KMT2D-mediated H3K4me1 recruits YBX1 to facilitate triple-negative breast cancer progression through epigenetic activation of c-Myc.

BACKGROUND: Lysine methyltransferase 2D (KMT2D) mediates mono-methylation of histone H3 lysine 4 (H3K4me1) in mammals. H3K4me1 mark is involved in establishing an active chromatin structure to promote gene transcription. However, the precise molecular mechanism underlying the KMT2D-mediated H3K4me1 mark modulates gene expression in triple-negative breast cancer (TNBC) progression is unresolved. METHODS AND RESULTS: We recognized Y-box-binding protein 1 (YBX1) as a "reader" of the H3K4me1 mark, and a point mutation of YBX1 (E121A) disrupted this interaction. We found that KMT2D and YBX1 cooperatively promoted cell growth and metastasis of TNBC cells in vitro and in vivo. The expression levels of KMT2D and YBX1 were both upregulated in tumour tissues and correlated with poor prognosis for breast cancer patients. Combined analyses of ChIP-seq and RNA-seq data indicated that YBX1 was co-localized with KMT2D-mediated H3K4me1 in the promoter regions of c-Myc and SENP1, thereby activating their expressions in TNBC cells. Moreover, we demonstrated that YBX1 activated the expressions of c-Myc and SENP1 in a KMT2D-dependent manner. CONCLUSION: Our results suggest that KMT2D-mediated H3K4me1 recruits YBX1 to facilitate TNBC progression through epigenetic activation of c-Myc and SENP1. These results together unveil a crucial interplay between histone mark and gene regulation in TNBC progression, thus providing novel insights into targeting the KMT2D-H3K4me1-YBX1 axis for TNBC treatment. HIGHLIGHTS: YBX1 is a KMT2D-mediated H3K4me1-binding effector protein and mutation of YBX1 (E121A) disrupts its binding to H3K4me1. KMT2D and YBX1 cooperatively promote TNBC proliferation and metastasis by activating c-Myc and SENP1 expression in vitro and in vivo. YBX1 is colocalized with H3K4me1 in the c-Myc and SENP1 promoter regions in TNBC cells and increased YBX1 expression predicts a poor prognosis in breast cancer patients.

Unveiling a novel entry gate: Insect foregut as an alternative infection route for fungal entomopathogens.

Insects and their natural microbial pathogens are intertwined in constant arms races, with pathogens continually seeking entry into susceptible hosts through distinct routes. Entomopathogenic fungi are primarily believed to infect host insects through external cuticle penetration. Here, we report a new variety, Beauveria bassiana var. majus (Bbm), that can infect insects through the previously unrecognized foregut. Dual routes of infection significantly accelerate insect mortality. The pH-responsive transcription factor PacC in Bbm exhibits rapid upregulation and efficient proteolytic processing via PalC for alkaline adaptation in the foregut. Expression of PalC is regulated by the adjacent downstream gene Aia. Compared to non-enteropathogenic strains such as ARSEF252, Aia in Bbm lacks a 249-bp fragment, resulting in its enhanced alkaline-induced expression. This induction promotes PalC upregulation and facilitates PacC activation. Expressing the active form of BbmPacC in ARSEF252 enables intestinal infection. This study uncovers the pH-responsive Aia-PalC-PacC cascade enhancing fungal alkaline tolerance for intestinal infection, laying the foundation for developing a new generation of fungal insecticides to control destructive insect pests.

Efficacy of Lenvatinib Combined with Anti-PD-1 Antibodies plus Transcatheter Arterial Chemoembolization for Hepatocellular Carcinoma with Portal Vein Tumor Thrombus: A Retrospective, Multicenter Study.

Purpose: The prognosis of patients with hepatocellular carcinoma (HCC) and portal vein tumor thrombus (PVTT) is extremely poor, and systemic therapy is currently the mainstream treatment. This study aimed to assess the efficacy and safety of lenvatinib combined with anti-PD-1 antibodies and transcatheter arterial chemoembolization (triple therapy) in patients with HCC and PVTT. Materials and Methods: This retrospective multicenter study included patients with HCC and PVTT who received triple therapy, were aged between 18 and 75 years, classified as Child Pugh class A or B, and had at least one measurable lesion. The overall survival (OS), progression-free survival (PFS), objective response rates, and disease control rates were analyzed to assess efficacy. Treatment-related adverse events were analyzed to assess safety profiles. Results: During a median follow-up of 11.23 months (range, 3.07-34.37 months), the median OS was greater than 24 months, and median PFS was 12.53 months. The two-year OS rate was 54.9%. The objective response rate and disease control rate were 69.8% (74/106) and 84.0% (89/106), respectively; 20.8% (22/106) of the patients experienced grade 3/4 treatment-related adverse events and no treatment-related deaths occurred. The conversion rate to liver resection was 31.1% (33/106), with manageable postoperative complications. The median OS was not reached in the surgery group, but was 19.08 months in the non-surgery group. The median PFS in the surgery and non-surgery groups were 20.50 and 9.00 months, respectively. Conclusion: Triple therapy showed promising survival benefits and high response rates in patients with HCC and PVTT, with manageable adverse effects.

Rapid identification of lactic acid bacteria at species/subspecies level via ensemble learning of Ramanomes.

Rapid and accurate identification of lactic acid bacteria (LAB) species would greatly improve the screening rate for functional LAB. Although many conventional and molecular methods have proven efficient and reliable, LAB identification using these methods has generally been slow and tedious. Single-cell Raman spectroscopy (SCRS) provides the phenotypic profile of a single cell and can be performed by Raman spectroscopy (which directly detects vibrations of chemical bonds through inelastic scattering by a laser light) using an individual live cell. Recently, owing to its affordability, non-invasiveness, and label-free features, the Ramanome has emerged as a potential technique for fast bacterial detection. Here, we established a reference Ramanome database consisting of SCRS data from 1,650 cells from nine LAB species/subspecies and conducted further analysis using machine learning approaches, which have high efficiency and accuracy. We chose the ensemble meta-classifier (EMC), which is suitable for solving multi-classification problems, to perform in-depth mining and analysis of the Ramanome data. To optimize the accuracy and efficiency of the machine learning algorithm, we compared nine classifiers: LDA, SVM, RF, XGBoost, KNN, PLS-DA, CNN, LSTM, and EMC. EMC achieved the highest average prediction accuracy of 97.3% for recognizing LAB at the species/subspecies level. In summary, Ramanomes, with the integration of EMC, have promising potential for fast LAB species/subspecies identification in laboratories and may thus be further developed and sharpened for the direct identification and prediction of LAB species from fermented food.

A retrospective study of occlusal reconstruction in patients with old jaw fractures and dentition defects.

PURPOSE: This study evaluated the methods and clinical effects of multidisciplinary collaborative treatment for occlusal reconstruction in patients with old jaw fractures and dentition defects. METHODS: Patients with old jaw fractures and dentition defects who underwent occlusal reconstruction at the Third Affiliated Hospital of Air Force Military Medical University from January 2018 to December 2022 were enrolled. Clinical treatment was classified into 3 phases. In phase I, techniques such as orthognathic surgery, microsurgery, and distraction osteogenesis were employed to reconstruct the correct three-dimensional (3D) jaw position relationship. In phase II, bone augmentation and soft tissue management techniques were utilized to address insufficient alveolar bone mass and poor gingival soft tissue conditions. In phase III, implant-supported overdentures or fixed dentures were used for occlusal reconstruction. A summary of treatment methods, clinical efficacy evaluation, comparative analysis of imageological examinations, and satisfaction questionnaire survey were utilized to evaluate the therapeutic efficacy in patients with traumatic old jaw fractures and dentition defects. All data are summarized using the arithmetic mean and standard deviation and compared using independent sample t-tests. RESULTS: In 15 patients with old jaw fractures and dentition defects (an average age of 32 years, ranging from 18 to 53 years), there were 7 cases of malocclusion of single maxillary fracture, 6 of malocclusion of single mandible fracture, and 2 of malocclusion of both maxillary and mandible fractures. There were 5 patients with single maxillary dentition defects, 2 with single mandibular dentition defects, and 8 with both maxillary and mandibular dentition defects. To reconstruct the correct 3D jaw positional relationship, 5 patients underwent Le Fort I osteotomy of the maxilla, 3 underwent bilateral sagittal split ramus osteotomy of the mandible, 4 underwent open reduction and internal fixation for old jaw fractures, 3 underwent temporomandibular joint surgery, and 4 underwent distraction osteogenesis. All patients underwent jawbone augmentation, of whom 4 patients underwent a free composite vascularized bone flap (26.66%) and the remaining patients underwent local alveolar bone augmentation. Free gingival graft and connective tissue graft were the main methods for soft tissue augmentation (73.33%). The 15 patients received 81 implants, of whom 11 patients received implant-supported fixed dentures and 4 received implant-supported removable dentures. The survival rate of all implants was 93.82%. The final imageological examination of 15 patients confirmed that the malocclusion was corrected, and the clinical treatment ultimately achieved occlusal function reconstruction. The patient satisfaction questionnaire survey showed that they were satisfied with the efficacy, phonetics, aesthetics, and comfort after treatment. CONCLUSION: Occlusal reconstruction of old jaw fractures and dentition defects requires a phased sequential comprehensive treatment, consisting of 3D spatial jaw correction, alveolar bone augmentation and soft tissue augmentation, and implant-supported occlusal reconstruction, achieving satisfactory clinical therapeutic efficacy.

Blockade of pan-viral propagation by inhibition of host cell PNPT1.

For successful viral propagation within infected cells, the virus needs to overcome the cellular integrated stress response (ISR), triggered during viral infection, which, in turn, inhibits general protein translation. This paper reports a tactic employed by viruses to suppress the ISR by upregulating host cell polyribonucleotide nucleotidyltransferase 1 (PNPT1). The propagation of adenovirus, murine cytomegalovirus and hepatovirus within their respective host cells induces PNPT1 expression. Notably, when PNPT1 is knocked down, the propagation of all three viruses is prevented. Mechanistically, the inhibition of PNPT1 facilitates the relocation of mitochondrial double-stranded RNAs (mt-dsRNAs) to the cytoplasm, where they activate RNA-activated protein kinase (PKR). This activation leads to eukaryotic initiation factor 2α (eIF2α) phosphorylation, resulting in the suppression of translation. Furthermore, by scrutinizing the PNPT1 recognition element and screening 17,728 drugs and bioactive compounds approved by the US Food and Drug Administration, lanatoside C was identified as a potent PNPT1 inhibitor. This compound impedes the propagation of adenovirus, murine cytomegalovirus and hepatovirus, and suppresses production of the severe acute respiratory syndrome coronavirus-2 spike protein. These discoveries shed light on a novel strategy to impede pan-viral propagation by activating the host cell mt-dsRNA-PKR-eIF2α signalling axis.

A multifunctional composite nanoparticle with antibacterial activities, anti-inflammatory, and angiogenesis for diabetic wound healing.

The treatment of chronic diabetic wounds remains challenging due to the rapid bacterial infection, severe inflammation, and insufficient angiogenesis. To address these challenges, a novel multifunctional composite nanoparticle is developed by co-assembling antisolvent-induced co-assembling silk-fibroin ε-poly-l-Lysine nanoparticles (nSF-EPL) and further assembling nSF-EPL with polydeoxyribonucleotide (PDRN) and exosome derived from human umbilical mesenchymal stem cells (Exo). Owing to the modification of EPL, PDRN and Exo, composite nanoparticles exhibited synergistic antibacterial action, anti-inflammatory and angiogenesis, which can significantly benefit for promoting wound healing. Release results show that the composite nanoparticles exhibit long-term sustained PDRN and Exo release profiles as well as outstanding release efficiency. Furthermore, in vitro studies show that the composite nanoparticles exhibit effective antibacterial activity, thus inducing an anti-inflammatory M2 macrophages phenotype and promoting angiogenesis. In vivo research results of investigations pertaining to diabetic wound healing show that the composite nanoparticles have good anti-inflammatory and angiogenesis capabilities, which can promote granulation tissue formation, collagen deposition, wound tissue epithelialization, and significantly accelerate skin healing. This study presents a promising strategy for the clinical treatment of chronic diabetic wounds.

EBF2 Links KMT2D-Mediated H3K4me1 to Suppress Pancreatic Cancer Progression via Upregulating KLLN.

Mono-methylation of histone H3 on Lys 4 (H3K4me1), which is catalyzed by histone-lysine N-methyltransferase 2D (KMT2D), serves as an important epigenetic regulator in transcriptional control. In this study, the authors identify early B-cell factor 2 (EBF2) as a binding protein of H3K4me1. Combining analyses of RNA-seq and ChIP-seq data, the authors further identify killin (KLLN) as a transcriptional target of KMT2D and EBF2 in pancreatic ductal adenocarcinoma (PDAC) cells. KMT2D-dependent H3K4me1 and EBF2 are predominantly over-lapped proximal to the transcription start site (TSS) of KLLN gene. Comprehensive functional assays show that KMT2D and EBF2 cooperatively inhibit PDAC cells proliferation, migration, and invasion through upregulating KLLN. Such inhibition on PDAC progression is also achieved through increasing H3K4me1 level by GSK-LSD1, a selective inhibitor of lysine-specific demethylase 1 (LSD1). Taken together, these findings reveal a new mechanism underlying PDAC progression and provide potential therapeutic targets for PDAC treatment.

[Evaluation of the Short-Term Efficacy and Safety of Orelabrutinib Combined with High-Dose Methotrexate in the First-line Treatment of Elderly Patients with High Risk Primary Central Nervous System Lymphoma].

OBJECTIVE: To explore the short-term efficacy and adverse reactions of orelabrutinib combined with high-dose methotrexate (HD-MTX) in the first-line treatment of elderly high-risk primary central nervous system lymphoma (PCNSL), as well as the survival of patients. METHODS: Twenty-five elderly patients with high-risk primary central nervous system diffuse large B-cell lymphoma admitted to Fujian Provincial Hospital from June 2016 to June 2022 were enrolled in this study, and complete clinical data from all patients were collected retrospectively, and the cut-off for follow-up was December 2022. 15 patients had received temmozolomide combined with HD-MTX regimen for at least four cycles, sequential lenalidomide maintenance therapy, while 10 patients had received orelabrutinib combined with HD-MTX regimen for at least four cycles, sequential orelabrutinib maintenance therapy. The short-term efficacy and adverse reactions of the two groups of patients after treatment were observed. Kaplan-Meier was used to analyze the progression-free survival (PFS) and time to progression (TTP). RESULTS: The objective response rate (ORR) and 2-year median FPS of orelabrutinib combined with HD-MTX regimen group were similar to the temozolomide combined with HD-MTX regimen group (ORR: 100% vs 66.7%; 2-year median PFS: 16 months vs 15 months, P>0.05). The 2-year median TTP of the orelabrutinib+HD-MTX regimen group was better than that of the temozolomide+HD-MTX regimen group (not reached vs 12 months, P<0.05). There were no significant differences in adverse reactions such as gastrointestinal reactions, bone marrow suppression, liver and kidney damage, cardiotoxicity, pneumonia and bleeding between these two groups (P>0.05). CONCLUSION: For elderly patients with high-risk PCNSL, orelabrutinib combined with HD-MTX has reliable short-term efficacy, good safety, and tolerable adverse reactions, which is worthy of clinical promotion.

Genome-wide identification and molecular expression profile analysis of FHY3/FAR1 gene family in walnut (Juglans sigillata L.) development.

BACKGROUND: Juglans sigillata L. (walnut) has a high economic value for nuts and wood and has been widely grown and eaten around the world. Light plays an important role in regulating the development of the walnut embryo and promoting nucleolus enlargement, which is one of the factors affecting the yield and quality of walnut. However, little is known about the effect of light on the growth and quality of walnuts. Studies have shown that far red prolonged hypocotyl 3 (FHY3) and far red damaged response (FAR1) play important roles in plant growth, light response, and resistance. Therefore, FHY3/FAR1 genes were identified in walnuts on a genome-wide basis during their growth and development to reveal the potential regulation mechanisms involved in walnut kernel growth and development. RESULTS: In the present study, a total of 61 FHY3/FAR1 gene family members in walnuts have been identified, ranging in length from 117 aa to 895 aa. These gene family members have FHY3 or FAR1 conserved domains, which are unevenly distributed on the 15 chromosomes (Chr) of the walnut (except for the Chr16). All 61 FHY3/FAR1 genes were divided into five subclasses (I, II, III, IV, and V) by phylogenetic tree analysis. The results indicated that FHY3/FAR1 genes in the same subclasses with similar structures might be involved in regulating the growth and development of walnut. The gene expression profiles were analyzed in different walnut kernel varieties (Q, T, and F). The result showed that some FHY3/FAR1 genes might be involved in the regulation of walnut kernel ripening and seed coat color formation. Seven genes (OF07056-RA, OF09665-RA, OF24282-RA, OF26012-RA, OF28029-RA, OF28030-RA, and OF08124-RA) were predicted to be associated with flavonoid biosynthetic gene regulation cis-acting elements in promoter sequences. RT-PCR was used to verify the expression levels of candidate genes during the development and color change of walnut kernels. In addition, light responsiveness and MeJA responsiveness are important promoter regulatory elements in the FHY3/FAR1 gene family, which are potentially involved in the light response, growth, and development of walnut plants. CONCLUSION: The results of this study provide a valuable reference for supplementing the genomic sequencing results of walnut, and pave the way for further research on the FHY3/FAR1 gene function of walnut.

Effect of epidural block on surgical conditions during pediatric subumbilical laparoscopic surgery involving a supraglottic airway: a randomized clinical trial.

Background: Few studies have examined the effect of epidural block on surgical conditions during pediatric subumbilical laparoscopic surgery involving a supraglottic airway (SGA). This study investigated the surgical condition scores for such procedures in cases where neuromuscular block, epidural block, or neither was used. Methods: A total of 150 patients aged 3-12 years undergoing laparoscopic orchiopexy with a ProSeal SGA device were randomly allocated to one of three groups: the control group (did not receive neuromuscular block and epidural block), the NMB group [received a neuromuscular block (train-of-four 1-2 twitches) using rocuronium], or the EDB group (received an epidural block using ropivacaine). The primary outcome was the quality of surgical conditions evaluated with the Leiden-Surgical Rating Scale by the blinded surgeon. The secondary outcome measures included intraoperative hemodynamic data (including mean arterial pressure and heart rate), the SGA device removal time, the PACU discharge time, the pain score in the PACU and intraoperative adverse events (including bradycardia, hypotension, peak airway pressure > 20 cmH2O, and poor or extremely poor surgical conditions occurred during the operation). Statistical analysis was performed with one-way analysis of variance, the Kruskal-Wallis test, the chi-square test or Fisher's exact test. Bonferroni corrections for multiple comparisons were made for primary and secondary outcomes. Results: Surgical condition scores were significantly higher in the NMB and EDB groups than in the control group (median difference: 0.8; 95% confidence interval [CI], 0.5-1.0; p < 0.0001; and median difference: 0.7; 95% CI, 0.5-0.8; p < 0.0001, respectively). Blood pressure and heart rate were significantly lower in the EDB group than in the other two groups (p < 0.0001 and p = 0.004). Patients in the EDB group had significantly lower pain scores during PACU than those in the other two groups (p < 0.0001). The sufentanil dose was lower in the EDB group than in the other two groups (p = 0.001). Conclusion: Epidural block can improve surgical conditions during pediatric subumbilical laparoscopic surgery involving a SGA to a degree comparable to that with moderate neuromuscular block.

YTHDF1 mitigates acute kidney injury via safeguarding m6A-methylated mRNAs in stress granules of renal tubules.

Acute kidney injury (AKI) presents a daunting challenge with limited therapeutic options. To explore the contribution of N6-methyladenosine (m6A) in AKI development, we have investigated m6A-modified mRNAs within renal tubular cells subjected to injuries induced by diverse stressors. Notably, while the overall level of m6A-modified RNA remains unaltered in renal tubular cells facing stress, a distinct phenomenon emerges-mRNAs bearing m6A methylation exhibit a pronounced tendency to accumulate within stress granules (SGs), structures induced in response to these challenges. Cumulation of m6A-modified mRNA in SGs is orchestrated by YTHDF1, a m6A 'reader' closely associated with SGs. Strikingly, AKI patients and various mouse AKI models showcase elevated levels of renal tubular YTHDF1. Depleting YTHDF1 within renal tubular cells leads to a marked reduction in m6A-modified mRNA accumulation within SGs, accompanied by an escalation in cell apoptosis under stress challenges. The significance of YTHDF1's protective role is further underscored by findings in AKI mouse models triggered by cisplatin or renal ischemia-reperfusion treatments. In particular, renal tubular-specific YTHDF1 knockout mice exhibit heightened AKI severity when contrasted with their wild-type counterparts. Mechanistic insights reveal that YTHDF1 fulfills a crucial function by safeguarding m6A-modified mRNAs that favor cell survival-exemplified by SHPK1-within SGs amid stress-challenged renal tubular cells. Our findings collectively shed light on the pivotal role of YTHDF1 in shielding renal tubules against AKI, through its adeptness in recruiting and preserving m6A-modified mRNAs within stress-induced SGs.

Controllable Star Cationic Poly(Disulfide)s Achieve Genetically Cascade Catalytic Therapy by Delivering Bifunctional Fusion Plasmids.

The absence of effective delivery vectors and suitable multifunctional plasmids limits cancer gene therapy development. The star cationic poly(disulfide)s with ß-cyclodextrin cores (termed ß-CD-g-PSSn ) for caveolae-mediated endocytosis are designed and prepared via mild and controllable disulfide exchange polymerization for high-efficacy cancer therapy. Then, ß-CD-g-PSSn /pDNA complexes are transported to the Golgi apparatus and endoplasmic reticulum. Disulfides in ß-CD-g-PSSn vectors are degraded by glutathione in tumor cells, which not only promotes intracellular pDNA release but also reduces in vitro and in vivo toxicity. One bifunctional fusion plasmid pCATKR, which expresses catalase (CAT) fused to KillerRed (KR) (CATKR) in the same target cell, is also proposed for genetically cascade catalytic therapy. When compared with pCAT-KR (plasmid expressing CAT and KR separately in the same cell), delivered pCATKR decomposes hydrogen peroxide, alleviates tumor hypoxia more effectively, generates stronger reactive oxygen species (ROS) capabilities under moderate irradiation, and leads to robust antitumor cascade photodynamic effects. These impressive results are attributed to fusion protein design, which shortens the distance between CAT and KR catalytic centers and leads to improved ROS production efficiency. This work provides a promising strategy by delivering a catalytic cascade functional plasmid via a high-performance vector with biodegradable and caveolae-mediated endocytosis characteristics.

HIF-1α drives resistance to ferroptosis in solid tumors by promoting lactate production and activating SLC1A1.

Solid tumors have developed robust ferroptosis resistance. The mechanism underlying ferroptosis resistance regulation in solid tumors, however, remains elusive. Here, we report that the hypoxic tumor microenvironment potently promotes ferroptosis resistance in solid tumors in a hypoxia-inducible factor 1α (HIF-1α)-dependent manner. In combination with HIF-2α, which promotes tumor ferroptosis under hypoxia, HIF-1α is the main driver of hypoxia-induced ferroptosis resistance. Mechanistically, HIF-1α-induced lactate contributes to ferroptosis resistance in a pH-dependent manner that is parallel to the classical SLC7A11 and FSP1 systems. In addition, HIF-1α also enhances transcription of SLC1A1, an important glutamate transporter, and promotes cystine uptake to promote ferroptosis resistance. In support of the role of hypoxia in ferroptosis resistance, silencing HIF-1α sensitizes mouse solid tumors to ferroptosis inducers. In conclusion, our results reveal a mechanism by which hypoxia drives ferroptosis resistance and identify the combination of hypoxia alleviation and ferroptosis induction as a promising therapeutic strategy for solid tumors.

CD8 T Cell-Derived Exosomal miR-186-5p Elicits Renal Inflammation via Activating Tubular TLR7/8 Signal Axis.

T cells play an important role in the development of focal segmental glomerulosclerosis (FSGS). The mechanism underlying such T cell-based kidney disease, however, remains elusive. Here the authors report that activated CD8 T cells elicit renal inflammation and tissue injury via releasing miR-186-5p-enriched exosomes. Continuing the cohort study identifying the correlation of plasma level of miR-186-5p with proteinuria in FSGS patients, it is demonstrated that circulating miR-186-5p is mainly derived from activated CD8 T cell exosomes. Renal miR-186-5p, which is markedly increased in FSGS patients and mice with adriamycin-induced renal injury, is mainly delivered by CD8 T cell exosomes. Depleting miR-186-5p strongly attenuates adriamycin-induced mouse renal injury. Supporting the function of exosomal miR-186-5p as a key circulating pathogenic factor, intravenous injection of miR-186-5p or miR-186-5p-containing T cell exosomes results in mouse renal inflammation and tissue injury. Tracing the injected T cell exosomes shows their preferential distribution in mouse renal tubules, not glomerulus. Mechanistically, miR-186-5p directly activates renal tubular TLR7/8 signal and initiates tubular cell apoptosis. Mutating the TLR7-binding sequence on miR-186-5p or deleting mouse TLR7 largely abolishes renal tubular injuries induced by miR-186-5p or adriamycin. These findings reveal a causative role of exosomal miR-186-5p in T cell-mediated renal dysfunction.

Metastasis Related Epithelial-Mesenchymal Transition Signature Predicts Prognosis and Response to Chemotherapy in Acute Myeloid Leukemia.

Background: Acute myeloid leukemia (AML) is a highly heterogenous disease with varying clinical outcomes among patients. Epithelial-mesenchymal transition (EMT) is an important mechanism underlying cancer metastasis and chemotherapy resistance. However, few EMT-based signatures have been established to predict AML prognosis and treatment efficacy. Methods: By conducting comparative RNA-seq analysis, we discovered the differential expression of EMT genes between AML patients with relapse and those without relapse. Based on the prognostic analysis of the differentially expressed EMT genes, a metastasis-related EMT signature (MEMTs) was constructed. An analysis was conducted on both TARGET and TCGA cohorts to explore the possible association between MEMTs and prognosis in AML. Three separate chemotherapy treatment cohorts were utilized to assess the predictive efficacy of MEMTs for chemotherapy response. In addition, the potential correlation between MEMTs and the tumor microenvironment was also investigated. Finally, random forest analysis and functional experiments were conducted to verify the key MEMTs gene associated with AML metastasis. Results: Based on expression and prognostic analysis, we constructed MEMTs that include three EMT genes (CDH2, LOX, and COL3A1). Our findings suggested that the MEMTs could act as a prognostic factor for AML patients, and furthermore, it proved to be a predictor of their response to chemotherapy. Specifically, high MEMTs was associated with worse prognosis and poor response to chemotherapy, while low MEMTs was linked to better prognosis and higher response rates. Random forest and functional experiments demonstrate that CDH2 is a key gene promoting leukemia cell metastasis among the three MEMTs genes. Conclusion: The identification of MEMTs could potentially act as a predictor for the prognosis and the response to chemotherapy in AML patients. Individual tumor evaluation based on MEMTs could provide personalized treatment options for AML patients in the future.

A Novel Pathway of Functional microRNA Uptake and Mitochondria Delivery.

Extracellular microRNAs (miRNAs) play a critical role in horizontal gene regulation. Uptake of extracellular miRNAs by recipient cells and their intracellular transport, however, remains elusive. Here RNA phase separation is shown as a novel pathway of miRNA uptake. In the presence of serum, synthetic miRNAs rapidly self-assembly into ≈110 nm discrete nanoparticles, which enable miRNAs' entry into different cells. Depleting serum cationic proteins prevents the formation of such nanoparticles and thus blocks miRNA uptake. Different from lipofectamine-mediated miRNA transfection in which majority of miRNAs are accumulated in lysosomes of transfected cells, nanoparticles-mediated miRNA uptake predominantly delivers miRNAs into mitochondria in a polyribonucleotide nucleotidyltransferase 1(PNPT1)-dependent manner. Functional assays further show that the internalized miR-21 via miRNA phase separation enhances mitochondrial translation of cytochrome b (CYB), leading to increase in adenosine triphosphate (ATP) and reactive oxygen species (ROS) reduction in HEK293T cells. The findings thus reveal a previously unrecognized mechanism for uptake and delivery functional extracellular miRNAs into mitochondria.

Advances in nanotechnology for the treatment of GBM.

Glioblastoma (GBM), a highly malignant glioma of the central nervous system, is the most dread and common brain tumor with a high rate of therapeutic resistance and recurrence. Currently, the clinical treatment methods are surgery, radiotherapy, and chemotherapy. However, owning to the highly invasive nature of GBM, it is difficult to completely resect them due to the unclear boundary between the edges of GBM and normal brain tissue. Traditional radiotherapy and the combination of alkylating agents and radiotherapy have significant side effects, therapeutic drugs are difficult to penetrate the blood brain barrier. Patients receiving treatment have a high postoperative recurrence rate and a median survival of less than 2 years, Less than 5% of patients live longer than 5 years. Therefore, it is urgent to achieve precise treatment through the blood brain barrier and reduce toxic and side effects. Nanotechnology exhibit great potential in this area. This article summarizes the current treatment methods and shortcomings of GBM, and summarizes the research progress in the diagnosis and treatment of GBM using nanotechnology.

Excessive consumption of mucin by over-colonized Akkermansia muciniphila promotes intestinal barrier damage during malignant intestinal environment.

Gut microbiota disorders damage the intestinal barrier, which causes intestinal disease. Thus, we screened the microbiota with significant changes using an in situ malignant colorectal cancer (CRC) model. Among the colonies with increased abundance, Akkermansia muciniphila (A. muciniphila) is known for its characteristic of breaking down mucin, which is an essential component of the intestinal barrier. The role of A. muciniphila remains controversial. To investigate the effect of excess A. muciniphila on the intestinal barrier, we established an over-colonized A. muciniphila mouse model by administering a live bacterial suspension after disrupting the original gut microbiome with antibiotics. The results showed that over-colonization of A. muciniphila decreased intestinal mucin content. The mRNA and protein expression levels of tight junction proteins also decreased significantly in the over-colonized A. muciniphila mouse model. Our findings reveal that excess colonization by A. muciniphila breaks the dynamic balance between mucin secretion and degradation, reduces the thickness of the intestinal mucus layer, and damages the intestinal barrier, which would eventually aggravate the development of colitis and CRC. These results will raise awareness about the safety of A. muciniphila serving as a probiotic.

Polynucleotide phosphorylase protects against renal tubular injury via blocking mt-dsRNA-PKR-eIF2α axis.

Renal tubular atrophy is a hallmark of chronic kidney disease. The cause of tubular atrophy, however, remains elusive. Here we report that reduction of renal tubular cell polynucleotide phosphorylase (PNPT1) causes renal tubular translation arrest and atrophy. Analysis of tubular atrophic tissues from renal dysfunction patients and male mice with ischemia-reperfusion injuries (IRI) or unilateral ureteral obstruction (UUO) treatment shows that renal tubular PNPT1 is markedly downregulated under atrophic conditions. PNPT1 reduction leads to leakage of mitochondrial double-stranded RNA (mt-dsRNA) into the cytoplasm where it activates protein kinase R (PKR), followed by phosphorylation of eukaryotic initiation factor 2α (eIF2α) and protein translational termination. Increasing renal PNPT1 expression or inhibiting PKR activity largely rescues IRI- or UUO-induced mouse renal tubular injury. Moreover, tubular-specific PNPT1-knockout mice display Fanconi syndrome-like phenotypes with impaired reabsorption and significant renal tubular injury. Our results reveal that PNPT1 protects renal tubules by blocking the mt-dsRNA-PKR-eIF2α axis.