Cushing's syndrome caused by giant Ewing's sarcoma of the kidney: A case report and review of literature.

BACKGROUND: Primary renal Ewing's sarcoma (ES) is extremely rare, and only two cases causing Cushing's syndrome (CS) have been reported to date. We report that the case of an 18-year-old patient is diagnosed primary renal ES with typical CS characterized by purple stripes, weight gain, and hypertension. CASE SUMMARY: CS was first diagnosed by laboratory testing. A huge tumor was revealed in the kidney following an imaging examination. Moreover, brain and bone metastases were observed. After comprehensive treatment, primarily based on surgery, primary renal ES was pathologically diagnosed with a typical EWSR1-FLI1 genetic mutation through genetic testing. Furthermore, the glucocorticoid level returned to normal. By the ninth postoperative month of follow-up, the patient was recovering well. Cushing-related symptoms had improved, and a satisfactory curative effect was achieved. CONCLUSION: Primary renal ES, a rare adult malignant tumor, can cause CS and a poor prognosis.

Optimized nitrogen application ameliorates the photosynthetic performance and yield potential in peanuts as revealed by OJIP chlorophyll fluorescence kinetics.

BACKGROUND: Nitrogen (N) is a crucial element for increasing photosynthesis and crop yields. The study aims to evaluate the photosynthetic regulation and yield formation mechanisms of different nodulating peanut varieties with N fertilizer application. METHOD: The present work explored the effect of N fertilizer application rates (N0, N45, N105, and N165) on the photosynthetic characteristics, chlorophyll fluorescence characteristics, dry matter, N accumulation, and yield of four peanut varieties. RESULTS: The results showed that N application increased the photosynthetic capacity, dry matter, N accumulation, and yield of peanuts. The measurement of chlorophyll a fluorescence revealed that the K-phase, J-phase, and I-phase from the OJIP curve decreased under N105 treatment compared with N0, and WOI, ET0/CSM, RE0/CSM, ET0/RC, RE0/RC, φPo, φEo, φRo, and Ψ0 increased, whereas VJ, VI, WK, ABS/RC, TR0/RC, DI0/RC, and φDo decreased. Meanwhile, the photosystem activity and electron transfer efficiency of nodulating peanut varieties decreased with an increase in N (N165). However, the photosynthetic capacity and yield of the non-nodulating peanut variety, which highly depended on N fertilizer, increased with an increase in N. CONCLUSION: Optimized N application (N105) increased the activity of the photosystem II (PSII) reaction center, improved the electron and energy transfer performance in the photosynthetic electron transport chain, and reduced the energy dissipation of leaves in nodulating peanut varieties, which is conducive to improving the yield. Nevertheless, high N (N165) had a positive effect on the photosystem and yield of non-nodulating peanut. The results provide highly valuable guidance for optimizing peanut N management and cultivation measures.

High cure rate and satisfaction in patients with periductal mastitis via the latissimus dorsi myocutaneous flap technique: a retrospective study.

Background: Periductal mastitis (PDM) is a complex benign breast disease with a prolonged course and a high probability of recurrence after treatment. There is a variety of available treatments for PDM, but none of these options have been widely accepted. A standard strategy has been especially difficult to establish in patients with PDM accompanied by large tumors or large skin ruptures, as these seriously affect the appearance of the breasts after surgeries, which can lead to feelings of lower self-esteem among patients. Therefore, finding a reliable volume replacement has become a focus of our research efforts. With the widespread use of latissimus dorsi in breast reconstruction, we attempted to use the latissimus muscle (skin) flap for stage I repair in patients with large-defect PDM. Our study is the first of its kind to evaluate the clinical effect and patient satisfaction of the latissimus dorsi myocutaneous flap (LDMF) technique in PDM. Methods: Thirty-two patients with PDM and more than about 20% loss of breast volume admitted to the Department of Breast Surgery of Shanxi Bethune Hospital from March 2017 to July 2021 were enrolled. After lesion removal, the LDMF technique was applied to these patients for immediate completion of breast contour revision. All patients were periodically followed up to assess the efficacy of the procedure and their satisfaction with the breasts' shape. Results: Three patients (9.4%) developed dorsal effusion after removal of the back drain; six patients (18.8%) developed mild limitation of the activity of the affected upper limb; and three patients (9.4%) experienced local recurrence of inflammation after the operation, all of whom underwent a second operation. The cure rate of the patients treated with LDMF was 90.6%, the overall satisfaction rate of the patients was 96.9%, and doctor's evaluation of satisfaction was 90.6%. Conclusions: In patients with poor results after anti-infective and local treatment and those with more than 20% defect volume following lesion removal, the LDMF technique yields a high cure rate and good patient satisfaction.

SKLB023 protects against inflammation and apoptosis in sepsis-associated acute kidney injury via the inhibition of toll-like receptor 4 signaling.

Sepsis-associated acute kidney injury (SA-AKI) is one of common critical illnesses with high morbidity and mortality. At present, effective therapeutic drugs for SA-AKI are remain lacking. SKLB023 is a synthetic small-molecule compound which exerts potent anti-inflammatory effects in our previous studies. Here, this study aimed to characterize the protective effect of SKLB023 on SA-AKI and explore its underlying mechanism. The SA-AKI experimental models have been established by cecum ligation/puncture (CLP) and lipopolysaccharide (LPS) injection in male C57BL/6J mice. SKLB023 was administered by gavage (50 or 25 mg/kg in CLP model and 50 mg/kg in LPS model) daily 3 days in advance and 30 min earlier on the day of modeling. Our results confirmed SKLB023 treatment could improve the survival of SA-AKI mice and ameliorate renal pathological injury, inflammation, and apoptosis in the two types of septic AKI mice. Mechanically, SKLB023 deceased the expression of TLR4 in LPS-triggered renal tubular epithelial cells, and inhibited the activation of downstream pathways including NF-κB and MAPK pathways. Our study suggested that SKLB023 is expected to be a potential drug for the prevention and treatment of septic AKI.

M2-type tumor-associated macrophages upregulated PD-L1 expression in cervical cancer via the PI3K/AKT pathway.

BACKGROUND AND PURPOSE: PD-1/PD-L1 inhibitors have become a promising therapy. However, the response rate is lower than 30% in patients with cervical cancer (CC), which is related to immunosuppressive components in tumor microenvironment (TME). Tumor-associated macrophages (TAMs), as one of the most important immune cells, are involved in the formation of tumor suppressive microenvironment. Therefore, it will provide a theoretical basis for curative effect improvement about the regulatory mechanism of TAMs on PD-L1 expression. METHODS: The clinical data and pathological tissues of CC patients were collected, and the expressions of PD-L1, CD68 and CD163 were detected by immunohistochemistry. Bioinformatics was used to analyze the macrophage subtypes involved in PD-L1 regulation. A co-culture model was established to observe the effects of TAMs on the morphology, migration and invasion function of CC cells, and the regulatory mechanism of TAMs on PD-L1. RESULTS: PD-L1 expression on tumor cells could predict the poor prognosis of patients. And there was a strong correlation between PD-L1 expression with CD163+TAMs infiltration. Similarly, PD-L1 expression was associated with M1/M2-type TAMs infiltration in bioinformatics analysis. The results of cell co-culture showed that M1/M2-type TAMs could upregulate PD-L1 expression, especially M2-type TAMs may elevate the PD-L1 expression via PI3K/AKT pathway. Meanwhile, M1/M2-type TAMs can affect the morphological changes, and enhance migration and invasion abilities of CC cells. CONCLUSIONS: PD-L1 expression in tumor cells can be used as a prognostic factor and is closely related to CD163+TAMs infiltration. In addition, M2-type TAMs can upregulate PD-L1 expression in CC cells through PI3K/AKT pathway, enhance the migration and invasion capabilities, and affect the tumor progression.

Chromodomain Y-like (CDYL) inhibition ameliorates acute kidney injury in mice by regulating tubular pyroptosis.

Acute kidney injury (AKI) is a common disease, but lacking effective drug treatments. Chromodomain Y-like (CDYL) is a kind of chromodomain protein that has been implicated in transcription regulation of autosomal dominant polycystic kidney disease. Benzo[d]oxazol-2(3H)-one derivative (compound D03) is the first potent and selective small-molecule inhibitor of CDYL (KD = 0.5 µM). In this study, we investigated the expression of CDYL in three different models of cisplatin (Cis)-, lipopolysaccharide (LPS)- and ischemia/reperfusion injury (IRI)-induced AKI mice. By conducting RNA sequencing and difference analysis of kidney samples, we found that tubular CDYL was abnormally and highly expressed in injured kidneys of AKI patients and mice. Overexpression of CDYL in cisplatin-induced AKI mice aggravated tubular injury and pyroptosis via regulating fatty acid binding protein 4 (FABP4)-mediated reactive oxygen species production. Treatment of cisplatin-induced AKI mice with compound D03 (2.5 mg·kg-1·d-1, i.p.) effectively attenuated the kidney dysfunction, pathological damages and tubular pyroptosis without side effects on liver or kidney function and other tissue injuries. Collectively, this study has, for the first time, explored a novel aspect of CDYL for tubular epithelial cell pyroptosis in kidney injury, and confirmed that inhibition of CDYL might be a promising therapeutic strategy against AKI.

Distinct dynamics of parental 5-hydroxymethylcytosine during human preimplantation development regulate early lineage gene expression.

The conversion of DNA 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) by TET enzymes represents a significant epigenetic modification, yet its role in early human embryos remains largely unknown. Here we showed that the early human embryo inherited a significant amount of 5hmCs from an oocyte, which unexpectedly underwent de novo hydroxymethylation during its growth. Furthermore, the generation of 5hmC in the paternal genome after fertilization roughly followed the maternal pattern, which was linked to DNA methylation dynamics and regions of sustained methylation. The 5hmCs persisted until the eight-cell stage and exhibited high enrichment at OTX2 binding sites, whereas knockdown of OTX2 in human embryos compromised the expression of early lineage genes. Specifically, the depletion of 5hmC affected the activation of embryonic genes, which was further evaluated by ectopically expressing mouse Tet3 in human early embryos. These findings revealed distinct dynamics of 5hmC and unravelled its multifaceted functions in early human embryonic development.

Associations of Multimorbidity with Cerebrospinal Fluid Biomarkers for Neurodegenerative Disorders in Early Parkinson's Disease: A Cross-sectional and Longitudinal Study.

OBJECT: The study aims to determine whether multimorbidity status is associated with cerebrospinal fluid (CSF) biomarkers for neurodegenerative disorders. METHODS: A total of 827 patients were enrolled from the Parkinson's Progression Markers Initiative (PPMI) database, including 638 patients with early-stage Parkinson's disease (PD) and 189 healthy controls (HCs). Multimorbidity status was evaluated based on the count of long-term conditions (LTCs) and the multimorbidity pattern. Using linear regression models, cross-sectional and longitudinal analyses were conducted to assess the associations of multimorbidity status with CSF biomarkers for neurodegenerative disorders, including α-synuclein (αSyn), amyloid-ß42 (Aß42), total tau (t-tau), phosphorylated tau (p-tau), glial fibrillary acidic protein (GFAP), and neurofilament light chain protein (NfL). RESULTS: At baseline, the CSF t-tau (p = 0.010), p-tau (p = 0.034), and NfL (p = 0.049) levels showed significant differences across the three categories of LTC counts. In the longitudinal analysis, the presence of LTCs was associated with lower Aß42 (ß < -0.001, p = 0.020), and higher t-tau (ß = 0.007, p = 0.026), GFAP (ß = 0.013, p = 0.022) and NfL (ß = 0.020, p = 0.012); Participants with tumor/musculoskeletal/mental disorders showed higher CSF levels of t-tau (ß = 0.016, p = 0.011) and p-tau (ß = 0.032, p = 0.044) than those without multimorbidity. CONCLUSION: Multimorbidity, especially severe multimorbidity and the pattern of mental/musculoskeletal/ tumor disorders, was associated with CSF biomarkers for neurodegenerative disorders in early-stage PD patients, suggesting that multimorbidity might play a crucial role in aggravating neuronal damage in neurodegenerative diseases.

Association Between Carotid Plaque and Alzheimer's Disease Cerebrospinal Fluid Biomarkers and Cognitive Function in Cognitively Intact Adults: The CABLE Study.

Background: The association between carotid plaque and cognitive decline has recently been reported. However, the current research evidence is insufficient, and the possible causes of cognitive changes are unknown. Objective: This study aims to explore the relationships between carotid plaque and cognition functions, cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers in cognitively intact adults, and try to study the underlying mechanisms. Methods: We enrolled 165 cognitively normal participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study, who had CSF AD biomarker measurements and carotid ultrasound. Linear modeling was used to assess the association of carotid plaque with CSF biomarkers and cognition. Additionally, mediation analysis was conducted through 10,000 bootstrapped iterations to explore potential links between carotid plaque, AD pathology, and cognition. Results: We found that carotid plaque exhibited significant correlations with Aß42 (ß = -1.173, p = 0.022), Aß42/Aß40 (ß = -0.092, p < 0.001), P-tau/Aß42 (ß = 0.110, p = 0.045), and T-tau/Aß42 (ß = 0.451, p = 0.010). A significant correlation between carotid plaque and cognition decline was also found in men (ß = -0.129, p = 0.021), and mediation analyses revealed that the effect of carotid plaque on cognitive function could be mediated by Aß42/Aß40 (proportion of mediation = 55.8%), P-tau/Aß42 (proportion of mediation = 51.6%, p = 0.015) and T-tau/Aß42 (proportion of mediation = 43.8%, p = 0.015) mediated. Conclusions: This study demonstrated the link between carotid plaque and CSF AD biomarkers in cognitively intact adults, and the important role that AD pathology may play in the correlation between carotid plaque and cognitive changes.

Integrin αM promotes macrophage alternative M2 polarization in hyperuricemia-related chronic kidney disease.

Hyperuricemia is an essential risk factor in chronic kidney disease (CKD), while urate-lowering therapy to prevent or delay CKD is controversial. Alternatively activated macrophages in response to local microenvironment play diverse roles in kidney diseases. Here, we aim to investigate whether and how macrophage integrin αM (ITGAM) contributes to hyperuricemia-related CKD. In vivo, we explored dynamic characteristics of renal tissue in hyperuricemia-related CKD mice. By incorporating transcriptomics and phosphoproteomics data, we analyzed gene expression profile, hub genes and potential pathways. In vitro, we validated bioinformatic findings under different conditions with interventions corresponding to core nodes. We found that hyperuricemia-related CKD was characterized by elevated serum uric acid levels, impaired renal function, activation of macrophage alternative (M2) polarization, and kidney fibrosis. Integrated bioinformatic analyses revealed Itgam as the potential core gene, which was associated with focal adhesion signaling. Notably, we confirmed the upregulated expression of macrophage ITGAM, activated pathway, and macrophage M2 polarization in injured kidneys. In vitro, through silencing Itgam, inhibiting p-FAK or p-AKT1 phosphorylation, and concurrent inhibiting of p-FAK while activating p-AKT1 all contributed to the modulation of macrophage M2 polarization. Our results indicated targeting macrophage ITGAM might be a promising therapeutic approach for preventing CKD.

CircRNA hsa_circ_0069,399 as a potential clinical prognostic marker in laryngeal squamous cell carcinoma.

Objective: Circular RNAs (circRNAs) significantly influence the invasion, metastasis, gene expression, proliferation, and apoptosis of tumor cells. However, the roles of circRNAs in laryngeal squamous cell carcinoma (LSCC) remain largely unexplored. This study aims to examine circRNA expression patterns in LSCC and adjacent non-tumorous tissues, with the goal of uncovering potential biomarkers for LSCC. Methods: Tissue samples were collected from both the tumor and adjacent normal tissues of ten patients who had undergone surgical resection. The profiling of circRNAs was conducted through transcriptomic sequencing and analytical bioinformatics approaches. A ternary regulatory network based on the competitive endogenous RNA (ceRNA) hypothesis was established, linking target circRNAs to clinical immunohistochemical parameters for comparison. Verification of target circRNAs in LSCC tissues was performed using quantitative real-time PCR (RT-qPCR), whereas target mRNAs were analyzed through immunohistochemistry. Results: A total of 126 significantly different circRNAs were identified, including 40 up-regulated genes and 86 down-regulated genes. Furthermore, 92 circRNA-miRNA-mRNA regulatory relationship axes related to clinical immunohistochemical indicators were found based on 5 candidate circRNAs. Interestingly, all axes related to the target genes MKI67 and TP53 were found to compete with the same circRNA: hsa_circ_0069,399. Further verification confirmed that the hsa_circ_0069,399 expression was overtly upregulated in tumor tissues from LSCC patients, which was consistent with the sequencing results. Conclusion: hsa_circ_0069,399 could be a potential prognostic marker for LSCC.

Study on the photoaging process and metal ion release of plastic films with two kinds of structures in marine environment: Aliphatic and aromatic polymers.

The prevalence of plastics in the oceans has significantly intensified microplastic pollution, contributing to broader marine secondary pollution issues. This paper examines how plastic structure affects the aging characteristics of plastics and the release of metal ions, to better understand this secondary source of marine pollution. This study simulate the photoaging of plastics in natural environments, focusing on aliphatic and aromatic polymers. The results showed that the photodegradation degree was higher for aliphatic than aromatic polymers. All polymers contained thirteen detectable metals, with their release increasing over time due to photoaging, The release dynamics of these metal ions correlated more strongly with the level of polymer degradation rather than with the polymer structure itself, adhering to a second-order kinetic model driven by surface and intraparticle diffusion processes. The results will help control and treat marine plastic pollution.

Irisin attenuates type 1 diabetic cardiomyopathy by anti-ferroptosis via SIRT1-mediated deacetylation of p53.

BACKGROUND: Diabetic cardiomyopathy (DCM) is a serious complication in patients with type 1 diabetes mellitus (T1DM), which still lacks adequate therapy. Irisin, a cleavage peptide off fibronectin type III domain-containing 5, has been shown to preserve cardiac function in cardiac ischemia-reperfusion injury. Whether or not irisin plays a cardioprotective role in DCM is not known. METHODS AND RESULTS: T1DM was induced by multiple low-dose intraperitoneal injections of streptozotocin (STZ). Our current study showed that irisin expression/level was lower in the heart and serum of mice with STZ-induced TIDM. Irisin supplementation by intraperitoneal injection improved the impaired cardiac function in mice with DCM, which was ascribed to the inhibition of ferroptosis, because the increased ferroptosis, associated with increased cardiac malondialdehyde (MDA), decreased reduced glutathione (GSH) and protein expressions of solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4), was ameliorated by irisin. In the presence of erastin, a ferroptosis inducer, the irisin-mediated protective effects were blocked. Mechanistically, irisin treatment increased Sirtuin 1 (SIRT1) and decreased p53 K382 acetylation, which decreased p53 protein expression by increasing its degradation, consequently upregulated SLC7A11 and GPX4 expressions. Thus, irisin-mediated reduction in p53 decreases ferroptosis and protects cardiomyocytes against injury due to high glucose. CONCLUSION: This study demonstrated that irisin could improve cardiac function by suppressing ferroptosis in T1DM via the SIRT1-p53-SLC7A11/GPX4 pathway. Irisin may be a therapeutic approach in the management of T1DM-induced cardiomyopathy.

NRSN2 promotes the malignant behavior of HPV-transfected laryngeal carcinoma cells through AMPK/ULK1 pathway mediated autophagy activation.

Neurensin-2 (NRSN2) performs a pro-carcinogenic function in multiple cancers. However, the function of NRSN2 in HPV-infected laryngeal carcinoma (LC) remains unclear. HPV transfection was performed in LC cells. The mRNA and protein levels were monitored using RT-qPCR, immunoblotting, and IF. Cell viability and proliferation were found using the CCK-8 assay and Edu staining. Cell invasion, migration, and apoptosis were probed using the Transwell, wound healing, and flow cytometry, respectively. The autophagosome was observed using TEM. NRSN2 was overexpressed in HPV-transfected LC cells. Inhibition of NRSN2 restrained the autophagy and malignant behavior of HPV-transfected LC cells. Meanwhile, the inhibition of AMPK/ULK1 pathway limited the increased autophagy of HPV-transfected LC cells caused by NRSN2 overexpression. Furthermore, NRSN2 knockdown inhibits autophagy by suppressing AMPK/ULK1 pathway, thereby restraining the malignant behavior of HPV-transfected LC cells. Our research confirmed that HPV transfection increased the autophagy and malignant behavior of LC cells by regulating the NRSN2-mediated activation of the AMPK/ULK1 pathway, offering a new target for cure of LC.

Multispecies Ion Acceleration in 3D Magnetic Reconnection with Hybrid-Kinetic Simulations.

Magnetic reconnection drives multispecies particle acceleration broadly in space and astrophysics. We perform the first 3D hybrid simulations (fluid electrons, kinetic ions) that contain sufficient scale separation to produce nonthermal heavy-ion acceleration, with fragmented flux ropes critical for accelerating all species. We demonstrate the acceleration of all ion species (up to Fe) into power-law spectra with similar indices, by a common Fermi acceleration mechanism. The upstream ion velocities influence the first Fermi reflection for injection. The subsequent onsets of Fermi acceleration are delayed for ions with lower charge-mass ratios (Q/M), until growing flux ropes magnetize them. This leads to a species-dependent maximum energy/nucleon ∝(Q/M)^{α}. These findings are consistent with in situ observations in reconnection regions, suggesting Fermi acceleration as the dominant multispecies ion acceleration mechanism.

[Ginsenoside Re regulates mitochondrial biogenesis through Nrf2/HO-1/PGC-1α pathway to reduce hypoxia/reoxygenation injury in H9c2 cells].

This article explored the mechanism by which ginsenoside Re reduces hypoxia/reoxygenation(H/R) injury in H9c2 cells by regulating mitochondrial biogenesis through nuclear factor E2-related factor 2(Nrf2)/heme oxygenase-1(HO-1)/peroxisome prolife-rator-activated receptor gamma coactivator-1α(PGC-1α) pathway. In this study, H9c2 cells were cultured in hypoxia for 4 hours and then reoxygenated for 2 hours to construct a cardiomyocyte H/R injury model. After ginsenoside Re pre-administration intervention, cell activity, superoxide dismutase(SOD) activity, malondialdehyde(MDA) content, intracellular reactive oxygen species(Cyto-ROS), and intramitochondrial reactive oxygen species(Mito-ROS) levels were detected to evaluate the protective effect of ginsenoside Re on H/R injury of H9c2 cells by resisting oxidative stress. Secondly, fluorescent probes were used to detect changes in mitochondrial membrane potential(ΔΨ_m) and mitochondrial membrane permeability open pore(mPTP), and immunofluorescence was used to detect the expression level of TOM20 to study the protective effect of ginsenoside Re on mitochondria. Western blot was further used to detect the protein expression levels of caspase-3, cleaved caspase-3, Cyto C, Nrf2, HO-1, and PGC-1α to explore the specific mechanism by which ginsenoside Re protected mitochondria against oxidative stress and reduced H/R injury. Compared with the model group, ginse-noside Re effectively reduced the H/R injury oxidative stress response of H9c2 cells, increased SOD activity, reduced MDA content, and decreased Cyto-ROS and Mito-ROS levels in cells. Ginsenoside Re showed a good protective effect on mitochondria by increasing ΔΨ_m, reducing mPTP, and increasing TOM20 expression. Further studies showed that ginsenoside Re promoted the expression of Nrf2, HO-1, and PGC-1α proteins, and reduced the activation of the apoptosis-related regulatory factor caspase-3 to cleaved caspase-3 and the expression of Cyto C protein. In summary, ginsenoside Re can significantly reduce I/R injury in H9c2 cells. The specific mechanism is related to the promotion of mitochondrial biogenesis through the Nrf2/HO-1/PGC-1α pathway, thereby increasing the number of mitochondria, improving mitochondrial function, enhancing the ability of cells to resist oxidative stress, and alleviating cell apoptosis.

[Tetrahydropalmatine inhibiting mitophagy through ULK1/FUNDC1 pathway to alleviate hypoxia/reoxygenation injury in H9c2 cells].

This study explored the specific mechanism by which tetrahydropalmatine(THP) inhibited mitophagy through the UNC-51-like kinase 1(ULK1)/FUN14 domain containing 1(FUNDC1) pathway to reduce hypoxia/reoxygenation(H/R) injury in H9c2 cells. This study used H9c2 cells as the research object to construct a cardiomyocyte H/R injury model. First, a cell viability detection kit was used to detect cell viability, and a micro-method was used to detect lactate dehydrogenase(LDH) leakage to evaluate the protective effect of THP on H/R injury of H9c2 cells. In order to evaluate the protective effect of THP on mitochondria, the chemical fluorescence method was used to detect intracellular reactive oxygen species, intramitochondrial reactive oxygen species, mitochondrial membrane potential, and autophagosomes, and the luciferin method was used to detect intracellular adenosine 5'-triphosphate(ATP) content. Western blot was further used to detect the ratio of microtubule-associated protein 1 light chain 3(LC3) membrane type(LC3-Ⅱ) and slurry type(LC3-Ⅰ) and activated cleaved caspase-3 expression level. In addition, ULK1 expression level and its phosphorylation degree at Ser555 site, as well as the FUNDC1 expression level and its phosphorylation degree of Ser17 site were detected to explore its specific mechanism. The results showed that THP effectively reduced mitochondrial damage in H9c2 cells after H/R. THP protected mitochondria by reducing the level of reactive oxygen species in cells and mitochondria, increasing mitochondrial membrane potential, thereby increasing cellular ATP production, enhancing cellular activity, reducing cellular LDH leakage, and finally alleviating H/R damage in H9c2 cells. Further studies have found that THP could reduce the production of autophagosomes, reduce the LC3-Ⅱ/LC3-Ⅰ ratio, and lower the expression of the apoptosis-related protein, namely cleaved caspase-3, indicating that THP could reduce apoptosis by inhibiting autophagy. In-depth studies have found that THP could inhibit the activation of the ULK1/FUNDC1 pathway of mitophagy and the occurrence of mitophagy by reducing the phosphorylation degree of ULK1 at Ser555 and FUNDC1 at Ser17. The application of ULK1 agonist BL-918 reversely verified the effect of THP on reducing the phosphorylation of ULK1 and FUNDC1. In summary, THP inhibited mitophagy through the ULK1/FUNDC1 pathway to reduce H/R injury in H9c2 cells.

Inhibition of ACSS2-mediated histone crotonylation alleviates kidney fibrosis via IL-1ß-dependent macrophage activation and tubular cell senescence.

Histone lysine crotonylation (Kcr), as a posttranslational modification, is widespread as acetylation (Kac); however, its roles are largely unknown in kidney fibrosis. In this study, we report that histone Kcr of tubular epithelial cells is abnormally elevated in fibrotic kidneys. By screening these crotonylated/acetylated factors, a crotonyl-CoA-producing enzyme ACSS2 (acyl-CoA synthetase short chain family member 2) is found to remarkably increase histone 3 lysine 9 crotonylation (H3K9cr) level without influencing H3K9ac in kidneys and tubular epithelial cells. The integrated analysis of ChIP-seq and RNA-seq of fibrotic kidneys reveal that the hub proinflammatory cytokine IL-1ß, which is regulated by H3K9cr, play crucial roles in fibrogenesis. Furthermore, genetic and pharmacologic inhibition of ACSS2 both suppress H3K9cr-mediated IL-1ß expression, which thereby alleviate IL-1ß-dependent macrophage activation and tubular cell senescence to delay renal fibrosis. Collectively, our findings uncover that H3K9cr exerts a critical, previously unrecognized role in kidney fibrosis, where ACSS2 represents an attractive drug target to slow fibrotic kidney disease progression.

Generation of rat forebrain tissues in mice.

Interspecies blastocyst complementation (IBC) provides a unique platform to study development and holds the potential to overcome worldwide organ shortages. Despite recent successes, brain tissue has not been achieved through IBC. Here, we developed an optimized IBC strategy based on C-CRISPR, which facilitated rapid screening of candidate genes and identified that Hesx1 deficiency supported the generation of rat forebrain tissue in mice via IBC. Xenogeneic rat forebrain tissues in adult mice were structurally and functionally intact. Cross-species comparative analyses revealed that rat forebrain tissues developed at the same pace as the mouse host but maintained rat-like transcriptome profiles. The chimeric rate of rat cells gradually decreased as development progressed, suggesting xenogeneic barriers during mid-to-late pre-natal development. Interspecies forebrain complementation opens the door for studying evolutionarily conserved and divergent mechanisms underlying brain development and cognitive function. The C-CRISPR-based IBC strategy holds great potential to broaden the study and application of interspecies organogenesis.

Recent Progress of Small Interfering RNA Delivery on the Market and Clinical Stage.

Small interfering RNAs (siRNAs) are promising therapeutic strategies, and five siRNA drugs have been approved by the Food and Drug Administration (FDA) and the European Commission (EC). This marks a significant milestone in the development of siRNA for clinical applications. The approved siRNA agents can effectively deliver siRNAs to the liver and treat liver-related diseases. Currently, researchers have developed diverse delivery platforms for transporting siRNAs to different tissues such as the brain, lung, muscle, and others, and a large number of siRNA drugs are undergoing clinical trials. Here, these delivery technologies and the latest advancements in clinical applications are summarized, and this Review provides a concise overview of the strategies employed for siRNA delivery to both hepatic and extrahepatic tissues.