Anti-PD-1/PD-L1 therapy for colorectal cancer: Clinical implications and future considerations.

Colorectal cancer (CRC) is the third most prevalent cancer in the world. The PD-1/PD-L1 pathway plays a crucial role in modulating immune response to cancer, and PD-L1 expression has been observed in tumor and immune cells within the tumor microenvironment of CRC. Thus, immunotherapy drugs, specifically checkpoint inhibitors, have been developed to target the PD-1/PD-L1 signaling pathway, thereby inhibiting the interaction between PD-1 and PD-L1 and restoring T-cell function in cancer cells. However, the emergence of resistance mechanisms can reduce the efficacy of these treatments. To counter this, monoclonal antibodies (mAbs) have been used to improve the efficacy of CRC treatments. mAbs such as nivolumab and pembrolizumab are currently approved for CRC treatment. These antibodies impede immune checkpoint receptors, including PD-1/PD-L1, and their combination therapy shows promise in the treatment of advanced CRC. This review presents a concise overview of the use of the PD-1/PD-L1 blockade as a therapeutic strategy for CRC using monoclonal antibodies and combination therapies. Additionally, this article outlines the function of PD-1/PD-L1 as an immune response suppressor in the CRC microenvironment as well as the potential advantages of administering inflammatory agents for CRC treatment. Finally, this review analyzes the outcomes of clinical trials to examine the challenges of anti-PD-1/PD-L1 therapeutic resistance.

Mucosal recombinant BCG vaccine induces lung-resident memory macrophages and enhances trained immunity via mTORC2/HK1-mediated metabolic rewiring.

Bacillus Calmette-Guérin (BCG) vaccination induces a type of immune memory known as "trained immunity", characterized by the immunometabolic and epigenetic changes in innate immune cells. However, the molecular mechanism underlying the strategies for inducing and/or boosting trained immunity in alveolar macrophages remains unknown. Here, we found that mucosal vaccination with the recombinant strain rBCGPPE27 significantly augmented the trained immune response in mice, facilitating a superior protective response against Mycobacterium tuberculosis and non-related bacterial reinfection in mice when compared to BCG. Mucosal immunization with rBCGPPE27 enhanced innate cytokine production by alveolar macrophages associated with promoted glycolytic metabolism, typical of trained immunity. Deficiency of the mammalian target of rapamycin complex 2 and hexokinase 1 abolished the immunometabolic and epigenetic rewiring in mouse alveolar macrophages after mucosal rBCGPPE27 vaccination. Most noteworthy, utilizing rBCGPPE27's higher-up trained effects: The single mucosal immunization with rBCGPPE27-adjuvanted coronavirus disease (CoV-2) vaccine raised the rapid development of virus-specific immunoglobulin G antibodies, boosted pseudovirus neutralizing antibodies, and augmented T helper type 1-biased cytokine release by vaccine-specific T cells, compared to BCG/CoV-2 vaccine. These findings revealed that mucosal recombinant BCG vaccine induces lung-resident memory macrophages and enhances trained immunity via reprogramming mTORC2- and HK-1-mediated aerobic glycolysis, providing new vaccine strategies for improving tuberculosis (TB) or coronavirus variant vaccinations, and targeting innate immunity via mucosal surfaces.

LncRNAs in colorectal cancer: Biomarkers to therapeutic targets.

Colorectal cancer (CRC) is the third leading cause of cancer-related death in men and women worldwide. As early detection is associated with lower mortality, novel biomarkers are urgently needed for timely diagnosis and appropriate management of patients to achieve the best therapeutic response. Long noncoding RNAs (lncRNAs) have been reported to play essential roles in CRC progression. Accordingly, the regulatory roles of lncRNAs should be better understood in general and for identifying diagnostic, prognostic and predictive biomarkers in CRC specifically. In this review, the latest advances on the potential diagnostic and prognostic lncRNAs as biomarkers in CRC samples were highlighted, Current knowledge on dysregulated lncRNAs and their potential molecular mechanisms were summarized. The potential therapeutic implications and challenges for future and ongoing research in the field were also discussed. Finally, novel insights on the underlying mechanisms of lncRNAs were examined as to their potential role as biomarkers and therapeutic targets in CRC. This review may be used to design future studies and advanced investigations on lncRNAs as biomarkers for the diagnosis, prognosis and therapy in CRC.

The efficacy and safety of tacrolimus in patients with dermatomyositis/polymyositis: A meta-analysis and systematic review.

OBJECTIVE: To evaluate the efficacy and safety of tacrolimus for dermatomyositis (DM) and polymyositis (PM) treatment. METHODS: We searched the Embase, PubMed, the Cochrane Central Register of Controlled Trials, and China National Knowledge Infrastructure were used as searching tools from inception up to October 2022. Two authors independently selected studies. The available studies were comprehensively reviewed and investigated. RESULTS: A total of 9 studies, including 350 patients, were analysed. Pooled results showed a higher overall survival rate in tacrolimus therapy group. Creatine kinase (CK) levels and forced vital capacity (FVC) showed significant improvement after tacrolimus therapy. The incidence of adverse events including infection and renal dysfunction showed no significant differences between the tacrolimus therapy group and conventional therapy group. CONCLUSION: The results of this meta-analysis indicated that GC therapy in combination with tacrolimus therapy could help improving overall survival rate, pulmonary function and had similar safety outcomes compared to conventional therapy in DM and PM patients.

High-Precision ADC Spectrum Testing under Non-Coherent Sampling Conditions.

Realizing coherent sampling is one of the major bottlenecks in high-precision ADC spectrum testing. In spectrum analysis, if coherent sampling is not implemented, spectral leakage will result, which in turn leads to inaccurate test results. In this paper, a combined four-parameter sine-curve-fitting algorithm is proposed incorporating non-coherent sampling, with the amplitude, initial phase, and frequency parameters of the sine wave being obtained by fitting. The corresponding coherent sine wave is then calculated and replaced according to the obtained sine wave to reconstruct the new test data, eliminating the requirement of coherent sampling. Numerous simulations demonstrated the functionality and robustness of the algorithm, which was then used to process and analyze the measured data of two commercial high-precision ADCs. The results show that our algorithm can achieve accurate testing of ADC parameters under relaxed test conditions, which verifies the effectiveness and superiority of the scheme.

Effects of YM155 on the proliferation and apoptosis of pulmonary artery smooth muscle cells in a rat model of high pulmonary blood flow-induced pulmonary arterial hypertension.

INTRODUCTION: Proliferation and apoptosis of pulmonary artery smooth muscle cells (PASMCs) play an important role in the occurrence and development of pulmonary arterial hypertension (PAH). The purpose of this study was to investigate the effects of survivin inhibitor YM155 on the proliferation and apoptosis of PASMCs in rats with PAH induced by high pulmonary blood flow. METHODS: Thirty male Sprague-Dawley (SD) rats were randomly divided into control, model, and YM155 intervention groups. A rat model of PAH induced by high pulmonary blood flow was established, and it was confirmed by assessments of right-ventricular pressure (RVP) and right ventricular hypertrophy index (RVHI). Immunohistochemical staining and western blot analysis were used to detect the expression of survivin, and the proliferation and apoptosis of PASMCs. Lastly, the effects of in vivo treatment of YM155 were tested. RESULTS: The increased expression of survivin mRNA and protein were observed in the model group, accompanied by pulmonary arteriolar wall thickening, lumen stenosis, and perivascular inflammatory cell infiltration. Elevated expression of survivin and pulmonary vascular remodeling were significantly mitigated after YM155 treatment. Specifically, the YM155 intervention group had a significantly lower PASMC proliferation rate and a higher PASMC apoptotic rate. CONCLUSION: YM155 suppressed PASMC proliferation and promoted PASMC apoptosis by inhibiting survivin expression and thereby reducing pulmonary vascular remodeling in high pulmonary blood flow-induced PAH in vivo.

Influencing Factors of International Students' Anxiety Under Online Learning During the COVID-19 Pandemic: A Cross-Sectional Study of 1,090 Chinese International Students.

Objective: We conducted the following cross-sectional study to comprehensively assess the anxiety among Chinese international students who studied online during the COVID-19 pandemic and its influencing factors. Methods: Questionnaires were distributed through "Sojump," and a total of 1,090 valid questionnaires were collected. The questionnaire was divided into two parts: general situation and anxiety assessment of students. The former used a self-made questionnaire, and the international general GAD-7 scale was used to measure anxiety. Chi-square test was used to analyze the differences between groups, and logistic regression analysis was performed for the factors with differences. Results: Anxiety was found in 707 (64.9%) of 1,090 international students. Chi-square test and multivariate Logistic regression analysis showed that the incidence of anxiety was higher in the group under 22 years of age than in the group over 22 years of age (68% vs. 61%, p = 0.015; OR = 1.186, 95% CI 1.045-1.347, p = 0.008); International students living in big cities had a higher incidence of anxiety than those living in rural areas (67% vs. 60%, p = 0.022; OR = 1.419, 95%CI 1.038-1.859, p = 0.011); international students who socialized 3 times or less monthly had a higher incidence of anxiety than those who socialized more than 3 times per month (68% vs. 58%, p = 0.003; OR = 1.52, 95%CI 1.160-1.992, p = 0.002); international students who expected purely online teaching had a higher incidence of anxiety than those who expected purely offline teaching or dual-track teaching (72% vs. 64%, p = 0.037; OR = 1.525, 95%CI 1.069-2.177, p = 0.02); international students with a subjective score of online learning experience of 6 or less had a higher incidence of anxiety than those with subjective scores of more than 6 (70% vs. 60%, p = 0.001, OR = 1.25, 95%CI 1.099-1.422, p = 0.001). However, gender, emotional status, BMI, major of study, vaccination status, and degree type had no significant difference in the incidence of anxiety among international students who studied online during the COVID-19 pandemic. Conclusion: During COVID-19, international students who were younger, came from big cities, had low social frequency, expected purely online teaching, and had poor experience of online classes were risk factors for anxiety during online classes.

New Insights in the Treatment of SAPHO Syndrome and Medication Recommendations.

Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome is a rare autoinflammatory disease characterized by dermatological disorders and osteoarticular inflammatory lesions. This article reviews the application of biologics and other treatments based on the therapeutic target and the size of molecules in SAPHO syndrome. We found that drugs, especially biologics, have different effects on bone, joint, and skin damage. This may relate to the different inflammatory pathways involved in the osteoarticular and cutaneous symptoms in SAPHO patients. In this study, we provide stratified medication recommendations for SAPHO syndrome. Patients with osteoarticular symptoms can consider tumor necrosis factor blockers, JAK inhibitor, interleukin (IL)-1 inhibitor, and IL-17 inhibitor. Patients with cutaneous symptoms should consider IL-17 and JAK inhibitors. Apremilast, Tripterygium wilfordii Hook F, and bisphosphonates are other effective treatments.

The Pathogenic Role of Long Non-coding RNA H19 in Atherosclerosis via the miR-146a-5p/ANGPTL4 Pathway.

The abnormally expressed long non-coding RNA (lncRNA) H19 has a crucial function in the development and progression of cardiovascular disease; however, its role in atherosclerosis is yet to be known. We aimed to examine the impacts of lncRNA H19 on atherogenesis as well as the involved mechanism. The outcomes from this research illustrated that the expression of lncRNA H19 was elevated in mouse blood and aorta with lipid-loaded macrophages and atherosclerosis. Adeno-associated virus (AAV)-mediated lncRNA H19 overexpression significantly increased the atherosclerotic plaque area in apoE-/- mice supplied with a Western diet. The upregulation of lncRNA H19 decreased the miR-146a-5p expression but increased the levels of ANGPTL4 in mouse blood and aorta and THP-1 cells. Furthermore, lncRNA H19 overexpression promoted lipid accumulation in oxidized low-density lipoprotein (ox-LDL)-induced THP-1 macrophages. However, the knockdown of lncRNA H19 served as a protection against atherosclerosis in apoE-/- mice and lowered the accumulation of lipids in ox-LDL-induced THP-1 macrophages. lncRNA H19 promoted the expression of ANGPTL4 via competitively binding to miR-146a-5p, thus promoting lipid accumulation in atherosclerosis. These findings altogether demonstrated that lncRNA H19 facilitated the accumulation of lipid in macrophages and aggravated the progression of atherosclerosis through the miR-146a-5p/ANGPTL4 pathway. Targeting lncRNA H19 might be an auspicious therapeutic approach for preventing and treating atherosclerotic disease.

The landscape of angiogenesis subtypes for breast cancer: a comprehensive analysis based on the Cancer Genome Atlas.

PURPOSE: Breast cancer is a common malignant tumor in women with a poor prognosis. This study aimed to investigate angiogenesis subtypes of breast cancer and unveil the etiology and molecular features of breast cancer. METHODS: Based on the angiogenesis gene set derived from AmiGO2, and breast cancer data in the Cancer Genome Atlas (TCGA), we define a novel cluster of angiogenesis subtypes for patients by consensus clustering. The gene regulation, immune landscape, molecular characteristics, and clinical features as well as enrichment pathways were explored in the angiogenesis subtypes of breast cancer. RESULTS: Two angiogenesis subtypes were established through consensus clustering, among which subtype1 included 275 patients and subtype2 included 813 patients. A total of 643 differential expressed genes and 109 miRNAs were found between the two subtypes. The gene set enrichment analysis showed that the enriched hallmark pathways in subtype2 were related to the cancer tumorigenesis and breast cancer progression, including estrogen response early estrogen response late, epithelial-mesenchymal transition (EMT), especially angiogenesis. The mutant-allele tumor heterogeneity and tumor mutation burden of non-angiogenesis subtype were significantly higher than that in the angiogenesis subtype. The stroma score, immune score and ESTIMATE score were significantly higher in angiogenesis subtype, while the tumor purity in angiogenesis subtype was considerably lower. Finally, most immune checkpoints were expressed higher in the angiogenesis subtype. CONCLUSIONS: The omics analysis has established a novel angiogenesis subtype of breast cancer and identified the characteristics of the immune microenvironment and genomic alteration of breast cancer. Thus, this angiogenesis subtype might provide new evidence for inhibiting the progression and immunotherapy response in breast cancer.

LncRNAs as Therapeutic Targets and Potential Biomarkers for Lipid-Related Diseases.

Lipid metabolism is an essential biological process involved in nutrient adjustment, hormone regulation, and lipid homeostasis. An irregular lifestyle and long-term nutrient overload can cause lipid-related diseases, including atherosclerosis, myocardial infarction (MI), obesity, and fatty liver diseases. Thus, novel tools for efficient diagnosis and treatment of dysfunctional lipid metabolism are urgently required. Furthermore, it is known that lncRNAs based regulation like sponging microRNAs (miRNAs) or serving as a reservoir for microRNAs play an essential role in the progression of lipid-related diseases. Accordingly, a better understanding of the regulatory roles of lncRNAs in lipid-related diseases would provide the basis for identifying potential biomarkers and therapeutic targets for lipid-related diseases. This review highlighted the latest advances on the potential biomarkers of lncRNAs in lipid-related diseases and summarised current knowledge on dysregulated lncRNAs and their potential molecular mechanisms. We have also provided novel insights into the underlying mechanisms of lncRNAs which might serve as potential biomarkers and therapeutic targets for lipid-related diseases. The information presented here may be useful for designing future studies and advancing investigations of lncRNAs as biomarkers for diagnosis, prognosis, and therapy of lipid-related diseases.

Targeting epigenetics and lncRNAs in liver disease: From mechanisms to therapeutics.

Early onset and progression of liver diseases can be driven by aberrant transcriptional regulation. Different transcriptional regulation processes, such as RNA/DNA methylation, histone modification, and ncRNA-mediated targeting, can regulate biological processes in healthy cells, as well also under various pathological conditions, especially liver disease. Numerous studies over the past decades have demonstrated that liver disease has a strong epigenetic component. Therefore, the epigenetic basis of liver disease has challenged our knowledge of epigenetics, and epigenetics field has undergone an important transformation: from a biological phenomenon to an emerging focus of disease research. Furthermore, inhibitors of different epigenetic regulators, such as m6A-related factors, are being explored as potential candidates for preventing and treating liver diseases. In the present review, we summarize and discuss the current knowledge of five distinct but interconnected and interdependent epigenetic processes in the context of hepatic diseases: RNA methylation, DNA methylation, histone methylation, miRNAs, and lncRNAs. Finally, we discuss the potential therapeutic implications and future challenges and ongoing research in the field. Our review also provides a perspective for identifying therapeutic targets and new hepatic biomarkers of liver disease, bringing precision research and disease therapy to the modern era of epigenetics.

Correlation analysis of expression of CC and CXC chemokines in children with autism spectrum disorder.

ABSTRACT: To investigate the relationship between the expression of CC and CXC chemokines and autism spectrum disorder (ASD).A total of 62 children with ASD (ASD group) and 60 gender- and age-matched normal children (control group) admitted to our hospital from January 2019 to January 2020 were included in the study. Monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), macrophage inflammatory protein-1ß (MIP-1ß), regulated upon activation, normal T-cell expressed and secreted (RANTES), interleukin-8 (IL-8), monokine induced by interferon (IFN)-γ (MIG), and purified human interferon-γ-induced protein-10 (IP-10) were detected in the ASD group. The correlation between the above indexes and the severity of the ASD group was analyzed.Significantly increased MCP-1 levels (P < .01) along with the markedly decreased MIP-1α and MIP-1ß levels (P < .01) were detected in the venous blood of the ASD group compared with the control group. In addition, they exhibited no significant difference (yet a downward trend) in the level of RANTES (P > .05). Children in the ASD group showed significantly decreased IP-10 levels (P < .01); however, they had no noticeable change (yet a decreasing trend) in the levels of IL-8 and MIG (P > .05). MCP-1 level was positively related to the Module 1 scores of Autism Diagnostic Observation Schedule-second edition (ADOS-2), whereas the levels of Childhood Autism Rating Scale MIP-1α, MIP-1ß, IL-8, IP-10, and MIG were negatively correlated with the ADOS-2 Module 1 scores (P < .01). However, no significant correlation was found between RANTES and the ADOS-2 Module 1 scores (P > .05).The levels of CC chemokines (MCP-1, MIP-1α, MIP-1ß, and RANTES) and CXC chemokines (IL-8, IP-10, and MIG) are positively correlated with the pathogenesis of ASD. Inflammation is an important contributing factor to ASD.

microRNA-630 Regulates Underglycosylated IgA1 Production in the Tonsils by Targeting TLR4 in IgA Nephropathy.

IgA nephropathy (IgAN) is the most common primary glomerular disease. The characteristic pathology involves immune complexes formed by the deposition of IgA1 and underglycosylated IgA1 aggregates in the mesangial area, which may be accompanied by the deposition of IgG and/or IgM and complement components. However, the molecular mechanisms of IgAN remain unclear. In the present study, microarray analysis showed that the expression of microRNA-630 (miR-630) was significantly reduced in palatal tonsils from IgAN patients compared with chronic tonsillitis. Additionally, bioinformatic analysis showed that Toll-like receptor 4 (TLR4) was the predicted target gene of miR-630 and was regulated by miR-630. When miR-630 was overexpressed in palatal tonsil mononuclear cells from IgAN patients, the expression of TLR4 was reduced and the content of IgA1 in the cell culture supernatant was decreased, and the level of galactosylation in the IgA1 hinge region was increased. Moreover, immunohistochemical analysis showed that the expression of TLR4 in IgAN patients was significantly increased. After knocking down the expression of TLR4, both the concentration of IgA1 and the binding force of IgA1 with broad bean lectin were significantly reduced in IgAN. Furthermore, the mechanism study demonstrated that TLR4 might regulate the expression of IL-1ß and IL-8 through NF-κB signaling pathway to modulate the concentration of IgA1 and the glycosylation level of IgA1. This interesting finding may offer new insight into the molecular mechanism of IgAN.

Eradication of Microorganisms Embedding in Biofilm by a Dose-Dependent Urokinase-Based Catheter Lock Solution in Chronic Hemodialysis Patients.

INTRODUCTION: Catheter-related blood stream infection (CRBSI), the most common complication of central vein catheter (CVC), was closely associated with high morbidity and mortality in hemodialysis (HD) patients. Conjunction with systemic antibiotic, antibiotic lock (ABL) is an important therapeutic option to salvage the catheter. With extra antimicrobial and biofilm removing properties, urokinase plasminogen activator (uPA)-based ABL could have a potential role in the treatment of CRBSI. OBJECTIVE: In this study, we aimed to explore effectiveness of uPA-based (ABL) on microorganisms embedded in biofilms in vitro and CVC salvage rate in HD patients with CRBSI. METHODS: In vitro, we induced biofilms formation on the surface of HD catheter by mimicking the development of CRBSI. Applying uPA with or without antibiotics on the kinds of microorganism biofilms to explore its antimicrobial and biofilm removing properties. In vivo, 86 HD patients diagnosed as CRBSI were retrospectively enrolled to see effectiveness of uPA-based ABL on catheter salvage rate as compare to heparin-based ABL. RESULTS: uPA was effect to Staphylococcus epidermidis biofilms compared to Staphylococcus aureus, Escherichia coli, and Candida albicans. Less biofilm residues made the regrowth of S. epidermidis also limited. The combination of uPA with antibiotic showed better antimicrobial and antibiofilm activity than uPA alone or heparin-based ABL in vitro and in vivo. Among HD patients, uPA-based ABL did not cause any obvious adverse affects, and it was more effective in treating coagulase-negative Staphylococci related CRBSI than other microorganisms. CONCLUSIONS: The combination of uPA and a therapeutic plasma concentration of sensitive antibiotic can work together to effectively remove coagulase-negative S. epidermidis embedded in biofilms in vitro. uPA-based ABL is safe and effective therapeutic intervention for HD patients with CRBSI, especially compared to heparin-based ABL.

The role of hypertriglyceridemia and treatment patterns in the progression of IgA nephropathy with a high proportion of global glomerulosclerosis.

PURPOSE: Many studies have focused on finding predictors for mild IgAN progression. However, the cases of severe IgAN with a high proportion of global glomerulosclerosis have received inadequate attention. METHODS: A group of 172 primary IgAN patients with 50-75% global glomerulosclerosis was studied retrospectively between April 2007 and October 2017. Patients were divided into three groups according to the serum triglyceride tertiles: < 1.42 µmol/L (Group 1), 1.42-2.29 µmol/L (Group 2), and > 2.29 µmol/L (Group 3). Groups 1 and 2 comprised non-hypertriglyceridemia subjects, while Group 3 was defined as the hypertriglyceridemia (HTG) group. The patients were followed for 4-96 months (median 39.43 months). The study end point was defined as a 50% decline in estimated glomerular filtration rate (eGFR) or ESRD. RESULTS: A high proportion of global glomerulosclerosis is not absolutely correlated with severe clinical features and poor renal outcome. In our retrospective observation, eGFR decreased by less than 10% of the baseline during follow-up in 43.6% of the patients. However, in our patients with HTG, the cumulative renal survival rate was significantly lower compared to those without HTG. Multivariate Cox regression analysis also showed that triglyceride is an independent predictor of poor renal outcomes. Furthermore, in the HTG group, the cumulative renal survival rates were higher in patients treated with Tripterygium wilfordii Hook F (TwHF) compared to those without TwHF. CONCLUSIONS: A high proportion of global glomerulosclerosis combined with HTG at biopsy have better predictive validity for the disease progression of IgAN than global glomerulosclerosis alone. TwHF may partially affect the renal outcome of severe IgAN with HTG, and this may relate to its regulation of lipid metabolism and immunoinflammatory response.

[Clinicopathological analysis for IgA nephropathy with isolated hematuria and/or mild proteinuria].

OBJECTIVE: To investigate the correlation of different types of urinary abnormalities or different proteinuria and hematuria with the pathological injury of kidney in IgA nephropathy with isolated hematuria and/or mild proteinuria.
 Methods: Patients with primary IgA nephropathy, isolated hematuria and/or mild proteinuria were enrolled in the Department of Nephrology, the Second Xiangya Hospital, Central South University from January 2013 to January 2018. According to the difference of red blood cell count in urinary sediment and quantitative of 24-hour urinary protein (24 h-UP) during renal biopsy, the patients were grouped in 3 ways: a simple hematuria group, a hematuria and proteinuria group, and a simple proteinuria group; a proteinuria I group, a proteinuria II group, and a proteinuria III group; a hematuria I group, a hematuria II group, and a hematuria III group. The clinical parameters such as age, mean arterial pressure, blood urea nitrogen, serum creatinine, blood uric acid, 24 h-UP, and renal pathological damage were compared.
 Results: A total of 157 patients met the inclusion criteria, including 71 males and 86 females. The most common pathological type was focal and/or segmental glomerulosclerosis. The Lee's classification were dominated by grade III and IV, and the renal pathological injury was heavy. Immunoglobulin deposition was dominated by simple IgA deposition. The most common fluorescence intensity of IgA deposition was +++. 97 (61.78%) patients were accompanied by complement deposition and were mainly composed of simple complement C3 deposition. There were 18 patients (11.47%) in the simple hematuria group, 111 patients (70.70%) in the hematuria and proteinuria group, and 28 patients (17.83%) in the simple proteinuria group. Compared with the simple hematuria group, the proportion of patients with mild injury was lower in the simple proteinuria group, and the proportion of patients with moderate-to-severe injuries was increased (χ2=7.053, P=0.008). Compared with the hematuria and proteinuria group, the proportion of patients with mild injury was lower in the simple proteinuria group, and the proportion of patients with moderate-to-severe injury was increased (χ2=4.294, P=0.038). Compared with the proteinuria I group, the proportion of patients with mild injury was lower in the proteinuria III group, and the proportion of patients with moderate-to-severe injury was increased (χ2=5.433, P=0.020). There was no significant difference in the proportion of patients with renal pathological injury among different hematuria groups (P>0.05).
 Conclusion: The clinical manifestations of patients with IgA nephropathy with hematuria and/or mild proteinuria are inconsistent with renal pathological damage. Some patients with mild clinical manifestations have severe renal pathological damage and the renal pathological damage is more serious in simple proteinuria. The more proteinuria, the heavier the renal pathological damage.

Protein arginine methyltranferase-1 induces ER stress and epithelial-mesenchymal transition in renal tubular epithelial cells and contributes to diabetic nephropathy.

BACKGROUND: In this study, we examined the association of PRMT1 with ER stress and epithelial-mesenchymal transition (EMT), two critical pathogenic mechanisms leading to DN development, in proximal tubular epithelial cells (PTECs). METHODS: The level of PRMT1 was compared between the serum from DN patients and healthy individuals by ELISA, and between renal tissues of DN mice and normal mice using RT-qPCR and immunohistochemistry. Using high-glucose-treated PTEC cell line, HK2 cells as the model system, the significance of PRMT1 in ER stress and EMT was assessed by shRNA targeting PRMT1 (sh-PRMT1) and/or by overexpressing PRMT1. Mechanistic studies focused on three major pathways controlling ER stress: protein kinase R-like ER kinase (PERK), inositol requiring-1α (IRE1α), and activating transcription factor 6 (ATF6). RESULTS: PRMT1 was up-regulated in the serum of DN patients and renal tissues of DN mice. High glucose administration induced elevation of PRMT1 expression in HK2 cells in vitro, accompanied with ER stress and EMT activation. PRMT1 knockdown attenuated high glucose-induced ER stress and apoptosis by inactivating PERK and ATF6, but not IRE1α. PRMT1 activated ATF6 by recruiting H4R3me2as to the promoter. Furthermore, PRMT1-induced ER stress was concomitant with the activation of an EMT-like state. Specifically, inhibition of ATF6, but not PERK blocked PRMT1-induced EMT in high-glucose-treatment HK2 cells. CONCLUSIONS: By activating ER stress, PRMT1 essentially regulates the apoptosis and EMT of PTECs in response to diabetic milieu. Thus, targeting PRMT1 may alleviate both tissue injury and renal fibrosis, and thus benefit the treatment of DN.

Piperine ameliorated lupus nephritis by targeting AMPK-mediated activation of NLRP3 inflammasome.

BACKGROUND: Lupus nephritis (LN) is a leading cause of mortality. The activation of NLRP3 inflammasome contributed to LN development and thus became a therapeutic target. Here we assessed the therapeutic potential of piperine, a bioactive compound known to target NLRP3 inflammasome, on LN development both in vivo and in vitro. METHODS: LN was induced in BALB/c mice via intraperitoneal injection of pristane. Upon treatment with increasing doses of piperine, we assessed renal lesions, measured serum levels of pro-inflammatory cytokines, and examined expressions of key components of NLRP3 inflammasome in kidney. To explore the molecular mechanisms, we treated the proximal tubular epithelial HK-2 cells with lipopolysaccharide (LPS) and ATP, and examined the effects of piperine on pyroptosis and the activation of NLRP3 inflammasome. Furthermore, we assessed the significance of AMPK signaling in piperine functions in HK-2 cells. RESULTS: In pristane-injected mice, piperine significantly ameliorated LN development in a dose-dependent manner, which was associated with the inhibition of NLRP3 inflammasome and the reduction of serum IL-1ß, but not of IL-18 level. In HK-2 cells, piperine potently inhibited pyroptosis and the activation of NLRP3 inflammasome in response to LPS + ATP. The effects of piperine were mediated by blocking AMPK activation, and the AMPK agonist metformin bypassed the activities of piperine, and resumed pyroptosis as well as the activation on NLRP3 inflammasome. CONCLUSIONS: By targeting AMPK, piperine significantly suppressed the activation of NLRP3 inflammasome, inhibited the release of pro-inflammatory cytokines, blocked the pyroptosis of tubular epithelial cells, and thus suppressed the development of LN.

Impact of GADD34 on Apoptosis of Tonsillar Mononuclear Cells from IgA Nephropathy Patients by Regulating Eif2α Phosphorylation.

BACKGROUND/AIMS: Tonsillectomy may be an important method to achieve a long-term remission of IgAN, but patients' physical status may limit their access to this surgery. We proposed an encouraging solution through inhibiting GADD34 expression in order to promote tonsillar mononuclear cells (TMCs) apoptosis and reduce nephropathic IgA secretion. METHODS: A total of 12 IgAN and 9 non-IgAN patients were involved from March 2015 to May 2016. After TMCs were extracted by density gradient centrifugation and stimulated by inactivated hemolytic streptococcus, the mRNA and protein expression of GADD34, GRP78, CHOP, Bcl-2, Bcl-XL, AID, Iα-Cα, and cleaved caspase-3 were examined by fluorescent RT-PCR and Western blotting. Guanabenz treatment and siRNA interference were applied to downregulate GADD34 in tonsillar mononuclear cells from IgAN patients, and P-eIF2α expression was examined by Western Blotting. Cell apoptosis was evaluated by Annexin V FITC/PI flowcytometry, and IgA secretion in cultural supernatant was inspected by enzyme linked immunosorbent assay. RESULTS: After stimulation, the expression of GADD34 was significantly increased in IgAN patients (P< 0.05). Cell apoptosis was mitigated and IgA secretion level was elevated (P< 0.05). To be noticed, CHOP expression had no significant difference between two groups. After guanabenz treatment and siRNA interference, a prolonged elevation of P-eIF2α expression was observed. Cell apoptosis was reinforced and IgA secretion level was decreased (P< 0.05). CONCLUSION: GADD34 may be a potential therapeutic target for IgAN treatment due to its effect on cell apoptosis.