Engineered Mitochondrial Transplantation as An Anti-Aging Therapy.

Aging is an inevitable and complex biological process involving multi-factorial mechanisms. Mitochondrial dysfunction is a critical factor in the aging process, characterized by a decline in mitochondrial quality and activity, leading to aging and aging-related diseases. Therefore, mitochondria have become an attractive target in anti-aging therapies. Several senolytic drugs targeting mitochondria and antioxidant agents have been used in anti-aging research in the past few years. However, these strategies may cause adverse effects with long-term medication. In this extensive review, we propose "mitochondrial transplantation," which transfers healthy mitochondria from donor cells to recipient cells to replace damaged or dysfunctional mitochondria, as a new alternative strategy for treating mitochondrial dysfunction and aging-associated diseases. In this review, we introduce the contemporary landscape of mitochondrial transplantation, then discuss intensely the successful applications of mitochondrial transplantation therapy in aging diseases such as neurodegenerative diseases, cardiovascular aging, and reproductive aging, highlighting its translational potential. Finally, we summarize and prospect the challenges and opportunities mitochondrial transplantation faces in anti-aging therapy.

Causal association of basal metabolic rate on systemic sclerosis: a bidirectional mendelian randomization study.

Prior evidence suggests that altered energy metabolism plays a crucial role in the development of fibrotic diseases. Recent research indicates that systemic sclerosis (SSc) patients have potentially benefited from energy management, implying that basal metabolic rate (BMR), a vital energy metabolic parameter, may be related to SSc. However, the causal effect of BMR on SSc remains unknown. Thus, we aimed to elucidate the causal links between BMR and SSc. Based on summary statistics from the genome-wide association studies (GWAS) database, two-sample Mendelian randomization (MR) was applied to explore causality between BMR and SSc. The causal relationships were assessed employing inverse variance weighted (IVW), MR-Egger, and weighted median (WM) methods. Meanwhile, several sensitivity analyses were carried out to ensure the robustness of the findings. There was an underlying genetic association of BMR on SSc (OR = 0.505, 95% CI: 0.272-0.936, P = 0.030). Moreover, no significant causal effect between SSc and BMR was observed in the reverse MR analysis (OR = 0.999, 95% CI: 0.997-1.001, P = 0.292). According to the sensitivity analysis, the presence of heterogeneity and genetic pleiotropy was not detected. Our findings, derived from a genetic perspective, provide robust evidence of a causal connection between BMR and SSc. To verify these results and clarify the potential mechanisms, further research is warranted.

Multi-regulatory potency of USP1 on inflammasome components promotes pyroptosis in thyroid follicular cells and contributes to the progression of Hashimoto's thyroiditis.

BACKGROUND: Inflammatory diseases are often initiated by the activation of inflammasomes triggered by pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs), which mediate pyroptosis. Although pyroptosis resulting from aberrant inflammasome triggering in thyroid follicular cells (TFCs) has been observed in Hashimoto's thyroiditis (HT) patients, the underlying mechanisms remain largely unknown. Given the extensive involvement of protein ubiquitination and deubiquitination in inflammatory diseases, we aimed to investigate how deubiquitinating enzymes regulate thyroid follicular cell pyroptosis and HT pathogenesis. METHODS: Our study specifically investigated the role of Ubiquitin-specific peptidase 1 (USP1), a deubiquitinase (DUB), in regulating the inflammasome components NLRP3 and AIM2, which are crucial in pyroptosis. We conducted a series of experiments to elucidate the function of USP1 in promoting pyroptosis associated with inflammasomes and the progression of HT. These experiments involved techniques such as USP1 knockdown or inhibition, measurement of key pyroptosis indicators including caspase-1, caspase-1 p20, and GSDMD-N, and examination of the effects of USP1 abrogation on HT using a mouse model. Furthermore, we explored the impact of USP1 on NLRP3 transcription and its potential interaction with p65 nuclear transportation. RESULTS: Our findings provide compelling evidence indicating that USP1 plays a pivotal role in promoting inflammasome-mediated pyroptosis and HT progression by stabilizing NLRP3 and AIM2 through deubiquitination. Furthermore, we discovered that USP1 modulates the transcription of NLRP3 by facilitating p65 nuclear transportation. Knockdown or inhibition of USP1 resulted in weakened cell pyroptosis, as evidenced by reduced levels of caspase-1 p20 and GSDMD-N, which could be restored upon AIM2 overexpression. Remarkably, USP1 abrogation significantly ameliorated HT in the mice model, likely to that treating mice with pyroptosis inhibitors VX-765 and disulfiram. CONCLUSIONS: Our study highlights a regulatory mechanism of USP1 on inflammasome activation and pyroptosis in TFCs during HT pathogenesis. These findings expand our understanding of HT and suggest that inhibiting USP1 may be a potential treatment strategy for managing HT.

The molecular phylogeny of Caenogastropoda (Mollusca, Gastropoda) based on mitochondrial genomes and nuclear genes.

Comprising about 60 % of gastropod diversity, caenogastropods display almost all kinds of shell forms and include many commercially important marine groups. Although the monophyly of Caenogastropoda has been widely accepted, thier internal phylogenetic relationships remain unclear. In the present study, a total of 27 caenogastropods belonging to eight superfamilies were sequenced and used for phylogenetic reconstruction. All newly sequenced mitogenomes adhered to the consensus gene order of caenogastropods, except for those of Vanikoroidea, Vermetoidea and Cerithioidea, which involved protein-coding genes. The reconstructed mitogenomic phylogeny suggested the monophylies of Architaenioglossa, Sorbeoconcha, Hypsogastropoda and the siphonate clade. The present study also identified a close affinity among Cypraeoidea, Ficoidea, Tonnoidea, and Neogastropoda, supported by the presence of a pleurembolic proboscis. The monophyly of Neogastropoda was not supported, as Cancellariidae was found to be sister to the limpet-shaped group Calyptraeoidea, and (Tonooidea + Ficoidea) were sister to the remaining neogastropods. This study provides important information for better understanding the evolution of caenogastropods, as well as for the protection and utilization of these diverse and economically significant marine resources.

Overexpression of miR-20a-5p in mesenchymal stem cell derived-exosomes from systemic lupus erythematosus patients restored therapeutic effect and Treg immune regulation.

We and other groups have documented that bone marrow-mesenchymal stem cells (BM-MSCs) from Systemic lupus erythematosus (SLE) patients demonstrated signs of senescence, including reduced ability of regulating Treg. Treg cell defects or Treg cell deficiency are regarded as significant factors in the progression of SLE. Exosomes, nanoscale vesicles, abound in molecular and genetic contents, play a critical role in intercellular communications. The purpose of this research is to investigate the mechanism of MSCs-exosomes regulating Tregs cells in SLE, further elucidate the mechanism of immune dysregulation of aging BM-MSCs, and provide theoretical basis and data support for new targets of SLE treatment. In the study, BM-MSCs and exosomes were isolated successfully. Exosomes could be up-taken by naïve CD4+T cells. MSCs-exosomes attenuated SLE clinical manifestation in vivo, but MSCs-exosomes from SLE patients were ineffective. MSCs-exosomes from SLE patients dysregulated Treg cells differentiation in vivo and in vitro. Exosomal miR-20a-5p contributed to the effect of MSCs-exosomes regulating Treg cells. Up-regulating the expression of miR-20a-5p in SLE MSCs-exosomes can restore their ability to promote Treg differentiation and treatment effect. This study further elucidated the role of in the immunomodulatory mechanism of BM-MSCs-exosomes and provided new ideas for the non-cellular autologous transplantation therapy of SLE.

Identification of novel biomarker hsa_circ_0003914 for rheumatoid arthritis from plasma exosomes.

Rheumatoid arthritis (RA) is a complex autoimmune disease featuring invasive and infiltrative fibroblast-like synoviocytes (FLS) that lead to joint damage. While current RA pathological mechanisms remain incompletely defined, exosomes have been implicated as having the potential to drive disease progression due to their ability to deliver different types of biomolecules to tissues effected by RA. One potentially disease exacerbating molecule type found in exosomes are Circular RNAs (circRNAs), which are highly stable and have been previously implicated in RA pathogenesis. Here, we examine hsa_circ_0003914, a circRNA found in exosomes located in blood plasma, for a role in RA. Plasma exosomes were isolated and injected into collagen-induced arthritis (CIA) mice, followed by functional experiments to analyze the influence of exosomes on FLS formation. Sequencing revealed the presence of hsa_circ_0003914 in exosomes, so we examined its association with clinical markers in RA. Finally, the role for hsa_circ_0003914 in RA was directly confirmed through in vivo and in vitro experiments. We found that plasma exosomes isolated from RA patients could aggravate the disease of CIA mice, compared to exosomes isolated from healthy control patients. Hsa_circ_0003914 was highly enriched in the exosomes of RA patients. Mechanistically, Hsa_circ_0003914 promoted abnormal cell proliferation, migration, invasion and stimulated the secretion of inflammatory cytokines in FLSs through targeting NF-κB/p65 signaling pathway. Interestingly, knockdown of hsa_circ_0003914 rescued disease phenotypes in CIA mice. Taken together, these data implicate hsa_circ_0003914 as a potential therapeutic target for the prevention and management of RA.

IGF2BP2 regulates the inflammation of fibroblast-like synoviocytes via GSTM5 in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease with an unknown etiology. RA cannot be fully cured and requires lengthy treatment, imposing a significant burden on both individuals and society. Due to the lack of specific drugs available for treating RA, exploring a key new therapeutic target for RA is currently an important task. Activated fibroblast-like synoviocytes (FLSs) play a crucial role in the progression of RA, which release interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α resulting in abnormal inflammatory reaction in the synovium. A previous study has highlighted the correlation of m6A reader insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) with inflammation-related diseases in human. However, the role of IGF2BP2 in the inflammatory reaction of FLSs during RA progression has not been assessed. In this study, IGF2BP2 expression was decreased in the synovial tissues of RA patients and collagen-induced arthritis (CIA) rats. Intra-articular injection of an adeno-associated virus (AAV) vector overexpressing IGF2BP2 relieved paw swelling, synovial hyperplasia and cartilage destruction in CIA rats. IGF2BP2 overexpression also inhibited lipopolysaccharide (LPS)-mediated RA fibroblast-like synoviocytes (RA-FLSs) migration and invasion accompanied by a decreased level of inflammatory factors in vitro. Conversely, IGF2BP2 suppression promoted RA-FLSs migration and invasion with an elevated level of inflammatory factors in vitro. The sequencing result showed that glutathione S-transferase Mu 5 (GSTM5), a key antioxidant gene, was the target mRNA of IGF2BP2. Further experiments demonstrated that IGF2BP2 strengthened the stability of GSTM5 mRNA, leading to weakened inflammatory reaction and reduced expression of matrix metalloproteinase 9 and 13 (MMP9, MMP13). Therefore, IGF2BP2-GSTM5 axis may represent a potential therapeutic target for RA treatment.

Macrophages communicate with mesangial cells through the CXCL12/DPP4 axis in lupus nephritis pathogenesis.

Lupus nephritis (LN) occurs in 50% of cases of systemic lupus erythematosus (SLE) and is one of the most serious complications that can occur during lupus progression. Mesangial cells (MCs) are intrinsic cells in the kidney that can regulate capillary blood flow, phagocytose apoptotic cells, and secrete vasoactive substances and growth factors. Previous studies have shown that various types of inflammatory cells can activate MCs for hyperproliferation, leading to disruption of the filtration barrier and impairment of renal function in LN. Here, we characterized the heterogeneity of kidney cells of LN mice by single-nucleus RNA sequencing (snRNA-seq) and revealed the interaction between macrophages and MCs through the CXC motif chemokine ligand 12 (CXCL12)/dipeptidyl peptidase 4 (DPP4) axis. In culture, macrophages modulated the proliferation and migration of MCs through this ligand-receptor interaction. In LN mice, treatment with linagliptin, a DPP4 inhibitor, effectively inhibited MC proliferation and reduced urinary protein levels. Together, our findings indicated that targeting the CXCL12/DPP4 axis with linagliptin treatment may serve as a novel strategy for the treatment of LN via the CXCL12/DPP4 axis.

Prediction of blood-brain barrier penetrating peptides based on data augmentation with Augur.

BACKGROUND: The blood-brain barrier serves as a critical interface between the bloodstream and brain tissue, mainly composed of pericytes, neurons, endothelial cells, and tightly connected basal membranes. It plays a pivotal role in safeguarding brain from harmful substances, thus protecting the integrity of the nervous system and preserving overall brain homeostasis. However, this remarkable selective transmission also poses a formidable challenge in the realm of central nervous system diseases treatment, hindering the delivery of large-molecule drugs into the brain. In response to this challenge, many researchers have devoted themselves to developing drug delivery systems capable of breaching the blood-brain barrier. Among these, blood-brain barrier penetrating peptides have emerged as promising candidates. These peptides had the advantages of high biosafety, ease of synthesis, and exceptional penetration efficiency, making them an effective drug delivery solution. While previous studies have developed a few prediction models for blood-brain barrier penetrating peptides, their performance has often been hampered by issue of limited positive data. RESULTS: In this study, we present Augur, a novel prediction model using borderline-SMOTE-based data augmentation and machine learning. we extract highly interpretable physicochemical properties of blood-brain barrier penetrating peptides while solving the issues of small sample size and imbalance of positive and negative samples. Experimental results demonstrate the superior prediction performance of Augur with an AUC value of 0.932 on the training set and 0.931 on the independent test set. CONCLUSIONS: This newly developed Augur model demonstrates superior performance in predicting blood-brain barrier penetrating peptides, offering valuable insights for drug development targeting neurological disorders. This breakthrough may enhance the efficiency of peptide-based drug discovery and pave the way for innovative treatment strategies for central nervous system diseases.

Effects of temperature and nitrogen sources on physiological performance of the coccolithophore Emiliania huxleyi.

Both temperature and nutrient levels are rising in worldwide ocean ecosystems, and they strongly influence biological responses of phytoplankton. However, few studies have addressed the interactive effects of temperature and nitrogen sources on physiological performance of the coccolithophore Emiliania huxleyi. In this study, we evaluated algal growth, photosynthesis and respiration, elemental composition, enzyme activity, and calcification under a matrix of two temperatures gradients (ambient temperature 20 °C and high temperature 24 °C) and two nitrogen sources (nitrate (NO3-) and ammonium (NH4+)). When the algae was cultured with NO3- medium, high temperature reduced algal photosynthesis and nitrate reductase activity, but it did not change other indicators significantly relative to ambient temperature. In addition, E. huxleyi preferred NO3- as the growth medium, whereas NH4+ had negative effects on physiological parameters. In the NH4+ medium, the growth rate, photosynthesis and photosynthetic rate, nitrate reductase activity, and particulate organic carbon and particulate organic nitrogen production rate of the algae decreased as temperature increased. Conversely, high temperature increased cellular particulate organic carbon, cellular particulate organic nitrogen, and particulate inorganic carbon levels. In summary, our findings indicate that the distribution and abundance of microalgae could be greatly affected under warming ocean temperature and different nutrient conditions.

ALOX5 drives the pyroptosis of CD4+ T cells and tissue inflammation in rheumatoid arthritis.

Pyroptosis, an inflammatory form of programmed cell death, is linked to the pathology of rheumatoid arthritis (RA). Here, we investigated the molecular mechanism underlying pyroptosis in T cells isolated from patients with RA. Compared with healthy individuals, patients with RA had more pyroptotic CD4+ T cells in blood and synovia, which correlated with clinical measures of disease activity. Moreover, the mRNA expression and protein abundance of arachidonate 5-lipoxygenase (ALOX5), which converts arachidonic acid to leukotriene A4 (LTA4), were increased in CD4+ T cells from patients with RA and, among patients with RA, were lowest in those in clinical remission. Knockdown or pharmacological inhibition of ALOX5 suppressed CD4+ T cell pyroptosis and improved symptoms in two rodent models of RA. Mechanistically, the increase in ALOX5 activity in RA CD4+ T cells enhanced the production of the LTA4 derivative LTB4, which stimulated Ca2+ influx through ORAI3 channels, leading to the activation of NLRP3 inflammasomes and pyroptosis. Our findings reveal a role for ALOX5 in RA and provide a molecular basis for further exploring the clinical utility of ALOX5 inhibition in RA and for using ALOX5 as a biomarker to distinguish active disease and remission in RA.

Single-Cell Profiling of Bone Marrow B Cells and Early B Cell Developmental Disorders Associated With Systemic Lupus Erythematosus.

OBJECTIVE: The peripheral B cell compartment is heavily disturbed in systemic lupus erythematosus (SLE), but whether B cells develop aberrantly in the bone marrow (BM) is largely unknown. METHODS: We performed single-cell RNA/B cell receptor (BCR) sequencing and immune profiling of BM B cells and classified patients with SLE into two groups: early B cell (Pro-B and Pre-B) normal (EBnor) and EB defective/low (EBlo) groups. RESULTS: The SLE-EBlo group exhibited more severe disease activity and proinflammatory status, overaction of type I interferon signaling and metabolic pathways within the B cell compartment, and aberrant BCR repertoires compared with the SLE-EBnor group. Moreover, in one patient with SLE who was initially classified in the SLE-EBlo group, early B cell deficiency and associated abnormalities were largely rectified in a second BM sample at the remission phase. CONCLUSION: In summary, this study suggests that early B cell loss in BM defines a unique pathological state in a subset of patients with SLE that may play an active role in the dysregulated autoimmune responses.

Single-cell transcriptome characteristics of testicular terminal epithelium lineages during aging in the Drosophila.

Aging is a complex biological process leading to impaired functions, with a variety of hallmarks. In the testis of Drosophila, the terminal epithelium region is involved in spermatid release and maturation, while its functional diversity and regulatory mechanism remain poorly understood. In this study, we performed single-cell RNA-sequencing analysis (scRNA-seq) to characterize the transcriptomes of terminal epithelium in Drosophila testes at 2-, 10 and 40-Days. Terminal epithelium populations were defined with Metallothionein A (MtnA) and subdivided into six novel sub-cell clusters (EP0-EP5), and a series of marker genes were identified based on their expressions. The data revealed the functional characteristics of terminal epithelium populations, such as tight junction, focal adhesion, bacterial invasion, oxidative stress, mitochondrial function, proteasome, apoptosis and metabolism. Interestingly, we also found that disrupting genes for several relevant pathways in terminal epithelium led to male fertility disorders. Moreover, we also discovered a series of age-biased genes and pseudotime trajectory mediated state-biased genes during terminal epithelium aging. Differentially expressed genes during terminal epithelium aging were mainly participated in the regulation of several common signatures, e.g. mitochondria-related events, protein synthesis and degradation, and metabolic processes. We further explored the Drosophila divergence and selection in the functional constraints of age-biased genes during aging, revealing that age-biased genes in epithelial cells of 2 Days group evolved rapidly and were endowed with greater evolutionary advantages. scRNA-seq analysis revealed the diversity of testicular terminal epithelium populations, providing a gene target resource for further systematic research of their functions during aging.

Development and validation of a nomogram for predicting fatigue in patients with primary Sjögren's syndrome.

OBJECTIVE: To develop and validate a nomogram to predict fatigue in patients with primary Sjögren's syndrome (pSS). METHODS: In this cross-sectional study, 251 patients with SS from the Affiliated Hospital of Nantong University were recruited. The patients were randomly divided into two groups: training group (n = 167) and validation group (n = 84). In the training group, univariate analysis and multivariate Cox regression analysis were performed on sociodemographic factors, disease activity, anxiety/depression, clinical indicators, and so on. According to the risk factors of fatigue in SS patients, a nomograph was established. In the training group and validation group, the performance of the nomogram was verified by three forms: receiver operating characteristic curve, calibration curve, and decision curve analysis (DCA). RESULT: The incidence of fatigue was 40.6%. EULAR Sjögren's Syndrome Disease Activity Index, EULAR SS patient reported index, and depression were independent risk factors of fatigue in SS patients. The C-index of nomogram was 0.8532 in training set and 0.7381 in verification set, respectively. As to the Hosmer-Lemeshow test, the P value of modeling patients is 0.996 in verification (P > 0.05). DCA further validated the clinical utility of this nomogram. CONCLUSION: The nomogram constructed in this study can effectively predict the occurrence of fatigue in SS patients, which is helpful for clinical decision-making and subsequent intervention implementation. Key Points • Fatigue was widespread in patients with primary Sjögren's syndrome, and the incidence of fatigue was 40.6%. • Disease activity and depression were independent risk factors of fatigue in patients with Sjögren's syndrome. • This was the first comprehensive nomogram to predict fatigue for Sjögren's syndrome patients.

Transcriptomic analysis revealed the dynamic response mechanism to acute ammonia exposure in the ivory shell, Babylonia areolata.

The ivory shell (Babylonia areolata) is an economically important shellfish in tropical and subtropical regions, but its intensive culture and biological characteristic of hiding in the sandy substrate make it highly susceptible to ammonia stress. In this study, we investigated the dynamic changes in histopathology, oxidative stress, and transcriptome of the ivory shell at different time points under high concentration (60 mg/L) ammonia exposure. With prolonged exposure to stress, vacuoles appeared in the hepatopancreas while cell volume and intercellular space increased. The activities of superoxide dismutase (SOD) and catalase (CAT) decreased significantly under high concentrations of ammonia-induced stress while malondialdehyde (MDA) levels increased significantly. Integrated analysis of differentially expressed genes (DEGs), weighted gene co-expression network analysis (WGCNA), and quantitative real-time polymerase chain reaction (qRT-PCR) revealed that lipid transport primarily contributed to maintaining cellular homeostasis during the early stage of stress (6 and 12 h). Subsequently, a significant upregulation of oxidation-reduction reactions occurred at the middle stage (24 h), leading to oxidative stress. Finally, during the later stage (48 h), metabolic decomposition provided energy for survival maintenance. Additionally, lysosome and apoptosis were identified as potential key pathways in response to acute ammonia toxicity. Overall, our findings suggest that ivory shells can respond to acute ammonia toxicity via immune and antioxidant defense mechanisms but sustained high concentrations may cause irreversible damage. This study provides valuable insights into the response mechanism of mollusks towards ammonia and serves as a data reference for breeding ammonia-tolerant varieties of ivory shells.

Mitogenomic Phylogeny of Tonnoidea Suter, 1913 (1825) (Gastropoda: Caenogastropoda).

The Tonnoidea Suter, 1913 (1825) is a moderately diverse group of large predatory gastropods, the systematics of which remain unclear. In the present study, the complete mitochondrial genomes of nine Tonnoidean species were sequenced. All newly sequenced mitogenomes contain 13 protein-coding genes (PCGs), 22 transfer RNA genes and two ribosomal RNA genes, showing similar patterns in genome size, gene order and nucleotide composition. The ratio of nonsynonymous to synonymous of PCGs indicated that NADH complex genes of Tonnoideans were experiencing a more relaxed purifying selection compared with the COX genes. The reconstructed phylogeny based on the combined amino acid sequences of 13 protein-coding genes and the nucleotide sequences of two rRNA genes supported that Ficidae Meek, 1864 (1840) is a sister to Tonnoidea. The monophylies of all Tonnoidean families were recovered and the internal phylogenetic relationships were consistent with the current classification. The phylogeny also revealed that Tutufa rebuta (Linnaeus, 1758) is composed of at least two different species, indicating that the species diversity within Bursidae Thiele, 1925 might be underestimated. The present study contributes to the understanding of the Tonnoidean systematics, and it could provide important information for the revision of Tonnoidean systematics in the future.

A pH-Responsive DNA Tetrahedron/Methotrexate Drug Delivery System Used for Rheumatoid Arthritis Treatment.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder that leads to progressive and aggressive joint inflammation. The disease process is characterized by the activation of macrophages, which then release tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß), accelerating tissue damage. Tackling tissue damage is a crucial target in the treatment of RA. In this study, a macrophage-targeted and pH-response DNA tetrahedron/methotrexate drug delivery system was constructed by loading methotrexate (MTX) onto a DNA duplex. MTX was used as a drug model, and a pH-response DNA tetrahedron (TET) was used as the drug carrier, which was modified with hyaluronic acid (HA) to target macrophages. The aim of this study was to evaluate the potential of TET as an effective drug carrier for the treatment of RA. On this basis, we successfully prepared TETs loaded with MTX, and in vitro assays showed that the MTX-TET treatment could successfully target macrophages and induce macrophages to polarize to M1 phenotype. At the same time, we also injected MTX-TET intravenously into collagen-induced arthritis (CIA) model mice, and the redness and swelling of the paws of mice were significantly alleviated, proving that the MTX-TET could successfully target inflamed joints and release MTX to treat joint swelling. In addition, the histochemical results showed that the MTX-TET could reduce synovitis and joint swelling in CIA mice, reduce the level of inflammatory factors in vivo, and improve the disease status while maintaining a good biosafety profile. This study showed that the MTX-TET treatment has beneficial therapeutic effects on RA, providing a new strategy for the clinical treatment of RA.

Factors associated with fertility intention among women with systemic lupus erythematosus in China: A cross-sectional study.

OBJECTIVE: This study aims to explore the status and influencing factors of fertility intention in women of childbearing age with systemic lupus erythematosus (SLE). METHODS: A total of 158 SLE patients admitted to the Affiliated Hospital of Nantong University from February 2021 to February 2022 were selected for a cross-sectional study. The dependent variable in this study was the fertility intention of lupus women of childbearing age, so the questionnaire was selected: "In view of your disease, do you plan to have children? Yes/no" as the measurement statement. Lupus patients were divided into fertility intention groups and non-fertility intention groups. The questionnaire survey comprises following scales: Hospital Anxiety and Depression Scale (HADS), Multidimensional Fatigue Inventory (MFI-20), Female Sexual Distress Scale-Revised (FSDS-R), and others. Independent t-test, one-way ANOVA, Mann-Whitney U test, and binary logistic regression were used for analysis. RESULTS: The results showed that 20.9% of lupus patients in this study had a fertility intention. The fertility intention was associated with age, reproductive history, reproductive concerns, sexual distress, fatigue, family function, social support, depression, and sleep. Binary logistic regression showed that physical fatigue (OR 3.56, 95% CI 1.048-12.07) and personal health (OR 2.50, 95% CI 1.065-5.853) had significant predictors of fertility intention. CONCLUSION: Our study identified a lower fertility intention in SLE patients who had reproductive concerns, sexual distress, family dysfunction, and fatigue. We encourage healthcare institutions to provide counseling services to all the SLE patients who have fertility intention and focus more on those who have requirements for fertility.

Placenta mesenchymal stem cell-derived extracellular vesicles alleviate liver fibrosis by inactivating hepatic stellate cells through a miR-378c/SKP2 axis.

BACKGROUND: Extracellular vesicles derived from mesenchymal stem/stromal cells (MSCs) have shown therapeutic effects on liver fibrosis. This study aimed to evaluate the effects of extracellular vesicles from placenta-derived MSCs (Pd-MSCs-EVs) on liver fibrosis at 3D/2D levels and explore the potential mechanisms. METHODS: The multicellular liver organoids, consisting of hepatocytes, hepatic stellate cells (HSCs), Kupffer cells, and liver sinusoidal endothelial cells, were observed for growth status, morphological changes, and metabolism. Human transformation growth factor- beta 1 (TGF-ß1) was used to induce fibrosis at optimal concentration. The anti-fibrosis effects of Pd-MSCs-EVs were evaluated in liver organoids and HSCs models. Anti-fibrotic content of Pd-MSCs-EVs was identified by multiple experimental validations. RESULTS: TGF-ß1 induced fibrosis in liver organoids, while Pd-MSCs-EVs significantly alleviated fibrotic phenotypes. Following serial verifications, miR-378c was identified as a potential key anti-fibrosis content. In contrast, miR-378c depletion decreased the anti-fibrotic effects of Pd-MSCs-EVs. Additionally, Pd-MSCs-EVs administration repressed TGF-ß1-mediated HSCs activation at 2D or 3D levels. Mechanistically, exosomal miR-378c inactivated HSCs by inhibiting epithelial-mesenchymal transition (EMT) through stabilizing E-cadherin via targeting its E3 ubiquitin ligase S-Phase Kinase Associated Protein 2 (SKP2). CONCLUSION: Pd-MSCs-EVs ameliorated TGF-ß1-induced fibrosis by deactivating HSCs in a miR-378c/SKP2-dependent manner, which may be an efficient therapeutic candidate for liver fibrosis.