Advances and challenges in identifying and characterizing G-quadruplex-protein interactions.

G-quadruplexes (G4s) are peculiar nucleic acid secondary structures formed by DNA or RNA and are considered as fundamental features of the genome. Many proteins can specifically bind to G4 structures. There is increasing evidence that G4-protein interactions involve in the regulation of important cellular processes, such as DNA replication, transcription, RNA splicing, and translation. Additionally, G4-protein interactions have been demonstrated to be potential targets for disease treatment. In order to unravel the detailed regulatory mechanisms of G4-binding proteins (G4BPs), biochemical methods for detecting G4-protein interactions with high specificity and sensitivity are highly demanded. Here, we review recent advances in screening and validation of new G4BPs and highlight both their features and limitations.

Characteristics of innate and adaptive immune disorder in IgA nephropathy based on integrated bioinformatics.

BACKGROUND: Our study aims to investigate the immunological pathogenesis underlying immunoglobulin A nephropathy (IgAN) and explore potential biomarkers for IgAN diagnosis. MATERIALS AND METHODS: Differentially expressed genes (DEGs) of formalin-fixed and paraffin-embedded (FFPE) samples were screened between IgAN patients and healthy people based on GSE115857. Gene oncology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) enrichment was performed to identify related biological processes and pathways. CIBERSORT was utilized to seek the relationship of immune cell infiltration with IgAN. Finally, the expression of paraoxonase 2 (PON2) related to innate immune response was verified in FFPE samples of minimal change disease and IgAN patients by immunohistochemistry and PAS staining. RESULTS: 25 down-regulated genes and 12 up-regulated genes were identified in IgAN patients, which mainly responded to endothelial cell proliferation, inflammatory response, and angiogenesis. Toll-like receptor signaling pathway and Epstein-Barr virus (EBV) infection might be involved in IgAN pathogenesis. In addition, the infiltration of macrophages M0, naïve B cells, and follicular helper T (Tfh) cells was positively correlated in IgAN patients. Macrophages M1 and M2 infiltration were up-regulated in IgAN patients, which indicated that innate immune response was closely associated with IgAN. Besides, the results of immunohistochemistry showed that PON2 was obviously positively expressed in acute and chronic lesions of IgAN patients. CONCLUSION: In addition to abnormalities in the adaptive immune response, macrophages M1/M2 and innate immune disorder may participate in IgAN pathogenesis. PON2 may become the feasible targets for further investigation of IgAN.

Discovery of A G-Quadruplex Unwinder That Unleashes the Translation of G-Quadruplex-Containing mRNA without Inducing DNA Damage.

To explore the mechanisms and therapeutic strategies for G-quadruplex (G4) mediated diseases, it is crucial to manipulate and intervene in intracellular G4 structures using small molecular tools. While hundreds of G4 stabilizers have been developed, there is a significant gap in the availability of G4 unwinding agents. Here, we propose a strategy to disrupt G-quadruplexes by forming G-C hydrogen bonds with chemically modified cytidine trimers. We validated a good G4 unwinder, the 2'-F cytidine trimer (2'-F C3). 2'-F C3 does not inhibit cell growth nor cause severe DNA damage at a concentration below 10 µM. Moreover, 2'-F C3 does not affect gene transcription nor RNA splicing, while it significantly enhances the translation of G4-containing mRNA and upregulates RNA splicing, RNA processing and cell cycle pathways. The discovery of this G4 unwinder provides a functional tool for the chemical modulation of G4s in living cells.

[Exploring the mechanism of IgA vasculitis pathogenesis through the interaction of thrombin and inflammatory factors using urinary proteomics]. / è¿ç”¨å°¿è›‹ç™½ç»„å­¦æŠ€æœ¯æŽ¢ç´¢å‡è¡€é ¶ä¸Žç‚Žç—‡å› å­ç›¸äº’ä½œç”¨å‚ä¸ŽIgAè¡€ç®¡ç‚Žå‘ç— çš„æœºåˆ¶.

OBJECTIVES: To explore the evidence, urinary biomarkers, and partial mechanisms of hypercoagulability in the pathogenesis of IgA vasculitis (IgAV). METHODS: Differential expression of proteins in the urine of 10 healthy children and 10 children with IgAV was screened using high-performance liquid chromatography-tandem mass spectrometry, followed by Reactome pathway analysis. Protein-protein interaction (PPI) network analysis was conducted using STRING and Cytoscape software. In the validation cohort, 15 healthy children and 25 children with IgAV were included, and the expression levels of differential urinary proteins were verified using enzyme-linked immunosorbent assay. RESULTS: A total of 772 differential proteins were identified between the IgAV group and the control group, with 768 upregulated and 4 downregulated. Reactome pathway enrichment results showed that neutrophil degranulation, platelet activation, and hemostasis pathways were involved in the pathogenesis of IgAV. Among the differential proteins, macrophage migration inhibitory factor (MIF) played a significant role in neutrophil degranulation and hemostasis, while thrombin was a key protein in platelet activation and hemostasis pathways. PPI analysis indicated that thrombin directly interacted with several proteins involved in inflammatory responses, and these interactions involved MIF. Validation results showed that compared to healthy children, children with IgAV had significantly higher urine thrombin/creatinine and urine MIF/creatinine levels (P<0.05). CONCLUSIONS: Thrombin contributes to the pathogenesis of IgAV through interactions with inflammatory factors. Urinary thrombin and MIF can serve as biomarkers reflecting the hypercoagulable and inflammatory states in children with IgAV.

Optimization of Selective Assembly for Shafts and Holes Based on Relative Entropy and Dynamic Programming.

Selective assembly is the method of obtaining high precision assemblies from relatively low precision components. For precision instruments, the geometric error on mating surface is an important factor affecting assembly accuracy. Different from the traditional selective assembly method, this paper proposes an optimization method of selective assembly for shafts and holes based on relative entropy and dynamic programming. In this method, relative entropy is applied to evaluate the clearance uniformity between shafts and holes, and dynamic programming is used to optimize selective assembly of batches of shafts and holes. In this paper, the case studied has 8 shafts and 20 holes, which need to be assembled into 8 products. The results show that optimal combinations are selected, which provide new insights into selective assembly optimization and lay the foundation for selective assembly of multi-batch precision parts.

NLRP3 inflammasome pathway is involved in olfactory bulb pathological alteration induced by MPTP.

Olfactory bulb, as one of sensory organs opening to the outside, is susceptible to toxic environment and easy to deteriorate. Recent studies in Parkinson's disease (PD) patients and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys have shown that abnormal α-synuclein is accumulated in the olfactory glomeruli, suggesting that the lesions of PD are not only confined to the substantia nigra (SN) but also located in the olfactory bulb. Thus, olfactory bulb might be the region of onset in PD pathogenesis and a targeted region for diagnosis and treatment of PD. However, the relationship between olfactory bulb and pathogenesis of PD remains unclear. In the present study, we investigated the inflammatory pathological alterations in olfactory bulb and the underlying mechanisms in chronic MPTP mice. Mice were treated with MPTP/P, i.e., MPTP (25 mg/kg, s.c.) plus probenecid (250 mg/kg, i.p.) every 4 days, for ten times. The mice displayed typical parkinsonian syndrome. Then we examined their olfactory function and the pathologic changes in olfactory bulb. The mice showed obvious olfactory dysfunction in a buried pellet test. Immunohistochemical studies revealed that tyrosine hydroxylase (TH) protein levels were significantly decreased, whereas abnormal α-synuclein was significantly increased in the olfactory bulbs. Furthermore, the olfactory bulbs in MPTP/P-treated mice showed significantly increased levels of interleukin-1ß (IL-1ß), caspase-1, glial fibrillary acidic protein (GFAP), Toll receptor 4 (TLR4), phosphorylation of p65, as well as activated molecules of NOD-like receptor protein 3 (NLRP3) that were associated with neuroinflammation. Our results demonstrate that MPTP/P-caused olfactory bulb damage might be related to NLRP3-mediated inflammation.

Spatial⁻Temporal Variations in NO2 and PM2.5 over the Chengdu⁻Chongqing Economic Zone in China during 2005⁻2015 Based on Satellite Remote Sensing.

The Chengdu⁻Chongqing Economic Zone (CCEZ), which is located in southwestern China, is the fourth largest economic zone in China. The rapid economic development of this area has resulted in many environmental problems, including extremely high concentrations of nitrogen dioxide (NO2) and fine particulate matter (PM2.5). However, current ground observations lack spatial and temporal coverage. In this study, satellite remote sensing techniques were used to analyze the variation in NO2 and PM2.5 from 2005 to 2015 in the CCEZ. The Ozone Monitoring Instrument (OMI) and the Moderate Resolution Imaging Spectroradiometer (MODIS) aerosol optical depth (AOD) product were used to retrieve tropospheric NO2 vertical columns and estimate ground-level PM2.5 concentrations, respectively. Geographically, high NO2 concentrations were mainly located in the northwest of Chengdu and southeast of Chongqing. However, high PM2.5 concentrations were mainly located in the center areas of the basin. The seasonal average NO2 and PM2.5 concentrations were both highest in winter and lowest in summer. The seasonal average NO2 and PM2.5 were as high as 749.33 × 1013 molecules·cm-2 and 132.39 µg·m-3 in winter 2010, respectively. Over 11 years, the annual average NO2 and PM2.5 values in the CCEZ increased initially and then decreased, with 2011 as the inflection point. In 2007, the concentration of NO2 reached its lowest value since 2005, which was 230.15 × 1013 molecules·cm-2, and in 2015, the concentration of PM2.5 reached its lowest value since 2005, which was 26.43 µg·m-3. Our study demonstrates the potential use of satellite remote sensing to compensate for the lack of ground-observed data when quantitatively analyzing the spatial⁻temporal variations in regional air quality.

A Novel Bibenzyl Compound (20C) Protects Mice from 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine/Probenecid Toxicity by Regulating the α-Synuclein-Related Inflammatory Response.

The novel bibenzyl compound 2-[4-hydroxy-3-(4- hydroxyphenyl) benzyl]-4-(4- hydroxyphenyl) phenol (20C) plays a neuroprotective role in vitro, but its effects in vivo have not yet been elucidated. In this study, we estimated the efficacy of 20C in vivo using a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid (MPTP/p) mouse model from behavior, dopamine, and neuron and then the possible mechanisms for these effects were further investigated. The experimental results showed that 20C improved behavioral deficits, attenuated dopamine depletion, reduced dopaminergic neuron loss, protected the blood-brain barrier (BBB) structure, ameliorated α-synuclein dysfunction, suppressed glial activation, and regulated both nuclear factor-κB (NF-κB) signaling and the NOD-like receptor protein (NLRP) 3 inflammasome pathway. Our results indicated that 20C may prevent neurodegeneration in the MPTP/p mouse model by targeting α-synuclein and regulating α-synuclein-related inflammatory responses, including BBB damage, glial activation, NF-κB signaling, and the NLRP3 inflammasome pathway.

Reassessment of subacute MPTP-treated mice as animal model of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model remains the most commonly used animal model of Parkinson's disease (PD). There are three MPTP-treatment schemes: acute, subacute and chronic. Considering the advantages of the period and similarity to PD, the subacute model was often chosen to assess the validity of new candidates, but the changes caused by the subacute MPTP treatment and the appropriate positive control for this model remain to be further confirmed. The aim of this study was: to estimate the value of the subacute MPTP mouse model in aspects of behavioral performance, biochemical changes and pathological abnormalities, and to find effective positive drugs. Male C57BL/6 mice were injected with MPTP (30 mg·kg-1·d-1, ip) for 5 consecutive days. Three days before MPTP injection, the mice were orally administered selegiline (3 mg·kg-1·d-1), pramipexole (3 mg·kg-1·d-1), or medopar (100 mg·kg-1·d-1) for 18 days. Behavioral performance was assessed in the open field test, pole test and rotarod test. Neurotransmitters in the striatum were detected using HPLC. Protein levels were measured by Western blot. Pathological characteristics were examined by immunohistochemistry. Ultrastructure changes were observed by electron microscopy. The subacute MPTP treatment did not induce evident motor defects despite severe injuries in the dopaminergic system. Additionally, MPTP significantly increased the α-synuclein levels and the number of astrocytes in the striatum, and destroyed the blood-brain barrier (BBB) in the substantia nigra pars compacta. Both selegiline and pramipexole were able to protect the mice against MPTP injuries. We conclude that the subacute MPTP mouse model does not show visible motor defects; it is not enough to evaluate the validity of a candidate just based on behavioral examination, much attention should also be paid to the alterations in neurotransmitters, astrocytes, α-synuclein and the BBB. In addition, selegiline or pramipexole is a better choice than medopar as an effective positive control for the subacute MPTP model.

Granulomatosis with polyangiitis presenting headache: A case report and review of literature.

RATIONALE: Central nervous system involvement is a rare manifestation of active-phaselocalized Granulomatosis with polyangiitis (GPA). In hypertrophic dura meningitis, GPA with headache is typical. In this case, cerebral magnetic resonance (MR) enhancement revealed no meningeal thickening, to our knowledge, this manifestation had not been found previously. PATIENT CONCERNS: The patient presented to the Rheumatology and Immunology Clinic with severe headache and hearing loss, and central nervous system granulomatosis with polyangiitis was confirmed after a series of examinations. The patient had no significant effect after treatment with cyclophosphamide (CTX), but after the use of rituximab, the headache and hearing loss were significantly improved, and laboratory indicators returned to normal levels. DIAGNOSIS: We comprehensively screened for craniocerebral infection and malignant tumors, diagnosed central nervous system granulomatosis with polyangiitis. INTERVENTIONS: We gave sequential treatment of rituximab. OUTCOMES: All indicators are mostly back to normal when the patient was monitored at the outpatient clinic. LESSONS: GPA and severe headache are more prevalent in hypertrophic dura meningitis, but the patient early headache could not be explained by hypertrophic dura meningitis or localized granulomatous lesions that invaded the central nervous system. Patients with severe headaches likely have vascular inflammation and local bone destruction at the base of the skull.

The application value of a vendor-specific deep learning image reconstruction algorithm in "triple low" head and neck computed tomography angiography.

Background: Head and neck computed tomography angiography (CTA) technology has become the noninvasive imaging method of choice for the diagnosis and long-term follow-up of vascular lesions of the head and neck. However, issues of radiation safety and contrast nephropathy associated with CTA examinations remain concerns. In recent years, deep learning image reconstruction (DLIR) algorithms have been increasingly used in clinical studies, demonstrating their potential for dose optimization. This study aimed to investigate the value of using a DLIR algorithm to reduce radiation and contrast doses in head and neck CTA. Methods: A total of 100 patients were prospectively enrolled and randomly divided into two groups. Group A (50 patients) consisted of those who underwent 70-kVp CTA with a low contrast volume and injection rate and who were classified according to the reconstruction algorithm into subgroups A1 [DLIR at high weighting (DLIR-H)], A2 [DLIR at low weighting (DLIR-L)], and A3 [volume-based adaptive statistical iterative reconstruction with 50% weighting (ASIR-V50%)]. Meanwhile, group B (50 patients) consisted of those who underwent standard radiation and contrast doses at 100 kVp with ASIR-V50% reconstruction. The computed tomography (CT) attenuation, background noise, signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and subjective image quality score (SIQS) were statistically compared for several vessels among the four groups. Results: Group A showed significant reductions in contrast dosage, injection rate, and radiation dose of 36.09%, 20.88%, and 47.80%, respectively, compared to group B (all P<0.001). The four groups differed significantly in terms of background noise (all P<0.05) with group A1 having the lowest value. Group A1 also had significantly higher SNR and CNR values compared to group B in all vessels (all P<0.05) except the M1 of the middle cerebral artery for the SNR. Group A1 also had the highest SIQS, followed by the A2, B, and A3 groups. The SIQS showed good agreement between the two reviewers in all groups, with κ values between 0.88 and 1. Conclusions: Compared to the standard-dose protocol using 100 kVp and ASIR-V50%, a protocol of 70 kVp combined with DLIR-H significantly reduces the radiation dose, contrast dose, and injection rate in head and neck CTA while still significantly improving image quality for patients with a standard body size.

Staphylococcus aureus acquires resistance to glycopeptide antibiotic vancomycin via CXCL10.

BACKGROUND: Glycopeptide antibiotic vancomycin is a bactericidal antibiotic available for the infection to Staphylococcus aureus (SA), however, SA has a strong adaptive capacity and thereby acquires resistance to vancomycin. This study aims to illuminate the possible molecular mechanism of vancomycin resistance of SA based on the 16S rRNA sequencing data and microarray profiling data. METHODS: 16S rRNA sequencing data of control samples and urinary tract infection samples were retrieved from the EMBL-EBI (European Molecular Biology Laboratory - European Bioinformatics Institute) database. Correlation of gut flora and clinical indicators was evaluated. The possible targets regulated by SA were predicted by microarray profiling and subjected to KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analysis. CXCL10 gene knockout and overexpression were introduced to evaluate the effect of CXCL10 on the virulence of SA and the resistance to vancomycin. SA strains were co-cultured with urethral epithelial cells in vitro. The presence of SA virulence factors was detected using PCR. Biofilm formation of SA strains was assessed using the microtiter plate method. Furthermore, the antibiotic sensitivity of SA strains was evaluated through vancomycin testing. RESULTS: Gut flora and its species abundance had significant difference between urinary tract infection and control samples. SA was significantly differentially expressed in urinary tract infection samples. Resistance of SA to vancomycin mainly linked to the D-alanine metabolism pathway. SA may participate in the occurrence of urinary tract infection by upregulating CXCL10. In addition, CXCL10 mainly affected the SA resistance to vancomycin through the TLR signaling pathway. In vitro experimental results further confirmed that the overexpression of CXCL10 in SA increased SA virulence and decreased its susceptibility to vancomycin. In vitro experimental validation demonstrated that the knockout of CXCL10 in urethral epithelial cells enhanced the sensitivity of Staphylococcus aureus (SA) to vancomycin. CONCLUSION: SA upregulates the expression of CXCL10 in urethral epithelial cells, thereby activating the TLR signaling pathway and promoting resistance to glycopeptide antibiotics in SA.

Dihydroartemisinin inhibits the development of colorectal cancer by GSK-3ß/TCF7/MMP9 pathway and synergies with capecitabine.

Patients with colorectal cancer (CRC) suffer from poor prognosis and lack effective drugs. Dihydroartemisinin (DHA) has anti-cancer potential but the mechanism remains unclear. We elucidated the effects and mechanism of DHA on CRC development with the aim of providing an effective, low-toxicity drug and a novel strategy for CRC. Herein, proliferation assay, transwell assay, tube formation assay, metastasis models, PDX model and AOM/DSS model were used to reveal the effects of DHA on CRC. The key pathway and target were identified by RNA-seq, ChIP, molecular docking, pull down and dual-luciferase reporter assays. As a result, DHA showed a strong inhibitory effect on the growth, metastasis and angiogenesis of CRC with no obvious toxicity, and the inhibitory effect was similar to that of the clinical drug Capecitabine (Cap). Indeed, DHA directly targeted GSK-3ß to inhibit CRC development through the GSK-3ß/TCF7/MMP9 pathway. Meaningfully, DHA in combination with Cap enhanced the anti-cancer effect, and alleviated Cap-induced diarrhoea, immunosuppression and inflammation. In conclusion, DHA has the potential to be an effective and low-toxicity drug for the treatment of CRC. Furthermore, DHA in combination with Cap could be a novel therapeutic strategy for CRC with improved efficacy and reduced side effects.

The Interface Strengthening of Multi-Walled Carbon Nanotubes/Polylactic Acid Composites via the In-Loop Hybrid Manufacturing Method.

In this study, a new in-loop hybrid manufacturing method is proposed for fabricating multi-walled carbon nanotube (MWCNTs)/polylactic acid (PLA) composites. Molecular dynamics simulations were conducted in conjunction with experiments to reveal the mechanism of the proposed method for improving the interfacial performance of MWCNTs/PLA. The superposed gradients in the PLA chain activity and conformation due to the plasma-actuating MWCNTs promoted intermolecular interaction and infiltration between the MWCNTs and PLA chains, forming an MWCNTs-stress-transfer bridge in the direction perpendicular to the interlayer interface, and finally enhancing the performance of the composites. The experimental results indicated that the interfacial shear strength of the specimen fabricated using the proposed method increased by 30.50% to 43.26 MPa compared to those without the addition of MWCNTs, and this value was 4.77 times higher than that of the traditional manufacturing method, demonstrating the effectiveness of the proposed method in improving the interfacial properties of MWCNTs/PLA composites.

Improving the Mechanical Properties of CCFRPLA by Enhancing the Interface Binding Energy and Strengthening the Anti-Separation Ability of a PLA Matrix.

Additive manufacturing (AM) can produce almost any product shape through layered stacking. The usability of continuous fiber-reinforced polymers (CFRP) fabricated by AM, however, is restricted owing to the limitations of no reinforcing fibers in the lay-up direction and weak interface bonding between the fibers and matrix. This study presents molecular dynamics in conjunction with experiments to explore how ultrasonic vibration enhances the performance of continuous carbon fiber-reinforced polylactic acid (CCFRPLA). Ultrasonic vibration improves the mobility of PLA matrix molecular chains by causing alternative fractures of chains, promoting crosslinking infiltration among polymer chains, and facilitating interactions between carbon fibers and the matrix. The increase in entanglement density and conformational changes enhanced the density of the PLA matrix and strengthened its anti-separation ability. In addition, ultrasonic vibration shortens the distance between the molecules of the fiber and matrix, improving the van der Waals force and thus promoting the interface binding energy between them, which ultimately achieves an overall improvement in the performance of CCFRPLA. The bending strength and interlaminar shear strength of the specimen treated with 20 W ultrasonic vibration reached 111.5 MPa and 10.16 MPa, respectively, 33.11% and 21.5% higher than those of the untreated specimen, consistent with the molecular dynamics simulations, and confirmed the effectiveness of ultrasonic vibration in improving the flexural and interlaminar properties of the CCFRPLA.

Novel therapeutic perspectives for crescentic glomerulonephritis through targeting parietal epithelial cell activation and proliferation.

INTRODUCTION: Kidney injury is clinically classified as crescentic glomerulonephritis (CrGN) when ≥50% of the glomeruli in a biopsy sample contain crescentic lesions. However, current strategies, such as systemic immunosuppressive therapy and plasmapheresis for CrGN, are partially effective, and these drugs have considerable systemic side effects. Hence, targeted therapy to prevent glomerular crescent formation and expansion remains an unmet clinical need. AREAS COVERED: Hyperproliferative parietal epithelial cells (PECs) are the main constituent cells of the glomerular crescent with cell-tracing evidence. Crescents obstruct the flow of primary urine, pressure the capillaries, and degenerate the affected nephrons. We reviewed the markers of PEC activation and proliferation, potential therapeutic effects of thrombin and thrombin receptor inhibitors, and how podocytes cross-talk with PECs. These experiments may help identify potential early specific targets for the prevention and treatment of glomerular crescentic injury. EXPERT OPINION: Inhibiting PEC activation and proliferation in CrGN can alleviate glomerular crescent progression, which has been supported by preclinical studies with evidence of genetic deletion. Clarifying the outcome of PEC transformation to the podocyte phenotype and suppressing thrombin, thrombin receptors, and PEC hyperproliferation in early therapeutic strategies will be the research goals in the next ten years.

It is clinically classified as crescentic glomerulonephritis (CrGN) when more than 50% of the glomeruli of the kidney in a biopsy sample contain crescentic lesions (crescent shaped injuries). However, current strategies, such as immunosuppressive therapy and plasmapheresis (the removal, treatment and returning of blood) for CrGN, are partially effective, and these drugs have considerable side effects. In order to seek targeted therapy for CrGN, we reviewed the current research evidences. First, the hyperproliferative parietal epithelial cells (PECs) are the main cells within the glomerular crescent seen with cell-tracing evidence. The activated PECs can express specific markers and altered biological characteristics, such as cell growth and multiplication, migration, and extracellular matrix production. CD44, CD74, CD9, and pERK-1/2 are specific markers for PEC activation, and also as the potential therapeutic targets with evidence of gene knockout and inhibitor. Second, during the formation of glomerular crescents, PECs grow and multiply also through cross-talking with podocyte cells by the AngII/SDF-1/CXCR4/ERK1/2, HB-EGF/EGFR/JAK/STAT3, and PDGF/PDGFR signaling pathways, suggesting that the intervention of key molecules in these disease processes may be promising therapeutic targets for CrGN. Third, thrombin and protease-activated receptors (PARs) participate in the excessive proliferation of PEC through activation of the coagulation cascade reaction, PAR-1 and PAR-2. Therefore, anticoagulation therapy, especially inhibition of PAR-1 and PAR-2, is expected to be an effective strategy for the early prevention and treatment of CrGN. The drug vorapaxar selectively antagonizes PAR-1 and is the most promising candidate. These findings will not only improve the outlook for CrGN treatment, but will also help in the treatment of other glomerular diseases with crescentic lesions. [Figure: see text].

PGC-1α promotes colorectal carcinoma metastasis through regulating ABCA1 transcription.

Colorectal cancer (CRC) is a highly aggressive cancer in which metastasis plays a key role. However, the mechanisms underlying metastasis have not been fully elucidated. Peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), a regulator of mitochondrial function, has been reported as a complicated factor in cancer. In this study, we found that PGC-1α was highly expressed in CRC tissues and was positively correlated with lymph node and liver metastasis. Subsequently, PGC-1α knockdown was shown to inhibit CRC growth and metastasis in both in vitro and in vivo studies. Transcriptomic analysis revealed that PGC-1α regulated ATP-binding cassette transporter 1 (ABCA1) mediated cholesterol efflux. Mechanistically, PGC-1α interacted with YY1 to promote ABCA1 transcription, resulting in cholesterol efflux, which subsequently promoted CRC metastasis through epithelial-to-mesenchymal transition (EMT). In addition, the study identified the natural compound isoliquiritigenin (ISL) as an inhibitor that targeted ABCA1 and significantly reduced CRC metastasis induced by PGC-1α. Overall, this study sheds light on how PGC-1α promotes CRC metastasis by regulating ABCA1-mediated cholesterol efflux, providing a basis for further research to inhibit CRC metastasis.

Connective tissue disease with macrophage activation syndrome: A case report.

RATIONALE: Macrophage activation syndrome (MAS), or secondary hemophagocytic lymphocytosis (sHLH), is a rare systemic inflammatory response syndrome that is fatal. Adult patients lack clear criteria for diagnosis and treatment, primarily derived from guidelines and protocols for treating family hemophagocytic lymphocytosis and systemic juvenile idiopathic arthritis (sJIA)-related MAS in children or from retrospective case reports. As a subtype of sHLH, MAS has a clinical presentation like sHLH, but treatment varies. Herein, we report the case of a 40-year-old female with MAS caused by a connective tissue disease. PATIENT CONCERNS: The patient presented to the Rheumatology and Immunology Clinic with recurrent fever and rash, and MAS was confirmed after a series of examinations. The patient had no significant effect after treatment with JAK inhibitors, but after the use of the IL-6 inhibitor tocilizumab, the fever and rash were significantly reduced, and laboratory indicators returned to normal levels. DIAGNOSIS: Considering the patient's condition and laboratory test results, we judged that the patient had connective tissue disease with MAS. INTERVENTIONS: We gave sequential treatment of tocilizumab. OUTCOMES: ALL indicators are mostly back to normal when the patient was monitored at the outpatient clinic. LESSONS: MAS/HLH lacks clear criteria for diagnosis or treatment in adult patients and is extremely difficult to distinguish from bacterial sepsis or other systemic inflammatory response syndromes. Consequently, early diagnosis and treatment are indispensable for enhancing patient survival.

Copackaging photosensitizer and PD-L1 siRNA in a nucleic acid nanogel for synergistic cancer photoimmunotherapy.

Packaging multiple drugs into a nanocarrier with rational design to achieve synergistic cancer therapy remains a challenge due to the intrinsically varied pharmacodynamics of therapeutic agents. Especially difficult is combining small-molecule drugs and macromolecular biologics. Here, we successfully graft pheophorbide A (PPA) photosensitizers on DNA backbone at predesigned phosphorothioate modification sites. The synthesized four PPA-grafted DNAs are assembled into a tetrahedron framework, which further associates with a programmed death ligand-1 (PD-L1) small interfering RNA (siRNA) linker through supramolecular self-assembly to form an siRNA and PPA copackaged nanogel. With dual therapeutic agents inside, the nanogel can photodynamically kill tumor cells and induce remarkable immunogenic cell death. Also, it simultaneously silences the PD-L1 expression of the tumor cells, which substantially promotes the antitumor immune response and leads to an enhanced antitumor efficacy in a synergistic fashion.

A Pan-cancer Analysis Reveals the Abnormal Expression and Drug Sensitivity of CSF1.

BACKGROUND: Colony-stimulating factor-1 (CSF1) is a cytokine that is closely related to normal organ growth and development as well as tumor progression. OBJECTIVE: We aimed to summarize and clarify the reasons for the abnormal expression of CSF1 in tumors and explore the role of CSF1 in tumor progression. Furthermore, drug response analysis could provide a reference for clinical medication. METHODS: The expression of CSF1 was analyzed by TCGA and CCLE. Besides, cBioPortal and MethSurv databases were used to conduct mutation and DNA methylation analyses. Further, correlations between CSF1 expression and tumor stage, survival, immune infiltration, drug sensitivity and enrichment analyses were validated via UALCAN, Kaplan-Meier plotter, TIMER, CTRP and Coexperia databases. RESULTS: CSF1 is expressed in a variety of tissues; meaningfully, it can be detected in the blood. Compared with normal tissues, CSF1 expression was significantly decreased in most tumors. The missense mutation and DNA methylation of CSF1 might cause the downregulated expression. Moreover, decreased CSF1 expression was related to higher tumor stage and worse survival. Further, the promoter DNA methylation level of CSF1 was prognostically significant in most tumors. Besides, CSF1 was closely related to immune infiltration, especially macrophages. Importantly, CSF1 expression was associated with a good response to VEGFRs inhibitors, which may be due to the possible involvement of CSF1 in tumor angiogenesis and metastasis processes. CONCLUSION: The abnormal expression of CSF1 could serve as a promising biomarker of tumor progression and prognosis in pan-cancer. Significantly, angiogenesis and metastasis inhibitors may show a good response to CSF1-related tumors.