Circ-IP6K2 suppresses tumor progression by modulating the miR-1292-5p/CAMK2N1 signal in clear cell renal cell carcinoma.

Renal cell carcinoma (RCC) is a malignant tumor originating from the epithelial cells of the renal tubules. The clear cell RCC subtype is closely linked to a poor prognosis due to its rapid progression. Circular RNA (circRNA) is a novel class of regulatory RNA molecules that play a role in the development of ccRCC, although their functions have not been fully elucidated. In this study, we identified a significant downregulation of circ-IP6K2 in ccRCC tissues based on data from the GSE100186 dataset. The decreased expression of circ-IP6K2 correlated with the progression of TNM stage and histological grade, and was also associated with decreased overall survival rates in ccRCC patients. Moreover, our findings revealed that circ-IP6K2 expression suppressed proliferation, migration, and invasion capabilities in vitro, and inhibited xenograft growth in vivo. Mechanistically, circ-IP6K2 acted as a sponge for miR-1292-5p in ccRCC cells, which in turn targeted the 3'UTR of CAMK2N1, leading to a decrease in its expression. CAMK2N1 was identified as a tumor suppressor that negatively regulated the ß-catenin/c-Myc oncogenic signaling pathway. Additionally, we confirmed a positive correlation between the expression of circ-IP6K2 and CAMK2N1 in ccRCC. Circ-IP6K2 functions to impede the progression of ccRCC by modulating the miR-1292-5p/CAMK2N1 axis. These findings shed new light on the molecular mechanisms driving ccRCC progression and suggest potential therapeutic targets for the treatment of ccRCC.

Ratiometric Imaging Detection of Amyloid-ß Fibrils by a Dual-Emissive Tris-Heteroleptic Ruthenium Complex.

Two dual fluorescent/phosphorescent tris-heteroleptic mononuclear Ru(ΙΙ) complexes (2 and 3) were designed and applied in amyloid-ß (Aß) sensing. These complexes have a general formula of [Ru(phen)(dppz)(L)](PF6)2, where L is (2-pyrazinyl)(2-pyridyl)(methyl)amine (H-L) with different substituents (-OMe for 2, -H for 3), phen is 1,10-phenanthroline, and dppz is dipyridophenazine, respectively. Compared with the previously reported ratiometric probe 1 with a di(pyrid-2-yl)(methyl)amine ligand, complex 2 can be employed for not only ratiometric emissive detection of Aß aggregation but also ratiometric imaging detection of Aß fibrils. In ratiometric emissive detection, as the incubation time of the Aß sample (Aß40 and Aß42) was prolonged, a new phosphorescence emission band appeared with gradual enhancement of the emission intensity, while the fluorescence emission was basically unchanged, which could be treated as an intrinsic internal reference signal. In comparison, a larger ratiometric photoluminescence enhancement (I640/I440) was observed for Aß40 aggregation with respect to Aß42. In ratiometric imaging detection, the imaging signals obtained from the phosphorescence emission are much brighter than the fluorescence emission in both Aß40 and Aß42 fibrils. As indicated by molecular docking results, stronger interactions were found between complex 2 with Aß40 fibrils, which included π/π, π/C-H, and π/H interactions between bidentate ligands dppz and phen with amino acid residues. Moreover, computational calculations were carried out to assist the interpretation of these experimental findings.

Development process and clinical application of collagenase chemonucleolysis in the treatment of lumbar disc herniation: a narrative review in China.

Lumbar disc herniation (LDH) is one of the most common causes of lumbocrural pain. In the past 20 years, the incidence of LDH has increased dramatically. There are many treatments for LDH, including conservative treatment (such as acupuncture and physiotherapy), minimally invasive interventional treatment (such as collagenase chemonucleolysis and radiofrequency ablation) and surgical treatment. The main purpose of this paper is to review the development process and application status of collagenase chemonucleolysis in the treatment of LDH at home and abroad and provide a reference for clinical treatment.

Development process and clinical application of collagenase chemonucleolysis in the treatment of lumbar disc herniation: a narrative review in China.

Lumbar disc herniation (LDH) is one of the most common causes of lumbocrural pain. In the past 20 years, the incidence of LDH has increased dramatically. There are many treatments for LDH, including conservative treatment (such as acupuncture and physiotherapy), minimally invasive interventional treatment (such as collagenase chemonucleolysis and radiofrequency ablation) and surgical treatment. The main purpose of this paper is to review the development process and application status of collagenase chemonucleolysis in the treatment of LDH at home and abroad and provide a reference for clinical treatment.

[Progress in application of adult endogenous neurogenesis in brain injury repair].

Persistent neurogenesis exists in the subventricular zone (SVZ) of the ventricles and the subgranular zone (SGZ) of the dentate gyrus of the hippocampus in the adult mammalian brain. Adult endogenous neurogenesis not only plays an important role in the normal brain function, but also has important significance in the repair and treatment of brain injury or brain diseases. This article reviews the process of adult endogenous neurogenesis and its application in the repair of traumatic brain injury (TBI) or ischemic stroke, and discusses the strategies of activating adult endogenous neurogenesis to repair brain injury and its practical significance in promoting functional recovery after brain injury.

Ketogenic diet protects myelin and axons in diffuse axonal injury.

BACKGROUND: Ketogenic diet (KD) has been identified as a potential therapy to enhance recovery after traumatic brain injury (TBI). Diffuse axonal injury (DAI) is a common type of traumatic brain injury that is characterized by delayed axonal disconnection. Previous studies showed that demyelination resulting from oligodendrocyte damage contributes to axonal degeneration in DAI. AIM: The present study tests a hypothesis that ketone bodies from the ketogenic diet confers protection for myelin and attenuates degeneration of demyelinated axon in DAI. METHODS: A modified Marmarou's model of DAI was induced in adult rats. The DAI rats were fed with KD and analyzed with western blot, transmission electron microscope, ELISA test and immunohistochemistry. Meanwhile, a co-culture of primary oligodendrocytes and neurons was treated with ketone body ß-hydroxybutryate (ßHB) to test for its effects on the myelin-axon unit. RESULTS: Here we report that rats fed with KD showed an increased fatty acid metabolism and ketonemia. This dietary intervention significantly reduced demyelination and attenuated axonal damage in rats following DAI, likely through inhibition of DAI-induced excessive mitochondrial fission and promoting mitochondrial fusion. In an in vitro model of myelination, the ketone body ßHB increased myelination significantly and reduced axonal degeneration induced by glucose deprivation (GD). ßHB robustly increased cell viability, inhibited GD-induced collapse of mitochondrial membrane potential and attenuated death of oligodendrocytes. CONCLUSION: Ketone bodies protect myelin-forming oligodendrocytes and reduce axonal damage. Ketogenic diet maybe a promising therapy for DAI.

Necrostatin-1 prevents the proapoptotic protein Bcl-2/adenovirus E1B 19-kDa interacting protein 3 from integration into mitochondria.

Necrostatin-1 (Nec-1) has previously been shown to protect neurons from death in traumatic and ischemic brain injuries. This study tests the hypothesis that Nec-1 protects neural cells against traumatic and ischemic brain injuries through inhibition of the Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3). We have used biochemical and morphological techniques to determine the inhibition of Nec-1 on BNIP3-induced cell death and to identify its mechanism of action in in vivo and in vitro models of neurodegeneration. Here we show that Nec-1 significantly increased neuronal viability following prolonged exposure to hypoxia in vitro, and attenuated myelin damage and neuronal death in traumatic brain injury and cerebral ischemia in Sprague-Dawley rats. Nec-1 alleviated traumatic brain injury-induced up-regulation of BNIP3 in mature oligodendrocytes. In isolated mitochondria, Nec-1 prevented BNIP3 from integrating into mitochondria by modifying its binding sites on the mitochondria. Consequently, Nec-1 robustly inhibited BNIP3-induced collapse of mitochondrial membrane potential and reduced the opening probability of mitochondrial permeability transition pores. Nec-1 also preserved mitochondrial ultrastructure and suppressed BNIP3-induced nuclear translocation of apoptosis-inducing factor. In conclusion, Nec-1 protects neurons and oligodendrocytes against traumatic and ischemic brain injuries by targeting the BNIP3-induced cell death pathway, and is a novel inhibitor for BNIP3. Cover Image for this issue: https://doi.org/10.1111/jnc.15056.

Isolation and molecular characterization of bovine herpesvirus 4 from cattle in mainland China.

Bovine herpesvirus 4 (BoHV-4) is one of the most important of the known viral respiratory and reproductive pathogens of both young and adult cattle. However, BoHV-4 has not been isolated or detected in mainland China prior to this study. In 2019, BoHV-4 strain 512 was isolated from cattle in Heilongjiang Province, China, using MDBK cells, and characterized by PCR, nucleotide sequence analysis, and transmission electron microscopy. Two other unknown herpesvirus strains, BL6010 and J4034, which were isolated from cattle in 2009 in China and stored at -70℃, were also propagated in MDBK cells and identified as BoHV-4 by PCR. Phylogenetic analysis based on partial nucleotide sequences of the thymidine kinase (TK) gene and glycoprotein B (gB) gene for the three isolates indicated that these three Chinese strains belong to BoHV-4 genotype 1. A preliminary virus neutralization test revealed that 64% of the 70 bovine sera (45/70) collected from Inner Mongolia Autonomous Region, China, had anti-BoHV-4 antibodies and that natural BoHV-4 infection occurred in cattle in China. Here, we report for the first time the isolation and molecular characterization of BoHV-4 from cattle in mainland China.

Fatal unexpected death due to familial hemophagocytic lymphohistiocytosis type 3.

Familial hemophagocytic lymphohistiocytosis is a rare autosomal recessive disorder of immune dysregulation associated with uncontrolled activation of cytotoxic T cells and macrophages. Herein, we report a case of a 14-month-old Chinese boy who presented with fever, abdominal distension and thrombopenia, and died within 3 days of admission to the hospital. Postmortem examination revealed pleuroperitoneal fluid, enlarged mesenteric lymph nodes and hepatosplenomegaly. Histopathological examination showed interstitial pneumonia, hepatonecrosis and hemophagocytosis. Immunohistochemical staining of the spleen, lymph node and liver specimens revealed numerous cytotoxic T cells (CD8+) and histiocytes (CD68+). EBER1-positive cells were observed in lymphocytes of the spleen, lymph node, liver and lungs by in situ hybridization. UNC13D mutation was identified, although the boy had no family history. The following medico-legal autopsy case is being reported for its rarity in the forensic setting. We addresses the need for genetic testing in addition to a thorough clinical history, appropriate laboratory tests, histological examination and immunohistochemical analysis for the rapid and accurate diagnosis of familial hemophagocytic lymphohistiocytosis.

Methamphetamine-induced toxic leukoencephalopathy: clinical, radiological and autopsy findings.

Toxic leukoencephalopathy represents a process of structural alteration of the white matter. It is caused by substance abuse including drugs such as heroin, cocaine, toluene and ethanol. We reported the clinical, radiological and autopsy findings of a rare case of toxic leukoencephalopathy following chronic methamphetamine (MA) usage. A 34-year-old man with a 3-year history of MA abuse experienced progressive sluggish state, limb weakness, inability to stand and eating disorders, followed by rapid progression to coma and death. Imaging revealed hypodense CT and long T1 and T2 signals in MRI in the white matter of the bilateral periventricular and centrum semiovale regions. Histologically, white matter rarefaction, loss of myelin and axonal injury were observed. This pattern of clinical presentation, radiological manifestations and histological findings show a certain degree of particularity in toxic leukoencephalopathy. Clinically, the condition may be easily misdiagnosed as withdrawal symptoms. In suspected cases, MRI is recommended for diagnosis. The case reported here reminds clinicians and forensic pathologist of the possibility of toxic leukoencephalopathy related to MA abuse.

Role of EFNB2/EPHB4 signaling in spiral artery development during pregnancy: An appraisal.

EFNB2 and EPHB4, which belong to a large tyrosine kinase receptor superfamily, are molecular markers of arterial and venous blood vessels, respectively. EFNB2/EPHB4 signaling plays an important role in physiological and pathological angiogenesis, and its role in tumor vessel development has been extensively studied. Pregnancy and tumors share similar features, including continuous cell proliferation and increased demand for a blood supply. Our previous studies showed that Efnb2 and Ephb4 were expressed dynamically in the spiral arteries, uterine natural killer cells, and trophoblasts during mouse gestation Days 6.5-12.5. Moreover, uterine natural killer cells and trophoblasts are required for the modification of spiral arteries. Oxygen tension within the pregnant uterus, which contributes to the vascular development, also affects EFNB2 and EPHB4 expression. Considering the role of EFNB2/EPHB4 signaling in embryonic and tumor vascular development, and its dynamic expression in the decidua and placenta, we hypothesize that EFNB2 and EPHB4 are involved in the regulation of spiral artery remodeling. Investigating this hypothesis will help clarify the mechanisms of pathological pregnancy that may underlie abnormal spiral artery development.

A rare type of drowning with a latent period following surviving an episode of immersion.

Drowning is a leading cause of accidental death worldwide and its diagnosis is an important part of forensic investigation. It is generally acknowledged that hypoxia due to airway obstruction by fluid is the primary mechanism of death in drowning. Drowned individuals are usually found dead in the water or show severe clinical signs once out of the water. However, sudden death due to drowning after a short period of recovery following immersion/submersion has rarely been reported. A case of a 40-year-old man who died suddenly due to severe pulmonary edema about 40 min after he was recovered from an episode of immersion is reported. We suspected delayed lung injury due to water aspiration as the prime cause of death. This rare type of drowning should be well recognized by a clinician or forensic pathologist.

ER stress triggers MCP-1 expression through SET7/9-induced histone methylation in the kidneys of db/db mice.

Epigenetics plays a key role in the pathogenesis of diabetic nephropathy (DN), although the precise regulatory mechanism is still unclear. Here, we examined the role of endoplasmic reticulum (ER) stress in histone H3 lysine 4 (H3K4) methyltransferase SET7/9-induced monocyte chemoattractant protein-1 (MCP-1) expression in the kidneys of db/db mice. Our results indicate that the expression of MCP-1 significantly increased in the kidneys of db/db mice in a time-dependent manner. An increased chromatin mark associated with an active gene (H3K4me1) at MCP-1 promoters accompanied this change in expression. The expression of SET7/9 and the recruitment to these promoters were also elevated. SET7/9 gene silencing with small interfering (si) RNAs significantly attenuated the expression of H3K4me1 and MCP-1. Furthermore, expression of signaling regulator glucose-regulated protein 78 (GRP78), a monitor of ER stress, significantly increased in the kidneys of db/db mice. The expression of spliced X-box binding protein 1 (XBP1s), an ER stress-inducible transcription factor, and recruitment to the SET7/9 promoters were also increased. XBP1s gene silencing with siRNAs significantly attenuated the expression of SET7/9, H3K4me1, and MCP-1. The chaperone betaine not only effectively downregulated the GRP78 and XBP1s expression levels but also markedly decreased the SET7/9, H3K4me1, and MCP-1 levels. Luciferase reporter assay demonstrated that XBP1s participated in ER stress-induced SET7/9 transcription, Taken together, these results reveal that ER stress can trigger the expression of MCP-1, in part through the XBP1s-mediated induction of SET7/9.

[Effects of BMAL2 on Aerobic Glycolysis and Cell Proliferation in Acute Myeloid Leukemia Cells].

OBJECTIVE: To explore the expression of basic helix-loop-helix ARNT like 2 (BMAL2) in acute myeloid leukemia (AML) patients and its correlation with prognosis, and analyze its effects on the aerobic glycolysis and proliferation of AML cells. METHODS: The expressions of BMAL2 in bone marrow mononuclear cells (BMMCs) of AML patients and normal control group were detected by RT-qPCR. The correlation of BMAL2 expression with prognosis of AML patients was analyzed using public database of National Center for Biotechnology Information (NCBI). The interfering in BMAL2 expression of HL-60 and Kasumi-1 cells was performed using lentiviral vector-mediated shRNA. Cell glucose metabolism and proliferation were detected by using glucose uptake experiment, lactate content test, CCK-8 assay and cell colony formation test. RESULTS: The expression level of BMAL2 mRNA in BMMCs of AML patients was significantly higher than normal control group (P < 0.01). The overall survival time of AML patients with high expression of BMAL2 was significantly shorter than those with low expression of BMAL2 (P < 0.05). Knockdown of BMAL2 significantly reduced glucose uptake and lactate production in AML cell line HL-60 and Kasumi-1 cells. The results of RT-PCR and Western blot showed that BMAL2 promoted aerobic glycolysis by enhancing the expression of HIF1A in AML cells, thereby promoting cell proliferation. CONCLUSION: BMAL2 is highly expressed in AML patients, and promotes aerobic glycolysis by enhancing the expression of HIF1A, thereby promoting cell proliferation.

SPAG6 regulates cell proliferation and apoptosis via TGF-ß/Smad signal pathway in adult B-cell acute lymphoblastic leukemia.

Adult B-cell acute lymphoblastic leukemia (B-ALL) prognosis remains unsatisfactory, and searching for new therapeutic targets is crucial for improving patient prognosis. Sperm-associated antigen 6 (SPAG6), a member of the cancer-testis antigen family, plays an important role in tumors, especially hematologic tumors; however, it is unknown whether SPAG6 plays a role in adult B-ALL. In this study, we demonstrated for the first time that SPAG6 expression was up-regulated in the bone marrow of adult B-ALL patients compared to healthy donors, and expression was significantly reduced in patients who achieved complete remission (CR) after treatment. In addition, patients with high SPAG6 expression were older (≥ 35 years; P = 0.015), had elevated white blood cell counts (WBC > 30 × 109/L; P = 0.021), and a low rate of CR (P = 0.036). We explored the SPAG6 effect on cell function by lentiviral transfection of adult B-ALL cell lines BALL-1 and NALM-6, and discovered that knocking down SPAG6 significantly inhibited cell proliferation and promoted apoptosis. We identified that SPAG6 knockdown might regulate cell proliferation and apoptosis via the transforming growth factor-ß (TGF-ß)/Smad signaling pathway.

Current Applications of Colorectal Cancer Organoids: A Review.

Colorectal cancer is a prevalent malignancy, with advanced and metastatic forms exhibiting poor treatment outcomes and high relapse rates. To enhance patient outcomes, a comprehensive understanding of the pathophysiological processes and the development of targeted therapies are imperative. The high heterogeneity of colorectal cancer demands precise and personalized treatment strategies. Colorectal cancer organoids, a three-dimensional in vitro model, have emerged as a valuable tool for replicating tumor biology and exhibit promise in scientific research, disease modeling, drug screening, and personalized medicine. In this review, we present an overview of colorectal cancer organoids and explore their applications in research and personalized medicine, while also discussing potential future developments in this field.

[Forensic analysis of death caused by fat embolism: A study of 20 autopsy cases].

OBJECTIVE: To analyze the general and forensic pathological characteristics of death due to fat embolism syndrome (FES) and to provide reference data for forensic identification. METHODS: Twenty autopsy cases due to FES were selected from the forensic center of a medical college from 1999 to 2012. The general and forensic pathological characteristics such as the ways and types of injuries, clinical manifestation and the pathological changes were summarized. RESULTS: Fat embolism mainly occurred after long bone fracture or a large area of soft tissue injury with the majority of cases being fat embolism of lung and occasional cases being combined embolisms of lung and brain as well. The onset of symptoms appeared shortly after the injury or surgery. Lipid droplets could be observed within small pulmonary vessels and verified by special staining. CONCLUSION: There are particular characteristics in death due to FES in concern with types of injuries, onset of symptoms and pathological findings. In order to find out the direct evidence of FES, special staining (oil red O staining) can be used in the forensic identification.

Efficacy of Flumatinib in CML Patients with F359V/C Mutation.

The BCR-ABL mutation is the main cause of tyrosine kinase inhibitors(TKI) resistance. The second-generation TKI can overcome most of the mutations. However, both dasatinib and nilotinib have a unique set of mutants with reduced sensitivity. All TKIs are associated with adverse events, which lead to treatment discontinuation and affect the quality of life of patients. Flumatinib showed higher activity against BCR-ABL mutants in vitro. Drug-related adverse events of flumatinib were mainly grade 1 or grade 2 events. There is no study that reported the efficacy of flumatinib against F359V/C mutation.We report two cases of chronic myelocytic leukemia(CML) patients with F359V/C mutation resistance to Imatinib therapy. One patient with F359V mutation was shifted to Dasatinib. Repeated massive pleural effusion and anemia occurred after Dasatinib treatment, forcing drug dosage reduction or withdrawal, affecting drug efficacy and quality of life of patient. Two patients were shifted to Flumatinib. MR4 was achieved and F359V/C mutation was not detected after treatment with Flumatinib. There was no significant side effect. The patients had a high quality of life. Flumatinib is effective against F359V/C mutation, has less drugrelated adverse reactions. Flumatinib may be a better choice for patients with F359V/C mutation. Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-022-01585-3.

Serum galactose-deficient immunoglobulin A1 in recurrent immunoglobulin a nephropathy after kidney transplantation: A meta-analysis.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is a main cause of end stage renal disease (ESRD). Many IgAN patients with ESRD accept kidney allograft for renal replacement. However, disease recurrence occurs after transplantation. Galactose-deficient immunoglobulin A1(Gd-IgA1) has been proved to be a crucial biomarker in the primary IgAN population. METHODS: This meta-analysis aimed to explore the association between serum Gd-IgA1 and IgAN recurrence after renal transplantation and was registered on PROSPERO: CRD42022356952; A literature search was performed and relevant studies were retrieved from the PubMed, Embase and Cochrane library databases from inception to April 27, 2023. The inclusion criteria were: 1) full-text studies; 2) patients with histological diagnosis of IgAN of their native kidneys who underwent kidney transplantation; 3) studies exploring the relationship between serum Gd-IgA1 and IgAN recurrence after kidney transplantation. The exclusion criteria were: 1) reviews, case reports, or non-clinical studies. 2) studies with insufficient original data or incomplete data. 3) studies with duplicated data. Study quality was assessed using Newcastle Ottawa Scale (NOS). Data were pooled using a random-effects model. RESULTS: 8 full-text studies including 515 patients were identified. The Newcastle-Ottawa Scale (NOS) score ranged from 6 to 8. The standard mean difference (SMD) of the level of Gd-IgA1 was significantly higher in recurrence group than in non-recurrence group (SMD = 0.50，95%CI = 0.15-0.85, p = 0.005). Furthermore, Gd-IgA1 levels were higher in recurrence patients than in non-recurrence in both Europe subgroup (SMD 0.45, 95%CI: 0.08-0.82, p = 0.02) and Asia subgroup (SMD 0.90, 95%CI: 0.10-1.70, p = 0.03). However, pretransplant Gd-IgA1 levels showed no significant difference between recurrence and non-recurrence group (SMD 0.46, 95%CI: 0.06-0.99, p = 0.08) in anther subgroup analysis while posttransplant Gd-IgA1 levels were significantly higher in recurrence population than in non-recurrence (SMD 0.57, 95%CI 0.21 to 0.92, p = 0.002). CONCLUSIONS: This meta-analysis showed that posttransplant serum Gd-IgA1 levels are associated with IgAN recurrence after kidney transplantation; however, pretransplant serum Gd-IgA1 levels are not.

Non-human primate models of focal cortical ischemia for neuronal replacement therapy.

Despite the high prevalence, stroke remains incurable due to the limited regeneration capacity in the central nervous system. Neuronal replacement strategies are highly diverse biomedical fields that attempt to replace lost neurons by utilizing exogenous stem cell transplants, biomaterials, and direct neuronal reprogramming. Although these approaches have achieved encouraging outcomes mostly in the rodent stroke model, further preclinical validation in non-human primates (NHP) is still needed prior to clinical trials. In this paper, we briefly review the recent progress of promising neuronal replacement therapy in NHP stroke studies. Moreover, we summarize the key characteristics of the NHP as highly valuable translational tools and discuss (1) NHP species and their advantages in terms of genetics, physiology, neuroanatomy, immunology, and behavior; (2) various methods for establishing NHP focal ischemic models to study the regenerative and plastic changes associated with motor functional recovery; and (3) a comprehensive analysis of experimentally and clinically accessible outcomes and a potential adaptive mechanism. Our review specifically aims to facilitate the selection of the appropriate NHP cortical ischemic models and efficient prognostic evaluation methods in preclinical stroke research design of neuronal replacement strategies.