A comparative study based on ainuovirine/lamivudine/tenofovir against HIV-1.

BACKGROUND: Ainuovirine, as a third-generation non-nucleoside reverse transcriptase inhibitor against HIV-1, is widely used in China. To evaluate its therapeutic efficacy and disadvantages, a comparative study based on Ainuovirine had been conducted. METHOD: We investigated 199 people living with HIV-1 who received Ainuovirine (ANV)/lamivudine/tenofovir and 202 people living with HIV-1 who received Efavirenz (EFV)/lamivudine/tenofovir. RESULTS: After 48 weeks of therapy, ANV and EFV showed similar viral inhibitory effects. However, in the ANV group, more participants had CD4/CD8 ratios restored to the normal range, lower levels of triglycerides and low-density lipoprotein, relatively normal liver alanine aminotransferase, and fewer adverse events. CONCLUSION: Therefore, due to its role in immune reconstitution, dyslipidemia, and safety, ANV may be a recommended option for people living with HIV-1.

A patient report scale research to access the symptom burden in patients with IgA nephropathy.

Patients diagnosed with IgA nephropathy (IgAN) commonly experience a substantial burden of symptoms encompassing both physical and psychological aspects. Presently, there's a dearth of standardized assessment tools to effectively gauge the extent of symptom burden in IgAN patients. Therefore, this study aims to devise an IgAN Symptom Assessment Tool that enables a comprehensive evaluation of patient symptom burden and their self-perceived severity. Employing a prospective observational design, this study conducted a survey among patients diagnosed with IgAN at a hospital in China. The research team formulated an IgAN Symptom Burden Assessment Scale and administered a questionnaire to gauge patient symptom burden. Severity assessment was conducted on a 5-point Likert scale, with higher scores indicating a more pronounced burden of symptoms. The finalized scale comprised 14 distinct symptom items, and the questionnaire survey garnered responses from 200 patients, achieving a 100% response rate. Statistical analysis unveiled that nearly all patients regarded these symptoms as prevalent and significantly impactful on their daily lives, resulting in a considerable burden. Notably, mild oliguria, moderate nasal congestion, bitter taste , throat discomfort, alongside severe manifestations such as muscle weakness, fatigue, and foamy urine, were frequently reported by patients. The findings underscore that a substantial proportion of IgAN patients grapple with a significant burden of symptoms, emphasizing the imperative for healthcare providers to prioritize symptom management and implement proactive measures to alleviate these challenges. This study presents an innovative tool tailored for evaluating symptom burden specifically in IgAN patients. Subsequent research should center on validating this tool within larger patient cohorts to optimize the efficacy of symptom management in this demographic.

Genomic Characteristics of a Carbapenem-Resistant Klebsiella pneumoniae Co-Carrying bla NDM-5 and bla KPC-2 Capsular Type KL25 Recovered from a County Level Hospital in China.

Background: Hypervirulent carbapenem-resistant K. pneumoniae (hv-CRKP) has been spreading rapidly worldwide. Here, we investigated the genomic characteristics of ST11 K. pneumoniae isolate SM117 with capsular serotype KL25, co-carrying bla NDM-5, two copies of bla KPC-2 and multiple plasmid-borne virulence genes from a county level hospital in China. Methods: Antimicrobial susceptibility of K. pneumoniae SM117 was evaluated. The Illumina NovaSeq 6000 and Oxford Nanopore MinION platforms were applied to sequence the genome and then de novo assembled. The genome sequence was annotated using the NCBI Prokaryotic Genome Annotation Pipeline and further subjected to identify the sequence type (ST), capsular type, antibiotic resistance genes, plasmid replicon types and virulence genes. The phylogenetic analysis was performed based on the core genome single nucleotide polymorphisms (cgSNPs) using CSI Phylogeny 1.4, and further visualized by Interactive Tree of Life (iTOL) V5 web server. Results: The whole-genome sequence of K. pneumoniae SM117 is made up of eight contigs totaling 6,104,486 bp, contain a 5,612,620 bp single chromosome and seven plasmids. The isolate was assigned to ST11 with capsular serotype KL25, co-carrying including bla NDM-5, bla KPC-2 and multiple plasmid-borne virulence genes including rmpA2 and aerobactin genes iucABCD-iutA. The coexistence of bla KPC and bla NDM in K. pneumoniae strains exhibit a high degree of resistance to ß-lactam antibiotics. The strain SM117 also carries multiple antibiotic resistance genes, making it resistant to all antibiotics except polymyxin. The closest relative of K. pneumoniae C793 was identified in 2023 from a hospital surface sample in Zhejiang, China, with just 52 SNPs difference. Conclusion: This study reported the genomic characteristics of a multidrug-resistant ST11 K. pneumoniae with capsular serotype KL25, co-carrying bla NDM-5, two copies of bla KPC-2 genes and multiple plasmid-borne virulence genes in China. These findings will provide important knowledge of the antibiotic resistance mechanisms, genomic epidemiological characteristics and transmission dynamics of multidrug-resistant K. pneumoniae.

Aurantiamide mitigates acute kidney injury by suppressing renal necroptosis and inflammation via GRPR-dependent mechanism.

Acute kidney injury (AKI) manifests as a clinical syndrome characterised by the rapid accumulation of metabolic wastes, such as blood creatinine and urea nitrogen, leading to a sudden decline in renal function. Currently, there is a lack of specific therapeutic drugs for AKI. Previously, we identified gastrin-releasing peptide receptor (GRPR) as a pathogenic factor in AKI. In this study, we investigated the therapeutic potential of a novel Chinese medicine monomer, aurantiamide (AA), which exhibits structural similarities to our previously reported GRPR antagonist, RH-1402. We compared the therapeutic efficacy of AA with RH-1402 both in vitro and in vivo using various AKI models. Our results demonstrated that, in vitro, AA attenuated injury, necroptosis, and inflammatory responses in human renal tubular epithelial cells subjected to repeated hypoxia/reoxygenation and lipopolysaccharide stimulation. In vivo, AA ameliorated renal tubular injury and inflammation in mouse models of ischemia/reperfusion and cecum ligation puncture-induced AKI, surpassing the efficacy of RH-1402. Furthermore, molecular docking and cellular thermal shift assay confirmed GRPR as a direct target of AA, which was further validated in primary cells. Notably, in GRPR-silenced HK-2 cells and GRPR systemic knockout mice, AA failed to mitigate renal inflammation and injury, underscoring the importance of GRPR in AA's mechanism of action. In conclusion, our study has demonstrated that AA serve as a novel antagonist of GRPR and a promising clinical candidate for AKI treatment.

Research on 3D virtual vision matching based on interactive color segmentation.

Given the prevalent issues surrounding accuracy and efficiency in contemporary stereo-matching algorithms, this research introduces an innovative image segmentation-based approach. The proposed methodology integrates residual and Swim Transformer modules into the established 3D Unet framework, yielding the Res-Swim-UNet image segmentation model. The algorithm estimates the disparateness of segmented outputs by employing regression techniques, culminating in a comprehensive disparity map. Experimental findings underscore the superiority of the proposed algorithm across all evaluated metrics. Specifically, the proposed network demonstrates marked improvements, with IoU and mPA enhancements of 2.9% and 162%, respectively. Notably, the average matching error rate of the algorithm registers at 2.02%, underscoring its efficacy in achieving precise stereoscopic matching. Moreover, the model's enhanced generalization capability and robustness underscore its potential for widespread applicability.

The Role of Lutheran/Basal Cell Adhesion Molecule in Hematological Diseases and Tumors.

Cell adhesion is a dynamic process that plays a fundamental role in cell proliferation, maintenance, differentiation, and migration. Basal cell adhesion molecule (BCAM), also known as Lutheran (Lu), belongs to the immunoglobulin superfamily of cell adhesion molecules. Lu/BCAM, which is widely expressed in red blood cells, endothelial cells, smooth muscle cells and epithelial cells across various tissues, playing a crucial role in many cellular processes, including cell adhesion, cell motility and cell migration. Moreover, Lu/BCAM, dysregulated in many diseases, such as blood diseases and various types of cancer, may act as a biomarker and target for the treatment of these diseases. This review explores the significance of Lu/BCAM in cell adhesion and its potential as a novel target for treating hematological diseases and tumors.

Effectiveness and safety of dolutegravir plus lamivudine in treating HIV in China, including outcomes of patients coinfected with tuberculosis.

Antiretroviral regimens for human immunodeficiency virus (HIV) infection have continuously evolved; however, antiretrovirals can cause severe adverse reactions. Two-drug regimen therapy can decrease lifetime cumulative drug exposure and long-term toxicities associated with multiple antiretrovirals. The preferred 2-drug regimen constitutes dolutegravir (DTG) and lamivudine (3TC). This study determined the rate of virological suppression and incidence of adverse events at week 48 in treatment-naïve people living with HIV initiated on DTG + 3TC. This was a single-center, retrospective, observational study. Treatment-naïve people aged ≥18 years who received at least 1 DTG + 3TC dose between May 2020 and May 2022 were included. Eighty-nine people living with HIV were enrolled. Twenty-five (28.1%) patients with a DTG + 3TC regimen at baseline were analyzed because of comorbidities, and 48% because of concomitant tuberculosis (TB). Viral suppression at 48 weeks was achieved in 91.67% of patients, and TB was well controlled. At week 48, 84 (94.38%) patients had viral loads < 50 copies/mL, and 21 (91.31%) of the 23 participants with a baseline HIV-1-RNA level ≥ 1 × 105 copies/mL achieved virological success. Fifteen (88.23%) of the 17 participants with a baseline CD4 + cell count of <200 cells/µL achieved virological suppression. The median CD4 + cell count change from baseline was 539.5 cells/µL. No significant changes in triglycerides, low-density lipoprotein cholesterol, weight, or creatinine were observed from baseline to 48 weeks. One patient had severe insomnia at 4 weeks. Our findings support the real-world effectiveness and low metabolic impact of DTG + 3TC. Using DTG + 3TC in patients coinfected with TB and HIV has favorable therapeutic outcomes.

Comparison of feasibility and effectiveness of tunneled dialysis catheter placement with or without DSA guidance: a propensity score-matched cohort study.

BACKGROUND: In some resource-limited regions, the placement of tunneled dialysis catheters (TDC) is often preferred under ultrasound guidance rather than fluoroscopy. This study compared ultrasound-and digital subtraction angiography-guided (DSA)-guided TDC in renal replacement therapy. METHODS: This retrospective cohort study included all TDC placements performed at our hospital between January 2020 and October 2022. We utilized 1:1 propensity score matching (PSM) to balance the demographic and clinical characteristics of the DSA-guided and ultrasound-guided groups. Dialysis prescriptions and actual dialysis completion were assessed using intraclass correlation coefficients (ICC). Multivariable logistic regression analyses determined the risk factors for early termination of dialysis. The differences in adverse events, catheter function, and catheter tip position were evaluated between the two groups. RESULTS: The study included 261 patients (142 in the DSA-guided group and 119 in the ultrasound-guided group). After PSM, 91 patients were included in each group, with no significant baseline differences (p > .1). Both groups achieved adequate catheter blood flow and ultrafiltration volumes without deviations from dialysis prescriptions (ICC ≥ 0.75). The DSA-guided group had fewer early dialysis terminations than the ultrasound-guided group (3.3 vs. 12.0%, p = .026). The position of the catheter tip in the right atrium was more consistent in the DSA-guided group (100 vs. 74.2%, p < .001). CONCLUSION: Hemodialysis catheters inserted under DSA guidance exhibited superior performance compared to those inserted under ultrasound guidance, primarily due to more accurate catheter tip positioning. DSA guidance is recommended when ensuring optimal catheter tip placement.

Role and mechanism of KIAA1429 in regulating cellular ferroptosis and radioresistance in colorectal cancer.

Colorectal cancer (CRC) is one of the most common non-cutaneous malignancies, causing significant mortality and a substantial burden. This study aims to explore the role of KIAA1429 (also known as vir-like m6A methyltransferase associated [VIRMA]) protein in the radioresistance of CRC. CRC cells and a radioresistant cell line were cultured, and KIAA1429 expression was detected. After the down-regulation of KIAA1429, its effect on the radioresistance and ferroptosis of cancer cells was analyzed. The role of ferroptosis in radioresistance was verified. The binding relationship among long non-coding RNA endogenous Bornavirus-like nucleoprotein 3, pseudogene (lncRNA EBLN3P), microRNA (miR)-153-3p, and KIAA1429 was analyzed. KIAA1429 and lncRNA EBLN3P were highly expressed in CRC, while miR-153-3p was poorly expressed. KIAA1429 and lncRNA EBLN3P were further increased/decreased in the radioresistant cells. KIAA1429 knockdown decreased the survival rate of the radioresistant cell line after X-ray irradiation and increased gamma H2A histone family member X (γ-H2AX), ferroptosis, and oxidative stress. A ferroptosis inhibitor alleviated the inhibitory effect of KIAA1429 knockdown on radioresistance. KIAA1429-mediated m6A modification up-regulated lncRNA EBLN3P, and lncRNA EBLN3P increased KIAA1429 by competitively binding to miR-153-3p. miR-153-3p silencing or lncRNA EBLN3P overexpression attenuated the promotion of ferroptosis and the inhibition of radioresistance induced by KIAA1429 knockdown. Overall, KIAA1429-mediated m6A modification up-regulated lncRNA EBLN3P expression, and lncRNA EBLN3P increased KIAA1429 expression by competitively binding to miR-153-3p, thus reducing ferroptosis and increasing the radioresistance of CRC.

Application of multimodality perception scene construction based on Internet of Things (IoT) technology in art teaching.

Numerous impediments beset contemporary art education, notably the unidimensional delivery of content and the absence of real-time interaction during instructional sessions. This study endeavors to surmount these challenges by devising a multimodal perception system entrenched in Internet of Things (IoT) technology. This system captures students' visual imagery, vocalizations, spatial orientation, movements, ambient luminosity, and contextual data by harnessing an array of interaction modalities encompassing visual, auditory, tactile, and olfactory sensors. The synthesis of this manifold information about learning scenarios entails strategically placing sensors within physical environments to facilitate intuitive and seamless interactions. Utilizing digital art flower cultivation as a quintessential illustration, this investigation formulates tasks imbued with multisensory channel interactions, pushing the boundaries of technological advancement. It pioneers advancements in critical domains such as visual feature extraction by utilizing DenseNet networks and voice feature extraction leveraging SoundNet convolutional neural networks. This innovative paradigm establishes a novel art pedagogical framework, accentuating the importance of visual stimuli while enlisting other senses as complementary contributors. Subsequent evaluation of the usability of the multimodal perceptual interaction system reveals a remarkable task recognition accuracy of 96.15% through the amalgamation of Mel-frequency cepstral coefficients (MFCC) speech features with a long-short-term memory (LSTM) classifier model, accompanied by an average response time of merely 6.453 seconds-significantly outperforming comparable models. The system notably enhances experiential fidelity, realism, interactivity, and content depth, ameliorating the limitations inherent in solitary sensory interactions. This augmentation markedly elevates the caliber of art pedagogy and augments learning efficacy, thereby effectuating an optimization of art education.

Integration analysis of miRNA-mRNA pairs between two contrasting genotypes reveals the molecular mechanism of jujube (Ziziphus jujuba Mill.) response to high-temperature stress.

With global warming, high temperature (HT) has become one of the most common abiotic stresses resulting in significant crop yield losses, especially for jujube (Ziziphus jujuba Mill.), an important temperate economic crop cultivated worldwide. This study aims to explore the coping mechanism of jujube to HT stress at the transcriptional and post-transcriptional levels, including identifying differentially expressed miRNAs and mRNAs as well as elucidating the critical pathways involved. High-throughput sequencing analyses of miRNA and mRNA were performed on jujube leaves, which were collected from "Fucumi" (heat-tolerant) and "Junzao" (heat-sensitive) cultivars subjected to HT stress (42 °C) for 0, 1, 3, 5, and 7 days, respectively. The results showed that 45 known miRNAs, 482 novel miRNAs, and 13,884 differentially expressed mRNAs (DEMs) were identified. Among them, integrated analysis of miRNA target genes prediction and mRNA-seq obtained 1306 differentially expressed miRNAs-mRNAs pairs, including 484, 769, and 865 DEMIs-DEMs pairs discovered in "Fucuimi", "Junzao" and two genotypes comparative groups, respectively. Furthermore, functional enrichment analysis of 1306 DEMs revealed that plant-pathogen interaction, starch and sucrose metabolism, spliceosome, and plant hormone signal transduction were crucial pathways in jujube leaves response to HT stress. The constructed miRNA-mRNA network, composed of 20 DEMIs and 33 DEMs, displayed significant differently expressions between these two genotypes. This study further proved the regulatory role of miRNAs in the response to HT stress in plants and will provide a theoretical foundation for the innovation and cultivation of heat-tolerant varieties.

Uric acid-lowering effect of harpagoside and its protective effect against hyperuricemia-induced renal injury in mice.

Hyperuricemia (HUA) is caused by increased synthesis and/or insufficient excretion of uric acid (UA). Long-lasting HUA may lead to a number of diseases including gout and kidney injury. Harpagoside (Harp) is a bioactive compound with potent anti-inflammatory activity from the roots of Scrophularia ningpoensis. Nevertheless, its potential effect on HUA was not reported. The anti-HUA and nephroprotective effects of Harp on HUA mice were assessed by biochemical and histological analysis. The proteins responsible for UA production and transportation were investigated to figure out its anti-HUA mechanism, while proteins related to NF-κB/NLRP3 pathway were evaluated to reveal its nephroprotective mechanism. The safety was evaluated by testing its effect on body weight and organ coefficients. The results showed that Harp significantly reduced the SUA level and protected the kidney against HUA-induced injury but had no negative effect on safety. Mechanistically, Harp significantly reduced UA production by acting as inhibitors of xanthine oxidase (XOD) and adenosine deaminase (ADA) and decreased UA excretion by acting as activators of ABCG2, OAT1 and inhibitors of GLUT9 and URAT1. Moreover, Harp markedly reduced infiltration of inflammatory cells and down-regulated expressions of TNF-α, NF-κB, NLRP3 and IL-1ß in the kidney. Harp was a promising anti-HUA agent.

Effects of high-temperature stress on gene expression related to photosynthesis in two jujube (Ziziphus jujuba Mill.) varieties.

Elevated temperatures critically impact crop growth, development, and yield, with photosynthesis being the most temperature-sensitive physiological process in plants. This study focused on assessing the photosynthetic response and genetic adaptation of two different heat-resistant jujube varieties 'Junzao' (J) and 'Fucuimi' (F), to high-temperature stress (42°C Day/30°C Night). Comparative analyses of leaf photosynthetic indices, microstructural changes, and transcriptome sequencing were conducted. Results indicated superior high-temperature adaptability in F, evidenced by alterations in leaf stomatal behavior - particularly in J, where defense cells exhibited significant water loss, shrinkage, and reduced stomatal opening, alongside a marked increase in stomatal density. Through transcriptome sequencing 13,884 differentially expressed genes (DEGs) were identified, significantly enriched in pathways related to plant-pathogen interactions, amino acid biosynthesis, starch and sucrose metabolism, and carbohydrate metabolism. Key findings include the identification of photosynthetic pathway related DEGs and HSFA1s as central regulators of thermal morphogenesis and heat stress response. Revealing their upregulation in F and downregulation in J. The results indicate that these genes play a crucial role in improving heat tolerance in F. This study unveils critical photosynthetic genes involved in heat stress, providing a theoretical foundation for comprehending the molecular mechanisms underlying jujube heat tolerance.

Case report: Experience and insights on the treatment of two cases of cryptococcal meningitis during the later stages of the COVID-19 pandemic.

In the late stages of the COVID-19 pandemic, there's an increasing trend in opportunistic infections, including bacterial and fungal infections. This study discusses the treatment process of two cases of cryptococcal meningitis during the COVID-19 pandemic. It highlights the importance of laboratory testing for these co-infections and stresses the need for vigilance, early diagnosis, and proactive treatment to improve patient outcomes in the post-pandemic era.

Budding mutation reprogrammed flavonoid biosynthesis in jujube by deploying MYB41 and bHLH93.

Budding mutations are known to cause metabolic changes in new jujube varieties; however, the mechanisms underlying these changes are still unclear. Here, we performed muti-omics analysis to decipher the detailed metabolic landscape of "Saimisu 1" (S1) and its budding mutation line "Saimisu 2" (S2) at all fruit stages. We found that the genes involved in the biosyntheses of flavonoids, phenylpropanoids, and amino acids were upregulated in S2 fruits at all stages, especially PAL and DFR, resulting in increased accumulation of related compounds in S2 mature fruits. Further co-expression regulatory network analysis showed that the transcription factors MYB41 and bHLH93 potentially regulated the expression of PAL and DFR, respectively, by directly binding to their promoters. Moreover, the overexpression of MYB41 or bHLH93 induced their expression levels to redirect the flux of the flavonoid biosynthetic pathway, eventually leading to high levels of related compounds in S2 fruits. Overall, this study revealed the metabolic variations between S1 and S2 and contributed to the understanding of the mechanisms underlying budding mutation-mediated metabolic variations in plants, eventually providing the basis for breeding excellent jujube varieties using budding mutation lines.

Bulk and single-cell transcriptome profiling identify potential cellular targets of the long noncoding RNA Gas5 in renal fibrosis.

The long noncoding RNA growth arrest-specific 5 (lncRNA Gas5) is implicated in various kidney diseases. In this study, we investigated the lncRNA Gas5 expression profile and its critical role as a potential biomarker in the progression of chronic kidney disease. Subsequently, we assessed the effect of lncRNA Gas5 deletion on renal fibrosis induced by unilateral ureteral obstruction (UUO). The results indicated that loss of lncRNA Gas5 exacerbates UUO-induced renal injury and extracellular matrix deposition. Notably, the deletion of lncRNA Gas5 had a similar effect on control mice. The fibrogenic phenotype observed in mice lacking lncRNA Gas5 correlates with peroxisome proliferator-activated receptor (PPAR) signaling pathway activation and aberrant cytokine and chemokine reprogramming. Single-cell RNA sequencing analysis revealed key transcriptomic features of fibroblasts after Gas5 deletion, revealing heterogeneous cellular states suggestive of a propensity for renal fibrosis. Our findings indicate that lncRNA Gas5 regulates the differentiation and activation of immune cells and the transcription of key genes in the PPAR signaling pathway. These data offer novel insights into the involvement of lncRNA Gas5 in renal fibrosis, potentially paving the way for innovative diagnostic and therapeutic targets.

Hydrangea serrata extract attenuates PM-exacerbated airway inflammation in the CARAS model by modulating the IL-33/ST2/NF-κB signaling pathway.

Particulate matter (PM) significantly contributes to the global health crisis of respiratory diseases. It is known to induce and exacerbate conditions such as asthma and respiratory infections. Long exposure to PM can increase the risk of combined allergic rhinitis and asthma syndrome (CARAS). Although therapeutic drugs can be used to improve symptoms of respiratory diseases caused by PM, their usage is often accompanied by side effects. Therefore, many studies are being conducted to discover functional food materials that can more effectively treat respiratory diseases while minimizing the side effects of these therapeutic drugs. This study was conducted to investigate the efficacy of Hydrangea serrata extract (HSE) in airway inflammation in a mouse model of CARAS exacerbated by PM. In the CARAS mouse model worsened by PM, the airway inflammation improvement effect of HSE was evaluated by analyzing allergic nasal symptoms, changes in inflammatory cells, OVA-specific immunoglobulin (Ig) levels, cytokines, mast cell activation, and histopathological findings of both nasal mucosa and lung tissue. HSE effectively reduced OVA-specific IgE and IgG1 and inhibited the production of T helper type 2 (Th2)-related cytokines such as IL-4 and IL-5. Importantly, HSE reduced IL-33 and ST2 expression and inhibited the activation of the NF-κB signaling pathway. In addition, HSE inhibited airway hypersensitivity, mucus production, and inflammatory cell infiltration. These results suggest that HSE may inhibit airway inflammation in CARAS/PM mice by regulating the IL-33/ST2/NF-κB signaling pathway, opening avenues for considering HSE as a potential material for treating allergic airway inflammation diseases in the future.

Cpd-A1 alleviates acute kidney injury by inhibiting ferroptosis.

Acute kidney injury (AKI) is defined as sudden loss of renal function characterized by increased serum creatinine levels and reduced urinary output with a duration of 7 days. Ferroptosis, an iron-dependent regulated necrotic pathway, has been implicated in the progression of AKI, while ferrostatin-1 (Fer-1), a selective inhibitor of ferroptosis, inhibited renal damage, oxidative stress and tubular cell death in AKI mouse models. However, the clinical translation of Fer-1 is limited due to its lack of efficacy and metabolic instability. In this study we designed and synthesized four Fer-1 analogs (Cpd-A1, Cpd-B1, Cpd-B2, Cpd-B3) with superior plasma stability, and evaluated their therapeutic potential in the treatment of AKI. Compared with Fer-1, all the four analogs displayed a higher distribution in mouse renal tissue in a pharmacokinetic assay and a more effective ferroptosis inhibition in erastin-treated mouse tubular epithelial cells (mTECs) with Cpd-A1 (N-methyl-substituted-tetrazole-Fer-1 analog) being the most efficacious one. In hypoxia/reoxygenation (H/R)- or LPS-treated mTECs, treatment with Cpd-A1 (0.25 µM) effectively attenuated cell damage, reduced inflammatory responses, and inhibited ferroptosis. In ischemia/reperfusion (I/R)- or cecal ligation and puncture (CLP)-induced AKI mouse models, pre-injection of Cpd-A1 (1.25, 2.5, 5 mg·kg-1·d-1, i.p.) dose-dependently improved kidney function, mitigated renal tubular injury, and abrogated inflammation. We conclude that Cpd-A1 may serve as a promising therapeutic agent for the treatment of AKI.

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.