The role of IgG4 in systemic lupus erythematosus: Implications for pathogenesis and therapy.

Immunoglobulin (Ig) G4 has a distinctive nature, and its involvement in autoimmune disorders is a subject of ongoing debate and uncertainty. A growing body of evidence indicates that IgG4 may play a pathogenic role in the development of systemic lupus erythematosus (SLE). The IgG4 autoantibodies have the capability to bind autoantigens in a competitive manner with other Ig classes, thereby forming immune complexes (ICs) that are noninflammatory in nature. This is due to the low affinity of IgG4 for both the Fc receptors and the C1 complement molecule, which results in a diminished inflammatory response in individuals with SLE. The present study aims to elucidate the significance of IgG4 in SLE. The present discourse pertains to the nascent and suggested modalities through which IgG4 might participate in the pathogenesis of SLE and the potential ramifications for therapeutic interventions in SLE.

A 9-10-Bit Adjustable and Energy-Efficient Switching Scheme for Successive Approximation Register Analog-to-Digital Converter with One Least Significant Bit Common-Mode Voltage Variation.

A 9-10-bit adjustable and energy-efficient switching scheme for SAR ADC with one-LSB common-mode voltage variation is proposed. Based on capacitor-splitting technology and common-mode conversion techniques, the proposed switching scheme reduces the DAC switching energy by 96.41% compared to the conventional scheme. The low complexity and the one-LSB common-mode voltage offset of this scheme benefit from the simultaneous switching of the reference voltages of the capacitors corresponding to the positive array and the negative array throughout the entire reference voltage switching process, and the reference voltage of each capacitor in the scheme does not change more than two voltages. The post-layout result shows that the ADC achieves the 54.96 dB SNDR, the 61.73 dB SFDR, and the 0.67 µw power consumption with the 10-bit mode and the 48.33 dB SNDR, the 54.17 dB SFDR, and the 0.47 µw power consumption with the 9-bit mode in a 180 nm process with a 100 kS/s sampling frequency.

Hypoxia induced-disruption of lncRNA TUG1/PRC2 interaction impairs human trophoblast invasion through epigenetically activating Nodal/ALK7 signalling.

Inadequate trophoblastic invasion is considered as one of hallmarks of preeclampsia (PE), which is characterized by newly onset of hypertension (>140/90 mmHg) and proteinuria (>300 mg in a 24-h urine) after 20 weeks of gestation. Accumulating evidence has indicated that long noncoding RNAs are aberrantly expressed in PE, whereas detailed mechanisms are unknown. In the present study, we showed that lncRNA Taurine upregulated 1 (TUG1) were downregulated in preeclamptic placenta and in HTR8/SVneo cells under hypoxic conditions, together with reduced enhancer of zeste homolog2 (EZH2) and embryonic ectoderm development (EED) expression, major components of polycomb repressive complex 2 (PRC2), as well as activation of Nodal/ALK7 signalling pathway. Mechanistically, we found that TUG1 bound to PRC2 (EZH2/EED) in HTR8/SVneo cells and weakened TUG1/PRC2 interplay was correlated with upregulation of Nodal expression via decreasing H3K27me3 mark at the promoter region of Nodal gene under hypoxic conditions. And activation of Nodal signalling prohibited trophoblast invasion via reducing MMP2 levels. Overexpression of TUG1 or EZH2 significantly attenuated hypoxia-induced reduction of trophoblastic invasiveness via negative modulating Nodal/ALK7 signalling and rescuing expression of its downstream target MMP2. These investigations might provide some evidence for novel mechanisms responsible for inadequate trophoblastic invasion and might shed some light on identifying future therapeutic targets for PE.

FAK contributes to proteinuria in hypercholesterolaemic rats and modulates podocyte F-actin re-organization via activating p38 in response to ox-LDL.

Focal adhesion kinase (FAK) is a non-receptor protein tyrosine kinase that regulates cell adhesion, proliferation and differentiation. In the present study, a rat model of high fat diet-induced hypercholesterolaemia was established to investigate the involvement of FAK in lipid disorder-related kidney diseases. We showed focal fusion of podocyte foot process that occurred at as early as 4 weeks in rats consuming high fat diet, preceding the onset of proteinuria when aberrant phosphorylation of FAK was found. These abnormalities were ameliorated by dietary intervention of TAE226, a reported inhibitor of FAK. FAK is also an adaptor protein initiating cascades of intracellular signals including c-Src, Rho GTPase and mitogen-activated protein kinase (MAPK). P38 MAPK belongs to the latter and is centrally involved in kidney diseases. Our cell culture data revealed oxidized low-density lipoprotein (ox-LDL) triggered hyper-phosphorylation of FAK and p38, ectopic expression of cellular markers (manifested as decreased WT1, podocin and NEPH1, and increased vimentin and mmp9), and re-arrangement of F-actin filaments with enhanced cell motility; these mutations were significantly rectified by FAK shRNA. Notably, pre-treatment of p38 inhibitor did not alter FAK activation, albeit its deletion of p38 hyper-activity and attenuation of cellular abnormalities, demonstrating that p38 acted as a downstream effector of FAK signalling and ox-LDL damaged podocytes in a FAK/p38-dependent manner. This was further identified by animal data that p38 activation was also abrogated by TAE226 treatment in hypercholesterolaemic rats, suggesting that FAK/p38 axis might also be involved in in vivo events. These findings provided a potential early mechanism of hypercholesterolaemia-related podocyte damage and proteinuria.

LncRNA MALAT1 is dysregulated in diabetic nephropathy and involved in high glucose-induced podocyte injury via its interplay with ß-catenin.

Metastasis associated lung adenocarcinoma transcript 1(MALAT1) is a long non-coding RNA, broadly expressed in mammalian tissues including kidney and up-regulated in a variety of cancer cells. To date, its functions in podocytes are largely unknown. ß-catenin is a key mediator in the canonical and non-canonical Wnt signalling pathway; its aberrant expression promotes podocyte malfunction and albuminuria, and contributes to kidney fibrosis. In this study, we found that MALAT1 levels were increased in kidney cortices from C57BL/6 mice with streptozocin (STZ)-induced diabetic nephropathy, and dynamically regulated in cultured mouse podocytes stimulated with high glucose, which showed a trend from rise to decline. The decline of MALAT1 levels was accompanied with ß-catenin translocation to the nuclei and enhanced expression of serine/arginine splicing factor 1 (SRSF1), a MALAT1 RNA-binding protein. Further we showed early interference with MALAT1 siRNA partially restored podocytes function and prohibited ß-catenin nuclear accumulation and SRSF1 overexpression. Intriguingly, we showed that ß-catenin was involved in MALAT1 transcription by binding to the promotor region of MALAT1; ß-catenin knock-down also decreased MALAT1 levels, suggesting a novel feedback regulation between MALAT1 and ß-catenin. Notably, ß-catenin deletion had limited effects on SRSF1 expression, demonstrating ß-catenin might serve as a downstream signal of SRSF1. These findings provided evidence for a pivotal role of MALAT1 in diabetic nephropathy and high glucose-induced podocyte damage.

Molecular mechanism and therapeutic significance of essential amino acids in metabolically associated fatty liver disease.

Non-alcoholic fatty liver disease (NAFLD), also known as metabolically associated fatty liver disease (MAFLD), is a systemic metabolic disease characterized by lipid accumulation in the liver, lipid toxicity, insulin resistance, intestinal dysbiosis, and inflammation that can progress from simple steatosis to nonalcoholic steatohepatitis (NASH) and even cirrhosis or cancer. It is the most prevalent illness threatening world health. Currently, there are almost no approved drug interventions for MAFLD, mainly dietary changes and exercise to control weight and regulate metabolic disorders. Meanwhile, the metabolic pathway involved in amino acid metabolism also influences the onset and development of MAFLD in the body, and most amino acid metabolism takes place in the liver. Essential amino acids are those amino acids that must be supplemented from outside the diet and that cannot be synthesized in the body or cannot be synthesized at a rate sufficient to meet the body's needs, including leucine, isoleucine, valine (collectively known as branched-chain amino acids), tryptophan, phenylalanine (which are aromatic amino acids), histidine, methionine, threonine and lysine. The metabolic balance of the body is closely linked to these essential amino acids, and essential amino acids are closely linked to the pathophysiological process of MAFLD. In this paper, we will focus on the metabolism of essential amino acids in the body and further explore the therapeutic strategies for MAFLD based on the studies conducted in recent years.

A comprehensive insight into the role of molecular pathways affected by the Angiopoietin and Tie system involved in hematological malignancies' pathogenesis.

Angiogenesis has been recognized as a critical factor in developing solid tumors and hematological malignancies. How angiogenesis affects the molecular pathways in malignancies is still a mystery. The angiopoietin family, one of the known molecular mediators for angiogenesis, encourages angiogenesis by attaching to Tie receptors on cell surfaces. Angiopoietin, Tie, and particularly the molecular pathways they mediate have all been the subject of recent studies that have established their diagnostic, prognostic, and therapeutic potential. Here, we've reviewed the function of molecular pathways impacted by the Angiogenin and Tie system in hematological malignancies.

Platelet-derived microvesicles (PMVs) in cancer progression and clinical applications.

Platelet-derived microvesicles (PMVs), the microvesicles with the highest concentration in the bloodstream, play a key role in the regulation of hemostasis, inflammation, and angiogenesis. PMVs have recently been identified as key factors in the link between platelets and cancer. PMVs bind to both cancer cells and nontransformed cells in the microenvironment of the tumor, and then transfer platelet-derived contents to the target cell. These contents have the potential to either stimulate or modulate the target cell's response. PMVs are encased in a lipid bilayer that contains surface proteins and lipids as well as components found inside the PMV. Each of these components participates in known and potential PMV roles in cancer. The complicated roles played by PMVs in the onset, development, and progression of cancer and cancer-related comorbidities are summarized in this study.

Aggrephagy-related patterns in tumor microenvironment, prognosis, and immunotherapy for acute myeloid leukemia: a comprehensive single-cell RNA sequencing analysis.

Acute myeloid leukemia (AML) is a complex mixed entity composed of malignant tumor cells, immune cells and stromal cells, with intra-tumor and inter-tumor heterogeneity. Single-cell RNA sequencing enables a comprehensive study of the highly complex tumor microenvironment, which is conducive to exploring the evolutionary trajectory of tumor cells. Herein, we carried out comprehensive analyses of aggrephagy-related cell clusters based on single-cell sequencing for patients with acute myeloid leukemia. A total of 11 specific cell types (T, NK, CMP, Myeloid, GMP, MEP, Promono, Plasma, HSC, B, and Erythroid cells) using t-SNE dimension reduction analysis. Several aggrephagy-related genes were highly expressed in the 11 specific cell types. Using Monocle analysis and NMF clustering analysis, six aggrephagy-related CD8+ T clusters, six aggrephagy-related NK clusters, and six aggrephagy-related Mac clusters were identified. We also evaluated the ligand-receptor links and Cell-cell communication using CellChat package and CellChatDB database. Furthermore, the transcription factors (TFs) of aggrephagy-mediated cell clusters for AML were assessed through pySCENIC package. Prognostic analysis of the aggrephagy-related cell clusters based on R package revealed the differences in prognosis of aggrephagy-mediated cell clusters. Immunotherapy of the aggrephagy-related cell clusters was investigated using TIDE algorithm and public immunotherapy cohorts. Our study revealed the significance of aggrephagy-related patterns in tumor microenvironment, prognosis, and immunotherapy for AML.

Platelet-related gene risk score: a predictor for pancreatic cancer microenvironmental signature, chemosensitivity and prognosis.

Recent studies have indicated that platelets may play a role in the advancement of pancreatic cancer by supporting tumor growth and increasing resistance to chemotherapy. This study aims to develop a prognostic model for pancreatic cancer using a platelet-related gene risk score. Prognostic platelet-related genes (PRGs) were identified from public databases and analyzed using cluster analysis. We investigated the microenvironment signatures and gene mutation patterns across different PRG-based molecular subtypes of pancreatic cancer. A prognostic model based on PRGs was developed using LASSO-Cox Regression Analysis. Additionally, we examined the correlation between the risk score and tumor clinical characteristics, as well as drug sensitivity. Two molecular subtypes, cluster C1 and C2, were identified. Cluster C2 was associated with a poorer prognosis compared to Cluster C1. The C1 group exhibited higher scores for activated CD8+ T cells, central memory CD4+ T cells, and natural killer T cells. The C2 group demonstrated a higher frequency of gene mutations. We established and validated a novel prognostic prediction model and platelet-related gene risk score for pancreatic cancer. The risk score was positively correlated with T stage, N stage, and tumor grade, and it presented a significant prognostic value compared to other clinical factors. In conclusion, a novel prognostic prediction model focusing on platelet involvement in pancreatic cancer has been developed, offering potential benefits for future drug therapies and clinical prognostic assessments.

A Hybrid Energy-Efficient, Area-Efficient, Low-Complexity Switching Scheme in SAR ADC for Biosensor Applications.

A hybrid energy-efficient, area-efficient, low-complexity switching scheme in SAR ADC for biosensor applications is proposed. This scheme is a combination of the monotonic technique, the MSB capacitor-splitting technique, and a new switching method. The MSB capacitor-splitting technique, as well as the reference voltage Vaq allow for more options for reference voltage conversion, resulting in higher area savings and higher energy efficiency. In a capacitor array, the circuit performs unilateral switching during all comparisons except for the second and last two comparisons, reducing the difficulty in designing the drive circuit. The proposed switching scheme saves 98.4% of the switching energy and reduces the number of unit capacitors by 87.5% compared to a conventional scheme. Furthermore, the SAR ADC employs low-noise and low-power dynamic comparators utilizing multi-clock control, low-sampling error-sampling switches based on the bootstrap technique, and dynamic SAR logic. The simulation results demonstrated that the proposed SAR ADC achieves 61.51 dB SNDR, 79.21 dB SFDR and consumes 0.278 µW of power in a 180 nm process with a 1 V power supply, a full swing input signal frequency of 23.33 kHz, and a sampling rate of 100 kS/s.

Implications of a Carbon Tax Mechanism in Remanufacturing Outsourcing on Carbon Neutrality.

Many governments have imposed methods such as a carbon tax that aim to even out the negative effects of carbon emissions. The taxes levied on different agents lead to different make-buy decisions for production structures and different environmental outcomes. Some original equipment manufacturers (OEMs) outsource remanufacturing to independent remanufacturers (IRs). Thus, a question arises: What are the implications of carbon taxes levied on different agents on remanufacturing outsourcing decisions? To answer this question, we developed two models: (1) acting as common brand owners, OEMs can be taxed for both new and remanufactured products, or (2) acting as different emitters for production and remanufacturing, OEMs are taxed for new products; however, all carbon taxes related to remanufacturing are levied on IRs. Our analysis reveals that, regarding economic performance, firms should undertake a carbon emission tax on their own initiative because this allows the taxpayer to choose more units for its preferred products and leaves its rivals at a huge disadvantage. Moreover, regarding environmental sustainability, carbon emission taxes indeed lead to mitigating the effects of carbon emissions per unit; however, environmental agencies should also pay attention to reducing the total carbon emissions by limiting the volume effects.

Long Non-Coding RNAs in the Pathogenesis of Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is one of the major microvascular complications of diabetes mellitus, with relatively high morbidity and mortality globally but still in short therapeutic options. Over the decades, a large body of data has demonstrated that oxidative stress, inflammatory responses, and hemodynamic disorders might exert critical influence in the initiation and development of DKD, whereas the delicate pathogenesis of DKD remains profoundly elusive. Recently, long non-coding RNAs (lncRNAs), extensively studied in the field of cancer, are attracting increasing attentions on the development of diabetes mellitus and its complications including DKD, diabetic retinopathy, and diabetic cardiomyopathy. In this review, we chiefly focused on abnormal expression and function of lncRNAs in major resident cells (mesangial cell, endothelial cell, podocyte, and tubular epithelial cell) in the kidney, summarized the critical roles of lncRNAs in the pathogenesis of DKD, and elaborated their potential therapeutic significance, in order to advance our knowledge in this field, which might help in future research and clinical treatment for the disease.

Chronic Kidney Disease and Cancer: Inter-Relationships and Mechanisms.

Chronic kidney disease (CKD) has been recognized as an increasingly serious public health problem globally over the decades. Accumulating evidence has shown that the incidence rate of cancer was relatively higher in CKD patients than that in general population, which, mechanistically, may be related to chronic inflammation, accumulation of carcinogenic compounds, oxidative stress, impairment of DNA repair, excessive parathyroid hormone and changes in intestinal microbiota, etc. And in patients with cancer, regardless of tumor types or anticancer treatment, it has been indicated that the morbidity and incidence rate of concomitant CKD was also increased, suggesting a complex inter-relationship between CKD and cancer and arousing increasing attention from both nephrologists and oncologists. This narrative review focused on the correlation between CKD and cancer, and underlying molecular mechanisms, which might provide an overview of novel interdisciplinary research interests and the potential challenges related to the screening and treatment of CKD and cancer. A better understanding of this field might be of help for both nephrologists and oncologists in the clinical practice.

Podocyte-specific Rac1 deficiency ameliorates podocyte damage and proteinuria in STZ-induced diabetic nephropathy in mice.

Activation of Ras-related C3 botulinum toxin substrate 1 (Rac1) has been implicated in diverse kidney diseases, yet its in vivo significance in diabetic nephropathy (DN) is largely unknown. In the present study, we demonstrated a podocyte-specific Rac1-deficient mouse strain and showed that specific inhibition of Rac1 was able to attenuate diabetic podocyte injury and proteinuria by the blockade of Rac1/PAK1/p38/ß-catenin signaling cascade, which reinstated the integrity of podocyte slit diaphragms (SD), rectified the effacement of foot processes (FPs), and prevented the dedifferentiation of podocytes. In vitro, we showed Rac1/PAK1 physically bound to ß-catenin and had a direct phosphorylation modification on its C-terminal Ser675, leading to less ubiquitylated ß-catenin, namely more stabilized ß-catenin, and its nuclear migration under high-glucose conditions; further, p38 activation might be responsible for ß-catenin nuclear accumulation via potentiating myocyte-specific enhancer factor 2C (MEF2c) phosphorylation. These findings provided evidence for a potential renoprotective and therapeutic strategy of cell-specific Rac1 deficiency for DN and other proteinuric diseases.

Fyn Mediates High Glucose-Induced Actin Cytoskeleton Reorganization of Podocytes via Promoting ROCK Activation In Vitro.

Fyn, a member of the Src family of tyrosine kinases, is a key regulator in cytoskeletal remodeling in a variety of cell types. Recent studies have demonstrated that Fyn is responsible for nephrin tyrosine phosphorylation, which will result in polymerization of actin filaments and podocyte damage. Thus detailed involvement of Fyn in podocytes is to be elucidated. In this study, we investigated the potential role of Fyn/ROCK signaling and its interactions with paxillin. Our results presented that high glucose led to filamentous actin (F-actin) rearrangement in podocytes, accompanied by paxillin phosphorylation and increased cell motility, during which Fyn and ROCK were markedly activated. Gene knockdown of Fyn by siRNA showed a reversal effect on high glucose-induced podocyte damage and ROCK activation; however, inhibition of ROCK had no significant effects on Fyn phosphorylation. These observations demonstrate that in vitro Fyn mediates high glucose-induced actin cytoskeleton remodeling of podocytes via promoting ROCK activation and paxillin phosphorylation.

Rac1/PAK1 signaling promotes epithelial-mesenchymal transition of podocytes in vitro via triggering ß-catenin transcriptional activity under high glucose conditions.

Ras-related C3 botulinum toxin substrate 1 (Rac1), together with its major downstream effector p21-activated kinase 1 (PAK1), has been identified a central role in cellular events such as cell cytoskeletal remodeling that contributed to cell migration and epithelial-mesenchymal transition (EMT). And there are data implicating that podocytes underwent EMT under pathological conditions. However, little is known about mechanisms of podocytes undergoing EMT. To address this, we assessed the cellular changes of podocytes after high glucose stimulation in vitro, detected the effects of Rac1/PAK1 signaling on podocytes in response to the stimuli, and investigated interactions of Rac1/PAK1 axis with ß-catenin and Snail under high glucose conditions. We found that in vitro high glucose treatment led to remarkable down-regulation of nephrin and P-cadherin, as well as significant up-regulation of α-SMA and FSP-1, suggesting that in the presence of high glucose, podocytes underwent EMT, during which Rac1/PAK1 signaling was activated. And these were notably ameliorated by Rac1 gene knockdown. Furthermore, ß-catenin and Snail nuclear translocation were triggered by Rac1/PAK1 axis, which were both markedly reversed via Rac1 gene knockdown or pretreatment of IPA-3, a PAK1 inhibitor. These findings elaborated that Rac1/PAK1 signaling contributed to high glucose-induced podocyte EMT via promoting ß-catenin and Snail transcriptional activities, which could be a potential mechanism involved in podocytes injury in response to stimuli under diabetic conditions.

The role of the p38 MAPK signaling pathway in high glucose-induced epithelial-mesenchymal transition of cultured human renal tubular epithelial cells.

BACKGROUND: Epithelial-mesenchymal transition of tubular epithelial cells, which is characterized by a loss of epithelial cell characteristics and a gain of ECM-producing myofibroblast characteristics, is an essential mechanism that is involved in tubulointerstitial fibrosis, an important component of the renal injury that is associated with diabetic nephropathy. Under diabetic conditions, p38 MAPK activation has been reported in glomeruli and mesangial cells; however, studies on p38 MAPK in TECs are lacking. In this study, the role of p38 MAPK in AP-1 activation and in the EMT in the human proximal tubular epithelial cell line (HK-2) under high glucose concentration conditions is investigated. METHODOLOGY/PRINCIPAL FINDINGS: A vector for small interfering RNA that targets p38 MAPK was constructed; the cells were then either transfected with p38 siRNA or pretreated with a chemical inhibitor of AP-1 and incubated with low glucose plus TGF-ß1 or high glucose for 48 h. Cells that were not transfected or pretreated and were exposed to low glucose with or without TGF-ß1 or high glucose for 48 h were considered to be the controls. We found that high glucose induced an increase in TGF-ß1. And high glucose-induced p38 MAPK activation was inhibited by p38 siRNA (P<0.05). A significant decline in E-cadherin and CK expression and a notable increase in vimentin and α-SMA were detected when exposed to low glucose with TGF-ß1 or high glucose, and a significant raise of secreted fibronectin were detected when exposed to high glucose; whereas these changes were reversed when the cells were treated with p38 siRNA or AP-1 inhibitor (P<0.05). AP-1 activity levels and Snail expression were up-regulated under high glucose conditions but were markedly down-regulated through knockdown of p38 MAPK with p38 siRNA or pretreatment with AP-1 inhibitor (P<0.05). CONCLUSION: This study suggests that p38 MAPK may play an important role in the high glucose-induced EMT by activating AP-1 in tubular epithelial cells.