Homozygous deleterious variants in the C-terminal of TDRD5 impair spermiogenesis, causing severe oligoasthenoteratozoospermia in humans.

BACKGROUND: PiRNA pathway factors, including evolutionarily conserved Tudor domain-containing proteins, play crucial roles in suppressing transposons and regulating post-meiotic gene expression. TDRD5 is essential for retrotransposon silencing and pachytene piRNA biogenesis; however, a causal link between TDRD5 variants and human infertility has not yet been established. OBJECTIVE: To identify the likely pathogenic variants of TDRD5 in infertile men, characterised by azoospermia or severe oligozoospermia. MATERIAL AND METHODS: Potential candidate variants were identified and confirmed using whole-exome and Sanger sequencing. Haematoxylin and eosin staining, immunofluorescence, and ultrastructural analyses were performed to investigate the structural and functional abnormalities of spermatozoa. The pathogenicity of the identified TDRD5 variants was verified using in vitro experiments. Functional effects of the C-terminal nonsense variant were assessed via histology, immunofluorescence staining, and small-RNA sequencing. Intracytoplasmic sperm injection (ICSI) was also performed to evaluate the efficacy of the clinical treatment. RESULTS: We identified a homozygous missense variant (c.3043G > A, p.A1015T) and a homozygous nonsense variant (c.2293G > T, p.E765*) of TDRD5 in two unrelated infertile men. Both patients exhibited severe oligoasthenoteratozoospermia, characterised by the presence of spermatozoa with multiple heads and/or flagella, as well as acrosomal hypoplasia. In vitro experiments revealed that the p.A1015T variant caused a diffuse distribution of TDRD5 granules, whereas the p.E765* variant led to the production of a C-terminal truncated protein with nuclear localisation, instead of the typical cytoplasmic localisation observed for the wild-type protein. Functional investigations also revealed that truncation of the C-terminal region of TDRD5 could potentially lead to a decline in the expression levels of intermitochondrial cement and chromatoid body components, such as MIWI (PIWIL1) and UPF1, and a slight decrease in the abundance of pachytene piRNA, ultimately resulting in compromised spermiogenesis. ICSI may be an effective treatment for these deficiencies. DISCUSSION AND CONCLUSION: This study implicates TDRD5 as a novel candidate gene in the pathogenesis of human male infertility, emphasising the contribution of piRNA pathway genes to male infertility. In addition, our data suggest that ICSI could be a promising treatment for infertile men harbouring TDRD5 variants.

Delayed femoral artery injury caused by heterotopic ossification: a rare case report and review of the literature.

BACKGROUND: Arterial injury caused by heterotopic ossification (HO) following fractures is rarely reported, yet it can have catastrophic consequences. This case report presents a unique instance of femoral artery injury and hematoma organization, occurring a decade after intramedullary nail fixation for a femoral shaft fracture complicated by HO. CASE PRESENTATION: A 56-year-old male presented with right femoral artery injury and organized hematoma, a decade after suffering bilateral femoral shaft fractures with mild head injury in a traffic accident. He had received intramedullary nailing for the right femoral shaft fracture and plate fixation for the left side in a local hospital. Physical examination revealed two firm, palpable masses with clear boundaries, limited mobility, and no tenderness. Peripheral arterial pulses were intact. Radiography demonstrated satisfactory fracture healing, while a continuous high-density shadow was evident along the inner and posterior aspect of the right thigh. Computed tomography angiography identified a large mixed-density mass (16.8 × 14.8 × 20.7 cm) on the right thigh's medial side, featuring central calcification and multiple internal calcifications. The right deep femoral artery coursed within this mass, with a smaller lesion noted on the posterior thigh. Surgical consultation with a vascular surgeon led to planned intervention. The smaller mass was completely excised, but the larger one partially, as it encased the femoral artery. The inability to remove all HO was due to excessive bleeding. Postoperatively, the patient experienced no complications, and one-year follow-up revealed a favorable recovery with restoration of full right lower limb mobility. CONCLUSION: This case underscores the potential gravity of vascular injury associated with heterotopic ossification. Surgeons should remain vigilant regarding the risk of vascular injury during HO excision.

A General Strategy for Food Traceability and Authentication Based on Assembly-Tunable Fluorescence Sensor Arrays.

Food traceability and authentication systems play an important role in ensuring food quality and safety. Current techniques mainly rely on direct measurement by instrumental analysis, which is usually designed for one or a group of specific foods, not available for various food categories. To develop a general strategy for food identification and discrimination, a novel method based on fluorescence sensor arrays is proposed, composed of supramolecular assemblies regulated by non-covalent interactions as an information conversion system. The stimuli-responsiveness and tunability of supramolecular assemblies provided an excellent platform for interacting with various molecules in different foods. In this work, five sensor arrays constructed by supramolecular assemblies composed of pyrene derivatives and perylene derivatives are designed and prepared. Assembly behavior and sensing mechanisms are investigated systematically by spectroscopy techniques. The traceability and authentication effects on several kinds of food from different origins or grades are evaluated and verified by linear discriminant analysis (LDA). It is confirmed that the cross-reactive signals from different sensor units encompassing all molecular interactions can generate a unique fingerprint pattern for each food and can be used for traceability and authentication toward universal food categories with 100% accuracy.

Adenylate kinase phosphate energy shuttle underlies energetic communication in flagellar axonemes.

The complexities of energy transfer mechanisms in the flagella of mammalian sperm flagella have been intensively investigated and demonstrate significant diversity across species. Enzymatic shuttles, particularly adenylate kinase (AK) and creatine kinase (CK), are pivotal in the efficient transfer of intracellular ATP, showing distinct tissue- and species-specificity. Here, the expression profiles of AK and CK were investigated in mice and found to fall into four subgroups, of which Subgroup III AKs were observed to be unique to the male reproductive system and conserved across chordates. Both AK8 and AK9 were found to be indispensable to male reproduction after analysis of an infertile male cohort. Knockout mouse models showed that AK8 and AK9 were central to promoting sperm motility. Immunoprecipitation combined with mass spectrometry revealed that AK8 and AK9 interact with the radial spoke (RS) of the axoneme. Examination of various human and mouse sperm samples with substructural damage, including the presence of multiple RS subunits, showed that the head of radial spoke 3 acts as an adapter for AK9 in the flagellar axoneme. Using an ATP probe together with metabolomic analysis, it was found that AK8 and AK9 cooperatively regulated ATP transfer in the axoneme, and were concentrated at sites associated with energy consumption in the flagellum. These findings indicate a novel function for RS beyond its structural role, namely, the regulation of ATP transfer. In conclusion, the results expand the functional spectrum of AK proteins and suggest a fresh model regarding ATP transfer within mammalian flagella.

Improved desalination performance of flow-electrode capacitive deionisation by a novel drop-shape channel.

As an emerging desalination technology, flow-electrode capacitive deionisation (FCDI) has the advantages of theoretically infinite adsorption capacity and applicability to high-concentration brine. However, during the operation of FCDI, the flow electrode in the S-shape channel is prone to sedimentation and clogging the channel. This undesirable phenomenon brings low efficiency and security issues. Therefore, a drop-shape channel was designed for FCDI to improve the flow regime of the flow electrode. The flow simulation of the drop-shape channel was performed to select the appropriate geometry to avoid the formation of the vortex and low-velocity region. The simulation results showed that the streamlined design of the drop-shape channel has insignificant velocity gradients. It significantly reduces the low-velocity region and improves the phenomenon of particle sedimentation. The desalination performance with varieties of electrode flow rate, AC content, and voltage was used to investigate the advantage between S-shape and drop-shape channels. It was found that under the conditions of low flow rate, high AC content, and high voltage, the drop-shape channel FCDI system could still obtain better ASRR and CE.

Expression of concern: A hypoxia-dissociable siRNA nanoplatform for synergistically enhanced chemo-radiotherapy of glioblastoma.

Expression of concern for 'A hypoxia-dissociable siRNA nanoplatform for synergistically enhanced chemo-radiotherapy of glioblastoma' by Yandong Xie, et al., Biomater. Sci., 2022, 10, 6791-6803, https://doi.org/10.1039/D2BM01145J.

Ze-Qi-Tang formula inhibits MDSCs glycolysis through the down-regulation of p21/Hif1α/Glut1 signal in psoriatic-like mice.

BACKGROUND: Psoriasis is a chronic immune-mediated inflammatory skin disease that affects the quality of life and mental health of approximately 150 million people worldwide. Ze-Qi-Tang (ZQT) is a classic compound used in China for lung disease; however, its mechanism of action in psoriasis remains unclear. This study aimed to investigate the therapeutic effect of the ZQT formula on psoriasis and explore the underlying molecular mechanisms. METHODS: Peripheral blood samples were collected from patients with psoriasis and healthy individuals. Flow cytometry was used to detect changes in the proportions of myeloid-derived suppressor cells (MDSCs) and other immune cells. Psoriasis was induced in mice by the daily application of imiquimod. ZQT was administered separately or in combination with anti-Gr1 antibody to deplete MDSC. The glycolysis levels of the MDSCs were detected using a Seahorse analyzer. The p21/Hif1α/Glut1 pathway was identified and validated by mRNA sequence, RT-qPCR, WB, IF, and the application of p21 inhibitor UC2288. RESULTS: The number of MDSCs was significantly increased in patients with psoriasis, with the increased expression of p21, Hif1α, and Glut1 in MDSCs. ZQT significantly alleviated psoriasis-like skin lesions in mice. ZQT formula significantly reduced the number of MDSCs in psoriatic-like mice and enhanced their suppressive capacity for T cells. The efficacy of ZQT in alleviating psoriatic dermatitis is compromised by MDSC depletion. ZQT decreased the expressions of p21, Hif1α, and Glut1-induced glycolysis in MDSCs, thereby inhibiting Th17 cell differentiation. CONCLUSION: These suggest that ZQT alleviates IMQ-induced psoriatic dermatitis, by inhibiting p21/Hif1α/Glut1-induced glycolysis in MDSCs.

Disruption in CYLC1 leads to acrosome detachment, sperm head deformity, and male in/subfertility in humans and mice.

The perinuclear theca (PT) is a dense cytoplasmic web encapsulating the sperm nucleus. The physiological roles of PT in sperm biology and the clinical relevance of variants of PT proteins to male infertility are still largely unknown. We reveal that cylicin-1, a major constituent of the PT, is vital for male fertility in both mice and humans. Loss of cylicin-1 in mice leads to a high incidence of malformed sperm heads with acrosome detachment from the nucleus. Cylicin-1 interacts with itself, several other PT proteins, the inner acrosomal membrane (IAM) protein SPACA1, and the nuclear envelope (NE) protein FAM209 to form an 'IAM-cylicins-NE' sandwich structure, anchoring the acrosome to the nucleus. WES (whole exome sequencing) of more than 500 Chinese infertile men with sperm head deformities was performed and a CYLC1 variant was identified in 19 patients. Cylc1-mutant mice carrying this variant also exhibited sperm acrosome/head deformities and reduced fertility, indicating that this CYLC1 variant most likely affects human male reproduction. Furthermore, the outcomes of assisted reproduction were reported for patients harbouring the CYLC1 variant. Our findings demonstrate a critical role of cylicin-1 in the sperm acrosome-nucleus connection and suggest CYLC1 variants as potential risk factors for human male fertility.

Salt tolerance evaluation and mini-core collection development in Miscanthus sacchariflorus and M. lutarioriparius.

Marginal lands, such as those with saline soils, have potential as alternative resources for cultivating dedicated biomass crops used in the production of renewable energy and chemicals. Optimum utilization of marginal lands can not only alleviate the competition for arable land use with primary food crops, but also contribute to bioenergy products and soil improvement. Miscanthus sacchariflorus and M. lutarioriparius are prominent perennial plants suitable for sustainable bioenergy production in saline soils. However, their responses to salt stress remain largely unexplored. In this study, we utilized 318 genotypes of M. sacchariflorus and M. lutarioriparius to assess their salt tolerance levels under 150 mM NaCl using 14 traits, and subsequently established a mini-core elite collection for salt tolerance. Our results revealed substantial variation in salt tolerance among the evaluated genotypes. Salt-tolerant genotypes exhibited significantly lower Na+ content, and K+ content was positively correlated with Na+ content. Interestingly, a few genotypes with higher Na+ levels in shoots showed improved shoot growth characteristics. This observation suggests that M. sacchariflorus and M. lutarioriparius adapt to salt stress by regulating ion homeostasis, primarily through enhanced K+ uptake, shoot Na+ exclusion, and Na+ sequestration in shoot vacuoles. To evaluate salt tolerance comprehensively, we developed an assessment value (D value) based on the membership function values of the 14 traits. We identified three highly salt-tolerant, 50 salt-tolerant, 127 moderately salt-tolerant, 117 salt-sensitive, and 21 highly salt-sensitive genotypes at the seedling stage by employing the D value. A mathematical evaluation model for salt tolerance was established for M. sacchariflorus and M. lutarioriparius at the seedling stage. Notably, the mini-core collection containing 64 genotypes developed using the Core Hunter algorithm effectively represented the overall variability of the entire collection. This mini-core collection serves as a valuable gene pool for future in-depth investigations of salt tolerance mechanisms in Miscanthus.

Comparative analysis of pregnancy outcomes in preimplantation genetic testing for aneuploidy and conventional in vitro fertilization and embryo transfer: a stratified examination on the basis of the quantity of oocytes and blastocysts from a multicenter randomized controlled trial.

OBJECTIVE: To investigate variations in pregnancy outcomes between preimplantation genetic testing for aneuploidy (PGT-A) and conventional in vitro fertilization and embryo transfer (IVF-ET) treatment across distinct groups categorized by oocyte and blastocyst counts. Because the live birth rate (LBR) of assisted reproductive technology treatment is influenced by the number of oocytes and blastocysts retrieved. Our previous study indicated comparable cumulative LBRs (CLBRs) between conventional IVF-ET and PGT-A. DESIGN: A post hoc exploratory secondary analysis of data from a multicenter randomized controlled trial compared the CLBRs between conventional IVF-ET and PGT-A. SETTING: Academic fertility centers. SUBJECTS: A total of 1,212 infertile women with a good prognosis for a live birth after PGT-A or conventional IVF-ET were included. INTERVENTION: Women underwent PGT-A or conventional IVF-ET. MAIN OUTCOME MEASURE(S): Cumulative LBR, cumulative clinical pregnancy loss (CPL) rate, and good birth outcome. RESULT(S): In the study, all participants were divided into 4 groups on the basis of quartiles of the number of oocytes retrieved, or blastocysts. There was an interaction between whether to perform PGT-A and the oocyte numbers category on cumulative CPL and biochemical pregnancy loss. Chi-square analysis revealed that the PGT-A group showed a lower cumulative frequency of CPL compared with the IVF-ET group (PGT-A vs. IVF-ET: 5.9% vs. 13.7%; relative risk = 0.430; 95% confidence interval, 0.243-0.763) when the number of oocytes retrieved was <15. Although there was no interaction on CLBR when the retrieved oocyte count ranged from 19-23 (19≤ oocytes <23) the PGT-A group exhibited a lower CLBR than the conventional IVF-ET group (PGT-A vs IVF-ET: 75.6% vs 87.1%; relative risk = 0.868; 95% confidence interval, 0.774-0.973), and the average body weight of newborns from the PGT-A group was approximately 142 g lower than that of the conventional IVF-ET group (PGT-A vs. IVF-ET: 3,334 ± 479 g vs. 3,476 ± 473 g). However, no statistically significant difference in the CLBR was observed between the PGT-A and IVF-ET groups in the other oocyte or blastocyst groups. CONCLUSION: When the number of retrieved eggs was <15, the PGT-A group exhibited a lower cumulative CPL rate but no higher CLBR than the conventional IVF-ET group. CLINICAL TRIAL REGISTRATION NUMBER: NCT03118141.

Centriolar appendages evolve into the inner sheath of mammalian flagella.

The annulus, a septin-based structure in vertebrate sperm connecting the MP and PP, has unclear migration mechanics. In this issue, Hoque et al. (https://doi.org/10.1083/jcb.202307147) report that the CBY3/CIBAR1 complex ensures its precise positioning by regulating membrane properties.

Endometrial BMP2 Deficiency Impairs ITGB3-Mediated Trophoblast Invasion in Women With Repeated Implantation Failure.

BACKGROUND: Repeated implantation failure (RIF) leads to a waste of high-quality embryos and remains a challenge in assisted reproductive technology. During early human placentation, the invasion of trophoblast cells into the decidua is an essential step for the establishment of maternal-fetal interactions and subsequent successful pregnancy. Bone morphogenetic protein 2 (BMP2) has been reported to regulate endometrial receptivity and promote trophoblast invasion. However, whether there is dysregulation of endometrial BMP2 expression in patients with RIF remains unknown. Additionally, the molecular mechanisms underlying the effects of BMP2 on human trophoblast invasion and early placentation remain to be further elucidated. METHODS: Midluteal phase endometrial samples were biopsied from patients with RIF and from routine control in vitro fertilization followed by quantitative polymerase chain reaction and immunoblotting analyses. Human trophoblast organoids, primary human trophoblast cells, and an immortalized trophoblast cell line (HTR8/SVneo) were used as study models. RESULTS: We found that BMP2 was aberrantly low in midluteal phase endometrial tissues from patients with RIF. Recombinant human BMP2 treatment upregulated integrin ß3 (ITGB3) in a SMAD2/3-SMAD4 signaling-dependent manner in both HTR8/SVneo cells and primary trophoblast cells. siRNA-mediated integrin ß3 downregulation reduced both basal and BMP2-upregulated trophoblast invasion and vascular mimicry in HTR8/SVneo cells. Importantly, shRNA-mediated ITGB3 knockdown significantly decreased the formation ability of human trophoblast organoids. CONCLUSION: Our results demonstrate endometrial BMP2 deficiency in patients with RIF. ITGB3 mediates both basal and BMP2-promoted human trophoblast invasion and is essential for early placentation. These findings broaden our knowledge regarding the regulation of early placentation and provide candidate diagnostic and therapeutic targets for RIF clinical management.

Application of Polymeric CO2 Thickener Polymer-Viscosity-Enhance in Extraction of Low-Permeability Tight Sandstone.

The conventional production technique employed for low-permeability tight reservoirs exhibits limited productivity. To solve the problem, an acetate-type supercritical carbon dioxide (scCO2) thickener, PVE, which contains a large number of microporous structures, was prepared using the atom transfer radical polymerization (ATRP) method. The product exhibited an ability to decrease the minimum miscibility pressure of scCO2 during a solubility test and demonstrated a favorable extraction efficiency in a low-permeability tight core displacement test. At 15 MPa and 70 °C, PVE-scCO2 at a concentration of 0.2% exhibits effective oil recovery rates of 5.61% for the 0.25 mD core and 2.65% for the 5 mD core. The result demonstrates that the incorporation of the thickener PVE can effectively mitigate gas channeling, further improve oil displacement efficiency, and inflict minimal damage to crude oil. The mechanism of thickening was analyzed through molecular simulation. The calculated trend of thickening exhibited excellent agreement with the experimental measurement rule. The simulation results demonstrate that the contact area between the polymer and CO2 increases in direct proportion to both the number of thickener molecules and the viscosity of the system. The study presents an effective strategy for mitigating gas channeling during scCO2 flooding and has a wide application prospect.

Wheat gluten deamidation: structure, allergenicity and its application in hypoallergenic noodles.

BACKGROUND: Wheat gluten (WG) containing gliadin and glutenin are considered the main allergens in wheat allergy as a result of their glutamine-rich peptides. Deamidation is a viable and efficient approach for protein modifications converting glutamine into glutamic acid, which may have the potential for allergenicity reduction of WG. RESULTS: Deamidation by citric acid was performed to investigate the effects on structure, allergenicity and noodle textural properties of wheat gluten (WG). WG was heated at 100 °C in 1 m citric acid to yield deamidated WG with degrees of deamidation (DD) ranging from DWG-25 (25% DD) to DWG-70 (70% DD). Fourier-transform infrared and intrinsic fluorescence spectroscopy results suggested the unfolding of WG structure during deamidation, and sodium dodecyl sulphate-polyacrylamide gel electrophoresis showed molecular weight shifts at the 35-63 kDa region, suggesting that the deamidation mainly occurred on low molecular weight glutenin subunits and γ- gliadin of the WG. An enzyme-linked immunosorbent assay of deamidated WG revealed a decrease in absorbance and immunoblotting indicated that the intensities of protein bands at 35-63 kDa decreased, which suggested that deamidation of WG might have caused a greater loss of epitopes than the generation of new epitopes caused by unfolding of WG, and thereby reduction of the immunodominant immunoglobulin E binding capacity, ultimately leading to the decrease in allergenicity. DWG-25 was used in the preparation of recombinant hypoallergenic noodles, and the hardness, elasticity, chewiness and gumminess were improved significantly by the addition of azodicarbonamide. CONCLUSION: The present shows the potential for deamidation of the WG products used in novel hypoallergenic food development. © 2023 Society of Chemical Industry.

Slc26a1 is not essential for spermatogenesis and male fertility in mice.

Thousands of genes are expressed in the testis of mice. However, the details about their roles during spermatogenesis have not been well-clarified for most genes. The purpose of this study was to examine the effect of Slc26a1 deficiency on mouse spermatogenesis and male fertility. Slc26a1-knockout (KO) mice were generated using CRISPR/Cas9 technology on C57BL/6J background. We found no obvious differences between Slc26a1-KO and Slc26a1-WT mice in fertility tests, testicular weight, sperm concentrations, or morphology. Histological analysis found that Slc26a1-KO mouse testes had normal germ cell types and mature sperm. These findings indicated that Slc26a1 was dispensable for male fertility in mice. Our results may save time and resources by allowing other researchers to focus on genes that are more meaningful for fertility studies. We also found that mRNAs of two Slc26a family members (Slc26a5 and Slc26a11) were expressed on higher mean levels in Slc26a1-KO total mouse testes, compared to Slc26a1-WT mice. This effect was not found in mouse GC-1 and GC-2 germ cell lines with the Slc26a1 gene transiently knocked down. This result may indicate that a gene compensation phenomenon was present in the testes of Slc26a1-KO mice.

Identification of novel first-trimester serum biomarkers for early prediction of preeclampsia.

BACKGROUND: Preeclampsia (PE) is a leading cause of maternal and perinatal mortality and morbidity worldwide, but effective early prediction remains a challenge due to the lack of reliable biomarkers. METHODS: Based on the extensive human biobank of our large-scale assisted reproductive cohort platform, the first-trimester serum levels of 48 cytokines, total immunoglobulins (Igs), anti-phosphatidylserine (aPS) antibodies, and several previously reported PE biomarkers [including placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and activin A] were measured in 34 women diagnosed with PE and 34 matched normotensive controls. RESULTS: The PE group has significantly higher first-trimester serum levels of interleukin (IL)-2Rα, IL-9, tumor necrosis factor-ß (TNF-ß), RANTES, hepatocyte growth factor (HGF), total IgM, and total IgG, and aPS IgG optical density (OD) value, as well as lower first-trimester serum levels of PlGF and total IgA and aPS-IgG immune complexes (IC) OD value than the control group. Combining top five first-trimester serum biomarkers (total IgM, total IgG, PlGF, aPS IgG, and total IgA) achieved superior predictive value [area under the curve (AUC) and 95% confidence interval (CI) 0.983 (0.952-1.000), with a sensitivity of 100% and a specificity of 94.1%] for PE development compared to PlGF and PlGF/sFlt-1 independently [AUC and 95% CI 0.825 (0.726-0.924) and 0.670 (0.539-0.800), respectively]. CONCLUSION: We identified novel first-trimester serum biomarkers and developed an effective first-trimester prediction model using immune-related factors and PlGF for PE, which could facilitate the development of early diagnostic strategies and provide immunological insight into the further mechanistic exploration of PE.

Targeting upregulation of the immunosuppressive activity of MDSCs with indirubin as a novel strategy to alleviate psoriasis.

BACKGROUND: Psoriasis is a chronic and incurable skin disorder that causes inflammation. There is an urgent clinical need for new treatments. We identified the natural compound indirubin as a potential potent agent for the treatment of psoriasis, but it's therapeutic effect and underlying mechanisms were not well understood. METHODS: Peripheral blood and skin tissues from psoriasis patients and healthy individuals were collected. Bioinformatics analysis was performed to investigate LAT1 expression and associated signal pathways in psoriasis skin lesions. A mouse model of psoriasis was established. Indirubin was administered separately or in combination with MDSCs depletion or adoptively transferred MDSCs. JPH203, rapamycin, siRNA, and NV5138 were further used to investigate the potential mechanism by which indirubin regulates MDSCs. RESULTS: Psoriasis patients had increased numbers of MDSCs in their blood and skin lesions, with high expression of Lat1. The upregulation of LAT1 expression and the arginine synthesis pathway was observed in psoriasis skin lesions. The number of MDSCs was increased, while their inhibitory effect on psoriatic T cells was decreased. Indirubin decreased Lat1 expression on the surface of MDSCs, inhibited mTOR pathway activation, upregulated Arg1 expression in MDSCs, and enhanced the immunosuppressive activity of MDSCs while inhibiting CD4+CCR6+ T cells. CONCLUSION: This study demonstrates indirubin's pharmacological and therapeutic effects, providing a basis for future clinical application in treating psoriasis.

Prolyl endopeptidase remodels macrophage function as a novel transcriptional coregulator and inhibits fibrosis.

Macrophages are immune cells crucial for host defense and homeostasis maintenance, and their dysregulation is involved in multiple pathological conditions, such as liver fibrosis. The transcriptional regulation in macrophage is indispensable for fine-tuning of macrophage functions, but the details have not been fully elucidated. Prolyl endopeptidase (PREP) is a dipeptidyl peptidase with both proteolytic and non-proteolytic functions. In this study, we found that Prep knockout significantly contributed to transcriptomic alterations in quiescent and M1/M2-polarized bone marrow-derived macrophages (BMDMs), as well as aggravated fibrosis in an experimental nonalcoholic steatohepatitis (NASH) model. Mechanistically, PREP predominantly localized to the macrophage nuclei and functioned as a transcriptional coregulator. Using CUT&Tag and co-immunoprecipitation, we found that PREP was mainly distributed in active cis-regulatory genomic regions and physically interacted with the transcription factor PU.1. Among PREP-regulated downstream genes, genes encoding profibrotic cathepsin B and D were overexpressed in BMDMs and fibrotic liver tissue. Our results indicate that PREP in macrophages functions as a transcriptional coregulator that finely tunes macrophage functions, and plays a protective role against liver fibrosis pathogenesis.