Gastrointestinal organs and organoids-on-a-chip: advances and translation into the clinics.

Microfluidic organs and organoids-on-a-chip models of human gastrointestinal systems have been established to recreate adequate microenvironments to study physiology and pathophysiology. In the effort to find more emulating systems and less costly models for drugs screening or fundamental studies, gastrointestinal system organoids-on-a-chip have arisen as promising pre-clinicalin vitromodel. This progress has been built on the latest developments of several technologies such as bioprinting, microfluidics, and organoid research. In this review, we will focus on healthy and disease models of: human microbiome-on-a-chip and its rising correlation with gastro pathophysiology; stomach-on-a-chip; liver-on-a-chip; pancreas-on-a-chip; inflammation models, small intestine, colon and colorectal cancer organoids-on-a-chip and multi-organoids-on-a-chip. The current developments related to the design, ability to hold one or more 'organs' and its challenges, microfluidic features, cell sources and whether they are used to test drugs are overviewed herein. Importantly, their contribution in terms of drug development and eminent clinical translation in precision medicine field, Food and Drug Administration approved models, and the impact of organoid-on-chip technology in terms of pharmaceutical research and development costs are also discussed by the authors.

The performance of interferon gamma release assays in patients with nontuberculous mycobacterial infection: a systematic review and meta-analysis.

BACKGROUND: The actual positive rate of interferon gamma release assays (IGRAs) in patients with nontuberculous mycobacteria (NTM) infections remains unclear. This review and meta-analysis present the prevalence of positive IGRAs (T-SPOT.TB and QuantiFERON [QFT] tests) among patients infected with NTM isolates (with or without ESAT-6/CFP-10). METHODS: Several databases, including PubMed, Scopus, Embase, and Web of Science were searched (until June 18th, 2022). Studies that had the following data were included: (1) results of T-SPOT.TB, QuantiFERON (QFT) test, or both, (2) NTM species, and (3) NTM diseases, or NTM colonization. The metaprop command that incorporates a Freeman-Tukey double arcsine transformation is used for pooling proportions. RESULTS: A total of 11 articles (n = 929) were deemed eligible for inclusion. Meta-analysis identified that the overall pooled positive and indeterminate rates of IGRA results in patients with NTM infections was 16% and 5%, respectively. Subgroup analysis showed that the positive rate of IGRAs in patients infected with NTM (without ESAT-6/CFP-10) was 7% (95% CI, 1%-18%), and 44% (95%CI, 22%-68%) in patients infected with NTM (with ESAT-6/CFP-10). In addition, the indeterminate rate of QFT (7%, 95% CI: 4%-12%) was higher than that of T-SPOT.TB (0%; 95% CI, 0%-2%) among the overall population with NTM infections. CONCLUSIONS: The IGRAs have a moderate positive rate for the diagnosis of NTM (expressing ESAT-6/CFP-10) infections, and a significant indeterminate rate is observed among the overall population infected with NTM. However, these findings should be interpreted with caution because of the high heterogeneity among studies.

[Remediation Effect and Mechanism of Biochar in Combination with Nitrogen Fertilizer on Cd-contaminated Paddy Soil].

Cadmium (Cd) heavy metal pollution has posed serious threats to soil health and the safe production utilization of agricultural products. A pot experiment was conducted to study the effects of biochar (BC) and nitrogen fertilizer with three levels, namely 2.6 g·pot-1 (N1), 3.5 g·pot-1 (N2), 4.4 g·pot-1 (N3) biochar combined with nitrogen fertilizer (BCN1, BCN2, and BCN3), on soil Cd fractions, Cd enrichment, the transport of rice, and soil enzyme activity, as well as the changes in microbial community composition and complex interactions between microorganisms through high-throughput sequencing. The results showed that biochar combined with nitrogen fertilizer led to the transformation of Cd from the exchangeable state to the residue state, and the proportion of the exchangeable state was significantly reduced by 6.2%-14.7%; by contrast, the proportion of the residue state increased by 18.6%-26.4% relative to that in CK. In addition, singular treatments of nitrogen fertilizer enhanced the accumulation capacities of Cd in roots, which increased by 22%-33.5% compared with that in CK. By contrast, the BC and BCN treatments reduced Cd accumulation in roots and the transfer capacity from stems to rice husks and husk to rice. Furthermore, the BCN treatments promoted soil enzyme activities (urease, acid phosphatase, invertase, and catalase). MiSeq sequencing showed that BCN treatments increased the abundance of the main species of soil bacterial microbes (such as Acidobacteriales, Solibacterales, Pedosphaerales, and Nitrospirales). Moreover, co-occurrence network analysis showed that the complexity of the soil bacterial network was enhanced under the N, BC, and BCN treatments. Overall, biochar combined with nitrogen fertilizer reduced soil Cd availability, inhibited the capacity of Cd accumulation and the transport of rice, and improved the soil eco-environmental quality. Thus, using BCN could be a feasible practice for the remediation of Cd-polluted agricultural soil.

Mendelian randomization analysis implicates bidirectional associations between brain imaging-derived phenotypes and ischemic stroke.

Brian imaging-derived phenotypes (IDPs) have been suggested to be associated with ischemic stroke, but the causality between them remains unclear. In this bidirectional two-sample Mendelian randomization (MR) study, we explored the potential causal relationship between 461 imaging-derived phenotypes (n = 33,224, UK Biobank) and ischemic stroke (n = 34,217 cases/406,111 controls, Multiancestry Genome-Wide Association Study of Stroke). Forward MR analyses identified five IDPs associated with ischemic stroke, including mean diffusivity (MD) in the right superior fronto-occipital fasciculus (1.22 [95% CI, 1.11-1.34]), MD in the left superior fronto-occipital fasciculus (1.30 [1.17-1.44]), MD in the anterior limb of the right internal capsule (1.36 [1.22-1.51]), MD in the right anterior thalamic radiation (1.17 [1.09-1.26]), and MD in the right superior thalamic radiation (1.23 [1.11-1.35]). In the reverse MR analyses, ischemic stroke was identified to be associated with three IDPs, including high isotropic or free water volume fraction in the body of corpus callosum (beta, 0.189 [95% confidence interval, 0.107-0.271]), orientation dispersion index in the pontine crossing tract (0.175 [0.093-0.257]), and volume of the third ventricle (0.219 [0.138-0.301]). This bidirectional two-sample MR study suggested five predictors and three diagnostic markers for ischemic stroke at the brain-imaging level. Further studies are warranted to replicate our findings and clarify underlying mechanisms.

Boerelasins A-D, Four Unprecedented Cytochalasins from the Endophytic Fungus Boeremia Exigua.

Four undescribed cytochalasins (1-4) were isolated from the endophytic fungus Boeremia exigua. Structurally, boerelasin A (1) represents the first example of a cytochalasin with a rare 5/5 bicyclic carbon core. Boerelasin B (2) possesses an unprecedented 5/6/5/6/8 pentacyclic ring system. Boerelasin C (3), a derivative from the common biosynthetic intermediate to 1, is a macrocyclic ring-opening cytochalasin, and boerelasin D (4) contains an uncommon six-carbon alkyl acid side chain. The structures were elucidated based on spectroscopic methods, electronic circular dichroism, spin-spin coupling constants, and calculated nuclear magnetic resonance with DP4+ analysis. These compounds exhibited significant cytotoxicity against the tumor cells.

NAT10 regulates the repair of UVB-induced DNA damage and tumorigenicity.

Chemical modifications in messenger RNA (mRNA) regulate gene expression and play critical roles in stress responses and diseases. Recently we have shown that N6-methyladenosine (m6A), the most abundant mRNA modification, promotes the repair of UVB-induced DNA damage by regulating global genome nucleotide excision repair (GG-NER). However, the roles of other mRNA modifications in the UVB-induced damage response remain understudied. N4-acetylcytidine (ac4C) is deposited in mRNA by the RNA-binding acetyltransferase NAT10. This NAT10-mediated ac4C in mRNA has been reported to increase both mRNA stability and translation. However, the role of ac4C and NAT10 in the UVB-induced DNA damage response remains poorly understood. Here we show that NAT10 plays a critical role in the repair of UVB-induced DNA damage lesions through regulating the expression of the key GG-NER gene DDB2. We found that knockdown of NAT10 enhanced the repair of UVB-induced DNA damage lesions by promoting the mRNA stability of DDB2. Our findings are in contrast to the previously reported role of NAT10-mediated ac4C deposition in promoting mRNA stability and may represent a novel mechanism for ac4C in the UVB damage response. Furthermore, NAT10 knockdown in skin cancer cells decreased skin cancer cell proliferation in vitro and tumorigenicity in vivo. Chronic UVB irradiation increases NAT10 protein levels in mouse skin. Taken together, our findings demonstrate a novel role for NAT10 in the repair of UVB-induced DNA damage products by decreasing the mRNA stability of DDB2 and suggest that NAT10 is a potential novel target for preventing and treating skin cancer.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple doses of aficamten in healthy Chinese participants: a randomized, double-blind, placebo-controlled, phase 1 study.

Objectives: Aficamten is a selective, small-molecule allosteric inhibitor of cardiac sarcomere being developed as a chronic oral treatment for patients with symptomatic obstructive hypertrophic cardiomyopathy. This was the first-in-Chinese study aiming to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of aficamten in healthy adults. Methods: This double-blind, randomized, placebo-controlled, phase 1 study was conducted in 28 healthy male and female Chinese participants after single ascending dose (SAD) and multi-dose (MD) administrations of aficamten. In the SAD cohort, 16 participants were randomized to receive a single oral dose of aficamten: 10 mg, 20 mg, or placebo. In the MD cohort, 12 participants were randomized to receive multiple doses of aficamten: 5 mg or placebo once daily for 14 days. Safety was monitored throughout the study with electrocardiograms, echocardiograms, clinical laboratory tests, and reporting of adverse events (AEs). Pharmacokinetic profiles of aficamten and metabolites, as well as CYP2D6 genetic impact, were evaluated. Results: A total of 35 treatment-emergent AEs were reported by 14 (50%) participants with mild severity. There were no serious AEs or adverse decreases in left ventricular ejection fraction below 50% during the study. Aficamten was dose-proportional over the dose range of 5-20 mg and accumulated in the MD cohort. Conclusion: Aficamten was safe and well-tolerated in the healthy Chinese adult participants. The pharmacokinetics of aficamten in the Chinese population was comparable to those previously found in Western participants. These phase 1 data support the progression of aficamten into future clinical studies in Chinese patients. Clinical Trial registration: https://clinicaltrials.gov, identifier: NCT04783766.

Paxlovid-tacrolimus drug-drug interaction caused severe diarrhea that induced combined diabetic ketoacidosis and a hyperglycemic hyperosmolar state in a kidney transplant patient: a case report.

BACKGROUND: Transplant recipients are at high risk of coronavirus disease 2019, and a timely supply of antivirals should be prioritized for those patients. Complicated drug‒drug interactions limit the use of Paxlovid (nirmatrelvir/ritonavir) coadministered with tacrolimus. Here, we report a patient with a kidney transplant who received Paxlovid and reduced-dose tacrolimus at the same time and suffered a severe tacrolimus toxicity. CASE PRESENTATION: We present a 56-year-old man of Han ethnicity with a kidney transplant who suffered from coronavirus disease 2019 twice. For the first infection, the immunosuppressants were substituted by dexamethasone when the patient used Paxlovid, and everything went well. For the second time, tacrolimus at a reduced dose concomitant with Paxlovid caused severe diarrhea, inducing combined diabetic ketoacidosis and a hyperglycemic hyperosmolar state. CONCLUSION: This case challenges the dose-adjustment strategy of managing drug‒drug interactions. We suggest that tacrolimus should be stopped when Paxlovid is applied and that corticosteroids could be a good substitution.

KAS-Analyzer: a novel computational framework for exploring KAS-seq data.

Motivation: Kethoxal-assisted ssDNA sequencing (KAS-seq) is rapidly gaining popularity as a robust and effective approach to study the nascent dynamics of transcriptionally engaged RNA polymerases through profiling of genome-wide single-stranded DNA (ssDNA). Its latest variant, spKAS-seq, a strand-specific version of KAS-seq, has been developed to map genome-wide R-loop structures by detecting imbalances of ssDNA on two strands. However, user-friendly, open-source computational tools tailored for KAS-seq data are still lacking. Results: Here, we introduce KAS-Analyzer, the first comprehensive computational framework aimed at streamlining and enhancing the analysis and interpretation of KAS-seq and spKAS-seq data. In addition to standard analyses, KAS-Analyzer offers many novel tools specifically designed for KAS-seq data, including, but not limited to: calculation of transcription-related metrics, identification of single-stranded transcribing (SST) enhancers, high-resolution mapping of R-loops, and differential RNA polymerase activity analysis. We provided a detailed overview of KAS-seq data and its diverse applications through the implementation of KAS-Analyzer. Using the example time-course KAS-seq datasets, we further showcase the robust capabilities of KAS-Analyzer for investigating dynamic transcriptional regulatory programs in response to UVB radiation. Availability and implementation: KAS-Analyzer is available at https://github.com/Ruitulyu/KAS-Analyzer.

Angle-resolved photoemission spectroscopy with an in situ tunable magnetic field.

Angle-resolved photoemission spectroscopy (ARPES) is a powerful tool for probing the momentum-resolved single-particle spectral function of materials. Historically, in situ magnetic fields have been carefully avoided as they are detrimental to the control of photoelectron trajectory during the photoelectron detection process. However, magnetic field is an important experimental knob for both probing and tuning symmetry-breaking phases and electronic topology in quantum materials. In this paper, we introduce an easily implementable method for realizing an in situ tunable magnetic field at the sample position in an ARPES experiment and analyze magnetic-field-induced artifacts in the ARPES data. Specifically, we identified and quantified three distinct extrinsic effects of a magnetic field: constant energy contour rotation, emission angle contraction, and momentum broadening. We examined these effects in three prototypical quantum materials, i.e., a topological insulator (Bi2Se3), an iron-based superconductor (LiFeAs), and a cuprate superconductor (Pb-Bi2Sr2CuO6+x), and demonstrate the feasibility of ARPES measurements in the presence of a controllable magnetic field. Our studies lay the foundation for the future development of the technique and interpretation of ARPES measurements of field-tunable quantum phases.

Construction of Zr-Metal-Organic Frameworks-Based Composite Materials toward Anhydrous Proton Conduction and Photocatalytic CO2 Reduction.

Metal-organic frameworks constructed from Zr usually possess excellent chemical and physical stability. Therefore, they have become attractive platforms in various fields. In this work, two families of hybrid materials based on ZrSQU have been designed and synthesized, named Im@ZrSQU and Cu@ZrSQU, respectively. Im@ZrSQU was prepared through the impregnation method and employed for proton conduction. Im@ZrSQU exhibited terrific proton conduction performance in an anhydrous environment, with the highest proton conduction value of 3.6 × 10-2 S cm-1 at 110 °C. In addition, Cu@ZrSQU was synthesized via the photoinduction method for the photoreduction of CO2, which successfully promoted the conversion of CO2 into CO and achieved the CO generation rate of up to 12.4 µmol g-1 h-1. The photocatalytic performance of Cu@ZrSQU is derived from the synergistic effect of Cu NPs and ZrSQU. Based on an in-depth study and discussion toward ZrSQU, we provide a versatile platform with applications in the field of proton conduction and photocatalysis, which will guide researchers in their further studies.

Mechanisms of Ferritinophagy and Ferroptosis in Diseases.

The discovery of the role of autophagy, particularly the selective form like ferritinophagy, in promoting cells to undergo ferroptosis has inspired us to investigate functional connections between diseases and cell death. Ferroptosis is a novel model of procedural cell death characterized by the accumulation of iron-dependent reactive oxygen species (ROS), mitochondrial dysfunction, and neuroinflammatory response. Based on ferroptosis, the study of ferritinophagy is particularly important. In recent years, extensive research has elucidated the role of ferroptosis and ferritinophagy in neurological diseases and anemia, suggesting their potential as therapeutic targets. Besides, the global emergence and rapid transmission of COVID-19, which is caused by SARS-CoV-2, represents a considerable risk to public health worldwide. The potential involvement of ferroptosis in the pathophysiology of brain injury associated with COVID-19 is still unclear. This review summarizes the pathophysiological changes of ferroptosis and ferritinophagy in neurological diseases, anemia, and COVID-19, and hypothesizes that ferritinophagy may be a potential mechanism of ferroptosis. Advancements in these fields will enhance our comprehension of methods to prevent and address neurological disorders, anemia, and COVID-19.

Traditional uses, phytochemistry, pharmacology, applications, and quality control of Gastrodia elata Blume: A comprehensive review.

ETHNOPHARMACOLOGICAL RELEVANCE: Gastrodia elata Blume (G. elata) has a long historical application in Asian countries and its tubers, seeds, and stalks are capable of being utilized for medicine, food, or health care products. AIM OF THE REVIEW: This study aimed to offer a systematic and up-to-date analysis of the current review of the G. elata research advances in traditional uses, phytochemistry, pharmacology, applications, and quality control, as well as a scientific reference for the development and utilization of this plant. MATERIALS AND METHODS: Electronic databases including PubMed, Web of Science, Google Scholar, ScienceDirect, SciFinder, and CNKI were used for the collection of publications on G. elata. The following keywords of G. elata were used truncated with other relevant topic terms, such as phenolic compounds, polysaccharides, glycosides, neuroprotection, learning and memory improvement effects, cardioprotection, applications, and quality control. RESULTS AND CONCLUSIONS: Approximately 134 chemical components mainly categorizing as phenolic compounds, polysaccharides, glycosides, organic acids, and sterols were reported from this plant. Moreover, preclinical studies indicated that G. elata performs several functions, including neuroprotection, learning and memory improvement effects, cardioprotection, vaso-modulatory effect, anti-depression, anti-cancer, and other effects. Currently, G. elata has been widely applied to clinics and foods. The available literature shows that the quality of G. elata might be affected by factors such as origin, fungus, and harvest time, which will have an impact on the drug efficacy. According to past research, G. elata is a potential medicinal and edible plant with several active components and pharmacological activity that has a high application value in medicine and the food business. Nevertheless, few studies have concentrated on characterization of polysaccharides structure and study of non-medicinal parts, implying that further comprehensive research on its polysaccharides structure and non-medicinal parts is critical for full utilization of resources of G. elata.

Chiral metasurface zone plate for transmission-reflection focusing of circularly polarized terahertz waves.

The properties of traditional Fresnel zone plates have been greatly enhanced by metasurfaces, which allow the control of polarization, orbital angular momentum, or other parameters on the basis of focusing. In this Letter, a new, to the best of our knowledge, method for circularly polarized wave manipulation based on a zone plate is proposed. Chiral meta-atoms and binary geometric phase are used for the simultaneous focusing of reflected and transmitted terahertz waves. The silicon-based dielectric chiral units, which show great performance of spin-selective transmission near 0.54 THz, separate the orthogonal circularly polarized components. A binary Pancharatnam-Berry (P-B) phase gradient is obtained by rotating the unit 90 degrees, then the phase zone plate can be easily designed. The simulation results show that the proposed chiral metasurface zone plate has the function of reflection-transmission separation and focusing for the circularly polarized terahertz waves. In addition, we also demonstrate the possibility of using a 1064-nm continuous infrared laser to adjust the intensity of our devices, based on photo-generated carriers in silicon. The design principle of the chiral metasurface zone plates can be extended to other wavelengths, providing new ideas for the regulation of circularly polarized light.

TGFß signaling links early life endocrine-disrupting chemicals exposure to suppression of nucleotide excision repair in rat myometrial stem cells.

Environmental exposure to endocrine-disrupting chemicals (EDCs) is linked to the development of uterine fibroids (UFs) in women. UFs, non-cancerous tumors, are thought to originate from abnormal myometrial stem cells (MMSCs). Defective DNA repair capacity may contribute to the emergence of mutations that promote tumor growth. The multifunctional cytokine TGFß1 is associated with UF progression and DNA damage repair pathways. To investigate the impact of EDC exposure on TGFß1 and nucleotide excision repair (NER) pathways, we isolated MMSCs from 5-month-old Eker rats exposed neonatally to diethylstilbestrol (DES), an EDC, or to vehicle (VEH). EDC-MMSCs exhibited overactivated TGFß1 signaling and reduced mRNA and protein levels of NER pathway components compared to VEH-MMSCs. EDC-MMSCs also demonstrated impaired NER capacity. Exposing VEH-MMSCs to TGFß1 decreased NER capacity while inhibiting TGFß signaling in EDC-MMSCs restored it. RNA-seq analysis and further validation revealed decreased expression of Uvrag, a tumor suppressor gene involved in DNA damage recognition, in VEH-MMSCs treated with TGFß1, but increased expression in EDC-MMSCs after TGFß signaling inhibition. Overall, we demonstrated that the overactivation of the TGFß pathway links early life exposure to EDCs with impaired NER capacity, which would lead to increased genetic instability, arise of mutations, and fibroid tumorigenesis. We demonstrated that the overactivation of the TGFß pathway links early life exposure to EDCs with impaired NER capacity, which would lead to increased fibroid incidence.

Efficient co-production of reducing sugars and xylooligosaccharides via clean hydrothermal pretreatment of rape straw.

Hydrothermal treatment was applied to pretreat rape straw for the efficient co-production of reducing sugars and xylooligosaccharides. It was observed that hydrothermal treatment using water as solvent and catalyst destructed the compact structure of rape straw and increased its enzymatic digestion efficiency from 24.6% to 92.0%. Xylooligosaccharide (3.3 g/L) was acquired after the treatment under 200 °C for 60 min (severity factor Log Ro = 4.7). With increasing pretreatment intensity from 3.1 to 5.4, the hemicellulose removal increased from 14.4% to 100%, and the delignification was raised from 12% to 44%. Various characterization proved that the surface morphology of treated material showed a porous shape, while the cellulose accessibility, lignin surface area and lignin hydrophobicity were greatly improved. Consequently, hydrothermal pretreatment played a vital role in the sustainable transformation of biomass to valuable biobased compounds, and had a wide range of application prospects in lignocellulosic biorefining.

Mini-PE, a prime editor with compact Cas9 and truncated reverse transcriptase.

Prime editor (PE) is a versatile genome editing tool that does not need extra DNA donors or inducing double-strand breaks. However, in vivo implementation of PE remains a challenge because of its oversized composition. In this study, we screened out the smallest truncated Moloney murine leukemia virus (MMLV) reverse transcriptase (RT) with the F155Y mutation to keep gene editing efficiency. We discovered the most efficient gene editing variants of MMLV RT with the smallest size. After optimization of the pegRNAs and incorporation with nick sgRNAs, the mini-PE delivered up to 10% precise editing at target sites in human and mouse cells. It also edited the mouse Hsf1 gene in the mouse retina precisely after delivery with adeno-associated viruses (AAVs), although the editing efficiency was lower than 1%. We will focus on improving the editing efficiency of mini-PE and exploiting its therapeutic potential against human genetic diseases.

RALF22 promotes plant immunity and amplifies Pep3 immune signal.

The rapid alkalinization factors (RALFs) have been reported to dampen pathogen-associated molecular pattern (PAMP)-triggered immunity via suppressing PAMP-induced complex formation between pattern recognition receptor (PRR) and its co-receptor BAK1. However, the direct and positive role of RALFs in plant immunity remains largely unknown. Here we report the direct and positive roles of a typical RALF, RALF22, in plant immunity. RALF22 alone directly elicited a variety of typical immune responses and triggered resistance against the devastating necrotrophic fungal pathogen Sclerotinia sclerotiorum in a FERONIA (FER) dependent manner. LORELEI (LRE)-like glycosylphosphatidylinositol (GPI)-anchored protein 1 (LLG1) and NADPH oxidase RBOHD were required for RALF22-elicited reactive oxygen species (ROS) generation. Mutation of cysteines conserved in C terminus of RALFs abolished while constitutive formation of two disulfide bridges between these cysteines promoted the RALF22-elicited ROS production and resistance against S. sclerotiorum, demonstrating the requirement of these cysteines in the functions of RALF22 in plant immunity. Additionally, RALF22 amplified Pep3-induced immune signal by dramatically increasing the PROPEP3 transcript and protein abundance. Supply with RALF22 induced resistance against S. sclerotiorum in Brassica crop plants. Collectively, our results revealed that RALF22 triggered immune responses and augmented Pep3-induced immune signal in a FER-dependent manner, and exhibited the potential to be exploited as an immune elicitor in crop protection. This article is protected by copyright. All rights reserved.

Comparative effects of hepatocyte growth factor and tacrolimus on acute liver allograft early tolerance.

Allostimulated CD8+ T cells (aCD8+ T cells), as the main mediators of acute liver rejection (ARJ), are hyposensitive to apoptosis due to the inactivation of death receptor FAS-mediated pathways and fail to allow tolerance induction, eventually leading to acute graft rejection. Although tacrolimus (FK506), the most commonly used immunosuppressant (IS) in the clinic, allows tolerance induction, its use is limited because its target immune cells are unknown and it is associated with increased incidences of malignancy, infection, and nephrotoxicity, which substantially impact long-term liver transplantation (LTx) outcomes. The dark agouti (DA)-to-Lewis rat LTx model is a well-known ARJ model and was hence chosen for the present study. We show that both hepatocyte growth factor (HGF) (cHGF, containing the main form of promoting HGF production) and recombinant HGF (h-rHGF) exert immunoregulatory effects mainly on allogeneic aCD8+ T cell suppression through FAS-mediated apoptotic pathways by inhibiting cMet to FAS antagonism and Fas trimerization, leading to acute tolerance induction. We also showed that such inhibition can be abrogated by treatment with neutralizing antibodies against cMet (HGF-only receptor). In contrast, we did not observe these effects in rats treated with FK506. However, we observed that the effect of anti-rejection by FK506 was mainly on allostimulated CD4+ T cell (aCD4+ T cell) suppression and regulatory T cell (Treg) promotion, in contrast to the mechanism of HGF. In addition, the protective mechanism of HGF in FK506-mediated nephrotoxicity was addressed. Therefore, HGF as a tolerance inducer, whether used in combination with FK506 or as monotherapy, may have good clinical value. Additional roles of these T-cell subpopulations in other biological systems and studies in these fields will also be meaningful.

Research Progress of Interleukin-27 in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) can be identified as an inflammatory disorder in the intestine, being characterized by maladjusted immune responses and chronic inflammation of the intestinal tract. However, as the etiology and pathogenesis are still unclear, more effective therapeutic approaches are needed. Recent studies have discovered a new cytokine, interleukin-27 (IL-27), which belongs to the superfamily of IL-6 and IL-12, demonstrating multiple functions in many infectious diseases, autoimmune diseases, and cancers. Interleukin-27 is mainly produced by antigen presentation cells (APCs) such as dendritic cells and mononuclear macrophages, playing a dual regulatory role in immunological response. Therefore, this updated review aims to summarize the new progress of the regulatory role of IL-27 in IBD and focus more on the interaction between IL-27 and immune cells, hoping to provide more evidence for the potential IBD treatment mediated by IL-27.