Identification of Differentially Expressed Genes in Cold Storage-associated Kidney Transplantation.

BACKGROUND: Although it is acknowledged that ischemia-reperfusion injury is the primary pathology of cold storage-associated kidney transplantation, its underlying mechanism is not well elucidated. METHODS: To extend the understanding of molecular events and mine hub genes posttransplantation, we performed bulk RNA sequencing at different time points (24 h, day 7, and day 14) on a murine kidney transplantation model with prolonged cold storage (10 h). RESULTS: In the present study, we showed that genes related to the regulation of apoptotic process, DNA damage response, cell cycle/proliferation, and inflammatory response were steadily elevated at 24 h and day 7. The upregulated gene profiling delicately transformed to extracellular matrix organization and fibrosis at day 14. It is prominent that metabolism-associated genes persistently took the first place among downregulated genes. The gene ontology terms of particular note to enrich are fatty acid oxidation and mitochondria energy metabolism. Correspondingly, the key enzymes of the above processes were the products of hub genes as recognized. Moreover, we highlighted the proximal tubular cell-specific increased genes at 24 h by combining the data with public RNA-Seq performed on proximal tubules. We also focused on ferroptosis-related genes and fatty acid oxidation genes to show profound gene dysregulation in kidney transplantation. CONCLUSIONS: The comprehensive characterization of transcriptomic analysis may help provide diagnostic biomarkers and therapeutic targets in kidney transplantation.

Inhibition of Drp1- Fis1 interaction alleviates aberrant mitochondrial fragmentation and acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is a common clinical disorder with complex etiology and poor prognosis, and currently lacks specific and effective treatment options. Mitochondrial dynamics dysfunction is a prominent feature in AKI, and modulation of mitochondrial morphology may serve as a potential therapeutic approach for AKI. METHODS: We induced ischemia-reperfusion injury (IRI) in mice (bilateral) and Bama pigs (unilateral) by occluding the renal arteries. ATP depletion and recovery (ATP-DR) was performed on proximal renal tubular cells to simulate in vitro IRI. Renal function was evaluated using creatinine and urea nitrogen levels, while renal structural damage was assessed through histopathological staining. The role of Drp1 was investigated using immunoblotting, immunohistochemistry, immunofluorescence, and immunoprecipitation techniques. Mitochondrial morphology was evaluated using confocal microscopy. RESULTS: Renal IRI induced significant mitochondrial fragmentation, accompanied by Dynamin-related protein 1 (Drp1) translocation to the mitochondria and Drp1 phosphorylation at Ser616 in the early stages (30 min after reperfusion), when there was no apparent structural damage to the kidney. The use of the Drp1 inhibitor P110 significantly improved kidney function and structural damage. P110 reduced Drp1 mitochondrial translocation, disrupted the interaction between Drp1 and Fis1, without affecting the binding of Drp1 to other mitochondrial receptors such as MFF and Mid51. High-dose administration had no apparent toxic side effects. Furthermore, ATP-DR induced mitochondrial fission in renal tubular cells, accompanied by a decrease in mitochondrial membrane potential and an increase in the translocation of the pro-apoptotic protein Bax. This process facilitated the release of dsDNA, triggering the activation of the cGAS-STING pathway and promoting inflammation. P110 attenuated mitochondrial fission, suppressed Bax mitochondrial translocation, prevented dsDNA release, and reduced the activation of the cGAS-STING pathway. Furthermore, these protective effects of P110 were also observed renal IRI model in the Bama pig and folic acid-induced nephropathy in mice. CONCLUSIONS: Dysfunction of mitochondrial dynamics mediated by Drp1 contributes to renal IRI. The specific inhibitor of Drp1, P110, demonstrated protective effects in both in vivo and in vitro models of AKI.

Optical coherence tomography angiography for the assessment of retinal microvasculature characteristics in preterm-born children: A systematic review and meta-analysis.

This study aimed to evaluate the usefulness of optical coherence tomography angiography (OCTA) in assessing retinal microvascular structural changes in preterm-born children and compare them with those in term-born children. The Web of Science Library, Cochrane Library, PubMed, Embase, CNKI, Wanfang, VIP, and Sino Med databases were searched systematically to extract studies published till April 25, 2023. Two independent reviewers searched all the literature and completed the data extraction and quality assessment. Mean differences (MDs) with 95% confidence intervals (CIs) were used to assess the continuous estimates. STATA software (v15.1; StataCorp, College Station, TX) was used to analyze the data. Twelve published studies were eligible for inclusion in this study. The meta-analysis revealed that the foveal avascular zone (FAZ) area of preterm-born children was remarkably smaller than that of term-born children, with the laser photocoagulation (LP)-ROP group showing the most pronounced reduction. The foveal superficial capillary plexus vessel density (SCP-VD) and deep capillary plexus vessel density (DCP-VD) were remarkably higher in the preterm-born group than in the control group, with variations in subgroups (LP-ROP, anti-VEGF-ROP, SR-ROP, and Pre-T-ROP). The parafoveal SCP-VD was remarkably lower in preterm-born children compared to that of the controls, while no significant difference was identified in the parafoveal DCP-VD. Preterm-born children had a smaller FAZ area, higher foveal SCP-VD and DCP-VD, and lower parafoveal SCP-VD compared to their term-born counterparts. The parafoveal DCP-VD did not differ substantially between preterm- and term-born children. OCTA is an effective modality for assessing alterations in the retinal microvasculature in preterm children.

Activation of autophagy by Citri Reticulatae Semen extract ameliorates amyloid-beta-induced cell death and cognition deficits in Alzheimer's disease.

JOURNAL/nrgr/04.03/01300535-202419110-00027/figure1/v/2024-03-08T184507Z/r/image-tiff Amyloid-beta-induced neuronal cell death contributes to cognitive decline in Alzheimer's disease. Citri Reticulatae Semen has diverse beneficial effects on neurodegenerative diseases, including Parkinson's and Huntington's diseases, however, the effect of Citri Reticulatae Semen on Alzheimer's disease remains unelucidated. In the current study, the anti-apoptotic and autophagic roles of Citri Reticulatae Semen extract on amyloid-beta-induced apoptosis in PC12 cells were first investigated. Citri Reticulatae Semen extract protected PC12 cells from amyloid-beta-induced apoptosis by attenuating the Bax/Bcl-2 ratio via activation of autophagy. In addition, Citri Reticulatae Semen extract was confirmed to bind amyloid-beta as revealed by biolayer interferometry in vitro, and suppress amyloid-beta-induced pathology such as paralysis, in a transgenic Caenorhabditis elegans in vivo model. Moreover, genetically defective Caenorhabditis elegans further confirmed that the neuroprotective effect of Citri Reticulatae Semen extract was autophagy-dependent. Most importantly, Citri Reticulatae Semen extract was confirmed to improve cognitive impairment, neuronal injury and amyloid-beta burden in 3×Tg Alzheimer's disease mice. As revealed by both in vitro and in vivo models, these results suggest that Citri Reticulatae Semen extract is a potential natural therapeutic agent for Alzheimer's disease via its neuroprotective autophagic effects.

Economic level, environmental regulation, and new energy industry development.

Using panel data of 30 provinces and new energy (NE)-listed enterprises in China from 2011 to 2020, this paper uses basic model to research the impact of various environmental policies in China on NE industry development firstly. Then, using economic level as a threshold variable, a threshold model was constructed to research the impact of economic level on the relationship between environmental regulation and NE industry development. The research results show that firstly, various environmental policies in China have significantly promoted the development of the NE industry. This is mainly manifested in two aspects. One is environmental regulations significantly increased the NE industry output value and profit, the other is environmental regulations enhanced the NE industry growth potential. Secondly, the regional economic level has a significant impact on the relationship between environmental regulations and NE industry development. The promotion effect of environmental regulations on NE industry development depends on the regional economic level. When the regional economic level exceeds the threshold, the promoting effect of environmental regulations on NE industry development significantly increases. The reason is that a weak economic foundation will affect investment in the NE industry. Insufficient capital investment will inevitably seriously hinder the development of the NE industry. Thirdly, residents' education status, financial support, and NE industry agglomeration degree have a positive impact on the development of the NE industry, while population size has no significant impact on NE industry development.

Prevalence, types, and risk factors of functional gastrointestinal diseases in Hainan Province, China.

To investigate the prevalence, types, and risk factors of functional gastrointestinal diseases (FGIDs) in Hainan Province, China, in order to provide insights for future prevention and treatment strategies. A questionnaire survey was conducted from July 2022 to May 2023, using stratified sampling to sample local residents in five cities (20 townships) in Hainan Province. Out of 2057 local residents surveyed, 659 individuals (32.0%) reported experiencing at least one FGID. The most prevalent FGIDs were functional dyspepsia (FD) (10.7%), functional constipation (FC) (9.3%), irritable bowel syndrome (IBS) (6.8%), functional bloating (2.2%), belching disorder (2.2%), functional diarrhea (FDr) (1.5%), functional heartburn (1.5%), and fecal incontinence (0.98%). The study revealed significant associations between FGIDs and factors such as age, sleep quality, anxiety, smoking, alcohol consumption, and the consumption of pickled food (P < 0.05). Older age, poor sleep quality, anxiety, and the consumption of pickled food were identified as independent risk factors for the prevalence of FGIDs (P < 0.05). In Hainan Province, the overall prevalence of FGIDs was found to be 32.0%, with higher prevalences of FC and FD. Older age, poor sleep quality, anxiety, and the consumption of pickled food were identified as risk factors for FGIDs.

Comprehensive exploration of hub genes involved in oxidative stress in rhegmatogenous retinal detachment based on bioinformatics analysis.

Rhegmatogenous retinal detachment (RRD) is a type of ophthalmologic emergency, if left untreated, the blindness rate approaches 100 %. The RRD patient postoperative recovery of visual function is unsatisfactory, most notably due to photoreceptor death. We conducted to identify the key genes for oxidative stress (OS) in RRD through bioinformatics analysis and clinical validation, thus providing new ideas for the recovery of visual function in RRD patients after surgery. A gene database for RRD was obtained from the Gene Expression Omnibus (GEO) database (GSE28133). Then we screened differentially expressed OS genes (DEOSGs) from the database and assessed the critical pathways in RRD with Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Protein-protein interaction (PPI) networks and hub genes among the common DEOSGs were identified. In addition, we collected general information and vitreous fluid from 42 patients with RRD and 22 controls [11 each of epiretinal membrane (EM) and macular hole (MH)], examined the expression levels of proteins encoded by hub genes in vitreous fluid by enzyme-linked immunosorbent assay (ELISA) to further assess the relationship between the ELISA data and the clinical characteristics of patients with RRD. Ten hub genes (CCL2, ICAM1, STAT3, CD4, ITGAM, PTPRC, CCL5, IL18, TLR2, VCAM1) were finally screened out from the dataset. The ELISA results showed that, compared with the control group, patients with RRD: TLR2 and ICAM-1 were significantly elevated, and CCL2 had a tendency to be elevated, but no statistically significant; RRD patients and MH patients compared with EM patients: STAT3 and VCAM-1 were significantly elevated. We found affected eyes of RRD patients compared with healthy eyes: temporal and nasal retinal nerve fiber layer (RNFL) were significantly thickened. By correlation analysis, we found that: STAT3 was negatively correlated with ocular perfusion pressure (OPP); temporal RNFL was not only significantly positively correlated with CCL2, but also negatively correlated with Scotopic b-wave amplitude. These findings help us to further explore the mechanism of RRD development and provide new ideas for finding postoperative visual function recovery.

Structures, functions, and regulatory networks of universal stress proteins in clinically relevant pathogenic Bacteria.

Universal stress proteins are a class of proteins widely present in bacteria, archaea, plants, and invertebrates, playing essential roles in bacterial adaptation to various environmental stresses. The functions of bacterial universal stress proteins are versatile, including resistance to oxidative stress, maintenance of cell wall integrity, DNA damage repair, regulation of cell division and growth, among others. When facing stresses such as temperature changes, pH shifts, fluctuations in oxygen concentration, and exposure to toxins, these proteins can bind to specific DNA sequences and rapidly adjust bacterial metabolic pathways and gene expression patterns to adapt to the new environment. In summary, bacterial universal stress proteins play a crucial role in bacterial adaptability and survival. A comprehensive understanding of bacterial stress response mechanisms and the development of new antibacterial strategies are of great significance. This review summarizes the research progress on the structure, function, and regulatory factors of universal stress proteins in clinically relevant bacteria, aiming to facilitate deeper investigations by clinicians and researchers into universal stress proteins.

The improving strategies and applications of nanotechnology-based drugs in hepatocellular carcinoma treatment.

Hepatocellular carcinoma (HCC) is one of the leading causes of tumor-related death worldwide. Conventional treatments for HCC include drugs, radiation, and surgery. Despite the unremitting efforts of researchers, the curative effect of HCC has been greatly improved, but because HCC is often found in the middle and late stages, the curative effect is still not satisfactory, and the 5-year survival rate is still low. Nanomedicine is a potential subject, which has been applied to the treatment of HCC and has achieved promising results. Here, we summarized the factors affecting the efficacy of drugs in HCC treatment and the strategies for improving the efficacy of nanotechnology-based drugs in HCC, reviewed the recent applications' progress on nanotechnology-based drugs in HCC treatment, and discussed the future perspectives and challenges of nanotechnology-based drugs in HCC treatment.

Mycobacterium tuberculosis Rv1043c regulates the inflammatory response by inhibiting the phosphorylation of TAK1.

Mycobacterium tuberculosis can manipulate the host immunity through its effectors to ensure intracellular survival and colonization. Rv1043c has been identified as an effector potentially involved in M. tuberculosis pathogenicity. To explore the function of M. tuberculosis Rv1043c during infection, we overexpressed this protein in M. smegmatis, a non-pathogenic surrogate model in tuberculosis research. Here, we reported that Rv1043c enhanced mycobacterial survival and down-regulated the release of pro-inflammatory cytokines in macrophages and mice. In addition, Rv1043c inhibited the activation of MAPK and NF-κB signaling by preventing the phosphorylation of TAK1 indirectly. In conclusion, these data suggest that Rv1043c regulates the immune response and enhances the survival of recombinant M. smegmatis in vitro and in vivo.

Lychee seed polyphenol ameliorates DR via inhibiting inflammasome/apoptosis and angiogenesis in hRECs and db/db mice.

Blood retinal barrier (BRB) damage is an important pathogenesis of diabetic retinopathy, and alleviating BRB damage has become a key target for DR treatment. We previously found that Lycopene seed polyphenols (LSP) maintained BRB integrity by inhibiting NLRP3 inflammasome-mediated inflammation. However, it is still unknown whether LSP inhibits retinal neovascularization with abnormal capillaries and its mechanism of action. Here, we employed db/db mice and hRECs to find that LSP increases the level of glycolipid metabolism, maintains the morphology of retinal endothelial cells and inhibits acellular capillary neogenesis. Mechanistic studies revealed that LSP inhibits the NLRP3 inflammasome, reduces cell apoptosis in retinal tissue, increases tight junction protein (TJ) expression, and reduces vascular endothelial growth factor (VEGF) and Ve-Cadherin in vivo and in vitro. Collectively, this study finds that LSP inhibits inflammation and angiogenesis to improve BRB function to ameliorate DR.

miR-147 Represses NDUFA4, Inducing Mitochondrial Dysfunction and Tubular Damage in Cold Storage Kidney Transplantation.

SIGNIFICANCE STATEMENT: Cold storage-associated transplantation (CST) injury occurs in renal transplant from deceased donors, the main organ source. The pathogenesis of CST injury remains poorly understood, and effective therapies are not available. This study has demonstrated an important role of microRNAs in CST injury and revealed the changes in microRNA expression profiles. Specifically, microRNA-147 (miR-147) is consistently elevated during CST injury in mice and in dysfunctional renal grafts in humans. Mechanistically, NDUFA4 (a key component of mitochondrial respiration complex) is identified as a direct target of miR-147. By repressing NDUFA4, miR-147 induces mitochondrial damage and renal tubular cell death. Blockade of miR-147 and overexpression of NDUFA4 reduce CST injury and improve graft function, unveiling miR-147 and NDUFA4 as new therapeutic targets in kidney transplantation. BACKGROUND: Kidney injury due to cold storage-associated transplantation (CST) is a major factor determining the outcome of renal transplant, for which the role and regulation of microRNAs remain largely unclear. METHODS: The kidneys of proximal tubule Dicer (an enzyme for microRNA biogenesis) knockout mice and their wild-type littermates were subjected to CST to determine the function of microRNAs. Small RNA sequencing then profiled microRNA expression in mouse kidneys after CST. Anti-microRNA-147 (miR-147) and miR-147 mimic were used to examine the role of miR-147 in CST injury in mouse and renal tubular cell models. RESULTS: Knockout of Dicer from proximal tubules attenuated CST kidney injury in mice. RNA sequencing identified multiple microRNAs with differential expression in CST kidneys, among which miR-147 was induced consistently in mouse kidney transplants and in dysfunctional human kidney grafts. Anti-miR-147 protected against CST injury in mice and ameliorated mitochondrial dysfunction after ATP depletion injury in renal tubular cells in intro . Mechanistically, miR-147 was shown to target NDUFA4, a key component of the mitochondrial respiration complex. Silencing NDUFA4 aggravated renal tubular cell death, whereas overexpression of NDUFA4 prevented miR-147-induced cell death and mitochondrial dysfunction. Moreover, overexpression of NDUFA4 alleviated CST injury in mice. CONCLUSIONS: microRNAs, as a class of molecules, are pathogenic in CST injury and graft dysfunction. Specifically, miR-147 induced during CST represses NDUFA4, leading to mitochondrial damage and renal tubular cell death. These results unveil miR-147 and NDUFA4 as new therapeutic targets in kidney transplantation.

Novel role of PE_PGRS47 in the alteration of mycobacterial cell wall integrity and drug resistance.

The proline-glutamic acid and proline-proline-glutamic acid (PE/PPE) family of proteins is widespread in pathogenic mycobacteria and plays different roles in mycobacterial physiology. While several PE/PPE family proteins have been studied, the exact function of most PE/PPE proteins in the physiology of Mycobacterium tuberculosis (Mtb) remains unknown. PE_PGRS47 belongs to the PE/PPE family of proteins reported to help Mtb evade protective host immune responses. In this study, we demonstrate a novel role of PE_PGRS47. Heterologous expression of the pe_pgrs47 gene in a non-pathogenic Mycobacterium smegmatis, intrinsically deficient of PE_PGRS protein, exhibits modulated colony morphology and cell wall lipid profile leading to a marked susceptibility to multiple antibiotics and environmental stressors. Using ethidium bromide/Nile red uptake assays, Mycobacterium smegmatis expressing PE_PGRS47 showed higher cell wall permeability than the control strain. Overall, these data suggested that PE_PGRS47 is cell surface exposed and influences cell wall integrity and the formation of mycobacterial colonies, ultimately potentiating the efficacy of lethal stresses against mycobacteria.

The advancements in targets for ferroptosis in liver diseases.

Ferroptosis is a type of regulated cell death caused by iron overload and lipid peroxidation, and its core is an imbalance of redox reactions. Recent studies showed that ferroptosis played a dual role in liver diseases, that was, as a therapeutic target and a pathogenic factor. Therefore, herein, we summarized the role of ferroptosis in liver diseases, reviewed the part of available targets, such as drugs, small molecules, and nanomaterials, that acted on ferroptosis in liver diseases, and discussed the current challenges and prospects.

Decreased natural killer T-like cells correlated to disease activity in systemic lupus erythematosus.

OBJECTIVES: To evaluate the absolute numbers and frequencies of natural killer T-like (NKT-like) cells in systemic lupus erythematosus (SLE) and to characterize the possible role of the cells. METHODS: Seventy-nine patients with SLE together with 30 age- and sex-matched healthy controls were enrolled. Flow cytometric determination of peripheral NKT-like cells was carried out for all participants by detecting the absolute counts (Abs) and percentage (%) of CD3 + CD16 + CD56 + cells. Disease activity index, laboratory parameters, and clinical manifestations were collected. The correlation between the cells and these parameters was analyzed. RESULTS: SLE patients had, with respect to controls, considerably decreased values of NKT-like cells (P < 0.001 in both absolute number and percentage). The absolute number of NKT-like cells was found to have positive correlations with WBC, RBC, PLT, C3, C4, IgM and negative correlations with the disease duration, SLEDAI-2 K, anti-dsDNA, anti-nucleosome, anti-ribosomal protein, CRP, ESR. Meanwhile, it was found that the percentage values of NKT-like cells decreased in SLE patients with nephritis which was correlated with anti-ribosomal protein and CRP in comparison to SLE patients without nephritis. Moreover, an increase in the NKT-like cell counts was also observed in the patients with a clinical response to the treatment. CONCLUSIONS: The absolute counts and frequencies of NKT-like cells decreased in SLE patients significantly, which correlated to disease activities and could recover to normal after the treatment. The NKT-like cells may play an important role in the pathogenesis of SLE and could be a useful marker in the disease assessment. Key Points • The absolute counts and frequencies of NKT-like cells decreased in SLE patients significantly. • NKT-like cells were related to the disease activities and could restore after the treatment. • NKT-like cells may be a useful marker in the disease assessment.

A GAN model encoded by CapsEEGNet for visual EEG encoding and image reproduction.

In last few decades, reading the human mind is an innovative topic in scientific research. Recent studies in neuroscience indicate that it is possible to decode the signals of the human brain based on the neuroimaging data. The work in this paper explores the possibility of building an end-to-end BCI system to learn and visualize the brain thoughts evoked by the stimulating images. To achieve this goal, it designs an experiment to collect the EEG signals evoked by randomly presented images. Based on these data, this work analyzes and compares the classification abilities by several improved methods, including the Transformer, CapsNet and the ensemble strategies. After obtaining the optimal method to be the encoder, this paper proposes a distribution-to-distribution mapping network to transform an encoded latent feature vector into a prior image feature vector. To visualize the brain thoughts, a pretrained IC-GAN model is used to receive these image feature vectors and generate images. Extensive experiments are carried out and the results show that the proposed method can effectively deal with the small sample data original from the less electrode channels. By examining the generated images coming from the EEG signals, it verifies that the proposed model is capable of reproducing the images seen by human eyes to some extent.

Application of oXiris-continuous hemofiltration adsorption in patients with sepsis and septic shock: A single-centre experience in China.

oXiris is a new, high-adsorption membrane filter in continuous hemofiltration adsorption to reduce the inflammatory response in sepsis. The investigators retrospectively reviewed patients with sepsis/septic shock who underwent at least one oXiris-treatment from November 2020 to March 2022. The demographic data, baseline levels before treatment, clinical datas, prognosis, and the occurrence of adverse events during treatment were recorded. 90 patients were enrolled in this study. The hemodynamic indices, sequential organ failure assessment score, lactate, inflammatory biomarkers levels were significantly improved at 12 h and 24 h after treatment. Procalcitonin and interleukin-6 reduction post-treatment of oXiris were most pronounced in infection from skin and soft tissue, urinary and abdominal cavity. Logistic regression analysis showed that pre-treatment sequential organ failure assessment score (p = 0.034), percentage decrease in sequential organ failure assessment score (p = 0.004), and age (p = 0.011) were independent risk factors for intensive care unit mortality. In conclusion, oXiris-continuous hemofiltration adsorption may improve hemodynamic indicators, reduce the use of vasoactive drugs, reduce lactate level and infection indicators. Of note, oXiris improve organ function in sepsis, which may result to higher survival rate.

Tonsillar Microbiome-Derived Lantibiotics Induce Structural Changes of IL-6 and IL-21 Receptors and Modulate Host Immunity.

Emerging evidence emphasizes the functional impacts of host microbiome on the etiopathogenesis of autoimmune diseases, including rheumatoid arthritis (RA). However, there are limited mechanistic insights into the contribution of microbial biomolecules especially microbial peptides toward modulating immune homeostasis. Here, by mining the metagenomics data of tonsillar microbiome, a deficiency of the encoding genes of lantibiotic peptides salivaricins in RA patients is identified, which shows strong correlation with circulating immune cells. Evidence is provided that the salivaricins exert immunomodulatory effects in inhibiting T follicular helper (Tfh) cell differentiation and interleukin-21 (IL-21) production. Mechanically, salivaricins directly bind to and induce conformational changes of IL-6 and IL-21 receptors, thereby inhibiting the bindings of IL-6 and IL-21 to their receptors and suppressing the downstream signaling pathway. Finally, salivaricin administration exerts both prophylactic and therapeutic effects against experimental arthritis in a murine model of RA. Together, these results provide a mechanism link of microbial peptides-mediated immunomodulation.