fresh feces of captured wild birds and assessed by the broth microdilution method and comparative genomics. Four Klebsiella pneumoniae isolates showed different resistance phenotypes; S90-2 and S141 were both resistant to ampicillin, cefuroxime, and cefazolin, while M911-1 and S130-1 were sensitive to most of the 14 antibiotics tested. S90-2 belongs to sequence type 629 (ST629), and its genome includes 30 resistance genes, including bla CTX-M-14 and bla SHV-11 , while its plasmid pS90-2.3 (IncR) carries qacEdelta1 , sul1 , and aph(3')-Ib . S141 belongs to ST1662, and its genome includes a total of 27 resistance genes, including bla SHV-217 . M911-1 is a new ST, carrying bla SHV-1 and fosA6 , and its plasmid pM911-1.1 (novel) carries qnrS1 , bla LAP-2 , and tet (A). S130-1 belongs to ST3753, carrying bla SHV-11 and fosA6 , and its plasmid pS130-1 [IncFIB(K)] carries only one resistance gene, tet (A). pM911-1.1 and pS90-2.3 do not have conjugative transfer ability, but their resistance gene fragments are derived from multiple homologous Enterobacteriaceae strain chromosomes or plasmids, and the formation of resistance gene fragments (multidrug resistance region) involves interactions between multiple mobile element genes, resulting in a complex and diverse resistance plasmid structure. The homologous plasmids related to pM911-1.1 and pS90-2.3 were mainly from isolated human-infecting bacteria in China, namely, K. pneumoniae and Escherichia coli. The multidrug-resistant K. pneumoniae isolates carried by wild birds in this study had drug resistance phenotypes conferred primarily by multidrug resistance plasmids that were closely related to human-infecting bacteria. IMPORTANCE Little is known about the pathogenic microorganisms carried by wild animals. This study found that the multidrug resistance phenotype of Klebsiella pneumoniae isolates carried by wild birds was mainly attributed to multidrug resistance plasmids, and these multidrug resistance plasmids from wild birds were closely related to human-infecting bacteria. Wild bird habitats overlap to a great extent with human and livestock habitats, which further increases the potential for horizontal transfer of multidrug-resistant bacteria among humans, animals, and the environment. Therefore, wild birds, as potential transmission hosts of multidrug-resistant bacteria, should be given attention and monitored.

Rheumatoid arthritis (RA) is a complex autoimmune disease characterized by chronic inflammation that affects synovial tissues of multiple joints. Granzymes (Gzms) are serine proteases that are released into the immune synapse between cytotoxic lymphocytes and target cells. They enter target cells with the help of perforin to induce programmed cell death in inflammatory and tumor cells. Gzms may have a connection with RA. First, increased levels of Gzms have been found in the serum (GzmB), plasma (GzmA, GzmB), synovial fluid (GzmB, GzmM), and synovial tissue (GzmK) of patients with RA. Moreover, Gzms may contribute to inflammation by degrading the extracellular matrix and promoting cytokine release. They are thought to be involved in RA pathogenesis and have the potential to be used as biomarkers for RA diagnosis, although their exact role is yet to be fully elucidated. The purpose of this review was to summarize the current knowledge regarding the possible role of the granzyme family in RA, with the aim of providing a reference for future research on the mechanisms of RA and the development of new therapies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zheng, Zhao, Shan, Guo, Schrodi and He.)

Rheumatoid arthritis (RA) is a highly disabling chronic autoimmune disease. Multiple factors contribute to the complex pathological process of RA, in which an abnormal autoimmune response, high survival of inflammatory cells, and excessive release of inflammatory factors lead to a severe chronic inflammatory response. Clinical management of RA remains limited; therefore, exploring and discovering new mechanisms of action could enhance clinical benefits for patients with RA. Important bidirectional communication occurs between the brain and immune system in inflammatory diseases such as RA, and circulating immune complexes can cause neuroinflammatory responses in the brain. The gamma-aminobutyric acid (GABA)ergic system is a part of the nervous system that primarily comprises GABA, GABA-related receptors, and GABA transporter (GAT) systems. GABA is an inhibitory neurotransmitter that binds to GABA receptors in the presence of GATs to exert a variety of pathophysiological regulatory effects, with its predominant role being neural signaling. Nonetheless, the GABAergic system may also have immunomodulatory effects. GABA/GABA-A receptors may inhibit the progression of inflammation in RA and GATs may promote inflammation. GABA-B receptors may also act as susceptibility genes for RA, regulating the inflammatory response of RA via immune cells. Furthermore, the GABAergic system may modulate the abnormal pain response in RA patients. We also summarized the latest clinical applications of the GABAergic system and provided an outlook on its clinical application in RA. However, direct studies on the GABAergic system and RA are still lacking; therefore, we hope to provide potential therapeutic options and a theoretical basis for RA treatment by summarizing any potential associations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shan, Zhao, Zheng, Guo, Schrodi and He.)

Busulfan, a chemotherapeutic agent for cancer, has detrimental effects on germ cells and fertility, yet the specific mechanisms remain largely uncertain. The blood-testis barrier (BTB) maintains a suitable microenvironment for germ cells self-renewal and spermatogenesis by blocking the interference and damage of deleterious substances. Therefore, we hypothesized that BTB abnormalities might be involved in busulfan-induced oligospermia. To verify the hypothesis, thirty male Balb/c mice were randomly administered with busulfan (at a total dose of 40 mg/kg body weight) by intraperitoneal injection for 4 weeks to establish the model of oligospermia. The results displayed that busulfan caused testicular histopathological lesions and spermatogenesis disorder. Meanwhile, busulfan disrupted BTB integrity and lessened the expressions of BTB junction proteins, including Occludin, Claudin-11 and Connexin-43. Furthermore, busulfan activated the endoplasmic reticulum (ER) stress and PERK-eIF2α signaling pathway, reflected by the increased protein expressions of GRP78, p-PERK, p-eIF2α, ATF4 and CHOP. Finally, to evaluate whether the ER stress is involved in busulfan-induced BTB destruction, the ER stress inhibitor 4-Phenylbutyric acid (4-PBA, 1 mM) was used to intervene in busulfan-exposed TM4 cells. The results displayed that inhibition of ER stress alleviated the reduction of BTB junction protein expressions induced by busulfan in TM4 cells. These data collectively indicated that busulfan-induced BTB impairment was mediated by triggering ER stress and activation of the PERK-eIF2α signaling pathway, thereby damaging the spermatogenesis, providing a new therapeutic target for male infertility induced by busulfan., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Detailed analysis the disparity and reduction potential of clinker emission factors at the provincial level is important for regional reduction policies. Using the surveyed data from 185 new suspension and pre-heater (NSP) process lines and 69 shaft kiln lines, this study firstly analyzed the disparity in emission factors based on production process, production scale, and regional distribution in 2015. We found that the emission factor of the shaft kiln process (898.24 kg/t) is higher than that of the NSP process (858.59 kg/t), and that small-scale production lines have higher emission factors than large-scale lines both for the two process. China's clinker emission factors increase from the eastern to the western regions. Then, we estimated the reduction potential of structural adjustment, raw material substitution, and energy saving and fuel substitution in regional emission factors by 2030. The result shows that emission factors of the surveyed provinces will decrease by 101.41-174.60 kg/t compared to the values in 2015, which mainly contributes by energy saving and fuel substitution (65.98%), and raw material substitution (25.72%). And structural adjustment contributes only a small part reduction for most investigated provinces. The national average emission factor is estimated to be 715.33 kg/t in 2030, which indicates a reduction of 16.65%. These results can provide valuable feedback to government officials on the effectiveness of existing measures and also serve as a reference for future decisions on emission reduction polices., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The emergence of multidrug resistance (MDR) in Proteus mirabilis clinical isolates is a growing public health concern and has serious implications for wildlife. What is the role of wildlife has been become one of the hot issues in disseminating antimicrobial resistance. Here, 54 P. mirabilis isolates from 12 different species were identified. Among them, 25 isolates were determined to be MDR by profile of antimicrobial susceptibility; 10 MDR P. mirabilis isolates were subjected to comparative genomic analysis by whole genome sequencing. Comprehensive analysis showed that chromosome of P. mirabilis isolates mainly carries multidrug-resistance complex elements harboring resistance to carbapenem genes bla OXA-1 , bla NDM-1 , and bla TEM-1 . Class I integron is the insertion hotspot of IS26; it can be inserted into type I integron at different sites, thus forming a variety of multiple drug resistance decision sites. At the same time, Tn21, Tn7, and SXT/R391 mobile elements cause widespread spread of these drug resistance genes. In conclusion, P. mirabilis isolates from wildlife showed higher resistance to commonly used clinic drugs comparing to those from human. Therefore, wild animals carrying MDR clinical isolates should be paid attention to by the public health., (© 2020 International Society of Zoological Sciences, Institute of Zoology/Chinese Academy of Sciences and John Wiley & Sons Australia, Ltd.)

In the past decade, G protein-coupled receptors have emerged as drug targets, and their physiological and pathological effects have been extensively studied. Among these receptors, GPR119 is expressed in multiple organs, including the liver. It can be activated by a variety of endogenous and exogenous ligands. After GPR119 is activated, the cell secretes a variety of incretins, including glucagon-like peptide-1 and glucagon-like peptide-2, which may attenuate the metabolic dysfunction associated with fatty liver disease, including improving glucose and lipid metabolism, inhibiting inflammation, reducing appetite, and regulating the intestinal microbial system. GPR119 has been a potential therapeutic target for diabetes mellitus type 2 for many years, but its role in metabolic dysfunction associated fatty liver disease deserves further attention. In this review, we discuss relevant research and current progress in the physiology and pharmacology of the GPR119/incretin axis and speculate on the potential therapeutic role of this axis in metabolic dysfunction associated with fatty liver disease, which provides guidance for transforming experimental research into clinical applications.

Most currently recommended therapies for metabolic dysfunction-associated fatty liver disease (MAFLD) involve diet control and exercise therapy. We searched PubMed and compiled the most recent research into possible forms of programmed cell death in MAFLD, including apoptosis, necroptosis, autophagy, pyroptosis and ferroptosis. Here, we summarize the state of knowledge on the signaling mechanisms for each type and, based on their characteristics, discuss how they might be relevant in MAFLD-related pathological mechanisms. Although significant challenges exist in the translation of fundamental science into clinical therapy, this review should provide a theoretical basis for innovative MAFLD clinical treatment plans that target programmed cell death.

Predicting the optimal administration doses of the inhaled Δ9-tetrahydrocannabinol (THC), i.e., one of the major natural compounds in cannabis, is critical for maximizing the therapeutic outcomes and minimizing the toxic side effects. Thus, it is essential to developing an aerosol dosimetry model to simulate the transport, deposition, and translocation of inhaled THC aerosols from the human respiratory system to the systemic region. In this study, a computational fluid-particle dynamics (CFPD) plus pharmacokinetics (PK) model was developed and validated to quantify the localized vapor and particle uptake rates of THC and the resultant THC-plasma concentrations using two human upper airway geometries. In addition, two different puff protocols (4.0/10.0 s and 1.6/11.4 s as the inhalation/holding time ratios) were employed, associated with two different inhaled THC doses (2.0 mg and 8.82 mg, respectively). The computational results demonstrated that multiple parameters had noticeable influences on THC particle deposition and vapor absorption in the upper airways, as well as the resultant pharmacokinetic behaviors. These factors include anatomical features of the upper airway, puff flow rate, duration, and holding time. The results indicated that puff protocol with 4.0/10.0 s inhalation/holding time ratio would be recommended if the treatment needs THC delivery to the deeper lung. Furthermore, the inhaled THC dose had a dominant effect on the THC-plasma PK profiles, which could override the influences of anatomical variability and puff protocols. The developed CFPD-PK modeling framework has the potential to provide localized lung absorption data and PK profiles for in vitro-in vivo correlation, as well as supporting the development and assessment of drug products containing cannabis or cannabis-derived compounds., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Computational Fluid-Particle Dynamics (CFPD) models have been employed to predict lung aerosol dynamics for decades, estimating the delivery efficiency of inhaled drugs into the tracheobronchial tree. However, existing CFPD models assume the glottis is static during the breathing cycle. Failing to capture the dynamic motion of the glottis may introduce significant errors in drug deposition estimations., Methods: A novel CFPD model was developed with the capability of modeling the glottis motion using the dynamic mesh method. To explore the causal relationships between the glottis motion and the inhaled drug particle dynamics, simulations were performed to compare static and different dynamic glottis models in a subject-specific mouth-to-trachea geometry under idealized sinusoidal and realistic breathing waveforms. By defining the movement of each node in the glottis region using a generalized glottis motion function (GGMF) validated with clinical data, the abduction and adduction of the glottis were accurately described. Transient transport characteristics of inhaled particle-laden airflows were investigated and analyzed, including the glottis motion effect on the inhaled particles with the aerodynamic diameters from 0.1 to 10 μm., Results: Numerical results indicate that the static glottis assumption deviates the total deposition fraction predictions by more than 8% in relative differences. Compared with the CFPD models with the static glottis assumption, the dynamic glottis model can more realistically predict the complexity of the secondary flows near the vocal fold and the resultant particle depositions. Inter-subject variabilities of the glottis motion patterns were observed, and their influences on particle transport dynamics are not uniform. Parametric analyses also demonstrate that the maximum deformation ratio of the glottis is a key feature to describe whether the glottis motion can enhance or reduce particle depositions in the mouth-to-trachea region, over the static glottis model., Conclusions: The glottis motion shows a significant influence on the accuracy of predicting inhaled particle dynamics, and it should be integrated into CFPD simulations validated by subject-specific glottis motion data from clinical studies in the future. Furthermore, the proposed dynamic glottis model has been demonstrated to be a computationally effective method to recover the physiologically realistic motions of the glottis, and ready to be added into the next-generation holistic virtual lung modeling approach., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Influenza A Virus (IAV) replications start from the deposition of inhaled virus-laden droplets on the epithelial cells in the pulmonary tracts. In order to understand the local deposition patterns and within-host dynamics of infectious aerosols, accurate information of high-resolution imaging capabilities, as well as real-time flow cytometry analysis, are required for tracking infected cells, virus agents, and immune system responses. However, clinical and animal studies are in deficit to meet the above-mentioned demands, due to their limited operational flexibility and imaging resolution. Therefore, this study developed an experimentally validated multiscale epidemiological computational model, i.e., the Computational Fluid-Particle Dynamics (CFPD) plus Host Cell Dynamics (HCD) model, to predict the transport and deposition of the low-strain IAV-laden droplets, as well as the resultant regional immune system responses. The hygroscopic growth and shrinkage of IAV-laden droplets were accurately modeled. The subject-specific respiratory system was discretized by generating the new polyhedral-core mesh. By simulating both mouth and nasal breathing scenarios, the inhalations of isotonic IAV-laden droplets with three different compositions were achieved. It is the first time that parametric analysis was performed using the multiscale model on how different exposure conditions can influence the virus aerodynamics in the lung and the subsequent immune system responses. Numerical results show a higher viral accretion followed by a faster immune system response in the supraglottic region when droplets with the higher salt concentration were inhaled. Consequently, more severe symptoms and longer recovery are expected at the pharynx. Furthermore, local deposition maps of IAV-laden droplets and post-deposition infection dynamics provide informative and direct evidence which significantly enhance the fundamental understanding of the underlying mechanisms for upper airway and lower airway infections.

Administering incorrect doses of conventional anesthetic agents through the pulmonary route can cause potential health risks such as blood coagulation, platelet dysfunction, and deteriorating organ function. As an alternative, xenon can minimize the impact on the cardiovascular system and provide the neuroprotective effect, hemodynamic stability, and fast recovery. However, the inhalation pattern still needs to be carefully monitored and controlled to avoid health risks caused by over administering xenon to patients during unconsciousness. Thus, high-resolution lung absorption and whole-body translocation data are critically needed to fully understand how to administer the gas and coordinate with the patient to accurately control the dose. Clinical studies are not able to provide accurate dosimetry data due to their limited operational flexibility and imaging resolution. Therefore, a computational fluid dynamics (CFD) model was employed in this study to simulate the transport and absorption of the inhaled xenon which is connected with a physiologically based pharmacokinetic (PBPK) model to predict the translocation into the systemic regions. To study the effects of different breathing patterns on xenon transport dynamics in the human body, a realistic breathing waveform and two steady-state flow rates with inhalation durations of 2 and 1.5 seconds were selected. For the realistic breathing cycle, the inhalation-exhalation periods are defined for a human at rest and the other two cases have a fixed volumetric flow rate of 15 L/min. As the two latter cases only simulate the inspiratory phase, a 1-second holding time was applied to represent the missing periods of the full breathing time. Simulations were performed in a subject-specific human upper airway configuration from mouth to G6. Numerical results show that with the accurate lung uptake predictions obtained from the CFD model, the hybrid CFD-PBPK model with TRANSIT compartments generates more precise and breath-specific trends compared to simple PBPK models. Numerical results demonstrate that breathing pattern can significantly influence the xenon uptake in the human body, which can be utilized as a critical factor to be coordinated by clinicians to achieve the optimized xenon dose. Furthermore, parametric analyses were performed for the influence of breathing patterns on local airflow distributions, gas species translocations, and lung elimination mechanisms followed by species diffusion into the systemic regions.