Mesenchymal stem cell-derived exosomes (MSC-Exos) have shown considerable therapeutic potential in regenerative medicine. However, the biosafety profile of these exosomes following repeated administration has not been adequately characterised, and this knowledge gap continues to hinder clinical translation. Human umbilical cord mesenchymal stem cell-derived exosomes (hucMSC-Exos) were produced on a xeno-free platform by replacing fetal bovine serum (FBS) with human platelet lysate (hPL). A relatively comprehensive and integrated repeated-dose preclinical biosafety profile assessment was then conducted using polyethylene glycol (PEG)-Liposomes as reference nanovesicles. The assessment included pharmacokinetic and distribution analyses using DiD labelling, haematological cytology testing, quantitative measurement of inflammatory cytokines and chemokines, histopathological scoring, and RNA sequencing. In this study, the safety assessment revealed that: (1) hucMSC-Exos primarily accumulated in the liver and spleen and exhibited an approximately 4-h circulation time; (2) repeated intravenous administration of hucMSC-Exos for 30 days did not result in overt systemic inflammation, and the evaluated haematological and biochemical parameters remained within the normal range; (3) RNA sequencing showed that hucMSC-Exos avoided immune pathway activation (e.g., IL-17/antigen presentation) triggered by PEG-Liposomes, instead enriching complement-coagulation cascades (e.g., C1qc, C6 upregulation) and metabolic pathways (steroidogenesis, retinol metabolism). Together, these findings suggest that hucMSC-Exos have a favourable biosafety profile in a murine model and support further preclinical evaluation for regenerative medicine applications. This study suggests that repeated intravenous administration of hucMSC-Exos confers a relatively favourable biosafety profile in a murine model and provides preliminary preclinical evidence for further investigation towards clinical translation.

Acute kidney injury (AKI) remains a major clinical challenge due to the lack of effective interventions. While mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) show therapeutic promise for AKI, their exact mechanisms are largely to be understood. Human umbilical cord-derived MSC-EVs were isolated, characterized, and tested in a murine bilateral renal ischemia reperfusion injury (bIRI) model and in hypoxia/reoxygenation (H/R) treated tubular epithelial cells in vitro. Integrated transcriptomic, miRNA, and biochemical analyses were performed to elucidate the metabolic pathways and molecular mechanisms underlying the renoprotective effects of MSC-EVs. MSC-EVs preferentially targeted injured kidneys and significantly improved renal function, ameliorated tubular injury, and suppressed inflammation in IRI-AKI. RNA sequencing and targeted metabolomics revealed substantial dysregulation of steroid metabolism after IRI, marked by activation of the cholesterol 25-hydroxylase (CH25H)/25-hydroxycholesterol (25HC) axis. Importantly, accumulated 25HC induced lipid peroxidation and ferroptosis in tubular epithelial cells. MSC-EVs treatment reversed these pathological changes by downregulating CH25H, lowering 25HC levels, and restoring redox homeostasis. miRNA profiling further identified miR-26b-5p as a key MSC-EVs cargo that directly targets the 3′UTR of CH25H mRNA to repress its expression. Notably, inhibiting miR-26b-5p within EVs abrogated their ability to suppress CH25H/25HC-driven ferroptosis, thereby demonstrating its essential role in the metabolic and cytoprotective actions of MSC-EVs. Our findings unveil the CH25H/25HC axis as a key metabolic checkpoint governing tubular ferroptosis in ischemic AKI. MSC-EVs deliver miR-26b-5p to suppress this axis, thereby rectifying oxysterol metabolism and preventing ferroptosis.

Key PointsIntegrated single-cell spatial transcriptomics and metabolomics identified cholesterol reprogramming as a driver of ferroptosis in proximal tubules.Targeting the Cyp7b1/27-hydroxycholesterol axis efficiently alleviated ferroptosis-induced proximal tubule injury during ischemic AKI.BackgroundCell death plays a pivotal role in ischemic AKI, with metabolic dysfunction emerging as a key contributor. However, the mechanism by which metabolism imbalance initiates renal tubular cell death is poorly understood.MethodsWe combined single-cell spatial transcriptomics and metabolomics to characterize the function and metabolites of murine renal proximal cell subpopulations during ischemic AKI to CKD transition.ResultsFerroptosis was identified as the predominant mode of cell death in severely injured proximal straight tubules after AKI. Additional investigation revealed a critical deficiency in Cyp7b1, an enzyme responsible for metabolizing 27-hydroxycholesterol (27-HC) into 7 alpha,27-dihydroxycholesterol, resulting in substantial 27-HC accumulation in proximal tubular cells during the early phase of ischemic AKI. Mechanistically, 27-HC acts as an endogenous ligand for estrogen receptor alpha, inducing downstream Hmox1 activation and thereby potentiating ferroptosis susceptibility in proximal tubular cells. Notably, adeno-associated virus-mediated Cyp7b1 overexpression in a murine ischemia-reperfusion injury model attenuated ferroptosis by enhancing 27-HC degradation, effectively mitigating ischemic AKI progression. These findings underscore the pivotal role of the Cyp7b1/27-HC axis in this pathologic context.ConclusionsOur study delineated a unique mechanism of Cyp7b1/27-HC axis in proximal tubular cell ferroptosis in early AKI.

AIM:Mitochondrial dysfunction, a characteristic pathological feature of renal Ischemic/reperfusion injury (I/RI), predisposes tubular epithelial cells to maintain an inflammatory microenvironment, however, the exact mechanisms through which mitochondrial dysfunction modulates the induction of tubular injury remains incompletely understood. METHODS:ESI-QTRAP-MS/MS approach was used to characterize the targeted metabolic profiling of kidney with I/RI. Tubule injury, mitochondrial dysfunction, and fumarate level were evaluated using qPCR, transmission electron microscopy, ELISA, and immunohistochemistry. RESULTS:We demonstrated that tubule injury occurred at the phase of reperfusion in murine model of I/RI. Meanwhile, enhanced glycolysis and mitochondrial dysfunction were found to be associated with tubule injury. Further, we found that tubular fumarate, which resulted from fumarate hydratase deficiency and released from dysfunctional mitochondria, promoted tubular injury. Mechanistically, fumarate induced tubular injury by causing disturbance of glutathione (GSH) hemostasis. Suppression of GSH with buthionine sulphoximine administration could deteriorate the fumarate inhibition-mediated tubule injury recovery. Reactive oxygen species/NF-κB signaling activation played a vital role in fumarate-mediated tubule injury. CONCLUSION:Our studies demonstrated that the mitochondrial-derived fumarate promotes tubular epithelial cell injury in renal I/RI. Blockade of fumarate-mediated ROS/NF-κB signaling activation may serve as a novel therapeutic approach to ameliorate hypoxic tubule injury.

The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) is a critical clinical issue. Although previous studies have suggested macrophages as a key player in promoting inflammation and fibrosis during this transition, the heterogeneity and dynamic characterization of macrophages are still poorly understood. Here, we used integrated single-cell RNA sequencing and spatial transcriptomic to characterize the spatiotemporal heterogeneity of macrophages in murine AKI-to-CKD model of unilateral ischemia-reperfusion injury. A marked increase in macrophage infiltration at day 1 was followed by a second peak at day 14 post AKI. Spatiotemporal profiling revealed that injured tubules and macrophages co-localized early after AKI, whereas in late chronic stages had spatial proximity to fibroblasts. Further pseudotime analysis revealed two distinct lineages of macrophages in this transition: renal resident macrophages differentiated into the pro-repair subsets, whereas infiltrating monocyte-derived macrophages contributed to chronic inflammation and fibrosis. A novel macrophage subset, extracellular matrix remodeling-associated macrophages (EAMs) originating from monocytes, linked to renal fibrogenesis and communicated with fibroblasts via insulin-like growth factors (IGF) signalling. In sum, our study identified the spatiotemporal dynamics of macrophage heterogeneity with a unique subset of EAMs in AKI-to-CKD transition, which could be a potential therapeutic target for preventing CKD development.

Acute kidney injury (AKI) transformed to chronic kidney disease (CKD) is a critical clinical issue characterized by tubulointerstitial inflammation (TII) and fibrosis. However, the exact mechanism remains largely unclear. In this study, we used single-cell RNA sequencing (scRNA-seq) to obtain a high-resolution profile of T cells in AKI to CKD transition with a mice model of unilateral ischemia-reperfusion injury (uIRI). We found that T cells accumulated increasingly with the progression of AKI to CKD, which was categorized into 9 clusters. A notably increased proportion of CD8 T cells via self-proliferation occurred in the early stage of AKI was identified. Further study revealed that the CD8 T cells were recruited through CXCL16-CXCR6 pathway mediated by macrophages. Notably, CD8 T cells induced endothelial cell apoptosis via Fas ligand-Fas signaling. Consistently, increased CD8 T cell infiltration accompanied with peritubular capillaries (PTCs) rarefaction was observed in uIRI mice. More impressively, the loss of PTCs and renal fibrosis was remarkably ameliorated after the elimination of CD8 T cells. In summary, our study provides a novel insight into the role of CD8 T cells in the transition from AKI to CKD via induction of PTCs rarefaction, which could suggest a promising therapeutic target for AKI.

The transcription factor hypoxia-inducible factor-1α (HIF-1α), as a master regulator of adaptive responses to hypoxia, possesses two transcriptional activation domains [TAD, N-terminal (NTAD), and C-terminal (CTAD)]. Although the roles of HIF-1α NTAD in kidney diseases have been recognized, the exact effects of HIF-1α CTAD in kidney diseases are poorly understood. Here, two independent mouse models of hypoxia-induced kidney injury were established using HIF-1α CTAD knockout (HIF-1α CTAD-/-) mice. Furthermore, hexokinase 2 (HK2) and mitophagy pathway are modulated using genetic and pharmacological methods, respectively. We demonstrated that HIF-1α CTAD-/- aggravated kidney injury in two independent mouse models of hypoxia-induced kidney injury, including ischemia/reperfusion-induced kidney injury and unilateral ureteral obstruction-induced nephropathy. Mechanistically, we found that HIF-1α CTAD could transcriptionally regulate HK2 and subsequently ameliorate hypoxia-induced tubule injury. Furthermore, it was found that HK2 deficiency contributed to severe renal injury through mitophagy inhibition, while mitophagy activation using urolithin A could significantly protect against hypoxia-induced kidney injury in HIF-1α C-TAD-/- mice. Our findings suggested that the HIF-1α CTAD-HK2 pathway represents a novel mechanism of kidney response to hypoxia, which provides a promising therapeutic strategy for hypoxia-induced kidney injury.

LncRNA, a class of non-coding RNA, is involved in regulating various life activities. However, the function and molecular mechanism of lncRNA involved in regulating innate immunity in response to Candida albicans, a kind of major opportunistic fungal pathogens, have not been elaborated in detail. Here, based on high-throughput sequencing and qRT-PCR analysis, we used Caenorhabditis elegans as a surrogate model for innate immunity research to screen out 13 dysregulated lncRNAs, including 12 down-regulated lncRNAs and 1 up-regulated lncRNA in response to C. albicans SC5314 infection. Among the 13 dysregulated lncRNAs, 4 lncRNAs of anr-41 , linc-18 , XLOC_003580 and XLOC_020760 were identified to be involved in regulating C. albicans -induced innate immunity by analyzing longevity, antimicrobial peptides and CFU of dysregulated lncRNA RNAi knockdown nematodes. RNAi knockdown of anr-41 , XLOC_003580 or XLOC_020760 induced susceptibility to C. albicans by suppressing the innate immunity. In contrast, RNAi knockdown of linc-18 induced resistance to C. albicans by activating the innate immune system. We further found that anr-41 mainly played a role in regulating innate immunity in the intestine, and intestinal anr-41 acted upstream of pmk-1 in the p38 MAPK signaling pathway to regulate innate immunity. In addition, intestinal anr-41 also acted upstream of daf-16 in insulin signaling pathway by further regulating fat-6 to participate in innate immune response. This study provides a reference for understanding how lncRNAs act in innate immunity, regulate immune signaling pathways, and participate to host defense responses.

Metabolic homeostasis is coordinated through a robust network of signaling pathways acting across all tissues. A key part of this network is insulin-like signaling, which is fundamental for surviving glucose stress. Here, we show that Caenorhabditis elegans fed excess dietary glucose reduce insulin-1 (INS-1) expression specifically in the BAG glutamatergic sensory neurons. We demonstrate that INS-1 expression in the BAG neurons is directly controlled by the transcription factor ETS-5, which is also down-regulated by glucose. We further find that INS-1 acts exclusively from the BAG neurons, and not other INS-1-expressing neurons, to systemically inhibit fat storage via the insulin-like receptor DAF-2. Together, these findings reveal an intertissue regulatory pathway where regulation of insulin expression in a specific neuron controls systemic metabolism in response to excess dietary glucose.

Significance: The disturbance of the hypoxia response system is closely related to human diseases, because it is essential for the maintenance of homeostasis. Given the significant role of the hypoxia response system in human health, therapeutic applications targeting prolyl hydroxylase-hypoxia-inducible factor (HIF) signaling have been attempted. Thus, systemically reviewing the hypoxia response-based therapeutic strategies is of great significance. Recent Advances: Disturbance of the hypoxia response is a characteristic feature of various diseases. Targeting the hypoxia response system is, thus, a promising therapeutic strategy. Interestingly, several compounds and drugs are currently under clinical trials, and some have already been approved for use in the treatment of certain human diseases. Critical Issues: We summarize the molecular mechanisms of the hypoxia response system and address the potential therapeutic implications in kidney diseases. Given that the effects of hypoxia response in kidney diseases are likely to depend on the pathological context, specific cell types, and the differences in the activation pattern of HIF isoforms, the precise application is critical for the treatment of kidney diseases. Although HIF-PHIs (HIF-PHD inhibitors) have been proven to be effective and well tolerated in chronic kidney disease patients with anemia, the potential on-target consequence of HIF activation and some outstanding questions warrant further consideration. Future Direction: The mechanism of the hypoxia response system disturbance remains unclear. Elucidation of the molecular mechanism of hypoxia response and its precise effects on kidney diseases warrants clarification. Considering the complexity of the hypoxia response system and multiple biological processes controlled by HIF signaling, the development of more specific inhibitors is highly warranted. Antioxid. Redox Signal. 37, 936-955.

In this study, the association of expressional alterations in neuronal G protein-coupled receptors (GPCRs) with induction of protective response to polystyrene nanoparticles (PS-NPs) was investigated in Caenorhabditis elegans. On the basis of both phenotypic analysis and expression levels, the alterations in expressions of NPR-1, NPR-4, NPR-8, NPR-9, NPR-12, DCAR-1, GTR-1, DOP-2, SER-4, and DAF-37 in neuronal cells mediated the protective response to PS-NPs exposure. In neuronal cells, NPR-9, NPR-12, DCAR-1, and GTR-1 controlled the PS-NPs toxicity by activating or inhibiting JNK-1/JNK MAPK signaling. Neuronal NPR-8, NPR-9, DCAR-1, DOP-2, and DAF-37 controlled the PS-NPs toxicity by activating or inhibiting MPK-1/ERK MAPK signaling. Neuronal NPR-4, NPR-8, NPR-9, NPR-12, GTR-1, DOP-2, and DAF-37 controlled the PS-NPs toxicity by activating or inhibiting DBL-1/TGF-β signaling. Neuronal NPR-1, NPR-4, NPR-12, and GTR-1 controlled the PS-NPs toxicity by activating or inhibiting DAF-7/TGF-β signaling. Our data provides an important neuronal basis for induction of protective response to PS-NPs in C. elegans.

Mesenchymal stem cells-derived exosomes (MSC-exos) have attracted great interest as a cell-free therapy for acute kidney injury (AKI). However, the in vivo biodistribution of MSC-exos in ischemic AKI has not been established. The potential of MSC-exos in promoting tubular repair and the underlying mechanisms remain largely unknown. Methods: Transmission electron microscopy, nanoparticle tracking analysis, and western blotting were used to characterize the properties of human umbilical cord mesenchymal stem cells (hucMSCs) derived exosomes. The biodistribution of MSC-exos in murine ischemia/reperfusion (I/R) induced AKI was imaged by the IVIS spectrum imaging system. The therapeutic efficacy of MSC-exos was investigated in renal I/R injury. The cell cycle arrest, proliferation and apoptosis of tubular epithelial cells (TECs) were evaluated in vivo and in HK-2 cells. The exosomal miRNAs of MSC-exos were profiled by high-throughput miRNA sequencing. One of the most enriched miRNA in MSC-exos was knockdown by transfecting miRNA inhibitor to hucMSCs. Then we investigated whether this candidate miRNA was involved in MSC-exos-mediated tubular repair. Results: Ex vivo imaging showed that MSC-exos was efficiently homing to the ischemic kidney and predominantly accumulated in proximal tubules by virtue of the VLA-4 and LFA-1 on MSC-exos surface. MSC-exos alleviated murine ischemic AKI and decreased the renal tubules injury in a dose-dependent manner. Furthermore, MSC-exos significantly attenuated the cell cycle arrest and apoptosis of TECs both in vivo and in vitro. Mechanistically, miR-125b-5p, which was highly enriched in MSC-exos, repressed the protein expression of p53 in TECs, leading to not only the up-regulation of CDK1 and Cyclin B1 to rescue G2/M arrest, but also the modulation of Bcl-2 and Bax to inhibit TEC apoptosis. Finally, inhibiting miR-125b-5p could mitigate the protective effects of MSC-exos in I/R mice. Conclusion: MSC-exos exhibit preferential tropism to injured kidney and localize to proximal tubules in ischemic AKI. We demonstrate that MSC-exos ameliorate ischemic AKI and promote tubular repair by targeting the cell cycle arrest and apoptosis of TECs through miR-125b-5p/p53 pathway. This study provides a novel insight into the role of MSC-exos in renal tubule repair and highlights the potential of MSC-exos as a promising therapeutic strategy for AKI.

After their uptake, environmental toxicants may cause toxicity to organisms by activating or inhibiting certain G protein-coupled receptors (GPCRs). Nevertheless, the roles of GPCRs in mediating the response of organisms to nanoplastic exposure are still largely unclear. We here employed Caenorhabditis elegans as an animal model and focused on the identification of intestinal GPCRs required for control of the toxicity of nanopolystyrene (100 nm). Based on gene expression and functional analysis, we identified 13 GPCRs (PAQR-2, NPR-1, DOP-2, CED-1, NPR-9, FSHR-1, DCAR-1, NPR-12, NPR-4, SER-4, DAF-37, GTR-1, and NPR-8) involved in the control of nanopolystyrene toxicity. Moreover, among these identified GPCRs, only PAQR-2 and FSHR-1 acted in the intestine to regulate nanopolystyrene toxicity. PAQR-2 and FSHR-1 regulated nanopolystyrene toxicity in the intestine by at least modulating the activities of insulin, Wnt, p38 mitogen-activated protein kinase (MAPK), ELT-2, and/or mitochondrial unfolded protein response (mt UPR) signaling pathways. Therefore, our results provide a crucial basis for understanding the functions of GPCRs in the intestine to mediate the response to nanoplastic exposure in organisms.

Tubules injury and immune cell activation are the common pathogenic mechanisms in acute kidney injury (AKI). However, the exact modes of immune cell activation following tubule damage are not fully understood. Here we uncovered that the release of cytoplasmic spliceosome associated protein 130 (SAP130) from the damaged tubular cells mediated necroinflammation by triggering macrophage activation via miRNA-219c(miR-219c)/Mincle-dependent mechanism in unilateral ureteral obstruction (UUO) and cisplatin-induced AKI mouse models, and in patients with acute tubule necrosis (ATN). In the AKI kidneys, we found that Mincle expression was tightly correlated to the necrotic tubular epithelial cells (TECs) with higher expression of SAP130, a damaged associated molecule pattern (DAMP), suggesting that SAP130 released from damaged tubular cells may trigger macrophage activation and necroinflammation. This was confirmed in vivo in which administration of SAP130-rich supernatant from dead TECs or recombinant SAP130 promoted Mincle expression and macrophage accumulation which became worsen with profound tubulointerstitial inflammation in LPS-primed Mincle WT mice but not in Mincle deficient mice. Further studies identified that Mincle was negatively regulated via miR-219c-3p in macrophages as miR-219c-3p bound Mincle 3'-UTR to inhibit Mincle translation. Besides, lentivirus-mediated renal miR-219c-3p overexpression blunted Mincle and proinflammatory cytokine expression as well as macrophage infiltration in the inflamed kidney of UUO mice. In conclusion, SAP130 is released by damaged tubules which elicit Mincle activation on macrophages and renal necroinflammation via the miR-219c-3p-dependent mechanism. Results from this study suggest that targeting miR-219c-3p/Mincle signaling may represent a novel therapy for AKI.

The deposition of a certain amount of nanopolystyrene (NPS) can be observed in the gonad of Caenorhabditis elegans. However, we still know little about the response of germline towards NPS exposure. In the germline of C. elegans, NPS (1-1000 μg L-1) increased the expression levels of two G protein-coupled receptors (GPCRs), namely PAQR-2 and CED-1. Moreover, susceptibility to NPS toxicity was observed in ced-1(RNAi) worms, which suggested that the protective response of germline was mediated by GPCR CED-1. In the germline, five proteins (CED-10, VPS-34, SNX-1, RAB-7, and RAB-14) functioned as downstream targets of GPCR CED-1 in controlling NPS toxicity. Furthermore, these five targets in the germline regulated NPS toxicity by affecting the activities of p38 MAPK and insulin signaling pathways in intestinal cells. Therefore, we raised a GPCR CED-1-mediated signaling cascade in the germline in response to NPS exposure, which is helpful for understanding the molecular basis of the germline in response to NPS exposure.

The aim of this study was to identify Gα proteins mediating function of neuronal G protein-coupled receptors (GPCRs) in controlling the response to polystyrene nanoparticles (PS-NPs). Caenorhabditis elegans was used as an animal model, and both gene expression and functional analysis were performed to identify the Gα proteins in controlling PS-NPs toxicity. In nematodes, exposure to PS-NPs (1–100 μg/L) significantly altered transcriptional expressions of some neuronal Gα genes, including gpa-5, gpa-10, gpa-11, gpa-15 gsa-1, egl-30, and goa-1. Among these 7 Gα genes, only neuronal RNAi knockdown of gsa-1, gpa-10, and goa-1 affected toxicity of PS-NPs in inducing ROS production and in decreasing locomotion behavior. Some neuronal GPCRs (such as GTR-1, DCAR-1, DOP-2, NPR-8, NPR-12, NPR-9, and DAF-37) functioned upstream of GOA-1, some neuronal GPCRs (such as DCAR-1, DOP-2, NPR-9, NPR-8, and DAF-37) functioned upstream of GSA-1, and some neuronal GPCRs (such as DOP-2, NPR-8, DAF-37, and DCAR-1) functioned upstream of GPA-10 to regulate the toxicity of PS-NPs. Moreover, GOA-1 acted upstream of MPK-1/ERK MAPK, JNK-1/JNK MAPK, DBL-1/TGF-β, and DAF-7/ TGF-β, GSA-1 functioned upstream of MPK-1/ERK MAPK, JNK-1/JNK MAPK, and DBL-1/TGF-β, and GPA-10 functioned upstream of GLB-1/Globin and DBL-1/TGF-β to control the PS-NPs toxicity. Therefore, neuronal Gα proteins of GOA-1, GSA-1, and GPA-10 functioned to transduce signals of multiple GPCRs to different downstream signaling pathways during the control of PS-NPs toxicity in nematodes. Our results provide clues for understanding the important function of GPCRs-Gα signaling cascade in the neurons in controlling response to nanoplastics in organisms.

Background AKI is a significant public health problem with high morbidity and mortality. Unfortunately, no definitive treatment is available for AKI. RNA interference (RNAi) provides a new and potent method for gene therapy to tackle this issue. Methods We engineered red blood cell-derived extracellular vesicles (REVs) with targeting peptides and therapeutic siRNAs to treat experimental AKI in a mouse model after renal ischemia/reperfusion (I/R) injury and unilateral ureteral obstruction (UUO). Phage display identified peptides that bind to the kidney injury molecule-1 (Kim-1). RNA-sequencing (RNA-seq) characterized the transcriptome of ischemic kidney to explore potential therapeutic targets. Results REVs targeted with Kim-1-binding LTH peptide(REVLTH) efficiently homed to and accumulated at the injured tubules in kidney after I/R injury. We identified transcription factors P65 and Snai1 that drive inflammation and fibrosis as potential therapeutic targets. Taking advantage of the established REVLTH, siRNAs targeting P65 and Snai1 were efficiently delivered to ischemic kidney and consequently blocked the expression of P-p65 and Snai1 in tubules. Moreover, dual suppression of P65 and Snai1 significantly improved I/R- and UUO-induced kidney injury by alleviating tubulointerstitial inflammation and fibrosis, and potently abrogated the transition to CKD. Conclusions A red blood cell-derived extracellular vesicle platform targeted Kim-1 in acutely injured mouse kidney and delivered siRNAs for transcription factors P65 and Snai1, alleviating inflammation and fibrosis in the tubules.

The increased application of graphene oxide (GO), a new carbon-based engineered nanomaterial, has generated a potential toxicity in humans and the environment. Previous studies have identified some dysregulated microRNAs (miRNAs), such as up-regulated mir-235, in organisms exposed to GO. However, the detailed mechanisms of the dysregulation of miRNA underlying GO toxicity are still largely elusive. In this study, we employed Caenorhabditis elegans as an in vivo model to investigate the biological function and molecular basis of mir-235 in the regulation of GO toxicity. After low concentration GO exposure, mir-235 (n4504) mutant nematodes were sensitive to GO toxicity, implying that mir-235 mediates a protection mechanism against GO toxicity. Tissue-specific assays suggested that mir-235 expressed in intestine is required for suppressing the GO toxicity in C. elegans. daf-12, a gene encoding a member of the steroid hormone receptor superfamily, acts as a target gene of mir-235 in the nematode intestine in response to GO treatment, and RNAi knockdown of daf-12 suppressed the sensitivity of mir-235(n4503) to GO toxicity. Further genetic analysis showed that DAF-12 acted in the upstream of DAF-16 in insulin/IGF-1 signaling pathway and PMK-1 in p38 MAPK signaling pathway in parallel to regulate GO toxicity. Altogether, our results revealed that mir-235 may activate a protective mechanism against GO toxicity by suppressing the DAF-12-DAF-16 and DAF-12-PMK-1 signaling cascade in nematodes, which provides an important molecular basis for the in vivo toxicity of GO at the miRNA level.

Our results highlight the crucial role of intestinal Gα subunits and their downstream signaling pathways in response to nanoplastics.

Arsenic (As) is a toxic element that is highly abundant in the environment. However, there has not been sufficient research into the mechanisms of arsenic-induced transgenerational effects. In biomedical and environmental toxicology research field, C. elegans are often used as the ideal model. In this study, F0 generation animals were cultured with arsenite, while subsequent generations animals (F1 - F6) were cultured in the absence of arsenic. Experiments were performed to examine the transgenerational glycometabolism and the associated mechanisms in all seven generations (F0 - F6) of C. elegans. Results show that arsenite exposure increased total glucose content but reduced glucose metabolites in F0 generation C. elegans. The total glucose content was also elevated in subsequent generations probably due to transgenerational downregulation of fgt-1. In addition, arsenite exposure induced transgenerational downregulation of histone demethyltransferase spr-5 and elevated histone dimethylation in F0 generation. This study highlights that single generation exposure to arsenite causes transgenerational changes in glycometabolism in C. elegans, which may be caused by downregulation of spr-5 and elevation of H3K4me2.